Etoricoxib Tablets

Etoricoxib is a nonsteroidal anti-inflammatory drug that has anti-inflammatory, analgesic and antipyretic effects in animal models. Within or above the clinical dose range, this product is an orally active, selective cyclooxygenase-2 inhibitor. Two isoforms of cyclooxygenase have been discovered: cyclooxygenase-1 (COX-1) and cyclooxygenase-2 (COX-2). COX-1 is involved in normal prostaglandin-mediated physiological functions such as gastric mucosal cell protection and platelet aggregation. Non-selective nonsteroidal anti-inflammatory drugs inhibit the production of COX-1, thereby causing gastric mucosal damage and reduced platelet aggregation. COX-2 is mainly involved in the production of inflammatory prostaglandins, causing pain, inflammation and fever. Etoricoxib is a selective inhibitor of cyclooxygenase-2, which can alleviate these symptoms and signs, reduce gastrointestinal side effects and do not affect platelet function. According to clinical pharmacology studies, within a daily dose of 150 mg, this product has a dose-dependent inhibitory effect on COX-2, but has no inhibitory effect on COX-1. In clinical trials, subjects were given 120 mg of this product (once a day), 500 mg of naproxen (twice a day) or placebo, and the level of prostaglandin synthesis in gastric mucosal biopsy specimens was monitored. Compared with placebo, this product did not inhibit the synthesis of prostaglandins in the gastric mucosa, while naproxen inhibited the synthesis of prostaglandins in the gastric mucosa by about 80%. These studies further support that this product is a selective inhibitor of COX-2. In a multiple-dose study, subjects took 150 mg of this product daily (for 9 days in total), and bleeding time was not affected compared with placebo. Single doses of 250 mg or 500 mg also had no effect on bleeding time. In vivo studies have shown that at a dose of 150 mg, when the blood concentration reaches steady state, in vitro arachidonic acid or collagen-mediated platelet aggregation is not inhibited. These results are consistent with the COX-2 selectivity of this product.

The main ingredient is etoricoxib.

This product is suitable for: 1. Treating the symptoms and signs of acute and chronic osteoarthritis. 2. Treating acute gouty arthritis.

1. This product is for oral administration and can be taken with or without food. Arthritis, osteoarthritis - the recommended dose is 30 mg once a day. For patients whose symptoms cannot be fully relieved, it can be increased to 60 mg once a day. When the efficacy of this product is still not obvious after 4 weeks of taking 60 mg once a day, other treatments should be considered. 2. Acute gouty arthritis - the recommended dose is 120 mg, once a day. This product 120 mg is only suitable for the acute onset of symptoms and can be used for up to 8 days. When the dose is higher than the recommended dose, it has not been proven to have better efficacy or has not been studied yet. Therefore, the maximum recommended dose for the treatment of osteoarthritis is no more than 60 mg per day. The maximum recommended dose for the treatment of acute gouty arthritis is no more than 120 mg per day, because the cardiovascular risk of selective cyclooxygenase-2 inhibitors increases with the increase of dose and the extension of medication time, so the medication time should be shortened as much as possible and the lowest effective daily dose should be used. The relief of patients' symptoms and their response to treatment should be evaluated regularly. (See Precautions) 3. Elderly, gender, race - No dose adjustment is required for the elderly, people of different genders and races. 4. Hepatic impairment - For patients with mild hepatic impairment (Child-Pugh score 5-6), the dose of this product should not exceed 60 mg once daily. For patients with moderate hepatic impairment (Child-Pugh score 7-9), the dose should be reduced and should not exceed 60 mg every other day. A dose of 30 mg once daily can be considered. For patients with severe hepatic impairment (Child-Pugh score 9), there is currently no clinical or pharmacokinetic data. (See Precautions) 5. Renal impairment - This product is not recommended for patients with advanced renal disease (creatinine clearance < 30 ml/min). No dose adjustment is required for patients with mild renal impairment (creatinine clearance > 30 ml/min). (See Precautions)

Osteoarthritis: In 10 Phase IIb/III placebo-controlled clinical trials of at least 6 weeks duration, 1572 patients with osteoarthritis were treated with etoricoxib 30 mg or 60 mg; 563 patients were treated with etoricoxib for up to 1 year. Adverse events that occurred in at least 2% of patients treated with the recommended dose of etoricoxib (30 mg and 60 mg) in 10 6-12 week placebo-controlled trials in patients with osteoarthritis are listed below. The causal relationship of these events to the drug is not considered when listing. Because the treatment duration of these 10 trials was different and the patients in the trials were exposed to the drug for different periods of time, these percentages do not represent cumulative incidence. In clinical trials of 6-12 weeks in patients with osteoarthritis, the safety of etoricoxib doses greater than 60 mg/day (90 mg and 120 mg/day) was similar, however, the incidence of dyspepsia and nausea was higher. Listed below are other adverse events in clinical trials of 6-12 weeks in patients with osteoarthritis using the recommended dose (30 mg and 60 mg). These adverse events are not considered to be causally related to the drug. The incidence in the etoricoxib group ranged from 0.1% to 2.0%, and the incidence was at least 0.1% higher than that in the placebo group. 1. Infections and infestations: herpes simplex, infection, pharyngitis, sinusitis, staphylococcal infection, tonsillitis. 2. Immune system abnormalities: seasonal allergies. 3. Metabolic and nutritional abnormalities: diabetes. 4. Psychiatric abnormalities: anxiety, anxiety depression. 5. Nervous system abnormalities: carpal tunnel syndrome, paresthesia, somnolence, vasovagal syncope, tremor. 6. Eye abnormalities: blepharitis, conjunctivitis, eye pain, blurred vision. 7. Ear and labyrinth abnormalities: tinnitus. 8. Cardiac abnormalities: palpitations. 9. Vascular abnormalities: diastolic hypertension, flushing, hot flashes. 10. Respiratory, thoracic and mediastinal abnormalities: cough, dyspnea, rales, sinus congestion, wheezing. 11. Gastrointestinal disorders: abdominal distension, aphthous stomatitis, abnormal bowel sounds, changes in bowel habits, constipation, dry mouth, frequent bowel movements, gastritis, glossitis, irritable bowel syndrome, oral ulcers, oral pain, retching, toothache. 12. Skin and subcutaneous tissue disorders: blisters, subcutaneous cysts, dermatitis, eczema, hyperhidrosis, rash, maculopapular rash, rosacea, skin ulcers. 13. Skeletal muscle and connective tissue disorders: neck pain, osteoporosis, periarthritis, rotator cuff syndrome, tendonitis, toe abnormalities; 14. Kidney and urinary system disorders: kidney stones, nocturia, polyuria. 15. Reproductive system and breast disorders: erectile dysfunction, vaginal bleeding. 16. Systemic reactions and administration site abnormalities: fatigue, facial edema, joint sprains, skin lacerations. Other serious adverse events listed below have the following characteristics: incidence le; 0.1%; occurred in 2 or more patients in placebo-controlled clinical trials (6-12 weeks); or occurred in 2 or more patients treated with etoricoxib in active-controlled trials (190 weeks), for which causality with the trial drug was not considered. The list includes events reported in clinical trials for osteoarthritis and non-osteoarthritis indications, with a dose range of 30 mg-120 mg/day. Data from the MEDAL project are presented separately. 1. Infections and infestations: abscesses, cellulitis, pneumonia, postoperative wound infection, pyelonephritis, rhinitis, staphylococcal infection. 2. Benign tumors and nonspecific hyperplasia (including cysts and polyps): bladder malignancies, breast malignancies, malignant melanoma, non-Hodgkin's lymphoma, uterine fibroids. 3. Nervous system abnormalities: cerebrovascular accident, grand mal epilepsy, intracranial hemorrhage, spinal stenosis, subarachnoid hemorrhage, syncope, transient ischemic attack; 4. Cardiac abnormalities: angina pectoris, arrhythmia, atrial fibrillation, cardiac arrest, coronary heart disease, congestive heart failure, ischemic heart disease, mitral valve regurgitation, unstable angina pectoris. 5. Vascular abnormalities: deep vein thrombosis, hypertensive crisis, hypovolemic shock, lacunar infarction. 6. Respiratory, thoracic and mediastinal abnormalities: dyspnea, pulmonary embolism, respiratory insufficiency. 7. Gastrointestinal abnormalities: gastroesophageal reflux disease, gastric ulcer bleeding, intestinal diverticulitis, pancreatitis, upper gastrointestinal bleeding, vomiting. 8. Hepatobiliary abnormalities: cholecystitis, cholelithiasis. 9. Skeletal muscle and connective tissue abnormalities: joint pain, chest pain, hip arthritis, knee arthritis, knee joint pain, osteoarthritis, rheumatoid arthritis, shoulder rotator cuff injury. 10. Kidney and urinary system disorders: renal colic, urolithiasis. 11. Pregnancy, puerperium and perinatal conditions: pregnancy. 12. General reactions and administration site abnormalities: chest tightness, fever, prolapse. 13. Injury, poisoning and complications during medication: overdose, femur fracture, hip fracture, humerus fracture, car accident, tendon rupture, wrist fracture. In clinical trials, 7152 individuals were evaluated for safety, including 4488 patients with osteoarthritis, rheumatoid arthritis or chronic low back pain (approximately 600 patients with osteoarthritis or rheumatoid arthritis were treated for 1 year or more). The following drug-related adverse events were reported in several clinical studies of up to 12 weeks in patients with osteoarthritis, rheumatoid arthritis or chronic low back pain. Adverse events that occurred at an incidence of ge;1% in patients treated with this product and were higher than those in the placebo group included weakness/fatigue, dizziness, lower limb edema, hypertension, dyspepsia, heartburn, nausea, headache, increased alanine aminotransferase (ALT), and increased aspartate aminotransferase (AST). The incidence of adverse events in patients with osteoarthritis or rheumatoid arthritis treated with this product for 1 year or longer was similar. In the MEDAL study, a cardiovascular endpoint outcome trial enrolled 23,504 patients to compare the safety of etoricoxib 60 or 90 mg daily and diclofenac 150 mg daily in the treatment of patients with osteoarthritis or rheumatoid arthritis (average treatment period of 20 months). In this large study, only serious adverse events and events of discontinuation of the trial due to any adverse events were recorded. The incidence of confirmed thrombotic cardiovascular serious adverse events was similar in the etoricoxib group and the diclofenac group. Discontinuation rates due to adverse events of hypertension were less than 3% in each treatment group; however, discontinuation rates due to these events were significantly higher in the etoricoxib 60 and 90 mg groups than in the diclofenac group. Rates of adverse events of congestive heart failure (discontinuation and serious events) and discontinuation rates due to edema were similar in the etoricoxib 60 mg and diclofenac groups, but higher in the etoricoxib 90 mg group than in the diclofenac group. Discontinuation rates due to atrial fibrillation were higher in the etoricoxib group than in the diclofenac group. The EDGE and EDCFⅡ studies, which enrolled 7111 patients with osteoarthritis (EDGE study, mean treatment duration 9 months) and 4086 patients with rheumatoid arthritis (EDGEⅡ study, mean treatment duration 19 months), respectively, compared the gastrointestinal tolerability of etoricoxib 90 mg daily (equivalent to 1.5 to 3 times the recommended dose for osteoarthritis) and diclofenac sodium 150 mg daily. In each study, the adverse event profile of etoricoxib was generally similar to that reported in Phase IIb or Phase III placebo-controlled clinical studies; however, the incidence of hypertension and edema was higher in the etoricoxib 90 mg daily group than in the diclofenac sodium 150 mg daily group. The incidence of confirmed thrombotic cardiovascular serious adverse events was similar in the two treatment groups. In a pooled analysis of all Phase IIb-V clinical trials of 4 weeks or longer (excluding the MEDAL program), there was no significant difference in the incidence of confirmed thrombotic cardiovascular serious adverse events between patients receiving etoricoxib ge; 30 mg and naproxen NSAIDs, and the rate of these events was higher in patients receiving etoricoxib than in patients receiving naproxen 500 mg twice daily. In a clinical study of ankylosing spondylitis, patients were treated with 90 mg of this product once daily for up to 1 year (126 patients were enrolled). The adverse event profile in this study was similar to the results of long-term studies in osteoarthritis, rheumatoid arthritis, and chronic low back pain. In a clinical study of acute gouty arthritis, patients were treated with 120 mg of this product once daily for 8 days. The adverse event profile in this study was similar to that reported in studies of osteoarthritis, rheumatoid arthritis, and chronic low back pain. In the acute analgesic clinical study, patients received 120 mg of this product once daily for 1 to 7 days. The adverse events in these studies were generally similar to the combined reports of osteoarthritis, rheumatoid arthritis and chronic low back pain studies. Post-marketing experience The following adverse reactions have been reported after the product was marketed: 1. Blood and lymphatic system abnormalities: thrombocytopenia. 2. Immune system abnormalities: allergic reactions, including anaphylactic or anaphylactic reactions including shock. 3. Metabolic and nutritional disorders: hyperkalemia. 4. Psychiatric disorders: insomnia, confusion, hallucinations, restlessness. 5. Nervous system abnormalities: taste disorders. 6. Respiratory, chest and mediastinal abnormalities: bronchospasm; 7. Gastrointestinal abnormalities: abdominal pain, oral ulcers, peptic ulcers including perforation and bleeding (mainly in elderly patients). 8. Hepatobiliary abnormalities: hepatitis, jaundice. 9. Skin and subcutaneous tissue abnormalities: angioedema, itching, erythema, Stevens-Johnson syndrome, toxic epidermal necrolysis, urticaria. 10. Kidney and urinary system disorders: renal insufficiency, including renal failure (see Precautions).

The following patients are contraindicated to use this product: 1. Allergic to any of its ingredients. 2. Patients with active peptic ulcer/bleeding, or patients with recurrent ulcer/bleeding in the past. 3. Patients who have asthma, urticaria or allergic reactions after taking aspirin or other nonsteroidal anti-inflammatory drugs. 4. Congestive heart failure (New York Heart Association [NYHA] heart function class II-IV). 5. Confirmed ischemic heart disease, peripheral arterial disease and/or cerebrovascular disease (including patients who have recently undergone coronary artery bypass grafting or angioplasty).

Precautions for children: The safety and efficacy of this product in pediatric patients have not been established. Precautions for pregnancy and lactation: Pregnant women: Reproduction studies in rats showed that no developmental abnormalities were found when this product was used at doses up to 15 mg/kg/day [equivalent to 1.5 times the human dose (90 mg)]. In experimental studies in rabbits, a very low incidence of cardiovascular malformations and an increased incidence of (post-implantation) failure were found at doses approximately equivalent to twice the human dose (90 mg), while no developmental abnormalities were found at doses approximately equivalent to or lower than the daily human dose (90 mg). Although animal reproduction studies do not always predict human responses, appropriate, strictly controlled studies have not been conducted in pregnant women. Therefore, during the first 6 months of pregnancy, this product should only be used if the possible benefits outweigh the potential risks to the fetus. Lactating women: This product can be secreted in the milk of lactating rats. Precautions for the elderly: The pharmacokinetic properties of the elderly (65 years and older) are similar to those of young patients. Clinical studies have shown that elderly patients have a higher incidence of adverse events than younger patients; the differences between the etoricoxib group and the control group for elderly and younger patients are similar. A greater sensitivity in some elderly patients cannot be excluded.

1. Warfarin - For patients who are stable on long-term warfarin treatment, the international normalized ratio (INR) of prothrombin time increases by about 13% when this product is used at 120 mg daily. For patients who are treated with warfarin or similar drugs, the INR value should be monitored when starting treatment with this product or changing the treatment regimen, especially in the first few days. 2. Rifampicin - Rifampicin is a strong inducer of liver metabolism. The combination of this product with it can reduce the plasma area under the curve (AUC) of this product by 65%. When this product is used in combination with rifampicin, its interaction should be considered. 3. Methotrexate - Two studies have observed the situation of rheumatoid arthritis patients who were treated with methotrexate 7.5 mg to 20 mg once a week receiving this product 60, 90 or 120 mg once a day for 7 consecutive days. This product had no effect on the plasma concentration of methotrexate (determining AUC) and renal clearance at the 60 and 90 mg levels. In one of the studies, 120 mg of this product had no effect on the plasma concentration of methotrexate (determining AUC) or renal clearance. In another study, 120 mg of this product increased the plasma concentration of methotrexate by 28% (determined by AUC) and reduced the renal clearance of methotrexate by 13%. When this product is used at a dose greater than 90 mg/day and combined with methotrexate, monitoring for methotrexate-related toxic reactions should be considered. 4. Diuretics, angiotensin-converting enzyme (ACE) inhibitors and angiotensin II antagonists (AIIAs) - There are reports that nonsteroidal anti-inflammatory drugs including cyclooxygenase-2 selective inhibitors can reduce the antihypertensive effect of diuretics, angiotensin-converting enzyme inhibitors and angiotensin II antagonists. When this product is used simultaneously with these products, their interactions should be considered. 5. For some patients with renal insufficiency who are being treated with nonsteroidal anti-inflammatory drugs including selective cyclooxygenase-2 inhibitors (e.g., elderly patients or patients with hypolytic disease, including those who are receiving diuretic therapy), the combined use of angiotensin-converting enzyme inhibitors or angiotensin II antagonists may cause further damage to renal function, including possible acute renal failure; but these effects are usually reversible. Therefore, combined use should be cautious, especially in elderly patients. 6. Lithium salts - There are reports that non-selective nonsteroidal anti-inflammatory drugs and cyclooxygenase-2 selective inhibitors can increase the plasma level of lithium salts. This interaction should be considered for patients taking this product and lithium salts at the same time. 7. Aspirin - This product can be used simultaneously with low-dose aspirin to prevent cardiovascular events. However, when used in combination with low-dose aspirin, the incidence of gastrointestinal ulcers or other complications is increased compared to using this product alone. In a stable state, 120 mg of this product once a day has no effect on the antiplatelet activity of low-dose aspirin (81 mg once a day) (see Precautions). 8. Oral contraceptives - The simultaneous use of 60 mg of this product and an oral contraceptive containing 35 micrograms of ethinyl estradiol (EE) and 0.5 to 1 mg of norethindrone for 21 consecutive days can increase the AUC0-24hr of EE at a steady state by 37%; 120 mg of this product and the same oral contraceptive are taken at the same time or 12 hours apart. It can increase the steady-state AUC0-24hr of EE by 50%-60%. When choosing an appropriate oral contraceptive to be taken with this product, the increase in EE concentration should be taken into account. The increase in EE concentration increases the incidence of oral contraceptive-related adverse events (such as the risk of venous thromboembolism in women). 9. Hormone replacement therapy: The simultaneous use of 120 mg of Fengpin and hormone replacement therapy containing conjugated estrogens (0.625 mg of Premarin) for 28 consecutive days can increase the average steady-state AUC0-24hr of unconjugated estrone, equilin and 17-beta;-estradiol by 41%, 76% and 22%, respectively. The combination of this product with the recommended dose (60 mg and 90 mg) for long-term use has not been studied. The effect of 120 mg of this product on the AUC0-24hr of these estrogens is less than half of that of Premarin alone and the dose is increased from 0.625 to 1.25 mg. The clinical significance of these elevated levels is unclear, and the use of higher doses of Premarin in combination with this product has not been studied. When choosing postmenopausal hormone replacement therapy and taking this product simultaneously, the elevated estrogen concentrations should be considered. 10. Others - In drug interaction studies, this product did not produce a clinically significant effect on the pharmacokinetics of prednisone/prednisolone or digoxin. 11. Antacids and ketoconazole (a strong CYP3A4 inhibitor) did not produce a clinically significant effect on the pharmacokinetics of this product.

Store tightly closed below 30°C (86°F).

120 mg

24 months.