Date of approval.
Date of revision.
Etoricoxib Tablets Instructions
Please read the instructions carefully and use under the guidance of a physician
Drug Name]
Generic name: Etoricoxib Tablets
English name: Etoricoxib Tablets
Hanyu Pinyin: Yituokaoxi Pian
Ingredients
The main ingredient is etoricoxib.
Chemical name: 5-Chloro-6′-methyl-3-[4-(methylsulfonyl)phenyl]-2,3′-bipyridine
Chemical structure formula.
Molecular formula: C18H15ClN2O2S
Molecular weight: 358.84
【Properties】.
This product is light green to green (30mg, 60mg and 120mg specifications) or white to off-white (90mg specifications) film-coated tablets, all appear white to off-white after removing the film coating.
Indications
This product is indicated for
Treatment of symptoms and signs of osteoarthritis in acute and chronic stages
Treatment of acute gouty arthritis
Treatment of primary dysmenorrhea
Prescription of selective cyclooxygenase-2 inhibitors should be based on a thorough assessment of individual patient risk (see [Precautions]).
【Specifications】.
(1) 30mg (2) 60mg (3) 90mg (4) 120mg
Dosage and Administration
This product is intended for oral administration and may be taken with food or alone. This product should be given at the lowest daily dose and administered for the shortest possible time.
Arthritis
Osteoarthritis
The recommended dose is 30mg once daily. This may be increased to 60 mg once daily for patients who do not achieve adequate symptomatic relief. In cases where the efficacy of 60 mg once daily is not evident after 4 weeks, other treatments should be considered.
Acute gouty arthritis
The recommended dose is 120 mg once daily. This product 120mg should only be used during the acute onset of symptoms for a maximum of 8 days.
Primary dysmenorrhea
The recommended dose is 120mg once daily for a maximum of 8 days.
The use of doses greater than the recommended dose has not been shown to have better efficacy or has not been studied at this time. 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.
The maximum recommended dose for the treatment of primary dysmenorrhea is no more than 120 mg per day.
Because the cardiovascular risk of selective cyclooxygenase-2 inhibitors increases with higher doses and longer dosing times, the duration of dosing should be kept as short as possible and the lowest effective daily dose should be used. Patient symptom relief and patient response to therapy should be evaluated periodically. (See Precautions)
Elderly, gender, race
No dose adjustment is required for the elderly, different genders and races.
Hepatic insufficiency
In patients with mild hepatic insufficiency (Child-Pugh score 5-6), the dose of this product should not exceed 60 mg once daily. In patients with moderate hepatic insufficiency (Child-Pugh score 7-9), the dose should be reduced and should not exceed 60 mg every other day, and a dose of 30 mg once daily may be considered. No clinical or pharmacokinetic information is available for patients with severe hepatic insufficiency (Child-Pugh score >9). (See Precautions)
Renal Insufficiency
It is not recommended in patients with advanced renal disease (creatinine clearance <30mL/min). No dose adjustment is required for patients with mild renal insufficiency (creatinine clearance ≥ 30 mL/min). (See Precautions)
[Adverse Reactions] According to foreign studies.
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 doses of etoricoxib (30 mg and 60 mg) in 10 placebo-controlled trials conducted in patients with osteoarthritis for 6 to 12 weeks are listed in the table below. The causal relationship between these events and the drug is not considered in the listing. Because these 10 did not have the same treatment period and the patients in the trials were not exposed to the drug for the same length of time, these percentages do not represent a cumulative incidence.
Table 1 Clinical adverse events occurring in ≥2.0% of patients treated with etoricoxib in osteoarthritis clinical trials
Placebo group (N=1035) Etoricoxib
30 mg group
(N=1014) Etoricoxib
60 mg group
(N=558) Celecoxib 200 mg group
(N=488) Ibuprofen 2400mg group
(N=756)Naproxen 1000mg
Group (N=494) Infections and infestations Nasopharyngitis 2.32.13.21.42.83.8 Upper respiratory tract infections 2.21.95.92.32.24.0 Urinary tract infections 1.32.92.92.52.52.6 Neurological abnormalities Dizziness 1.11.62.22.71.33.4 Headache 3.23.35.63.74.23.8 Vascular abnormalities Hypertension2.33.04.50.85.43.0 Gastrointestinal abnormalities Epigastric pain1.41.42.00.84.64.7 Diarrhea3.13.63.92.54.44.3 Dyspepsia4.82.94.11.47.89.9 Nausea3.12.23.01.82.96.3 General reactions and administration site abnormalities Peripheral edema1.52. 72.92.53.02.6 In 6- to 12-week clinical trials in patients with osteoarthritis, the safety profile 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 additional adverse events in clinical trials conducted over a 6- to 12-week period in patients with osteoarthritis using the recommended doses (30 mg and 60 mg). These adverse events were not considered causally related to the drug, and the incidence in the etoricoxib group ranged from 0.1% to 2.0% and exceeded the incidence in the placebo group by at least 0.1%.
Infections and infestations: herpes simplex, infections, pharyngitis, sinusitis, staphylococcal infections, tonsillitis.
Immune system abnormalities: seasonal allergies.
Metabolic and nutritional abnormalities: diabetes mellitus.
Psychiatric abnormalities: anxiety, anxiety disorders, depression.
Neurological abnormalities: carpal tunnel syndrome, sensory abnormalities, somnolence, vasovagal syncope, tremor.
Ocular abnormalities: blepharitis, conjunctivitis, ocular pain, blurred vision.
Ear and vagus abnormalities: tinnitus.
Cardiac abnormalities: palpitations.
Vascular abnormalities: diastolic hypertension, flushing, hot flashes.
Respiratory, thoracic and mediastinal abnormalities: cough, dyspnea, rales, sinus congestion, wheezing.
Gastrointestinal abnormalities: abdominal distension, sore mouth stomatitis, abnormal bowel sounds, altered bowel habits, constipation, dry mouth, frequent bowel movements, gastritis, tongue inflammation, irritable bowel syndrome, oral ulcers, oral pain, dry heaving, toothache.
Skin and subcutaneous tissue abnormalities: blisters, subcutaneous cysts, dermatitis, eczema, hyperhidrosis, rash, maculopapular rash, rosacea, skin ulcers.
Skeletal muscle and connective tissue abnormalities: neck pain, osteoporosis, periarthritis, rotator cuff syndrome, tendonitis, toe abnormalities.
Kidney and urinary system abnormalities: kidney stones, nocturia, polyuria.
Reproductive system and breast abnormalities: erectile dysfunction, vaginal bleeding.
Systemic reactions and administration site abnormalities: malaise, facial edema, joint sprain, skin laceration.
Other serious adverse events listed below have the following characteristics: incidence ≤ 0.1%; occurrence in 2 or more patients in placebo-controlled clinical trials (6 to 12 weeks); or occurrence in 2 or more patients treated with etoricoxib in an active drug-controlled trial (190 weeks); for these events, causality with the trial drug was not considered. The list includes events reported in clinical trials with osteoarthritis and non-osteoarthritis as indications, administered at doses ranging from 30 mg to 120 mg/day. data from the MEDAL program are presented separately.
Infections and Infections: abscesses, cellulitis, pneumonia, postoperative wound infections, pyelonephritis, sinusitis, staphylococcal infections.
Benign tumors and nonspecific hyperplasia (including cysts and polyps): malignant tumors of the bladder, malignant tumors of the breast, malignant melanoma, non-Hodgkin’s lymphoma, and uterine fibroids.
Neurological abnormalities: cerebrovascular accident, grand mal seizure, intracranial hemorrhage, spinal stenosis, subarachnoid hemorrhage, syncope, transient ischemic attack.
Cardiac abnormalities: angina pectoris, arrhythmia, atrial fibrillation, cardiac arrest, coronary artery disease, congestive heart failure, ischemic heart disease, mitral regurgitation, unstable angina pectoris.
Vascular abnormalities: deep vein embolism, hypertensive crisis, hypovolemic shock, lacunar infarction.
Respiratory, thoracic and mediastinal abnormalities: dyspnea, pulmonary artery embolism, respiratory insufficiency.
Gastrointestinal abnormalities: gastroesophageal reflux disease, bleeding gastric ulcer, intestinal diverticulitis, pancreatitis, upper gastrointestinal bleeding, vomiting.
Hepatobiliary abnormalities: cholecystitis, cholelithiasis.
Skeletal muscle and connective tissue abnormalities: arthralgia, chest pain, hip arthritis, knee arthritis, knee pain, osteoarthritis, rheumatoid arthritis, shoulder piriformis muscle group injury.
Kidney and urinary system abnormalities: renal colic, urolithiasis.
Pregnancy, puerperium and perinatal conditions: pregnancy.
General reactions and administration site abnormalities: tightness in the chest, fever, prolapse.
Injury, poisoning and complications during drug administration: drug overdose, femur fracture, hip fracture, humerus fracture, car accident, tendon rupture, wrist fracture.
As reported in foreign studies
In clinical trials, safety was evaluated in 7152 individuals, including 4488 patients with osteoarthritis, rheumatoid arthritis, or chronic low back pain (about 600 patients with osteoarthritis or rheumatoid arthritis treated for 1 year or longer).
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 and occurred at an incidence >1% in patients treated with this product and were higher than those in the placebo group: weakness/fatigue, dizziness, lower extremity edema, hypertension, dyspepsia, heartburn, nausea, headache, increased glutathione transaminase ( ALT) increased, glutathione aminotransferase (AST) increased, etc.
The incidence of adverse events was similar in patients with osteoarthritis or rheumatoid arthritis treated with this product for 1 year or longer.
In the foreign MEDAL study, the Cardiovascular Endpoint Outcomes Trial enrolled 23,504 patients to compare the safety of etoricoxib 60 or 90 mg daily with diclofenac 150 mg daily in patients with osteoarthritis or rheumatoid arthritis (mean treatment period of 20 months). In this large study, only serious adverse events and discontinuation of the trial due to any adverse event were recorded. The incidence of diagnosed thrombotic cardiovascular serious adverse events was similar in the etoricoxib and diclofenac groups. The incidence of trial discontinuation due to hypertensive adverse events was less than 3% in each treatment group; however, the incidence of trial discontinuation due to these events was significantly higher in the etoricoxib 60 and 90 mg groups than in the diclofenac group. The incidence of adverse events (discontinuations and serious events) in congestive heart failure and the incidence of trial discontinuations due to edema were similar in the etoricoxib 60 mg and diclofenac groups, but were higher in the etoricoxib 90 mg group than in the diclofenac group. The incidence of trial discontinuation due to atrial fibrillation was higher in the etoricoxib group than in the diclofenac group.
The EDGE and EDGE II studies enrolling 7,111 patients with osteoarthritis (EDGE study; mean treatment period 9 months) and 4086 patients with rheumatoid arthritis (EDGE II study; mean treatment period 19 months) compared etoricoxib 90 mg daily (equivalent to 1.5 to 3 times the recommended dose for osteoarthritis) with diclofenac sodium 150 mg daily for gastrointestinal tolerability. In each study, the incidence of adverse events was broadly similar to those reported in phase IIb or III placebo-controlled clinical studies; however, the incidence of hypertension and edema adverse events was higher in the 90 mg daily group than in the diclofenac 150 mg daily group. The incidence of confirmed thrombotic cardiovascular serious adverse events was similar in both treatment groups.
In a pooled analysis of all phase II b to V clinical trials of 4 weeks or longer (excluding the MEDAL program), the incidence of confirmed thrombotic cardiovascular serious adverse events did not differ significantly between patients receiving etoricoxib ≥30 mg and non-naproxen-based NSAIDs. The rate of these events was higher in patients treated with etoricoxib than in those 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 (number of patients enrolled 126). The incidence of adverse events in this study was similar to those seen in long-term studies of osteoarthritis, rheumatoid arthritis, and chronic low back pain.
In a clinical study of acute gouty arthritis in which patients received 120 mg of this product once daily for 8 days, the incidence of adverse events in this study was similar to that reported in studies on osteoarthritis, rheumatoid arthritis, and chronic low back pain.
Acute pain (including primary dysmenorrhea).
In the acute analgesic clinical study, approximately 800 patients were treated with 120 mg of this product. In the primary dysmenorrhea study, patients were treated with this product for up to 3 days.
The incidence of adverse events in the acute analgesia study was broadly similar to that reported in the osteoarthritis study combined. In addition to this, taste disturbances were observed in patients treated with this product (≥2%).
Post-marketing dosing experience.
The following adverse reactions have been reported with this product post-marketing.
Hematologic and lymphatic system abnormalities: thrombocytopenia
Immune system abnormalities: allergic reactions, including anaphylactic or anaphylactoid reactions including shock
Metabolic and nutritional disorders: hyperkalemia
Mental abnormalities: insomnia, confusion, hallucinations, irritability
Neurological abnormalities: taste disorders
Respiratory, thoracic and mediastinal abnormalities: bronchospasm
Gastrointestinal abnormalities: abdominal pain, mouth ulcers, peptic ulcers including perforation and bleeding (mainly in elderly patients)
Hepatobiliary abnormalities: hepatitis, jaundice, liver failure
Skin and subcutaneous tissue abnormalities: angioedema, pruritus, erythema, Stevens-Johnson syndrome, toxic epidermal necrolysis, rubella, fixed drug rash.
Renal and urinary system abnormalities: renal insufficiency, including renal failure (see precautions).
Contraindications
This product is contraindicated in the following patients.
Hypersensitivity to any of its ingredients.
Patients with active peptic ulcers/bleeding, or previous recurrent ulcers/bleeding.
Patients with asthma, urticaria or allergic reactions induced by aspirin or other non-steroidal anti-inflammatory drugs.
Congestive heart failure (New York Heart Association [NYHA] cardiac function class II-IV).
Confirmed ischemic heart disease, peripheral arterial disease and/or cerebrovascular disease (including patients who have had recent coronary artery bypass grafting or angioplasty).
[Caution].
Foreign studies have reported that clinical trials suggest an increased risk of thrombotic events (especially myocardial infarction and stroke) with selective cyclooxygenase-2 inhibitors compared to placebo and some NSAIDs (naproxen). Because the cardiovascular risk of selective cyclooxygenase-2 inhibitors may increase with higher doses and longer dosing times, the duration of dosing and the lowest effective daily dose should be kept as short as possible. Patient symptom relief and patient response to therapy should be evaluated periodically.
Patients with significant risk factors for cardiovascular events (e.g., hypertension, hyperlipidemia, diabetes mellitus, smoking) or peripheral arterial disease should be carefully evaluated before receiving this product.
Physicians and patients should be alert for the occurrence of such events even in the absence of prior cardiovascular symptoms. Patients should be informed of the signs and/or symptoms of serious cardiovascular safety and the steps to be taken if they occur.
Patients should be alert for signs and symptoms such as chest pain, shortness of breath, weakness, slurred speech, etc. and should seek medical help as soon as any of these signs or symptoms occur.
Because selective cyclooxygenase-2 inhibitors do not have an effect on platelets, they should not be used as a substitute for aspirin in the prevention of cardiovascular disease. It is one of these drugs and does not inhibit platelet clumping, so antiplatelet therapy should not be discontinued.
Avoid combining with any other NSAID or aspirin.
The risk of gastrointestinal adverse events (gastrointestinal ulcers or other gastrointestinal complications) is increased when etoricoxib, other selective cyclooxygenase-2 inhibitors, and NSAIDs are combined with aspirin (even at low doses). Long-term clinical trials comparing selective cyclooxygenase-2 inhibitors in combination with aspirin and NSAIDs in combination with aspirin on gastrointestinal safety differences have not been adequately evaluated.
Treatment with this product is not recommended for patients with advanced renal disease. Clinical experience with the use of this product in patients with creatinine clearance <30 ml/min is very limited. If treatment with this product must be initiated in these patients, close monitoring of the patient’s renal function is recommended.
Prolonged use of NSAIDs can lead to renal papillary necrosis and other renal injury. Prostaglandins secreted by the kidneys may play a compensatory role in maintaining renal perfusion. Therefore, in cases of impaired renal perfusion, the use of this product may lead to a decrease in prostaglandin production and subsequent decrease in renal blood flow, thereby impairing renal function. Patients most likely to experience this reaction include those who already have significant renal insufficiency, decompensated heart failure, or cirrhosis of the liver. Monitoring of renal function should be considered in these patients.
This product should be used with caution in patients with significant signs of dehydration. Hydration is recommended prior to initiation of treatment with this product.
As with other drugs known to inhibit prostaglandin synthesis, some patients have experienced fluid retention, edema, and hypertension after taking this product. The possibility of fluid retention, edema, or hypertension should be considered when using this product in patients with pre-existing edema, hypertension, or heart failure. All nonsteroidal anti-inflammatory drugs (NSAIDs), including etoricoxib, have been associated with new-onset and recurrent congestive heart failure (see Adverse Reactions). Especially at high doses, hypertension may occur more frequently and be more severe than in users of other NSAIDs and selective cyclooxygenase-2 inhibitors, so special attention should be paid to blood pressure monitoring during treatment with this product. If blood pressure is significantly elevated, other treatment should be considered.
The risk of adverse reactions of gastrointestinal bleeding, ulceration, and perforation may occur at any time during treatment with all NSAIDs and may be fatal. These adverse reactions may or may not be accompanied by warning signs and symptoms, and regardless of whether the patient has a history of adverse gastrointestinal reactions or a history of serious gastrointestinal events. Physicians should be aware that complications of upper gastrointestinal (GI) ulcers/ulcers unrelated to treatment may occur in some patients. Although the risk of gastrointestinal toxicity with etoricoxib cannot be ruled out, results from the MEDAL program abroad showed that patients taking etoricoxib 60 mg or 90 mg once daily had a significantly lower risk of gastrointestinal toxicity than diclofenac sodium 150 mg daily. in clinical studies comparing ibuprofen and naproxen, patients taking 120 mg of this product once daily had an endoscopically detectable The risk of upper gastrointestinal ulcers was lower than in patients on non-selective NSAIDs, but higher than in the placebo group. Complications of upper gastrointestinal ulcers/ulcers occur in patients treated with this product. These events can occur at any time of use without any prior indication. In addition to therapeutic factors, patients with a previous history of gastrointestinal perforation, ulceration and bleeding (PUB), including patients with a history of ulcerative colitis, Crohn’s disease, and patients older than 65 years of age have a higher risk of PUB and should be used with caution to avoid worsening of the condition.
Foreign clinical trials have shown that approximately 1% of patients treated with 60 mg and 90 mg of this product daily for 1 year have experienced elevated glutathione and/or glutamic acid aminotransferases (approximately 3 times or more the upper limit of normal). In clinical trials comparing with the active drug, the incidence of elevated glutathione and/or ghrelin in patients treated with 60 and 90 mg of this product daily was similar to that in the group treated with naproxen 1000 mg daily, but significantly lower than that in the diclofenac 150 mg group. In patients treated with this product, elevated glutathione and/or ghrelin recovered, and approximately half of the patients had normalized glutathione and/or ghrelin with continued treatment.
Patients with symptoms and/or signs suggestive of abnormal liver function, or with laboratory-confirmed abnormal liver function, should be evaluated for persistent abnormal liver function. If liver function is persistently abnormal (3 times the upper limit of normal), treatment with this product should be discontinued.
Appropriate monitoring should be maintained in the elderly and in patients with renal, hepatic, or cardiac dysfunction who are taking etoricoxib. If deterioration occurs during treatment, appropriate measures should be taken, including discontinuation of therapy.
Serious skin reactions associated with the use of NSAIDs and certain selective cyclooxygenase-2 inhibitors, including partially fatal reactions including exfoliative dermatitis, Stevens-Johnson syndrome, and toxic epidermolysis bullosa-type rubella (see [ADVERSE REACTIONS]), have been reported during postmarketing surveillance to be extremely rare. These serious events can occur without any warning. Patients are at highest risk when the following reactions occur early in the treatment period: most cases occur in the first month of treatment initiation. Serious hypersensitivity reactions (e.g., allergic reactions and angioedema) have been reported in patients receiving etoricoxib (see [Adverse Reactions]). Certain selective cyclooxygenase-2 inhibitors can increase the risk of inducing skin reactions in patients with a history of drug hypersensitivity. Etoricoxib should be discontinued at the first sign of rash, mucosal injury, or any other allergic symptom.
In addition, this product may mask signs of infection-fever. Caution should be taken especially when administering this product to patients undergoing anti-infective therapy.
For Pregnant and Lactating Women
Pregnant women
This product, like other drugs known to inhibit prostaglandin synthesis, can cause premature closure of the ductus arteriosus and should be avoided during late pregnancy.
Reproduction studies in rats have shown no developmental abnormalities with doses of up to 15 mg/kg/day [1.5 times the human dose (90 mg)]. In experimental studies in rabbits treated with etoricoxib, an increase in the incidence of cardiovascular malformations and post-arrival abortions observed at applied doses approximately equivalent to 2 times the human dose (90 mg) was observed, but the incidence was low. In contrast, no developmental abnormalities were observed at doses approximately equal to or lower than the daily human dose (90 mg). However, animal reproduction studies do not always predict the response in humans. Appropriate, rigorously controlled studies in pregnant women have not been performed. Therefore, during the first 6 months of pregnancy, this product should be administered only if the potential benefit to be gained outweighs the potential risk to the fetus.
Lactating women
This product may be secreted with the milk of lactating rats. It is not known whether this product is secreted through human milk. Because many drugs are secreted in human milk and because drugs that inhibit prostaglandin synthesis may have adverse effects on the nursing infant, the importance of the drug to the mother should be carefully considered in deciding whether to discontinue nursing or to discontinue the drug.
Pediatric Dosage]
The safety and efficacy of this product have not been established in pediatric patients.
Geriatric Use]
The pharmacokinetic properties of the elderly (65 years and older) are similar to those of younger adults. Clinical studies have shown that older patients have a higher incidence of adverse events than younger patients; the differences between the etoricoxib and control groups are similar for older and younger patients. A higher sensitivity in some elderly patients cannot be excluded.
[Drug Interactions].
According to foreign studies, the International Normalized Ratio (INR) of prothrombin time was increased by approximately 13% with the application of this product 120 mg daily in patients who were stable on warfarin- long-term treatment with warfarin. INR values should be monitored when starting treatment with this product or changing treatment regimens in patients receiving warfarin or similar drugs, especially during the initial days.
Rifampicin – Rifampicin is a strong inducer of hepatic metabolism, and its combination with this product can reduce the area under the plasma curve (AUC) of this product by 65%. The interaction should be considered when this product is combined with rifampicin.
Methotrexate – Two studies looked at patients with rheumatoid arthritis treated with methotrexate 7.5 mg to 20 mg once a week for 7 consecutive days at 60, 90 or 120 mg once a day. There was no effect of this product at the 60 and 90 mg levels on methotrexate plasma concentrations (measured AUC) or renal clearance. In one study, 120 mg of this product had no effect on methotrexate plasma concentrations (measured AUC) or renal clearance. In another study, 120 mg increased methotrexate plasma concentrations (measured AUC) by 28% and decreased methotrexate renal clearance by 13%. When this product is used at doses greater than 90 mg/day and in combination with methotrexate, monitoring for methotrexate-related toxic reactions should be considered.
Diuretics, Angiotensin-Converting Enzyme (ACE) Inhibitors and Angiotensin II Antagonists (AIIAs) – NSAIDs including cyclooxygenase-2 selective inhibitors have been reported to reduce the antihypertensive effects of diuretics, angiotensin-converting enzyme inhibitors and angiotensin II antagonists. When this product is used concomitantly with these products, the interactions should be considered.
The combination of angiotensin-converting enzyme inhibitors or angiotensin II antagonists in some patients with renal insufficiency (e.g., elderly patients or patients with hypocapnia, including those being treated with diuretics) who are being treated with NSAIDs, including selective cyclooxygenase-2 inhibitors, may result in further impairment of renal function, including possible acute renal failure. However, these effects are usually reversible. Therefore, combined medications should be administered with caution, especially in elderly patients.
Lithium salts-Nonselective NSAIDs and selective inhibitors of cyclooxygenase-2 have been reported to elevate plasma levels of lithium salts. This interaction should be taken into account in patients taking both this product and lithium salts.
Aspirin-This product can be administered concomitantly with low-dose aspirin for the prevention of cardiovascular events. However, when combined with low-dose aspirin, the incidence of gastrointestinal ulceration or other complications is increased compared to the use of this product alone. At steady state, this product 120 mg once daily has no effect on the antiplatelet activity of low-dose aspirin (81 mg once daily) (Caution).
Oral contraceptives – Concurrent application of 60 mg of this product and oral contraceptives containing 35 mcg of ethinyl estradiol (EE) and 0.5 to 1 mg of norethindrone for 21 consecutive days increased the steady-state AUC0-24hr of EE by 37%; 120 mg of this product and the same oral contraceptives taken concurrently or 12 hours apart increased the steady-state AUC0-24hr of EE The increase in EE concentration should be taken into account when selecting the appropriate oral contraceptive to be administered with this product; the increase in EE concentration increases the incidence of oral contraceptive-related adverse events (e.g., the risk of venous thromboembolism in women).
Hormone Replacement Therapy: Concomitant use of 120 mg of this product and hormone replacement therapy containing bound estrogen (0.625 mg of Pemetrex) for 28 consecutive days resulted in a 41%, 76%, and 22% increase in mean steady-state AUC 0-24hr for unbound estrone, marenyl estrone, and 17-beta-estradiol, respectively. The combination of the recommended doses of this product for long-term use (60 mg and 90 mg) with them has not been studied. The effect of 120 mg of this product on these estrogen AUC0-24hr was less than half that of Pemerix alone and at doses rising from 0.625 to 1.25 mg. The clinical significance of these elevations is not known, and higher doses of Pemerix in combination with this product have not been studied. Elevated estrogen concentrations need to be taken into account when selecting postmenopausal hormone replacement therapy for concomitant administration with this product.
Other – In drug interaction studies, this product did not have a clinically meaningful effect on the pharmacokinetics of prednisone/prednisolone or digoxin.
Antacids and ketoconazole (a strong inhibitor of CYP3A4) did not have a clinically significant effect on the pharmacokinetics of this product.
[Drug overdose].
According to foreign studies, no significant toxic effects occurred in clinical trials using single doses of this product up to 500 mg and multiple doses of this product up to 150 mg/day given for 21 consecutive days. Although no adverse events have been reported in most cases, acute overdose of this product has been reported. The most commonly observed adverse events are related to the safety aspects of the product (e.g., gastrointestinal events, renal vascular events).
In the event of an overdose, routine supportive measures such as removal of unabsorbed drug from the gastrointestinal tract, clinical monitoring, and supportive therapy if necessary may be used.
This product is not cleared by hemodialysis and it is not known if it can be cleared by peritoneal dialysis.
Pharmacology and Toxicology
Pharmacological effects
Etoricoxib is a non-steroidal anti-inflammatory drug, which has anti-inflammatory, analgesic and antipyretic effects in animal models. It is an orally active, selective cyclooxygenase-2 inhibitor within the clinical dose range or at higher doses. Two isoforms of cyclooxygenase have been identified: cyclooxygenase-1 (COX-1) and cyclooxygenase-2 (COX-2).COX-1 is involved in prostaglandin-mediated normal physiological functions such as gastric mucosal cytoprotection and platelet agglutination. Non-selective NSAIDs inhibit COX-1 production and therefore can cause gastric mucosal damage and diminished platelet aggregation.COX-2 is mainly involved in prostaglandin production, which can cause pain, inflammation and fever. Etoricoxib, a selective inhibitor of cyclooxygenase-2, reduces these signs and symptoms, decreases gastrointestinal side effects and does not affect platelet function.
According to clinical pharmacological studies, the inhibition of COX-2 was dose-dependent up to a daily dose of 150 mg, but there was no inhibition of COX-1.
Prostaglandin synthesis levels in gastric mucosal biopsy specimens were measured in clinical trials in which subjects received 120 mg (once daily), naproxen 500 mg (twice daily) or placebo, respectively. Compared to placebo, this product did not inhibit prostaglandin synthesis in the gastric mucosa, whereas naproxen inhibited prostaglandin synthesis in the gastric mucosa by approximately 80%. These studies further support that this product is a selective inhibitor of COX-2.
Platelet function
In a multi-dose study, subjects taking 150 mg of this product daily (for a total of 9 days) had no effect on bleeding time compared to placebo. Single doses of 250 mg or 500 mg also had no effect on bleeding time. In vivo studies showed no inhibition of either in vitro arachidonic acid or collagen-mediated platelet aggregation at the 150 mg dose when blood concentrations reached steady state. These results are consistent with the COX-2 selectivity of this product.
Toxicological studies
Genotoxicity: etoricoxib is not genotoxic or mutagenic.
Etoricoxib is secreted in the milk of lactating rats (see [Pregnancy and Lactation]).
Reproductive toxicity: Studies in rats have shown no developmental abnormalities when administered at doses up to 15 mg/kg/day (exposure approximately 1.5 times the exposure in humans at 90 mg). In rabbits, a low incidence of cardiovascular malformations and an increase in post-arrival abortions were observed when drug exposure was approximately twice that of human exposure at 90 mg. No developmental abnormalities were found at drug exposures equal to or lower than those seen in humans taking 90 mg of the drug.
Carcinogenicity: The mouse test did not find etoricoxib to be carcinogenic. Hepatocellular adenoma and follicular cell adenoma of the thyroid gland can occur in rats administered continuously for about 2 years at a daily drug exposure more than 6 times the human clinical dose (90 mg).
[Pharmacokinetics] According to foreign studies.
Absorption
Etoricoxib is well absorbed orally. The mean oral bioavailability is close to 100%, and peak plasma concentration (geometric mean Cmax=3.6mcg/ml) occurs approximately 1 hour after administration (Tmax) when 120mg is given orally once daily on an empty stomach until steady state is reached in adults. The geometric mean AUC0-24hr was 37.8mcg.hr/ml. The pharmacokinetics of this product are linear over the clinical dose range.
If etoricoxib 120 mg is administered daily, normal meals have no significant effect on the extent and rate of absorption. In clinical trials, etoricoxib was administered without regard to meals.
In 12 healthy subjects, the pharmacokinetics of etoricoxib were similar (comparable AUC, Cmax within approximately 20%) whether administered alone, in combination with a magnesium hydroxide/aluminum antacid, or in combination with a calcium carbonate antacid (with an acid neutralizing capacity of approximately 50 mEq).
Distribution
Etoricoxib is 92% bound to human plasma proteins over a concentration range of 0.05-5mcg/ml. In humans, the volume of distribution (Vdss) at steady state is approximately 120 liters.
Etoricoxib crosses the placenta of rats and rabbits, and the blood-brain barrier of rats.
Metabolism
The product is completely metabolized, with less than 1% of the drug in its original form in the urine. The main metabolic pathway is catalyzed by cytochrome P450 (CYP) enzymes to form 6′-hydroxymethyl derivatives.
Five metabolites have been identified in humans. The main metabolites are 6′-carboxylic acid derivatives, formed by further oxidation of 6′-hydroxymethyl derivatives. These major metabolites either showed no detectable activity or only weak activity as cyclooxygenase-2 inhibitors. None of these metabolites inhibited cyclooxygenase-1.
Clearance
In healthy individuals given a single 25 mg dose of radiolabeled etoricoxib intravenously, 70% of the radioactivity is detectable in urine and 20% in feces, mostly as metabolites, with less than 2% of the drug excreted in its original form.
The clearance of etoricoxib is almost always metabolized and then excreted by the kidneys. Steady-state concentrations of etoricoxib are achieved within 7 days when administered at 120 mg once daily. The accumulation ratio is approximately 2 and the corresponding accumulation half-life is approximately 22 hours. The plasma clearance is about 50 ml/min.
Storage
Store below 30℃.
Package】
Aluminum-plastic pillow package with silica gel desiccant in solid pharmaceutical paper bag.
2 tablets/plate, 1 plate/bag, 1 bag/box or 2 bags/box.
5 tablets/board, 1 board/bag, 1 bag/box or 2 bags/box.
7 tablets/plate, 1 plate/bag, 1 sachet/box or 2 sachets/box.
12 tablets/plate, 1 plate/bag, 1 bag/box or 2 bags/box.
【Validity】 24 months
【Execution Standard】.
【Approval number】
【Manufacturer】
Company name: Qilu Pharmaceutical Co.
Address: No. 317 Xinluo Street, Jinan High-tech Zone
Zip code: 250100
Telephone number: 0531-83126000, 83126111, 83126333, 83126548
Fax number: 0531-83126288, 83126545
Web address: http://www.qilu-pharma.com