Approval date: May 20, 2011
Date of modification.
Ereximab Tablets Instructions
Please read the instructions carefully and use under the guidance of a physician
Drug Name]
Generic name: Ereximab Tablets
Trade name: Heng Yang
English name: Imrecoxib Tablets
Hanyu Pinyin: Airuixibu Pian
Ingredients
The main ingredient of this product is Airuixib, whose chemical name is: 1-n-propyl-3-(4-methylphenyl)-4-(4-methanesulfonylphenyl)-2,5-dihydro-1H-2-pyrrolone.
Its chemical structure formula is
Molecular formula: C21H23NO3S
Molecular weight: 369.48
Properties
This product is a film-coated tablet, which appears off-white after removing the film coating.
Indications
This product is used to relieve the painful symptoms of osteoarthritis.
Specification
0.1 g
Dosage and Administration
Use after meals. Take orally. The usual adult dose is 0.1 g (1 tablet) twice a day for 8 weeks. The cumulative duration of multiple courses of treatment is temporarily limited to 24 weeks (including 24 weeks).
Adverse reactions]
In clinical trials of this product, no adverse reactions with an incidence greater than 10% have been observed. Common adverse drug reactions (incidence greater than 1%) include: epigastric discomfort, fecal occult blood, alanine aminotransferase (ALT) elevation. Rare adverse drug reactions (incidence 0.1%-1%) include: abdominal pain, constipation, peptic ulcer, nausea, vomiting, burning sensation, chronic superficial gastritis, subxiphoid paroxysmal pain, gastric erosion foci, fundic/gastric body bleeding spots, rash, swelling, chest tightness, palpitations, microscopic hematuria, elevated serum urea nitrogen (BUN), decreased white blood cells, elevated aspartate aminotransferase (AST), elevated Positive urine protein, positive urine sugar, positive urine red blood cells.
1. Phase II clinical trials.
In the phase II clinical trial, 214 patients with knee osteoarthritis were treated with this product, including 72 patients taking 50 mg of this product twice daily, 71 patients taking 100 mg of this product twice daily, and 71 patients taking 200 mg of this product twice daily. Seventy patients with osteoarthritis of the knee were treated with the control drug celecoxib capsules, with patients taking celecoxib capsules 200 mg once daily. The duration of treatment was 12 weeks in all cases.
The following adverse reactions occurred at an incidence of >2.0% (patients taking ereciclib tablets 100 mg twice daily)
Gastrointestinal system: fecal occult blood (7.69%), epigastric discomfort (4.62%)
Hepatobiliary system: ALT elevation (4.62%)
Hematologic and lymphatic system: leukopenia (3.08%)
The following adverse reactions occurred between 1.0% and 2.0% (patients taking ericiclib tablets 100 mg twice daily)
Gastrointestinal system: nausea, vomiting, burning sensation, chronic superficial gastritis, paroxysmal pain under the glabella
Systemic: edema
Skin and its appendages: rash
Hepatobiliary system: elevated AST
Urinary system: positive urine protein, positive urine sugar, positive urine red blood cells
2. Phase III clinical trials.
In the phase III clinical trial, 344 patients with osteoarthritis of the knee were treated with this product. Patients received 100 mg of this product twice daily, and 117 patients with osteoarthritis of the knee were treated with the control drug celecoxib capsules, and patients received celecoxib capsules 200 mg once daily. The treatment course was 8 weeks.
No adverse reactions with an incidence greater than 2% were observed in the treatment group of ereciclib tablets in the phase III clinical trial.
The following adverse reactions with an incidence between 1.0% and 2.0% (patients taking ereciclib tablets 100 mg twice daily)
Gastrointestinal system: epigastric discomfort (1.16%), peptic ulcer (1.16%)
The following are adverse reactions with an incidence of less than 1% (0.1% to 0.9%) (patients taking ericiclib tablets 100 mg twice daily)
Gastrointestinal system: abdominal pain, constipation, foci of gastric erosion, bleeding spots in the fundus/body of the stomach
Hepatobiliary system: elevated aminotransferase
Heart rate and rhythm: palpitations
Urologic system: microscopic hematuria
Metabolic and nutritional: elevated serum urea nitrogen (BUN)
Respiratory system: chest tightness
Hematologic and lymphatic system: leukopenia
Systemic: edema
Skin and its appendages: rash
3. Adverse reaction profile of celecoxib capsules abroad.
Due to the small clinical sample size of this product, the following adverse events have been reported in the literature for the similar drug celecoxib capsules in a large sample of clinical studies, and patients should be aware of them when using ereciclib tablets.
The following adverse events (patients taking celecoxib capsules 100-200 mg twice daily or 200 mg once daily) occurred at an incidence of >2% regardless of whether they were causally related to treatment.
Gastrointestinal system: abdominal pain (4.1%), diarrhea (5.6%), dyspepsia (8.8%), gastrointestinal distention (2.2%), nausea (3.5%) Systemic: back pain (2.8%), peripheral edema (2.1%), accidental injury (2.9%)
Central and peripheral nervous system: dizziness (2.0%), headache (15.8%)
Psychiatric: insomnia (2.3%)
Respiratory system: pharyngitis (2.3%), rhinitis (2.0%), sinusitis (5.0%), upper respiratory tract infection (8.1%)
Skin and its appendages: rash (2.2%)
The following adverse events (patients taking celecoxib capsules 100-200 mg twice daily or 200 mg once daily) with an incidence of less than 2% (0.1% to 1.9%) regardless of whether they were causally related to treatment.
Gastrointestinal system: constipation, diverticulitis, dysphagia, hiccups, esophagitis, gastritis, gastroenteritis, gastroesophageal reflux, hemorrhoids, hiatal hernia, black fecal syndrome, dry mouth, stomatitis, lining, dental discomfort, vomiting
Cardiovascular system: exacerbation of hypertension, angina pectoris, coronary artery lesions, myocardial infarction
Systemic: exacerbation of allergies, allergic reactions, debilitation, chest pain, non-specific cysts, generalized edema, facial edema, fatigue, fever, facial flushing, flu-like symptoms, pain, peripheral pain
Immune system disorders: herpes simplex, herpes zoster, bacterial infections, fungal infections, soft tissue infections, viral infections, candidiasis, genital candidiasis, otitis media
Central peripheral nervous system: leg cramps, hypertonia, dullness of sensation, migraine, neuralgia, neuropathy, sensory abnormalities, vertigo
Female reproductive system: breast fibroadenoma, breast tumor, breast pain, dysmenorrhea, menstrual disorders, vaginal bleeding, vaginitis
Male reproductive system: prostate disorders
Hearing and vestibular: deafness, hearing disorders, ear pain, tinnitus
Heart rate and rhythm: palpitations, tachycardia
Hepatobiliary system: abnormal liver function, elevated ALT, elevated AST
Metabolic and nutritional: elevated BUN, elevated creatine phosphokinase (CPK), diabetes mellitus, hypercholesterolemia, hyperglycemia, hypokalemia, increased non-protein nitrogen, increased creatinine, increased alkaline phosphatase, weight gain
Musculoskeletal: arthralgia, arthrosis, bone disease, accidental fracture, myalgia, cervical ankylosis, synovitis, tendonitis
Platelet (clotting) bruising, rhinorrhea, thrombocytosis
Psychiatric: anorexia, anxiety, increased appetite, depression, neuroticism, lethargy
Hematologic: anemia
Respiratory system: bronchitis, bronchospasm, worsening of bronchospasm, cough, dyspnea, laryngitis, pneumonia
Skin and its appendages: baldness, dermatitis, nail lesions, photosensitivity reactions, pruritus, erythematous rash, maculopapular rash, skin lesions, dry skin, hyperhidrosis, rubella
Drug administration site lesions: cellulitis, contact dermatitis, injection site reactions, skin nodules
Special sensations: taste disorders
Urinary system: proteinuria, cystitis, dysuria, hematuria, urinary frequency, kidney stones, urinary incontinence, urinary tract infection
Vision: blurred vision, cataracts, conjunctivitis, eye pain, glaucoma
The following are other very rare serious adverse reactions with an incidence of <0.1%, whether or not causally related to treatment
(The following serious adverse events were rare in patients taking celecoxib capsules and are only reported in post-marketing cases in italics.)
Cardiovascular system: syncope, congestive heart failure, ventricular fibrillation, pulmonary embolism, cerebrovascular accident, peripheral gangrene, thrombophlebitis, vasculitis, deep vein thrombosis
Gastrointestinal system: small bowel obstruction, intestinal perforation, gastrointestinal bleeding, hemorrhagic colitis, esophageal perforation, pancreatitis, intestinal obstruction
Hepatobiliary system: cholelithiasis, hepatitis, jaundice, liver failure
Blood and lymphatic system: thrombocytopenia, granulocyte deficiency, aplastic anemia, holoblood cell anemia, leukopenia
hypoglycemia
Metabolic: hypoglycemia, hyponatremia
Neurological: aseptic meningitis, ataxia, suicide, hypoesthesia, loss of smell, fatal intracranial hemorrhage
Renal: acute renal failure, interstitial nephritis
Cutaneous: erythema multiforme, exfoliative dermatitis, Stevens-Johnson syndrome (SJS), toxic epidermolysis bullosa (TEN)
Systemic: sepsis, sudden death, allergic reaction, angioedema
Contraindications
Contraindicated in the following patients.
1. patients with known hypersensitivity to this product or other cibotropic agents and sulfonamide.
2. Patients with asthma, urticaria or allergic reactions induced by the administration of aspirin or other NSAIDs. 3.
3. contraindicated in the treatment of perioperative pain during coronary artery bypass graft surgery (CABG).
4. Patients with a history of gastrointestinal bleeding or perforation after application of NSAIDs.
5. Patients with active peptic ulcers/bleeding, or previous recurrent ulcers/bleeding.
6. Patients with severe heart failure.
[Caution].
Cardiovascular risk
Clinical trials of multiple cyclooxygenase-2 (COX-2) selective or non-selective NSAIDs for durations up to 3 years have shown that this product may cause an increased risk of serious cardiovascular thrombotic adverse events, myocardial infarction and stroke, the risk of which may be fatal. All NSAIDs, including COX-2 selective or non-selective agents, may have similar risks. Patients with cardiovascular disease or risk factors for cardiovascular disease are at greater risk.
Gastrointestinal Risks
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 regardless of the patient’s history of gastrointestinal adverse reactions or history of serious gastrointestinal events, patients with prior ulcerative colitis, Crohn’s disease should use NSAIDs with caution to avoid worsening their condition. The drug should be discontinued when patients experience gastrointestinal bleeding or ulcers while taking the drug. The risk of adverse reactions, especially gastrointestinal bleeding and perforation, increases in frequency with NSAIDs in elderly patients and can be fatal.
Warnings
Cardiovascular effects
Cardiovascular thrombotic events
Long-term use of this product may cause an increased risk of serious cardiovascular thrombotic adverse events, myocardial infarction and stroke, the risk of which may be fatal. All NSAIDs, including COX-2 selective or non-selective agents, may have similar risks. Patients with cardiovascular disease or risk factors for cardiovascular disease are at greater risk. To minimize the potential risk of cardiovascular adverse events in patients treated with this product, the lowest effective dose should be used for the shortest possible course of therapy. Physicians and patients should remain vigilant 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 attention as soon as any of these signs or symptoms occur.
Hypertension
As with all NSAIDs, this product can cause new-onset hypertension or worsen existing hypertensive symptoms, either of which can lead to an increased incidence of cardiovascular events. The efficacy of these drugs may be compromised when NSAIDs are administered to patients taking thiazide or myeloid diuretics. NSAIDs, including this product, should be used with caution in patients with hypertension. Blood pressure should be monitored closely during initiation and throughout the course of therapy with this product.
Congestive Heart Failure and Edema
No events of congestive heart failure or edema have occurred in clinical studies of this product. Fluid retention and edema have been reported in the literature in some patients taking NSAIDs (including celecoxib capsules). It should be used with caution in patients with a history of heart failure (e.g., fluid retention and edema) or heart failure.
Gastrointestinal (GI) Effects – Risk of GI ulceration, bleeding, and perforation
NSAIDs (including this product), when applied, may cause serious and potentially fatal gastrointestinal events, including bleeding, ulceration, and perforation of the stomach, small intestine, or large intestine. 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 symptoms and regardless of whether the patient has a history of adverse gastrointestinal reactions or a history of serious gastrointestinal events. With long-term use of NSAIDs, there is a trend toward an increased likelihood of serious gastrointestinal events during treatment. However, even short-term treatment is not without risk.
Patients with a prior history of peptic ulcer and/or gastrointestinal bleeding have a 10-fold higher risk of gastrointestinal bleeding with NSAIDs than patients without these risk factors. Other factors that increase the risk of gastrointestinal bleeding in patients treated with NSAIDs include concomitant oral corticosteroids or anticoagulants, long-term treatment with NSAIDs, smoking, alcohol consumption, old age, and poor general health. Most spontaneous reports of fatal gastrointestinal events occur in elderly and debilitated patients, so special care should be taken when treating such patients.
Patients with a previous history of gastrointestinal disease (ulcerative colitis, Crohn’s disease) should use NSAIDs with caution to avoid worsening their condition. When a patient experiences gastrointestinal bleeding or ulceration while taking the drug, it should be discontinued. Elderly patients have an increased frequency of adverse reactions with NSAIDs, especially gastrointestinal bleeding and perforation, the risk of which can be fatal.
To minimize potential gastrointestinal events, the lowest effective dose should be used for the shortest treatment time possible. Physicians and patients should remain alert for signs and symptoms of gastrointestinal ulceration and bleeding during treatment with this product and should promptly initiate additional evaluation and treatment if a serious gastrointestinal adverse event is suspected. For patients at high risk, conversion to a regimen without NSAIDs should be considered.
Renal Effects
This product has not been studied in patients with renal insufficiency and is therefore not recommended for use in patients with renal insufficiency.
Long-term use of NSAIDs can lead to renal papillary necrosis and other renal damage. Nephrotoxicity has also been seen in patients in whom prostaglandins play a compensatory role in renal perfusion maintenance. In these patients, NSAID use leads to a dose-dependent reduction in prostaglandin production and a subsequent reduction in renal blood flow, which will contribute to significant renal failure. Patients at highest risk in this category are those with renal insufficiency, heart failure, hepatic insufficiency, patients on diuretics and angiotensin-converting enzyme (ACE) inhibitors, and elderly patients. Discontinuation of NSAIDs usually results in a return to pre-treatment status. Clinical trials have shown that ereciclib tablets have similar renal effects to celecoxib capsules.
Progressive renal disease
In the available controlled clinical studies, there is no information on the use of this product in patients with progressive renal disease. Therefore, the use of this product in patients with progressive renal disease is not recommended. If this product must be used, close monitoring of the patient’s renal function is recommended.
Allergic reactions
As with NSAIDs in general, allergic reactions can occur in patients who have not taken this product before. No anaphylactic reactions or angioneurotic edema have occurred in patients in clinical studies taking ereciclib tablets. This product should not be used in patients with aspirin triad syndrome. These syndromes characteristically occur in patients with asthma who have rhinitis with or without nasal polyps or in patients who develop severe, potentially fatal bronchospasm after taking aspirin or other nonsteroidal anti-inflammatory drugs. Emergency treatment should be administered if an allergic reaction occurs.
Skin reactions
NSAIDs, including this product, may cause fatal, serious skin adverse reactions such as exfoliative dermatitis, SJS, and TEN. these serious events can occur without warning. Patients should be informed of the signs and symptoms of serious skin reactions and the product should be discontinued at the first sign of skin rash or other signs of an allergic reaction.
Precautions.
Avoid coadministration with other NSAIDs, including selective COX-2 inhibitors.
Adverse effects can be minimized by using the lowest effective dose for the shortest duration of treatment as needed to control symptoms.
The carcinogenicity test of this product has not been completed, and the cumulative duration of dosing is temporarily limited to 24 weeks (inclusive).
Generally: This product should not be used to replace corticosteroids or to treat corticosteroid deficiency. Abrupt discontinuation of corticosteroids can lead to worsening of corticosteroid-controlled disease. Patients on long-term corticosteroid therapy should be tapered if they decide to discontinue the drug.
The pharmacological properties of this product in reducing inflammation and relieving fever may diminish the value of these positive signs in diagnosing infection, assuming that non-infectious pain is present in combination with infection.
Effects on the liver.
This product has not been studied in patients with hepatic insufficiency; therefore, it is not recommended for use in patients with hepatic insufficiency.
In clinical studies on NSAIDs, up to 15% of patients taking it will have a critical increase in one or more hepatic laboratory markers, and about 1% of patients will have a significant elevation of ALT or AST (three or more times above the upper limit of normal). With continued treatment, these abnormal laboratory values may progress, remain stable, or return to normal. There have been rare reports of serious liver reactions in the treatment of NSAIDs, including celecoxib capsules, including jaundiced and fatal fulminant hepatitis, hepatic necrosis and liver failure (some of which can be fatal). Patients taking this product should be carefully monitored for evidence of progression of worsening liver function if they have signs and/or symptoms suggestive of hepatic insufficiency or if there is laboratory evidence of hepatic insufficiency. If signs and symptoms are suggestive of progressive liver disease or if there are systemic manifestations (e.g., eosinophilia, rash, etc.), the product should be discontinued.
Hematologic effects.
Patients in clinical studies of this product did not develop anemia, which has been reported in the literature to sometimes occur in patients treated with celecoxib capsules. Patients on long-term use of this product should have their hemoglobin and hematocrit checked if they develop any signs and symptoms of anemia or blood loss.
Concomitant asthma.
Asthma may be triggered by aspirin allergy in patients with asthma. Aspirin use in patients with aspirin-induced asthma can lead to severe and potentially fatal bronchospasm. Because cross-reactivity between aspirin and other NSAIDs (including bronchospasm) has been reported in these aspirin-allergic patients, this product should not be used in this type of aspirin-allergic patient and should be used with caution in patients with concomitant asthma.
Note to patients.
Patients should be informed of the following information prior to initiating treatment with this product and periodically during the course of treatment
1. This product, like other NSAIDs, may cause serious cardiovascular adverse reactions, such as myocardial infarction or stroke, which may result in hospitalization or even death. Although serious cardiovascular events may occur without any signs, patients should be alert for signs and symptoms of chest pain, shortness of breath, malaise, and slurred speech and should seek medical help if these signs and symptoms occur. Patients should be informed of the importance of follow-up (see [PRECAUTIONS] – WARNINGS – Cardiovascular Effects).
2. This product, like other NSAIDs, may cause gastrointestinal discomfort and rare but more serious adverse reactions such as ulceration and bleeding, which may lead to hospitalization or even death. Although severe gastrointestinal ulceration and bleeding may occur without any signs, patients should be alert for signs and symptoms of ulceration and bleeding and seek medical help if they notice any signs and symptoms indicative of these disorders, including epigastric pain, dyspepsia, dark stools, and vomiting of blood. Patients should be informed of the importance of follow-up (see [Precautions] – Warnings – Gastrointestinal (GI) Effects – Risk of GI ulcers, bleeding, and perforation).
3. Patients should be informed that if any type of rash develops, the drug should be discontinued immediately and the physician should be contacted as soon as possible. Sulfonamides can cause serious adverse skin reactions leading to hospitalization or even death, such as exfoliative dermatitis, SJS, and TENS. these reactions can occur with all, even non-sulfonamide NSAIDs. Although the onset of a serious skin reaction may not be indicated, patients should be alert for signs and symptoms of rash and blistering, fever, or other signs of an allergic reaction such as pruritus, and should seek medical help if any of the signs and symptoms are detected. Patients with a previous history of sulfonamide allergy should not take this product.
4. Patients should promptly report unexplained weight gain or signs and symptoms of edema to their physician.
Patients should be informed of signs and symptoms that predict a hepatotoxic reaction (e.g., nausea, fatigue, drowsiness, pruritus, jaundice, right upper abdominal tenderness, and “flu-like” symptoms). If these signs and symptoms occur, discontinue the drug and seek immediate treatment.
The patient should be informed of the signs and symptoms of an allergic reaction (e.g., dyspnea, facial or laryngeal edema). If these signs or symptoms occur, medication should be discontinued and treatment should be sought immediately.
Laboratory tests.
Because severe gastrointestinal ulcers and bleeding can occur without any signs, physicians should monitor for signs and symptoms of gastrointestinal bleeding that occurs. Patients on long-term treatment with NSAIDs should have regular complete blood counts (CBC) and blood biochemistry tests and discontinue the product if abnormalities in liver or kidney function persist or worsen.
[For pregnant and lactating women].
Pregnancy.
The results of preclinical rat reproductive toxicity tests showed that ericlib was not significantly teratogenic. The results of the embryo-fetal developmental toxicity test in rabbits showed no treatment-related toxic effects of ericlib at oral doses up to 300 mg/kg on both maternal and embryo-fetal development in pregnancy.
There are no studies of its use in pregnant women and it is not recommended for use in pregnant women.
Lactation.
Studies in lactating rats have shown that celecoxib can be secreted via the milk at concentrations similar to plasma concentrations. It is not known whether ereciclib can be secreted through the milk of lactating women. Because many drugs are secreted through the milk of nursing women, this product is not recommended for use in nursing women.
Pediatric Use]
Adequate and well-controlled studies on the efficacy and safety of this product have not been conducted in children and adolescents, and there are no reliable references, so this product is not recommended for use in children and adolescents.
Geriatric Use]
No systematic clinical studies have been conducted on the use of this product in elderly patients, so it should be used with caution under medical supervision.
Drug Interactions]
The interaction between this product and other drugs has not been systematically studied.
Ereximab is a selective COX-2 inhibitor and has been shown to be metabolized in humans primarily by the cytochrome oxidase CYP2C9.
In vitro enzyme inhibition assays showed that ericlib weakly inhibited cytochrome oxidase CYP1A2, CYP2C9, CYP2C19, CYP2D6, CYP2E1 and CYP3A4.
In an in vitro enzyme inhibition assay, the hydroxylation metabolism of glipizide and warfarin, which are mainly metabolized by cytochrome oxidase CYP2C9, was weakly inhibited by ericiclib at a concentration of 50 μM (IC50>50 μM).
Drug overdose]
No specific signs and symptoms of drug overdose have been observed. If an overdose occurs, the patient should be monitored and given conventional supportive therapy; hemodialysis is not an effective way to remove the overdose.
Clinical trials
Phase II clinical.
A multicenter, randomized, double-blind, double-model, positive drug parallel-controlled phase II clinical study enrolled 284 patients with osteoarthritis of the knee and evaluated the clinical efficacy and safety of ereciclib tablets in the treatment of osteoarthritis using celecoxib capsules as the positive control drug.
All patients were randomly divided into four groups: 72 patients in group A received ericiclib tablets 50 mg twice daily; 71 patients in group B received ericlib tablets 100 mg twice daily; 71 patients in group C received ericlib tablets 200 mg twice daily; and 70 patients in group D received celecoxib capsules 200 mg once daily. The treatment course was 12 weeks.
The total effective rate (total effective rate = [(number of significant effect + number of effective + number of improvement)/total number] ╳100%) of the FAS analysis set is indicated in the following table.
Dose
Dosing time Ereximab tablets Celecoxib capsules 50 mg
Twice a day (N=68) 100mg
Twice daily (N=65) 200 mg
Twice daily (N=66) 200 mg
Once daily
(N=65) 2 weeks 27.94% 29.69% 30.77% 42.86% 4 weeks 51.47% 50.00% 52.31% 65.08% 8 weeks 58.82% 64.06% 64.62% 74.60% 12 weeks 69.12% 64.06% 75.38% 74.60%
The difference of total effective rate in the FAS analysis set among the above four groups was not statistically significant (p>0.05); the results of the PPS analysis set were basically consistent with the FAS set at all time points except that after 8 weeks of drug administration, the total effective rate was the highest in group D and the lowest in group A, and the difference among the four groups was statistically significant.
For comparison between groups, the patient evaluation items at 2, 4 and 8 weeks of drug administration, group D had the best efficacy and group A the worst, and the difference between the two groups was statistically significant (P < 0.05).
Phase III clinical.
A multicenter, randomized, double-blind, double-model, positive drug parallel-controlled phase III clinical study evaluated the clinical efficacy and safety of ereciclib tablets for the treatment of knee osteoarthritis, using celecoxib capsules as the control drug.
The 461 patients with knee osteoarthritis were randomly divided into two groups: 344 patients in the test group, who took Ereximab tablets 100 mg twice daily, and 117 patients in the control group, who took Celecoxib capsules 200 mg once daily. It was taken orally after meals. The drug was administered for 8 weeks. Efficacy was evaluated in all subjects during the treatment period (2 weeks, 4 weeks and 8 weeks of dosing). Results: The pain level of walking on flat ground was significantly reduced in both groups at all time points after treatment compared with that before treatment, and the differences were statistically significant (P<0.0001) in all before and after comparisons within the groups, and the differences were not statistically significant (P>0.05) in all points between the groups.
The results of the efficacy evaluation showed that the total pain level score decreased by 5.30±6.22(4.65,5.96) and 5.42±5.98(4.33,6.51) in the test and control subjects, respectively, in 2 weeks of treatment, and by 8.16±7.53(7.37,8.96), respectively, in the test and control subjects in 4 weeks of treatment, compared with the pre-treatment period. 7.62±8.50(6.07,9.17), and after 8 weeks of treatment, the total pain score decreased by 10.22±8.87(9.29,11.15) and 10.28±9.48(8.55,12.01) in the test and control groups, respectively, compared with the pre-treatment period, with no statistically significant difference between the two groups (P>0.05). After 8 weeks of treatment, the conclusion of the non-inferiority test (non-inferiority cut-off value δ=1cm) for the decrease in score values in both groups showed that the test drug was non-inferior to the control drug.
Pharmacology and toxicology]
Pharmacological effects
Ereximab is a non-steroidal anti-inflammatory drug, which exerts analgesic effects by inhibiting cyclooxygenase (COX). In vitro tests have shown that the inhibition of COX isoenzyme cyclooxygenase-1 (COX-1) and COX-2 of erexib is selective, and the inhibition of COX-2 is stronger than that of COX-1. The selectivity of its inhibition of COX-2 is higher than that of indomethacin, slightly stronger or equivalent to meloxicam, but lower than that of celecoxib.
In the analgesic test induced by hot plate method in mice and the analgesic test by acetic acid torsion method in mice, erexib showed analgesic effects. Ereximab has a preventive effect on primary lesions of adjuvant arthritis in rats, and also has a preventive and therapeutic effect on secondary lesions of adjuvant-induced arthritis in rats. In addition, ericiclib inhibited the inflammation caused by keratan gum in rats to varying degrees.
Toxicological studies
Genotoxicity: Ereximab showed negative results in the Salmonella typhimurium revertant mutation test (AMES), the Chinese hamster lung fibroblast chromosome aberration test and the mouse bone marrow cell micronucleus test.
Reproductive toxicity: At doses up to 300 mg/kg/day, ericiclib did not produce abnormal effects on fertility and embryo and fetal development in rats. However, oral administration of ericiclib at 150 mg/kg/day and above in perinatal rats resulted in increased stillbirth rate and delayed maturation of F1 generation litters, and 300 mg/kg/day also resulted in decreased live fetal rate and increased fetal resorption rate in F2 generation litters. The results of the embryo-fetal developmental toxicity test in rabbits showed no treatment-related toxic effects on maternal and embryo-fetal development at oral doses of up to 300 mg/kg of ericiclib.
The results of embryo-fetal developmental toxicity test in rabbits showed that there was no significant difference in Cmax and AUC0-24h between GD6 and GD18 in the three dose groups of pregnant rabbits after continuous oral administration of ericiclib at 60, 150 and 300 mg/kg for 13 days (GD18).
Carcinogenicity: The carcinogenicity test of this product has not been completed.
Pharmacokinetics]
The results of human pharmacokinetic study showed that this product is in accordance with the two-compartment pharmacokinetic model. According to the pharmacokinetic parameters, it is known that.
1. The correlation between ericiclib dose and pharmacokinetic parameters (AUC and Cmax) was investigated, and the AUC and Cmax were linear in four dose groups of 30, 60, 90 and 200 mg for a single administration.
2. Cmax was reached approximately 2 h after oral administration of a single dose of erexib in the fasted state, and Cmax and AUC were approximately proportional to the administered dose.
The Cmax and AUC are approximately proportional to the administered dose. The half-life of the prodrug in plasma is about 20 h. The excretion rate of free metabolites in urine is 40%, and the total excretion rate of metabolites in urine is 50% after enzymatic hydrolysis.
3. The pharmacokinetic results of single administration of 90 mg on fasting and after meal showed that the AUC and Cmax of postprandial administration were significantly greater than those of
fasting administration, but Tmax and t1/2 were not significantly different.
Effect of diet on the main pharmacokinetic parameters of ericiclib
Main pharmacokinetic parameters Effect of diet on pharmacokinetics 90 mg fasting (n=8) 90 mg postprandial (n=8) t1/2 (h) 22.1 ± 8.2 19.5 ± 7.1 AUC0-t (ng∙h/ml) 198.8 ± 124.0 363.8 ± 248.6 AUC0-¥ (ng∙h/ml) 221.6 ± 134.2 384.6 ± 267.2 4. The main pharmacokinetic parameters (Tmax, Cmax, t1/2β, AUC0-t, etc.) of ereciclib prodrug in the 200 mg single dose versus 200 mg multiple dose groups (twice daily for 11 days) showed no accumulation of ereciclib in vivo. the AUC0- and AUC0-t in the 200 mg multiple dose groups M1 and M2 t and AUC0-¥
were significantly higher than those of single dosing. The Cmax of M2 after multiple dosing was significantly higher than that of single dosing.
Major pharmacokinetic parameters of ericiclib and its two major metabolites M1 and M2 after 200 mg single dose and multiple doses
Major pharmacokinetic parameters Administration (postprandial) 200 mg single dose (n=12) 200 mg multiple doses (n=12) Ereximab Tmax (h) 2.71 ± 1.21 2.23 ± 1.22 Cmax (ng/ml) 107 ± 71 126 ± 70 Cmin (ng/ml) 23.4 ± 18.1 Cav (ng/ml) 57.3 ± 35.5 t1/2 (h) 19.1 ± 8.5 AUC0-t (ng∙h/ml) 893 ± 637 AUC0-¥ (ng∙h/ml) 997 ± 726 AUCss (ng∙h/ml) 687 ± 426 DF (%) 195 ± 54 M1 Tmax (h) 2.65 ± 1.11 2.44 ± 1.07 Cmax (ng/ml) 134 ± 55 162 ± 58 Cmin (ng/ml) 19.5 ± 7.3Cav (ng/ml) 65.9 ± 17.5 t1/2 (h) 26.0 ± 22.0 AUC0-t (ng∙h/ml) 958 ± 395 AUC0-¥ (ng∙h/ml ) 1110 ± 507 AUCss (ng∙h/ml) 790 ± 210 DF (%) 214 ± 54 M2 Tmax (h) 2.71 ± 0.99 2.83 ± 1.39 Cmax (ng/ml) 1215 ± 369 1573 ± 477 Cmin (ng/ml) 216 ± 110 Cav (ng/ml) 697 ± 216 t1/2 (h) 15.7 ± 6.3 AUC0-t (ng∙h/ml) 8840 ± 3458 AUC0-¥ (ng∙h/ml) 9438 ± 4404 AUCss (ng∙h/ml) 8362 ± 2586 DF (%) 199 ± 41
5. Pharmacokinetic tests have not been conducted in special populations, including the elderly, children and patients with hepatic and renal insufficiency.
Storage】Store in a dry place under 25℃ under shade and seal.
Package】Packaged in aluminum-plastic blister plate. 6 tablets/plate/box; 10 tablets/plate/box.
Expiration date】24 months
【Executive Standard】YBH01802011
Approval Number】State Drug Registration H20110041
【Manufacturing enterprise
Company Name: Jiangsu Hengrui Pharmaceutical Co.
Production Address: No. 38, Huanghe Road, Lianyungang Economic and Technological Development Zone
Postal Code: 222047
Telephone number: 800-8283900 400-8283900
Fax number: 0518-85453845
Web address: http://www.hrs.com.cn