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Clopidogrel Hydrogen Sulfate Tablets Instructions
Please read the instructions carefully and use under the guidance of your physician
[Drug Name]
Generic Name: Clopidogrel Hydrogen Sulfate Tablets
Trade Name: TEGA
English Name: Clopidogrel Bisulfate Tablets
Hanyu Pinyin: Liusuan Qinglübigelei Pian
[Ingredients]
Chemical name: Methyl (+)-(S)-α-O-chlorophenyl-6,7-dihydrothiophene[3,2-C] pyridine-5(4H)-acetate hydrogen sulfate.
Chemical structure formula:
Molecular Formula:C16H16ClNO2S-H2SO4
Molecular weight: 419.9
[Properties]
This product is a white or off-white round film-coated tablet, which appears white or off-white after removing the coating.
[Indications]
Clopidogrel is used to prevent atherosclerotic thrombotic events in the following patients:
Patients with recent myocardial infarction (from a few days to less than35days), patients with recent ischemic stroke (from 7day to less than 6months) or patients with confirmed peripheral arterial disease.
Patients with acute coronary syndrome
Non-STsegment elevation acute coronary syndrome (including unstable angina or non-Qwave myocardial infarction), including patients with stent placement after percutaneous coronary intervention, in combination with aspirin.
forPatients with STsegment elevation acute coronary syndrome, in combination with aspirin, may be combined in thrombolytic therapy. .
[Specifications]
25 mg(byC16H16ClNO2Scount)
[dosage]
Adults and Elderly:
The recommended dose of clopidogrel is 75 mg once daily. Take orally, with or without food.
For patients with acute coronary syndrome:
non-STsegment elevation acute coronary syndrome (unstable angina or non-Qwave myocardial infarction), patients should be treated with a single loading dose of clopidogrel300 mg to start (in combination with aspirin75 mg to 325 mg/day), followed by 75mgdaily1times continuously. Because of the higher risk of bleeding with higher doses, the recommended daily maintenance dose of aspirin should not exceed100 mg. The optimal course of therapy has not been formally determined. Clinical trial data support dosing for 12months with 3months to show maximum effect(see [clinical trial]).
STsegment elevation acute myocardial infarction: should be treated with a loading dose of clopidogrel300 mgstarted with75mgdaily1time in combination with aspirin, with or without thrombolytic agents. For patients older than 75 years, clopidogrel loading doses are not used. Combination therapy should be initiated as soon as possible after the onset of symptoms and administered for at least 4weeks. No studies have conclusively demonstrated benefit after more than4weeks of combined clopidogrel and aspirin(see [Clinical Trials]).
Patients with recent myocardial infarction (from a few days to less than 35days): the recommended dose is75mg daily1times.
Patients with recent ischemic stroke (from7 days to less than6 months):
Recommended dose is 75mg once daily per dose. Depending on age, weight, and symptoms, the dose may be adjusted to 50 mg once daily.
Patients with confirmed peripheral arterial disease:
Recommended dose for each75mg daily1 times.
If you miss a dose:
at the regular dosing time ofwithin 12 hours of the regular dosing time: the patient should take a standard dose immediately and the next dose according to the regular dosing time;
After the regular dosing time12 hours after the missed dose: The patient should take the standard dose at the next regular dosing time without dose doubling.
Children and Minors:
18 The safety effectiveness in patients under the age of 18 years has not been established.
Renal impairment:
Limited experience with treatment of patients with kidney injury. (See [Caution])
Hepatic impairment:
Limited experience in the treatment of patients with moderate liver injury who have a tendency to bleed. (See [Caution])
[Adverse Reactions]
Clopidogrel Hydrogen Sulfate Tablets Japanese clinical study experience (no aspirin used as primary therapy)
Total2,268 cases in 29.1% of cases (660cases) of patients experienced Adverse reactions (including abnormal laboratory test values), with the main symptom being subcutaneous bleeding2.0%(46 cases) and other bleeding tendencies. The main abnormal laboratory test values wereALT(GPT) is elevated5.1% family:isoline”>(115examples), γ-GTPelevated4.6%(104examples),AST(GOT) rose4.1%((93cases) and other abnormalities of liver function and decreased hemoglobin1.9%(44cases), decreased white blood cells1.7%(39examples), etc. (when the expanded indication is approved)
Experience with Japanese clinical studies of clopidogrel sulfate tablets ( using aspirin as the base treatment)
Total1,243 cases, 35.6%of family:equivocal”>(443cases) of patients experienced adverse reactions (including abnormal laboratory test values), the main symptom being subcutaneous bleeding5.7%((71 cases) and other bleeding tendencies. The main abnormal laboratory test values wereALT(GPT) is up7.9% family:isoline”>(98examples), AST(GOT) higher5.6%(69examples),γ-GTPelevation5.1%(64cases) and other abnormalities of liver function such as neutrophilia0.9%(11cases), etc. (when the expanded indication is approved)
Experience with Clopidogrel Hydrogen Sulfate Tablets in Japan after launch
13,078examples with 13.1% (1,710cases) of patients experienced adverse reactions (including abnormal laboratory test values) as, the main symptom was abnormal liver function1.7% (225cases), anemia0.8% () (103cases), rash0.8% (101cases), gastrointestinal bleeding0.5% (65examples), etc. Abnormal values of the main laboratory tests γ-GTProse0.9% (113example),ALT(GPT) up0.8% (103examples),AST(GOT) up0.5% () (67cases), etc. (ischemic cerebrovascular disorder (except cardiogenic cerebral embolism) suppression after recurrence, applied to ischemic percutaneous transluminal coronary angioplasty (PCI) (at the end of cardiac recurrence).
Global clinical study experience with clopidogrel sulfate tablets
Has been studied in44,000 Roman”>44,000plus patients in whom the safety of clopidogrel was evaluated,12, 000 patients treated with no less than1year. In CAPRIE, , CURE,CLARITYandCOMMIT clinically relevant adverse reactions observed in are discussed below. In the CAPRIEstudy, the same as in the aspirin325 mg/day compared with clopidogrel75 mg/day was better tolerated. In this study, the overall tolerability of clopidogrel was similar to that of aspirin, independent of age, sex, and race. In addition to the clinical study experience, there were spontaneous reports of adverse reactions.
Bleeding was the most common adverse reaction in clinical studies and post-marketing reports, often reported in the first month of treatment.
In CAPRIE study, the overall incidence of bleeding events was 9.3% in patients treated with either clopidogrel or aspirin span>. The incidence of serious events with clopidogrel was similar to that with aspirin.
In CUREstudy, discontinuing the drug before surgery5 family:Arial”>day or more, major bleeding within 7 days after coronary artery bypass grafting is uncommon. In patients who continued treatment within 5 days of bypass surgery, clopidogrel+aspirin, placebo+aspirin had an event rate of 9.6%, respectively, 6.3%.
In CLARITY study, compared with placebo+aspirin group compared with the clopidogrel+aspirin group, bleeding was increased. The incidence of major bleeding was similar in both groups. This was consistent across subgroups by baseline characteristics, type of fibrinolytic agent, or with or without heparin therapy.
In COMMIT study, the overall rate of intracranial hemorrhage and non-intracranial major bleeding was lower and more similar in both groups.
The clinical studies and spontaneously reported adverse reactions are shown in the following table. The frequency of adverse reactions was defined as common (≥1/100, 1/10); uncommon (≥1/1,000, , 1/100); rare (≥1/10,000, 1/1,000); very rare (1/10) ,000), unknown (based on available data and cannot be determined). Within each organ system subgroup, adverse reactions were ranked in decreasing order of severity.
System organ classification CommonUnusualrareVery rare, unknown*
Blood and Lymphatic System
Abnormal Thrombocytopenia, Leukopenia, EosinophiliaNeutropenia, including Severe neutropeniaThrombotic thrombocytopenic purpura (TTP), aplastic anemia, pancytopenia,
granulocyte deficiency, severe thrombocytopenia, acquired hemophiliaA, granulocytopenia, anemia Immune system abnormalities Serum sickness, allergic reaction, Thienopyridines have allergic cross-reactivity with each other (e.g., ticlopidine and prasugrel) (see Precautions)*
Mental abnormality hallucinations, consciousness confusionNervous system abnormalities Intracranial hemorrhage (reported
tract fatal), headache, abnormal sensation, dizziness Disordered taste Eye abnormalities Ocular hemorrhage (conjunctiva, Eyes, Retina)Eyes, Retina “padding-left: 7px; padding-right: 7px; border-left: none; border-bottom: solid black 0.625pt; border-right: solid black 0.625pt”> Ear and disorientation abnormalities Glare Vascular abnormalitiesHematoma severe bleeding, surgical wound bleeding, vasculitis, hypotension Respiratory, Chest and
Mediastinal abnormalitiesNose bleed Respiratory bleeding (coughing up blood, pulmonary hemorrhage), bronchospasm, interstitial pneumonia, eosinophilic granulocytic pneumonia Gastrointestinal system abnormalities
Gastrointestinal bleeding, diarrhea, abdominal pain, indigestion
Gastric ulcers and duodenal
Intestinal ulcers, gastritis,
vomiting, nausea, stool
Constipation, gas and bloating
Retroperitoneal hemorrhage
Fatal gastrointestinal and retroperitoneal bleeding, pancreatitis, colitis (including ulcerative or lymphocytic colitis), stomatitisAbnormalities of the hepatobiliary system
Acute Liver Failure, Hepatitis, Abnormal Liver Function Testsskin and subcutaneous tissue
Abnormal
Bruising
Rash, scratching, skin
skin bleeding (purpura)
Dermatitis herpetiformis (toxic epidermolysis bullosa,Stevens Johnson syndrome, erythema multiforme, acute generalized eruptive pustulosis (AGEP)), angiohematoma, drug
induced hypersensitivity syndrome, drug rash with eosinophilia and systemic symptoms syndrome (DRESS), urticaria, eczema, erythema or exfoliative rash, lichen planusMusculoskeletal and connective
Tissue abnormalities Skeletal muscle bleeding (joint hematoma), arthritis, arthralgia, myalgiaRenal and urinary system
Abnormal Hematuria
Glomerulonephritis with elevated blood creatinineReproductive System and Breast
Abnormalities Male Breast DevelopmentSystemic diseases and giving
Various reactions at the drug siteInjection site bleeding
Fever
Check Prolonged bleeding time,
Neutropenia
Low, thrombocytopenia *Information related to taking clopidogrel is “unknown”.
[Contraindicated]
Sensitivity to the active substance of this product or hypersensitivity to any of the ingredients of this product.
Severe liver damage.
Patients with bleeding (hemophilia, intracranial hemorrhage Gastrointestinal bleeding, urinary bleeding, hemoptysis, vitreous hemorrhage, etc.)[There is a risk of exacerbation of bleeding].
[Note]
Bleeding and Hematologic Abnormalities span style=”font-family:Times New Roman”>
Because of the risk of bleeding and hematologic adverse reactions, blood counts and / or other appropriate tests. As with other antiplatelet agents, patients at increased risk of bleeding due to trauma, surgery, or other pathologic conditions and those receiving aspirin, nonsteroidal anti-inflammatory drugs(NSAIDS) includeCox-2inhibitors, heparin, platelet glycoproteinIIb/IIIa(GPIIb/IIIa) antagonists,selective5-hydroxytryptamine reuptake inhibitors (SSRIs) and5-hydroxytryptamine noradrenaline reuptake inhibitors (serotonin norepinephrine reuptake inhibitors, SNRIs) or patients treated with thrombolytic drugs should be treated with clopidogrel with caution. Patients should be followed closely for any signs of bleeding including occult bleeding, especially during the first weeks of treatment and / or cardiac interventions, surgical procedures After. Clopidogrel is not recommended in combination with warfarin because of the potential to worsen bleeding.
In patients requiring elective surgery, if antiplatelet therapy is not necessary, preoperative7days to discontinue clopidogrel. Before scheduling any surgery and before taking any new medication, patients should inform their physicians that they are taking clopidogrel. Clopidogrel prolongs bleeding and should be used with caution in patients with bleeding disorders (especially gastrointestinal and intraocular disorders).
Patients should be informed that it may take longer than usual to stop bleeding when they are taking clopidogrel (alone or in combination with aspirin) and that the patient should report abnormal bleeding (site and duration of bleeding) to the physician. The patient should report abnormal bleeding (site and duration of bleeding) to the physician.
Discontinue
Interruption of therapy should be avoided and if clopidogrel must be discontinued, it needs to be resumed as soon as possible. Premature discontinuation of clopidogrel may lead to an increased risk of cardiovascular events.
Patients with ischemic cerebrovascular disease at high risk of recurrence
For patients with ischemic cerebrovascular disease at high risk of recurrence, severe bleeding has been reported abroad in combination with aspirin compared with clopidogrel alone. The incidence is increased, so adequate attention should be paid when coadministering the drug.
Thrombotic thrombocytopenic purpura (TTP))
Thrombotic thrombocytopenic purpura rarely occurs after clopidogrel application (TTP), sometimes after a short period(<2 weeks)after medication. TTP may be life-threatening to the patient. It is characterized by thrombocytopenia, microangiopathic hemolytic anemia with abnormal neurological manifestations, renal impairment, or fever. TTP is a condition that requires urgent treatment, including plasma exchange.
Recent ischemic stroke =”font-family:Times New Roman”>
Due to lack of data, acute ischemic stroke episodes after7days after an acute ischemic stroke attack, clopidogrel is not recommended.
Acquired hemophilia. “font-family:Times New Roman”>
Cases of acquired hemophilia have been reported after the application of clopidogrel. Acquired hemophilia should be considered in the presence of a definite prolonged in vitro activated partial thromboplastin time (aPTT) with or without bleeding. Patients with confirmed acquired hemophilia should be managed and treated by a specialist, and clopidogrel should be discontinued.
CytochromeP450 2C19(CYP2C19)
Genetic Pharmacology: CYP2C19slow metabolizers on recommended doses of clopidogrel have reduced blood concentrations of its active metabolite and reduced antiplatelet effects. Methods are available to detect the patientCYP2C19genotype.
Because clopidogrel is partially mediated throughCYP2C19metabolism to its active metabolite, administration of drugs that inhibit this enzyme activity may reduce the level of clopidogrel conversion to the active metabolite. The clinically relevant significance of drug interactions cannot be determined. Combination use of potent or moderateCYP2C19inhibitors is not recommended.
Patients with recent transient ischemic event episodes or ischemic stroke who are at higher risk for recurrent ischemic events, the combination of aspirin and clopidogrel was not shown to be more effective than clopidogrel alone, yet increased the risk of bleeding.
Cross-allergic reactions with thienopyridine
Thienopyridine may cause mild to severe allergic reactions such as rash, angioedema, or hematologic adverse reactions such as thrombocytopenia and neutropenia. granulocytopenia. Because cross-allergic reactions between thienopyridines have been reported, patients should be evaluated for history of allergy to other thienopyridines (e.g., ticlopidine and prasugrel) (see [Adverse Reactions]). Patients with prior allergic reactions to one thienopyridine and/ or hematologic adverse reactions to another thienopyridine may be at increased risk of developing the same or other The risk of adverse reactions may be increased. Monitoring for cross-reactivity is recommended.
Renal impairment
Limited experience with clopidogrel in patients with renal impairment; therefore, clopidogrel should be used with caution in these patients.
Hepatic impairment
In patients with moderate hepatic disease who may have a tendency to bleed, clopidogrel should be used with caution in such patients because of the limited experience with clopidogrel in such patients.
No effects on driving or mechanical handling have been seen after clopidogrel administration.
This drug contains hydrogenated castor oil, which may cause stomach upset and diarrhea.
[For pregnant and lactating women]
Pregnancy
As there is no clinically available information regarding the use of clopidogrel for pregnancy, it is prudent to avoid administration of clopidogrel to women during pregnancy. There is no direct or indirect evidence from animal studies that clopidogrel has harmful effects on pregnancy, embryonic/fetal development, delivery, or postnatal growth(see [Pharmacological Toxicology]).
Lactation
The results of animal experiments showedclopidogrel and/ or its metabolites can be excreted from breast milk, but it is not clear whether this drug is excreted from human breast milk. It is prudent to discontinue breastfeeding during treatment with clopidogrel sulfate tablets.
Fertility
Clopidogrel has not been found to alter reproductive function in animal studies.
[Pediatric Use]
No experience with use in children.
[Geriatric use]
See [Dosage].
[Drug Interactions]
Oral anticoagulants: Combining clopidogrel with warfarin is not advocated because of the ability to increase bleeding intensity(see [Precautions]). Although daily dosing of 75 mg Clopidogrel does not alter the pharmacokinetics or international normalized ratio of S-warfarin in patients receiving long-term warfarin therapy due to each independently inhibiting the hemostatic process, the combination of warfarin and clopidogrel increases the risk of bleeding.
Glycoprotein IIb/IIIaAntagonists: Clopidogrel and glycoprotein should be combined with cautionII b/ III a antagonist.
Acetylsalicylic acid (aspirin): aspirin does not alter the effect of clopidogrel on the effects caused byADPinduced platelet aggregation, but clopidogrel potentiates the inhibitory effect of aspirin on collagen-induced platelet aggregation. However, co-administration of aspirin500 mg, taken twice a day for one day of use, did not significantly increase the prolonged bleeding time caused by clopidogrel. There may be pharmacodynamic interactions between clopidogrel and aspirin that increase the risk of bleeding, so the two drugs should be observed when combined (see [Precautions]). However, there have been people who have used clopidogrel in combination with aspirin for more than one year.
Heparin: Studies in healthy volunteers have shown that clopidogrel does not alter the effect of heparin on coagulation,no need to change the dose of heparin. Combination of heparin does not affect the inhibitory effect of clopidogrel on platelet aggregation. There may be pharmacodynamic interactions between clopidogrel and heparin that increase the risk of bleeding, so care should be taken when combining the two drugs(see [Precautions]).
Thrombolytic drugs: in patients with acute myocardial infarction, the safety of clopidogrel in combination with fibrin-specific or nonspecific thrombolytic agents and heparin was evaluated. The incidence of clinical bleeding was similar to that seen with the combination of thrombolytic agents, heparin, and aspirin(see [Adverse Reactions]).
NSAIDs () NSAIDs): clopidogrel in combination with naproxen increased occult bleeding in the gastrointestinal tract in clinical trials conducted in healthy volunteers. Because of the lack of studies on the interaction of clopidogrel with other NSAIDs, it is not known whether the combination with all NSAIDs increases the risk of gastrointestinal bleeding events. Therefore, caution should be exercised when combining NSAIDs, including Cox-2inhibitors, with clopidogrel(see [Precautions]).
Selective5 -hydroxytryptamine reuptake inhibitors (SSRIs) and5-hydroxytryptamine norepinephrine reuptake inhibitors ( “font-family:Times New Roman”>SNRIs): because they affect platelet activation, SSRIs and SNRIs in combination with clopidogrel may increase the risk of bleeding.
Other combination therapies:
As clopidogrel is partially regulated byCYP2C19metabolized to the active metabolite, the use of drugs that inhibit this enzyme activity will result in a decrease in the level of the active metabolite of clopidogrel. The clinically relevant significance of drug interactions cannot be determined. Combination use of potent or moderateCYP2C19inhibitors (e.g., omeprazole) is not recommended (see [Precautions] and [Pharmacokinetics ).
Proton pump inhibitors (PPI):
Omeprazole 80 mg once daily with clopidogrel or at intervals12 family:Arial”>hours, both decreased the blood concentration of the active metabolite of clopidogrel by 45%(loading dose) and40% (maintenance dose). This decrease in blood levels resulted in a reduction in platelet aggregation inhibition by 39% (loading dose) and 21%(maintenance dose). Esomeprazole may interact with clopidogrel in a similar manner.
About Pharmacokinetics (PK)/pharmacodynamic (PD) interactions in terms of clinical outcomes such as major cardiovascular events, and observational studies and clinical study results are inconsistent. The combination of clopidogrel with omeprazole or esomeprazole is not recommended (see [Precautions]).
A substantial decrease in blood concentrations of clopidogrel metabolites was not observed with pantoprazole and lansoprazole in combination with clopidogrel.
Co-administration of pantoprazole80 mg once daily, the plasma concentrations of the active metabolite of clopidogrel decreased by 20%(loading dose) and 14%(maintenance dose) and were accompanied by 15% and 11% reduction in mean platelet aggregation inhibition. These results suggest that clopidogrel can be co-administered with pantoprazole.
There is no evidence that other drugs that inhibit gastric acid secretion such asH2blockers (excludingCYP2C19) span>inhibitor cimetidine) or antacids interfere with the antiplatelet activity of clopidogrel.
Other drugs:
Pharmacodynamic and pharmacokinetic interactions of clopidogrel with other co-administered drugs have been studied through numerous other clinical studies. No clinically meaningful pharmacodynamic interactions were observed when clopidogrel was combined with atenolol and nifedipine alone or concomitantly. In addition, the combination of clopidogrel with phenobarbital and estradiol had no significant effect on the pharmacodynamic activity of clopidogrel.
Clopidogrel does not alter the pharmacokinetics of digoxin or theophylline. Acidulators do not alter the degree of absorption of clopidogrel.
CAPRIE The studydatashows that phenytoin and toluenosulfonylurea can be safely combined with clopidogrel.
Riglitazone: clopidogrel sulfate given to healthy adults (1day1time, administered3days, day1day dosing300 mg, administered on day2 to 375 mg) on day1and on day3and on daycombined with Repaglinide (0.25 mg), showed that, compared with the administration of repaglinide alone, the combination of repaglinide with clopidogrelCmaxandAUC0-∞th1day respectively to 2.5,,5.1 times on day3day increased to 2.0, 3.9 times. In addition,t1/2 respectively1.4, 1.2 times.
In addition to the clear drug interaction information described above, interactions between drugs commonly used in patients with atherosclerotic thrombotic disease and clopidogrel have been studied. However, in clinical trials, patients receiving clopidogrel along with multiple concomitant medications, including diuretics,β blockers, ACEI, calcium antagonists, lipid-lowering agents, coronary vasodilators, antidiabetic agents (including insulin), antiepileptics, hormone replacement therapy, andGPIIb/IIIareceptor antagonists, no clinically meaningful adverse interactions were identified.
[Drug overdose]
Clopidogrel overdose may cause prolonged bleeding and bleeding complications. Appropriate management should be performed if bleeding is detected.
No antidote has been identified for the pharmacologic activity of clopidogrel. Platelet transfusions can reverse the effects of clopidogrel if rapid correction of prolonged bleeding is required.
[Clinical Trial]
The efficacy and safety of clopidogrel have been demonstrated in a total of overclopidogrel trials including ultra. family:Times New Roman”>88,000patients,5 evaluated in 5 double-blind clinical studies:CAPRIEstudy i.e. comparison of clopidogrel and aspirin;CURE,CLARITY, COMMIT, and ACTIVE-A study is comparing clopidogrel with placebo on the basis of aspirin as well as other standard treatments.
Recent myocardial infarction (MI), recent stroke or confirmed peripheral arterial disease
CAPRIEstudy enrolled a total of19185 cases presenting with recent myocardial infarction (<35days), recent ischemic stroke (7days) days to 6months) or diagnosed peripheral arterial disease with atherosclerotic thrombosis (PAD) formation. Patients were randomized to receive clopidogrel75 mg/day or aspirin325mg/day, followed by follow-up1to3years. In the subgroup with myocardial infarction, most patients received aspirin in the first few days of acute myocardial infarction.
Clopidogrel significantly reduced the incidence of new ischemic events (joint endpoints including myocardial infarction, ischemic stroke, and vascular death) compared with aspirin. After an intention-to-treat analysis, it was found that the clopidogrel and aspirin groups had 939events and 1020events (associated hazard reduction () RRR)8.7%,[95% CI:0.2 to 16.4];P=0.045), which is equivalent to 1,000 patients per case treated with clopidogrel2years and prevented10more compared to aspirin >Example[CI:0-20]patients with a new ischemic event. In the analysis that included total mortality as a secondary end point, no new ischemic events were shown in the clopidogrel group (5.8%) and the aspirin group (6.0%) and any significant difference between the aspirin group ().
In a subgroup analysis of the eligible conditions (myocardial infarction, ischemic stroke, and peripheral arterial disease), it was shown that because peripheral arterial disease (especially those with concurrent with a history of myocardial infarction) (RRR=23.7%;CI:8.9~36.2) and the enrolled patients appeared to have the greatest benefit (statistically significant,P=0.003), while stroke patients (RRR=7.3%;CI:-5.7 to 18.7[p=0.258]) with weaker gains (no difference compared to the aspirin group statistically significant). In those patients enrolled with only recent myocardial infarction, the clopidogrel group was numerically slightly worse compared with the aspirin group, but the difference was not statistically significant (RRRR=-4.0%;CI:-22.5-11.7[p=0.639]). In addition, subgroup analysis according to age showed that the benefit of clopidogrel was lower in patients aged >75 years than in those aged ≤75year-old patients.
Since CAPRIEstudy’s individual subgroup efficacy evaluations are not evaluated with sufficient certainty, it is unclear whether differences in relative risk reduction between subgroups do exist or are due to chance.
Acute coronary syndrome
CUREstudies were selected for a total of 12,562cases of non family:Times New Roman”>STsegment elevation in acute coronary syndrome (unstable angina or non-Qwave myocardial infarction) presenting as24I or “font-family:Times New Roman”>T was elevated at least twice the upper limit of normal. Patients were randomized to receive clopidogrel (loading dose300 mg, followed by75mg/day,N=6259) or placebo (N=6303), both groups combined with aspirin (75 to 325 mg once daily) and other standard treatments in both groups. Patients were treated for up to one year. In the CURE study,823823(6.6%) patients were treated with GPIIb/IIIareceptor antagonist combination therapy. More than 90% of patients were treated with heparin, and the relative incidence of bleeding between the clopidogrel and placebo groups was not significantly affected by combination heparin therapy.
Occurrence of primary endpoint events in the clopidogrel and placebo treatment groups[Cardiovascular death (CV), myocardial infarction (MI), or stroke] respectively, the number of patients with 582cases (9.3%) and “font-family:Times New Roman”>719 cases (11.4%), the clopidogrel treatment group (relative risk reduction in conservatively treated patients was 17% and the relative risk reduction for patients treated withPTCA with or without stenting was29%, and patients receivingCABGrelative risk reduction for patients undergoing10%) relative risk reduction for span>20%() 95% CI:10% to 28%. P=0.00009). New cardiovascular events (primary endpoint) were prevented at 0 to 1, , 1~3,3~6,6~9andand9 to 12months of the study period, the relative risk reduction was 22%(CI:8.6,33.4 ), 32% (CI:12.8 span style=”font-family:equinox”>,46.4),4%(CI:-26.9,26.7), 6% (CI::-33.5,34.3) and 14% (CI:-31.6 (,44.2). Thus, after more than three months of treatment, the benefit observed in the clopidogrel combined with aspirin treatment group was no longer further increased, while the risk of bleeding persisted (see [Caution]).
InCUREstudy, the use of clopidogrel resulted in thrombolytic therapy (RRRR=43.3%;CI:24.3%, 57.5%) andGPIIb/IIIa inhibitors (RRR=18.2%;CI:6.5%,28.3%) have seen a reduction in demand for their use.
In the clopidogrel-treated and placebo-treated groups, the number of patients with a joint primary endpoint event (cardiovascular death, myocardial infarction, stroke, or intractable ischemia) 1035 cases, respectively (16.5%) and 1187 cases (18.8%). The relative risk was reduced by 14% in the clopidogrel-treated group. This benefit was primarily from a significant reduction in the incidence of myocardial infarction[in the clopidogrel and placebo groups, respectively287 cases (4.6%) and 363 cases (5.8%)]. No effect was observed on the rate of rehospitalization for unstable angina.
From people with different characteristics (eg, unstable angina or nonCURE trial in the 2,172 patients who received stents (of all patients enrolled inCURE17% of all patients enrolled in the clinical trial) were analyzed using a causal analysis The resulting data showed that the relative risk of the primary endpoint event (cardiovascular death, myocardial infarction, stroke) was reduced by 26.2% with clopidogrel compared with placebo :isoline”>% and the relative risk reduction for secondary endpoint events (cardiovascular death, myocardial infarction, stroke, or intractable ischemia) with clopidogrel was 23.9%. In addition, the CUREstent placement subgroup of the study did not suggest a safety issue with clopidogrel. Accordingly, this result is consistent with the overall results of the CUREstudy.
The benefits observed with clopidogrel were independent of other acute and long-term cardiovascular treatments (e.g., heparin). style=”font-family:Times New Roman”>/low-molecular heparin,GPIIb/ IIIareceptor antagonists, lipid-lowering drugs, beta-blockers and ACEI). The observed efficacy of clopidogrel was also independent of the dose of aspirin (75 to 325 mg/day).
CALRITY andCOMMIT, two randomized, double-blind, placebo-controlled clinical studies of acuteSafety and efficacy of clopidogrel in patients with STsegment elevation myocardial infarction were evaluated.
CALRITY The trial was enrolled in 3,,491examples12 Patients with STsegment elevation myocardial infarction occurring within hours and ready for thrombolytic therapy. Patients received a loading dose of clopidogrel (300 mg, respectively, followed by 75mg/day,n=1752) or placebo (n=1739), both in combination with aspirin (first with loading dose150 to 325 mg, followed by75 to 162 mg/day), fibrinolytics, and heparin (when appropriate). Patients were followed up for 30days. The primary end point included the finding of an infarct-related artery occlusion on pre-discharge angiography, or death or recurrent myocardial infarction before coronary angiography. For patients without angiography, the primary end point was death or recurrent myocardial infarction within day 8or before discharge. The patient population included19.7% of women and29.2% of ≥65 of family:equinox”>year-old patients. Of these, fibrinolytics were used (fibrin-specific:68.7%, non-fibrin-specific:31.1%) of patients:99.7% , patients on heparin:89.5%, beta-blockers:78.7%, ACE inhibitors 54.7%, and statins:63%.
in the clopidogrel treatment group15.0% of patients and in the placebo group21.7%patients met the primary endpoint, indicating that clopidogrel reduced the absolute risk by 6.7%and the relative risk by 36% () 95% CI:24,47%;p<0.001), mainly associated with a significant reduction in infarct-related arterial occlusion. This benefit was consistent across all prespecified subgroup analyses, including patient age sex, infarct site, and type of fibrinolytic or heparin used.
In22 span>×2 of the analytic design ofCOMMIT trial was enrolled in the 45,852 cases in24hours or less with symptoms of suspected myocardial infarction and corresponding ECG abnormalities (e.g.STelevation,STdepression or left bundle branch block) in patients. Patients received clopidogrel (75 mg/day,n=22,961) or placebo (n=22,,891) in combination with aspirin (162 mg/day). Treatment28 days or until patient discharge. The primary composite end point included death from any cause and the composite end point of the occurrence of reinfarction, stroke, or death. The patient population included27.8% of women with58.4% of patients ≥60years (26%≥70 years old), with 54.5%of the patients used fibrinolytics.
Clopidogrel reduces the relative risk of death from any cause7%(p=0.029), the relative risk of the composite endpoint of reduction in reinfarction, stroke, and death9%(p=0.022) with absolute hazard reduction values of 0.022, respectively Roman”>0.5% and 0.7%. This benefit was consistent across age, sex, and use versus non-use of fibrinolytics, and was observed as early as 24hours.
Ischemic cerebrovascular disease (except cardiogenic cerebral embolism)
A study was completed in Japan on the effectiveness of oral clopidogrel sulfate tablets (as clopidogrel75 mg/day) with ticlopidine hydrochloride200 mg/day as a control drug in a double-blind trial (1,151cases), comparing the incidence of vascular events, the incidence in the ticlopidine hydrochloride group2.6%(15/578cases) and the incidence in the clopidogrel group was3.0%(17/573cases), indicating that clopidogrel and ticlopidine hydrochloride are equivalent in reducing the risk of vascular events (risk ratio of 0.977). In addition, the overall incidence of leukopenia, neutropenia, platelet reduction, abnormal liver function, nontraumatic bleeding, and other serious adverse reactions in the ticlopidine hydrochloride group15.1%(87/578cases), significantly higher than the clopidogrel group7.0%(40/573example), (p 0.001).
[Pharmacology and Toxicology]
Pharmacodynamic Properties
Pharmacotherapeutic classification: platelet aggregation inhibitors, excluding heparin,ATCNo:BO1AC-04
Clopidogrel is a precursor drug and one of its metabolites is a platelet aggregation inhibitor. Clopidogrel must be metabolized by the CYP450enzyme to generate active metabolites that inhibit platelet aggregation. The active metabolite of clopidogrel selectively inhibits adenosine diphosphate (ADP) from its platelet =”font-family:Times New Roman”>Binding of P2Y12receptors and secondaryADP span>mediated glycoproteinGPIIb/IIIa activation of the complex and therefore inhibits platelet aggregation. Because of irreversible binding, the remaining lifespan of platelets exposed to clopidogrel (approximately 7 to 10 days) is compromised, and the normal function of platelets recovery rate is consistent with platelet renewal. The platelet-activated aggregation pathway induced by blocking the releasedADP also inhibits the platelet-activated aggregation pathway exceptADPinduced platelet inhibition by other agonists.
Due to active metabolites viaCYP450enzyme formation, some CYP450enzyme is polymorphic or inhibited by other drugs, so not all patients will achieve adequate platelet inhibition.
Clopidogrel 75 mg, administered orally once daily in humans in repeated doses, significantly inhibitedADP from day 1 “font-family:isoline”>induced platelet aggregation, and the inhibition gradually increased and reached steady state in 3 to 7days. At steady state, the mean level of inhibition with clopidogrel75 mg per day was40% to 60%, generally after discontinuation of treatment5day platelet aggregation and bleeding time gradually return to baseline levels.
Toxicology Study
In preclinical studies conducted in rats and baboons, the most common reactions were hepatic changes. These hepatic changes were the result of drug effects on hepatic metabolizing enzymes administered at doses of 75 mg/day of clopidogrel exposure obtained in humans. span>25fold. Humans receiving therapeutic doses of clopidogrel have no effect on hepatic metabolizing enzymes.
Rats and baboons receiving very high doses of clopidogrel had effects on gastric tolerance (gastritis, gastric ulcer, and/ or vomiting). At doses as high as 77 mg/kg per day, mice taking78weeks for mice and104weeks of clopidogrel showed no evidence of carcinogenesis. Blood levels at this dose are higher than the recommended human dose (75 mg per day). family:Times New Roman”>25 times.
The absence of genotoxic effects of clopidogrel has been confirmed in a series of in vivo and in vitro tests.
Clopidogrel had no effect on fertility in female and male rats, and was not teratogenic in rats or rabbits. Clopidogrel administration to lactating rats slightly delayed the development of pups. Pharmacokinetic studies have shown that clopidogrel and / or its metabolites are excreted from breast milk. Therefore, a direct or indirect effect of clopidogrel cannot be excluded.
[Pharmacokinetics]
Absorption
Single and multiple oral doses per day75 mg, clopidogrel was rapidly absorbed. The mean plasma concentration of clopidogrel in the prototype compound peaked at approximately 45minutes after administration (single oral75mgafter approximately2.22.2 span>to2.5ng/mL). At least 50% of the drug was absorbed based on the urinary excretion of clopidogrel metabolites.
Distribution
In vitro assays have shown that clopidogrel and its major circulating metabolite (inactive) bind reversibly to human plasma proteins (respectively98% and94%), which is non-saturated over a wide range of concentrations.
Metabolism
Clopidogrel is primarily metabolized by the liver. The in vivo and in vitro metabolism of clopidogrel occurs through two major metabolic pathways: one pathway is mediated by esterases and metabolized by hydrolysis to inactive acid derivatives (85% of circulating metabolites), and another pathway is mediated by multiple cytochromesP450. Clopidogrel is first metabolized to2-oxy-Clopidogrel intermediate metabolite. 2-oxy-clopidogrel intermediate metabolite is subsequently metabolized to form the active metabolite, a clopidogrel thiol derivative. In vitro, the metabolic pathway is mediated by CYP3A4, CYP2C19,CYP1A2andCYP2B6mediated. The active thiol derivatives isolated in vitro rapidly and irreversibly bind to platelet receptors, thereby inhibiting platelet aggregation.
Single300mg CmaxC of the active metabolite after clopidogrel loading dose administration style=”font-family:equivocal”>is75mgmaintenance dose administration4days after2times. Cmaxappears approximately after administration30 to 60 minutes after administration.
Elimination
Oral administration in humans14Clabeled clopidogrel after120hour approximately50%is excreted by urine and approximately46%is excreted in the feces. After a single oral dose of clopidogrel75 mg, the half-life of clopidogrel is6hours, and the half-life of the active metabolite is approximately30minutes. The elimination half-life of circulating inactive metabolites (inactive) is 8hours after single and repeated dosing.
Genetic Pharmacology
CYP2C19involved in the active and intermediate metabolites2-oxygen-clopidogrel formation. The pharmacokinetics and antiplatelet effects of the active metabolites of clopidogrel (the latter measured by in vitro measurements of platelet aggregation rates) vary with CYP2C19Varied by genotype.
CYP2C19*1 alleles correspond to the complete functional metabolic phenotype, while CYP2C19*2 and CYP2C19*3 alleles are loss-of-function. CYP2C19*2 and CYP2C19*2 and CYP2C19*3 alleles account for 85% of slow metabolic alleles in whites style=”font-family:allele”>and in Asians accounted for 99%. Other alleles associated with the slow metabolic phenotype includeCYP2C19*4, *5,*6,*7andand*8, but these are much less common. Patients with the slow metabolic phenotype carry two loss-of-function alleles as described above. The reportedCYP2C19 distribution frequencies of the slow metabolic genotypes are white approximately2% and blacks about4%, and Chinese about14%. Existing methods to detect the genotype of patientsCYP2C19.
In a 40 span>crossover trial in 40 healthy subjects with a total of 4 groups of CYP2C19metabolic subjects (ultra-fast metabolism, fast metabolism, intermediate metabolism, slow metabolism), each group was included in each 10 subjects and evaluate the pharmacokinetic profile and antiplatelet function in each group with the following dosing regimen: first dose300 mg and subsequently75 mg/day; first dose600mgand subsequentdays span>150mg/day; both regimens were administered for a total of5 days (steady state). No differences in clopidogrel active metabolite blood concentrations and mean platelet aggregation inhibition (IPA were observed between subjects with ultrafast, fast, and intermediate metabolic types ) The apparent difference in the data. Blood concentrations of active metabolites in slow metabolizers were lower63% to 71% than in fast metabolizers. After administration at 300 mg/75 mg regimen, the antiplatelet effect was reduced in slow metabolizers, whose mean style=”font-family:Times New Roman”>IPA(5 μM ADP) for 24%(24hours) and37%(day 5), while among the fast metabolizersIPA was 39%(24hours) and58% (theth) 5day) in the intermediate metabolizers and IPA is37%(24hours) and 60% (the 5thday). Slowly metabolizing subjects receiving 600 mg/150 mgdosing regimens had higher blood concentrations of active metabolites than those receiving 300 mg/75 mgdosing regimen. In addition, subjects receiving the 600mg/150mgdosing regimenIPAwas32%(24hours) andhours) and61% (the5day), higher than values for slow metabolizing subjects receiving 300 mg/75 mgdosing regimens. In slow metabolizing subjects receiving 600 mg/150 mg, the active metabolite blood concentrations andIPA values, which can reach acceptable 300mg/75mg levels in other metabolic subjects. There is a lack of clinical endpoint studies in slow metabolizers to help determine the appropriate dose and dosing regimen for this patient population.
A study including6items in a total of335 cases treated with clopidogrel patients at steady stateMetaanalysis showed similar results as above: reduced exposure to active metabolites in intermediate metabolizers compared with fast metabolizers28% and slow metabolizers lower72%; while platelet aggregation inhibition (5μm ADP) was also reduced, and the IPA differences with fast metabolizers were5.9%and21.4%.
Prospective, randomized, controlled trial results are lacking to evaluateCYP2C19genotype on clinical outcomes in patients treated with clopidogrel. However, there are some retrospective analysis results evaluating the changes in clinical outcomes in patients carrying different genotypes treated with clopidogrel:CURE(n=2721),CHARISMA(n=2428),CLARITY-TIMI 28(n=227),TRITON-TIMI 38(n=1477), ACTIVE-A(n =601); and a number of published cohort studies.
InTRITON -TIMI38 and 3 item cohort study (Collet, Sibbing,Giusti), a higher incidence of cardiovascular events (death, myocardial infarction, and stroke) or stent thrombosis was observed in the analysis of patients with combined intermediate and slow metabolic phenotypes than in patients with fast metabolic phenotypes.
In CHARISMA and a cohort study (Simon) observed higher event rates only in patients with slow metabolic phenotypes than in patients with fast metabolic phenotypes.
InCURE,CLARITY, ACTIVEAand a cohort study (Trenk) in which differentCYP2C19an elevated rate of cardiovascular events was not observed in patients with metabolic phenotypes.
The number of subjects in these analyses may not be sufficient to detect differences in clinical endpoints in patients with slow metabolic phenotypes.
Special Populations
The pharmacokinetics of the active metabolites of clopidogrel in these special populations are unknown.
Renal impairment: clopidogrel75 mgonce daily after repeated dosing in patients with severe renal impairment (creatinine clearance5 to 15 ml/min) compared with healthy subjects, the inhibition of ADPinduced The inhibition of platelet aggregation was lower (25%), but the prolonged bleeding time was associated with daily clopidogrel75 mg per day in healthy volunteers. Moreover, it was well tolerated clinically in all patients.
Hepatic impairment: patients with severe hepatic impairment on daily oral clopidogrel75 mg repeatedly10days later, the inhibition of ADPinduced platelet aggregation was observed in healthy subjects similarly. The prolongation of mean bleeding time was also similar in both groups.
[Storage]Store in a dry place, protected from light and sealed.
[Package]Medicinal plastic bottle:10tablets/bottle,20pieces/bottle,30bottles,pieces/bottles,40pieces/bottle.
[Expiration date]36months.
[Executive Standard 2015Establishment II, State Food and Drug Administration Standard2015YBH01042013and the State Food and Drug Administration Supplementary Application Approval for Drugs2015B01004
[Approval number]State Drug CertificateH20000542
[Manufacturer]
Company Name: Shenzhen Xinlitai Pharmaceutical Co. family:Times New Roman”>
Manufacturing Address: Petrochemical Avenue West, Daya Bay Economic and Technological Development Zone, Huizhou City, Guangdong Province42No.
Postal Code: 516083
Phone Number: ( 0755)83867888
Fax Number: () 0755)83867338
Website: =”font-family:Times New Roman”>www.salubris.cn