Clopidogrel Hydrogen Sulfate Tablets
Drug name
Generic name: Clopidogrel Hydrogen Shlfate Tablets
English name: PLAVIX
Chinese Pinyin: liusuanjinglubigelei. Part and its chemical name: clopidogrel bisulfate
properties
The oral poliovir is a pink, round, biconvex, notched film-coated tablet with 75 on one side and 1171 on the other, containing 97.875mg of clopidogrel bisulfate, which is equivalent to 75mg of clopidogrel base.
Pharmacology and Toxicology
Pharmacodynamics
Clopidogrel is a platelet aggregation inhibitor. ATC classification: BO1AC/4.
Clopidogrel selectively inhibits the binding of adenosine diphosphate (ADP) to its platelet receptor and the secondary ADP-mediated activation of glycoprotein GPlllb/llla complex, so it can inhibit platelet aggregation. Clopidogrel must be biotransformed to inhibit platelet aggregation, but no active metabolites have been isolated to produce this effect. Besides ADP, clopidogrel can inhibit platelet aggregation induced by other agonists by blocking the amplification of platelet activation caused by released ADP. Clopidogrel can not inhibit phosphodiesterase activity. Clopidogrel works by irreversibly modifying ADP receptors on platelets. The life span of platelets exposed to clopidogrel is affected. The recovery rate of normal platelet function is related to platelet renewal.
clopidogrel 75mg was given repeatedly every day from the first day to inhibit ADP-induced platelet aggregation, and the inhibition reached a steady state in 3-7 days. In the steady state, the average inhibition level of clopidogrel 75mg per day is maintained at 4%-6%, and the platelet aggregation and bleeding time gradually return to the baseline within about 5 days after the treatment is stopped.
The clinical efficacy of clopidogrel comes from CAPRIE clinical trial. There are 19,185 patients enrolled in this trial, which are multi-centers and multi-countries. Randomly and double-blind parallel clinical studies were conducted to compare the effects of clopidogrel (75mg/ day) and aspirin (325mg/ day) < P >.
Patients randomly selected are:
1) Patients with recent myocardial infarction (within 35 days)
2) Patients with recent ischemic stroke (within 7 days to 6 months) who still have secondary nervous system symptoms for at least one week.
3) Patients with diagnosed peripheral arterial disease (PAD)
were randomly treated for 1-3 years. In the myocardial infarction group, most patients took aspirin at the early stage after acute myocardial infarction.
Compared with aspirin, clopidogrel can significantly reduce the incidence of new ischemic events, including myocardial infarction, ischemic stroke and death from other vascular diseases. Among them, 939 cases occurred in the clopidogrel treatment group and 12 cases occurred in the aspirin treatment group (relative risk reduction (RRR) was 8.7% [95% CI: .2-16.4]; P=.45), which means that every 1 patients receive 2 years of treatment, and 1[CI:-2] patients can avoid an ischemic event. The overall mortality rates of clopidogrel treatment group and aspirin treatment group were 5.8% and 6.%, respectively, and there was no significant difference.
According to the death of myocardial infarction, ischemic stroke and other vascular diseases, due to PAD (especially those patients with a history of myocardial infarction) (RRR=23.7%; CI:8.9-36.2) Patients and patients with severe ischemic stroke (no significant difference compared with aspirin treatment group) (RRR=7.3%; CI-5.7-18.7) patients benefited the most (p=.3). The effective rate of patients selected for recent myocardial infarction in clopidogrel treatment group was slightly lower than that in aspirin treatment group, but there was no statistical difference (RRR=4.%; CI:-22.5-11.7）。 Moreover, according to the age group analysis, the therapeutic effect of clopidogrel on patients under 75 years old is better than that of patients over 75 years old.
Because the clinical trial of CAPRIE was not deliberately designed to evaluate whether clopidogrel is more effective for a certain group of patients, it is not clear whether this difference is true or accidental.
study on preclinical safety
the most common preclinical reaction in rats and baboons is liver changes. The dosage taken is 25 times that of the human body after taking 75mg/ day clopidogrel. These liver changes are the result of the influence of drugs on liver metabolic enzymes.
rats and baboons have poor stomach tolerance (gastritis, gastric ulcer and/or dizziness) after taking high doses of clopidogrel.
Mice took clopidogrel for 78 weeks, and rats took clopidogrel for 14 weeks, and no evidence of cancer was found. The plasma concentration of this dose is 25 times higher than the recommended dose of human beings (75mg per day).
A series of in vivo and in vitro tests confirmed that clopidogrel had no mutagenic effect.
Clopidogrel has no effect on the fertility of female and male rats, and has no teratogenic effect on rats and rabbits. Taking clopidogrel in nursing rats can slightly delay the development of young children. Pharmacokinetic studies show that clopidogrel and/or its metabolites are excreted from milk, so it is not excluded that clopidogrel has direct (slight toxicity) or indirect (bad taste) effects.
pharmacokinetics
after taking clopidogrel 75mg orally for many times, clopidogrel is absorbed rapidly, and the plasma concentration of the parent compound is very low, which is generally below the quantitative limit (.25mg/L) after 2 hours of administration. According to the excretion of clopidogrel metabolites in urine, at least 5% of the drugs were absorbed.
clopidogrel is mainly metabolized by the liver. The main metabolites in blood are carboxylate derivatives, which have no effect on platelet aggregation, accounting for 85% of drug-related compounds in plasma. After repeated oral administration of 75mg of clopidogrel, the plasma concentration reached a peak of (3 mg/L) about 1 hour later < P > Clopidogrel was mainly composed of a drug precursor, which was oxidized to form 2- oxy-clopidogrel, and then hydrolyzed to form an active metabolite (a thiol derivative). Oxidation is mainly regulated by cytochrome P45 isoenzymes 2B6 and 3A4, and 1A1, 1A2 and 2C19 also have some regulatory effects. The isolation of this active metabolite in vitro shows that it can bind to platelet receptor rapidly and irreversibly, thus inhibiting platelet aggregation. However, this metabolite was not detected in blood.
in the range of 5-15mg of clopidogrel, the pharmacokinetics of the main metabolites increased linearly (the plasma concentration was proportional to the dose).
In a wide range of concentrations, clopidogrel and its main metabolites can reversibly bind to human plasma proteins in vitro (98% and 94% respectively).
After 14C-labeled clopidogrel is taken orally, about 5% of it is excreted in urine and 46% in feces within 5 days. After one and repeated administration, the elimination half-life of major metabolites in plasma is 8 hours.
patients with severe renal damage (creatinine clearance rate of 5-15ml/min) and healthy volunteers after taking 75mg of poliovir repeatedly every day. Although the inhibitory effect of ADP on platelet aggregation is lower than that of healthy volunteers by 25%, the bleeding time is the same as that of healthy volunteers taking clopidogrel 75mg every day. Moreover, all patients have good clinical tolerance.
healthy volunteers and patients with liver cirrhosis (Child-Pugh classA or b) were given clopidogrel in single and multiple doses, while patients with pharmacodynamic sclerosis of clopidogrel were given clopidogrel in single and multiple doses, and the pharmacodynamics and pharmacokinetics of clopidogrel were studied. The results showed that clopidogrel 75mg once a day for 1 days was safe and well tolerated by the subjects. The peak plasma concentration of clopidogrel in patients with liver cirrhosis was several times higher than that in healthy volunteers. However, the concentration of main metabolites in blood, the inhibitory effect of ADP on platelet aggregation and the bleeding time are similar between cirrhosis group and healthy volunteers group.
Indications
Plavix is suitable for patients with recent stroke, myocardial infarction and peripheral arterial disease. The medicine can reduce the occurrence of atherosclerotic events (such as myocardial infarction, stroke and vascular death). )
Usage and Dosage
The recommended dosage of Plavix is 75mg per day, with or without food, and there is no need to adjust the dosage for elderly patients.
adverse reactions
the safety of clopidogrel was evaluated through the treatment of more than 11,3 patients, of which more than 7, patients received treatment for one year or more. In the large-scale clinical study (CAPRIE), taking 75mg/ day of clopidogrel was well tolerated compared with taking 325mg/ day of aspirin. Regardless of age, sex and race, the overall tolerance of clopidogrel is similar to that of aspirin. The main clinical adverse reactions in CAPRIE trial are discussed as follows: < P > Bleeding: < P > The total incidence of bleeding in patients treated with clopidogrel or aspirin is 9.3%. The incidence of serious bleeding events in clopidogrel and aspirin was 1.4% and 1.6%, respectively.
The incidence of gastrointestinal bleeding was 2.% in patients treated with flupiogrel, .7% in patients requiring hospitalization, and 2.7% and 1.1% in patients treated with aspirin.
compared with aspirin, the incidence of other bleeding events in patients taking clopidogrel is higher (7.3%vs6.5%), but the incidence of serious events in the two treatment groups is similar (.6%vs.4%). The most common adverse events in the two treatment groups are purpura/contusion/hematoma, nosebleed, hematoma, hematuria and eye hemorrhage (mainly conjunctival hemorrhage).
The incidence of intracranial hemorrhage was .4% for clopidogrel and .5% for aspirin.
Hematological diseases:
There were 6 patients with severe neutropenia (neutrophil < .45× 19/1), 4 patients in clopidogrel group (.4%) and 2 patients in aspirin group (.2%). Two of the 9599 patients in the clopidogrel group had zero neutrophil count, while none of the 9586 patients in the aspirin group had it. A case of aplastic anemia occurred in clopidogrel group.
The incidence of severe thrombocytopenia (< 8× 19/1) was .2% in the clopidogrel group and .1% in the aspirin group. It is very rare that the platelet count is ≤3×19/1.
gastrointestinal tract:
generally speaking, the incidence of gastrointestinal reactions (such as abdominal pain, dyspepsia, gastritis and constipation) was 27.1% in clopidogrel group and 29.8% in aspirin group. Moreover, 3.2% of the patients in the clopidogrel group and 4.% in the aspirin group withdrew from treatment due to gastrointestinal side effects. However, there was no statistical difference in the incidence of serious clinical side effects among the groups (3.%vs.3.6%). The most common adverse events in the two treatment groups were abdominal pain, dyspepsia, diarrhea and nausea. Others include constipation, dental diseases, dizziness and gastritis.
The incidence of diarrhea in clopidogrel group was 4.5%, which was significantly higher than that in aspirin group (3.4%). The incidence of severe diarrhea was similar between the two treatment groups (.2% vs .1%). The incidence of digestive tract, stomach and duodenal ulcer was .7% in clopidogrel group and 1.2% in aspirin group.
Rash and other skin diseases:
The incidence of skin and its affiliated tissues diseases in clopidogrel group was 15.8%(.7% serious), which was significantly higher than that in aspirin group (4.2%vs.3.5%). The incidence of clopidogrel-grade itching was also higher than that of aspirin group (3.3%vs.1.6%)
Central and peripheral system diseases:
The total incidence of central and peripheral system diseases (such as headache, dizziness and sensory abnormality) in clopidogrel group was significantly lower than that in aspirin group (22.3%vs.23.8%).
Liver and biliary tract diseases:
The total incidence of liver and biliary tract diseases in the two treatment groups is similar (3.5%vs.3.4%)
Post-marketing use:
Post-marketing use has confirmed the safety of clopidogrel, and allergic symptoms have occurred, mainly including skin reactions (maculopapules or erythema, urticaria …) and/or itching. Bronchospasm, angioedema or anaphylactoid reaction are rare.
after marketing, very few patients have experienced thrombotic thrombocytopenic purpura (TTP) (1 in 2, patients)
contraindications
1. Allergy to drugs or any component of this product.
2. Severe liver injury
3. Active pathological bleeding, such as peptic ulcer or intracranial hemorrhage.
Precautions
Clopidogrel treatment is not recommended for patients with acute myocardial infarction in the first few days.
Clopidogrel is not recommended to treat unstable angina pectoris, PTCA (with stent), CABG and acute ischemic stroke (less than 7 days) due to lack of relevant data.
Clopidogrel should be used with caution in patients with increased bleeding due to trauma, surgery or other pathological reasons. The patient underwent elective surgery without antiplatelet therapy, and stopped using clopidogrel one week before operation.
Clopidogrel prolongs the bleeding time, and should be used with caution for patients with wounds (especially in gastrointestinal tract and eyes) that are prone to bleeding.
patients should know that it may take longer than usual to take clopidogrel to stop bleeding, and they should report abnormal bleeding to the doctor. Before operation and taking other new drugs, patients should inform the doctor that they are taking clopidogrel.
Because patients with renal injury have very limited experience in using clopidogrel, these patients should use clopidogrel with caution.
Patients with severe liver disease may have bleeding tendency, and such patients have very limited experience in using this medicine, so they should be careful with clopidogrel.
Because warfarin also tends to bleed, it is not recommended to use warfarin at the same time when taking this medicine.
Taking aspirin, nonsteroidal antipyretic and analgesic drugs, heparin and thrombolytic agents at the same time can increase the risk of bleeding, so taking them at the same time is not recommended (see drug interaction).
Clopidogrel should be used with caution for patients who take drugs that are prone to gastrointestinal damage (such as non-steroidal antipyretic and analgesic drugs) (see [Drug Interaction]).
There is no influence on driving or psychological test after using this medicine.
pregnant women and lactating women take drugs
Reproductive studies in rats and rabbits show that clopidogrel has no effect on fertilization and fetus. As there are not enough strict controlled studies on pregnant women, it is not recommended to take this medicine during pregnancy.
Studies on rats show that clopidogrel and/or its metabolites are excreted from milk, but it is not clear whether this drug is excreted from human milk.
the safety and effectiveness of this product for children in pediatrics have not been clear.
drug use in elderly patients
the plasma concentration of major metabolites in the elderly (not less than 75 years old) is significantly higher than that in young healthy volunteers, but the higher plasma concentration has nothing to do with the difference of platelet aggregation and bleeding time, so it is not necessary to adjust the dose for the elderly.
drug interaction
warfarin: see precautions.
aspirin (ASA)
aspirin does not.