Clopidogrel bisulfate tablets

Drug name

Generic name: clopidogrel bisulfate tablets

Product name: Boliwei

English name: clopidogrel bisulfate tablets

English trade name: PLAVIX

Hanyu Pinyin: Liusuan Qinglu Bigelei Tablet

The main component of this product and its chemical name: clopidogrel bisulfate.

Character; Role; letter

Plavix, an oral preparation, is a pink, round, biconvex film-coated tablet with 75 on one side and 1 17 1 on the other side. It contains 97.875mg of clopidogrel bisulfate, which is equivalent to 75mg of clopidogrel base.

Pharmacology and toxicology

Pharmacodynamic characteristics

Clopidogrel is a platelet aggregation inhibitor. ATC classification: BO 1AC/04.

Clopidogrel selectively inhibits the binding of adenosine diphosphate (ADP) to its platelet receptor and ADP-mediated activation of glycoprotein GPlllb/llla complex, so it can inhibit platelet aggregation. Clopidogrel must undergo biotransformation 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 ADP released. Clopidogrel could 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 speed 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 a steady state, the average inhibition level of 75mg clopidogrel per day was maintained at 40%-60%, and the platelet aggregation and bleeding time gradually returned to the baseline within about 5 days after drug withdrawal.

The clinical efficacy of clopidogrel comes from CAPRIE clinical trial. There are 65,438+09 and 65,438+085 patients in this experiment, who come from many centers and countries. Randomly and double-blind compare the efficacy of clopidogrel (75 mg/day) and aspirin (325 mg/day).

Parallel clinical study.

Randomly selected patients are:

1) has a recent history of myocardial infarction (within 35 days)

2) Recent history of ischemic stroke (within 7 days to 6 months) with secondary nervous system symptoms for at least one week.

3) Diagnosis of peripheral arterial diseases

Patients were randomly treated for 1-3 years. In the myocardial infarction group, most patients take aspirin early after acute myocardial infarction.

Compared with aspirin, clopidogrel can significantly reduce the incidence of new ischemic events, including myocardial infarction, ischemic stroke and other vascular diseases. Among them, 939 cases occurred in clopidogrel treatment group and 1020 cases occurred in aspirin treatment group (relative risk reduction (RRR) was 8.7% [95% CI: 0.2-16.4]; P=0.045), which is equivalent to 2 years of treatment for every 1000 patients, and 10[CI:0-20] patients can avoid an ischemic event. The total mortality of clopidogrel treatment group and aspirin treatment group were 5.8% and 6.0%, respectively, with no significant difference.

According to the death of myocardial infarction, ischemic stroke and other vascular diseases, due to PAD (especially patients with a history of myocardial infarction) (RRR = 23.7%; CI:8.9-36.2) and severe ischemic stroke (no significant difference compared with aspirin treatment group) (RRR = 7.3%; Patients in CI-5.7- 18.7) group benefited the most (p=0.003). The effective rate of clopidogrel treatment group in patients with recent myocardial infarction was slightly lower than that of aspirin treatment group, but there was no statistical difference (RRR = 4.0%; CI:-22.5- 1 1.7). And 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 CAPRIE clinical trials are not designed to evaluate whether clopidogrel is more effective for a certain group of patients, it is not clear whether this difference is real or accidental.

Preclinical safety study

The most common preclinical reaction in rats and baboons is liver changes. The dosage of clopidogrel is 25 times that of 75 mg/day. These liver changes are the result of drugs affecting liver metabolic enzymes.

Rats and baboons taking high doses of clopidogrel have poor stomach tolerance (gastritis, gastric ulcer and/or dizziness).

At the daily dose of 77mg/kg, mice took clopidogrel for 78 weeks and rats took clopidogrel 104 weeks, and no evidence of carcinogenesis was found. The plasma concentration of this dose is 25 times higher than the recommended dose for humans (75 mg per day).

A series of in vivo and in vitro experiments confirmed that clopidogrel had no mutagenic effect.

Clopidogrel has no effect on 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

Clopidogrel absorbed rapidly after taking 75mg orally for many times, and the plasma concentration of the parent compound was very low, which was generally below the quantitative limit (0.00025mg/L) after 2 hours of administration. According to the excretion of clopidogrel metabolites in urine, at least 50% drugs are 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 clopidogrel, the plasma concentration reached its peak (30mg/l) about 65438 0 hours later.

Clopidogrel is mainly a prodrug, which forms 2- oxy-clopidogrel by oxidation and then forms an active metabolite (a thiol derivative) by hydrolysis. Oxidation is mainly regulated by cytochrome P450 isoenzymes 2B6 and 3A4, and 1A 1, 1A2 and 2C 19 also have some regulatory effects. The in vitro separation of this active metabolite 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 50- 150mg, the pharmacokinetics of clopidogrel increased linearly (the plasma concentration was proportional to the dose).

In a wide concentration range, clopidogrel and its main metabolites can reversibly bind to human plasma protein in vitro (98% and 94% respectively).

After oral administration of clopidogrel labeled with 14C, about 50% was excreted in urine and 46% in feces within 5 days. The elimination half-life of major metabolites in plasma is 8 hours after one or more doses.

Patients with severe renal damage (creatinine clearance rate of 5- 1.5 ml/min) and healthy volunteers after taking 75mg of polivir repeatedly every day. Although the inhibitory effect of ADP on platelet aggregation is 25% lower than that of healthy volunteers, 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 treated with single and multiple doses of clopidogrel, and patients with pharmacodynamic sclerosis of clopidogrel were treated with single and multiple doses of clopidogrel. Pharmacodynamics and pharmacokinetics of clopidogrel were studied. The results showed that it was safe and well tolerated for the subjects to take 75 mg of clopidogrel 10 once a day. The peak plasma concentration of clopidogrel in patients with liver cirrhosis is 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 bleeding time are similar between liver cirrhosis group and healthy volunteers group.

indicate

Plavix is suitable for patients with recent stroke, myocardial infarction and confirmed peripheral arterial disease. The medicine can reduce the occurrence of atherosclerotic events (such as myocardial infarction, stroke and vascular death). )

dosage

The recommended dose of Plavix is 75mg per day, which is dispensable, and elderly patients do not need to adjust the dose.

counteraction

The safety of clopidogrel was evaluated by treating more than 1 1 300 patients, of which more than 7000 patients received 1 year or more. In a large-scale clinical study (CAPRIE), compared with taking 325mg aspirin every day, taking 75mg clopidogrel every day is well tolerated. Regardless of age, sex and race, the overall tolerance of clopidogrel is similar to that of aspirin. The main clinical adverse reactions in CAPRIE test are discussed as follows:

Bleeding:

The total incidence of bleeding in patients treated with clopidogrel or aspirin was 9.3%. The incidence of serious bleeding events in clopidogrel and aspirin were 65,438 0.4% and 65,438 0.6%, respectively.

The incidence of gastrointestinal bleeding was 2.0% in patients receiving clopidogrel treatment, 0.7% in patients needing hospitalization, and 2.7% in aspirin and 1. 1% respectively.

Compared with aspirin, patients taking clopidogrel had a higher incidence of other bleeding events (7.3%vs6.5%), but the incidence of serious events in the two treatment groups was similar (0.6%vs0.4%). The most common adverse events in the two treatment groups were purpura/contusion/hematoma and nosebleed, while others were hematoma, hematuria and ocular hemorrhage (mainly conjunctival hemorrhage).

The incidence of intracranial hemorrhage in clopidogrel and aspirin was 0.4% and 0.5% respectively.

Blood diseases:

There were 6 patients with severe neutropenia (neutrophils < 0.45× 109/ 1), 4 patients in clopidogrel group (0.04%) and 2 patients in aspirin group (0.02%). Two of the 9599 patients in the clopidogrel group had zero neutrophil count, while none of the 9586 patients in the aspirin group had zero neutrophil count. Aplastic anemia occurred in clopidogrel group 1 case.

The incidence of severe thrombocytopenia (< 80× 109/ 1) was 0.2% in the clopidogrel group and 0. 1% in the aspirin group. Platelet count ≤30× 109/ 1 is very rare.

Gastrointestinal tract:

Generally speaking, the incidence of gastrointestinal reactions (such as abdominal pain, dyspepsia, gastritis and constipation) was 27.65438 0% in clopidogrel group and 29.8% in aspirin group. In addition, 3.2% of patients in clopidogrel group and 4.0% in 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 (3.0% 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 in the two treatment groups was similar (0.2% vs 0. 1%+0%). The incidence of digestive tract, stomach and duodenal ulcer in clopidogrel group was 0.7%, and that in aspirin group was 65438 0.2%.

Rashes and other skin diseases:

The incidence of skin and its affiliated tissue diseases in clopidogrel group was 65438 05.8% (0.7% serious), which was significantly higher than that in aspirin group (4.2% vs 3.5%). The incidence of clopidogrel 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 nervous system diseases (such as headache, dizziness, vertigo and abnormal sensation) in clopidogrel group was significantly lower than that in aspirin group (22.3% vs 23.8%).

Liver and biliary diseases:

The total incidence of hepatobiliary diseases in the two treatment groups was similar (3.5% compared with 3.4%).

Use after listing:

The safety of clopidogrel has been confirmed by its post-marketing use, and it has allergic symptoms, mainly including skin reactions (maculopapules or erythema, urticaria ...) and/or itching. Bronchospasm, angioedema or allergic reactions are rare.

After marketing, very few patients (65,438+0/200,000 patients) developed thrombotic thrombocytopenic purpura (TTP).

taboo

1, allergic to drugs or any components of this product.

2. Severe liver injury

3, active pathological bleeding, such as peptic ulcer or intracranial hemorrhage.

Matters needing attention

Clopidogrel 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 clopidogrel one week before operation.

Clopidogrel can prolong the bleeding time, and patients with bleeding wounds (especially gastrointestinal tract and eyes) should use it with caution.

Patients should know that taking clopidogrel may take longer than usual to stop bleeding, and patients should report abnormal bleeding to their doctors. Patients should inform their doctors that they are taking clopidogrel before surgery and before taking other new drugs.

Because the experience of using clopidogrel in patients with renal injury is very limited, these patients should use clopidogrel with caution.

Patients with severe liver disease may have bleeding tendency, and their experience in using this drug is very limited, so clopidogrel should be used with caution.

Because warfarin is also prone to bleeding, it is not recommended to use warfarin at the same time when taking this drug.

Taking aspirin, nonsteroidal antipyretic and analgesic drugs, heparin and thrombolytic agents at the same time will increase the risk of bleeding, so taking them at the same time is not recommended (see drug interaction).

Clopidogrel should be used with caution in patients who take drugs (such as non-steroidal antipyretic and analgesic drugs) that can easily cause gastrointestinal damage (see Drug Interaction).

Using this medicine has no effect on driving and psychological test.

Medication for pregnant and lactating women

Reproductive studies in rats and rabbits show that clopidogrel has no effect on fertilization and fetus. It is not recommended to take this medicine during pregnancy because there is no strict controlled study on pregnant women.

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 pediatric children are not clear.

Medication for elderly patients

The plasma concentration of main 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 the elderly do not need to adjust the dose.

drug interaction

Warfarin: See the notes.

Aspirin

Aspirin does not change the inhibitory effect of clopidogrel on ADP-induced platelet aggregation, but clopidogrel enhances the effect of aspirin on collagen-induced platelet aggregation. Taking aspirin 500mg with clopidogrel twice a day once will not significantly increase the bleeding time caused by clopidogrel, and the safety of taking aspirin and clopidogrel at the same time for a long time has not been determined. (See [Precautions]).

Heparin:

In the study of healthy volunteers, clopidogrel does not change the role of heparin in coagulation and does not need to change the dose of heparin. Taking heparin at the same time does not affect the inhibitory effect of clopidogrel on platelet aggregation. Because the safety of taking it at the same time is uncertain, it should be used with caution.

Thrombolytic agent:

To evaluate the safety of clopidogrel, rt-PA and heparin in patients with recent myocardial infarction. The incidence of clinical bleeding is similar to that of taking aspirin simultaneously with rt-PA and heparin. Because the safety of clopidogrel combined with other thrombolytic agents has not been determined, it should be used with caution. ([Precautions])

Nonsteroidal antipyretic and analgesic drugs

Taking naproxen and clopidogrel simultaneously in healthy volunteers is related to potential gastrointestinal bleeding. Due to the lack of research on the interaction between clopidogrel and other non-steroidal antipyretic and analgesic drugs, whether to take it with all non-steroidal antipyretic and analgesic drugs at the same time will improve gastrointestinal bleeding. Therefore, caution should be exercised when non-steroidal antipyretics and clopidogrel are taken orally at the same time. ([Precautions])

Other combination therapies:

Pharmacodynamic interaction and pharmacokinetic interaction of clopidogrel were studied through a large number of clinical trials. There is no significant clinical pharmacodynamic interaction between clopidogrel, atenolol and nifedipine, and the combination of clopidogrel with phenobarbital, cimetidine or estradiol will not significantly affect the pharmacodynamic activity of clopidogrel.

When combined with clopidogrel, the pharmacokinetic characteristics of digoxin and theophylline did not change. At the same time, the use of acid generator will not change the absorption of clopidogrel.

Studies on human liver microsomal enzymes show that the carboxyl metabolites of clopidogrel can inhibit P450(2C9) activity. Therefore, clopidogrel may increase the plasma concentration of some drugs, such as phenytoin sodium, tolbutamide and other non-steroidal antipyretic and analgesic drugs metabolized by P450(2C9). CAPRIE studies show that phenytoin, tolbutamide and clopidogrel are safe.

excessive

There was a case of overdose of Plavix. A 34-year-old woman once took 1.050mg of clopidogrel (equivalent to 0.50 mg/tablet 14 tablet) without any related side effects and special treatment. The patient has no sequelae after recovery.

When healthy volunteers took 600 mg orally (equivalent to 8 tablets of 75 mg/tablet), no side effects were reported. The prolonging factor of bleeding time was 1.7, which was the same as that observed in the routine dose (75mg/ day).

Clopidogrel has no antidote. If the normal bleeding time needs to be restored quickly, platelet transfusion can be used to antagonize the pharmacological effect of clopidogrel.

Specification 75mg/tablet

Packaging Double aluminum film packaging, 7 tablets/box, 14 tablets/box, 28 tablets/box.

There are no special storage requirements for storage.

Valid for 3 years.

Hangzhou Sanofi Shengdebao Minsheng Pharmaceutical Co., Ltd.