Clopidogrel-VK 75mg An Thien 3x10

Pharmacology

Pharmacological group: Platelet inhibitors.

ATC code: b01ac04.

Clopidogrel is a thienopyridine derivative with similar pharmacological and pharmacological effects ticlopidin, a platelet aggregation inhibitor.

Clopidogrel is a precursor with the effect of inhibiting platelet aggregation depending on the metabolism in the liver into activity thiol metabolites.

Biological metabolism occurs through 2 steps: Clopidogrel is initially oxidized into intermediate metabolites, 2-oxo-clopidogrel, then converted into active thiol metabolites. The metabolic path associated with some isenzyme cytochrom P450 (such as CYP3A4, CYP2C19, CYP1A2, CYP2B6).

Clopidogrel is an Adenosin Triphosphate (ADP Receptor) receptor inhibitor (ADP Receptor), the activity of clopidogrel selectively and not compete with low affinity to the P2Y12 position of the ADP receptor on platelet surface, thus inhibiting ADP's attachment to the receptor and leading to the inhibition of Glycoprotein GPILB/Illa complex in this case Necessary to attach two platelets, make and copy platelets. Clopidogrel also inhibits concentrated seed release (containing ADP, calcium and serotonin) platelet through ADP intermediaries and Alfa beads (containing fibrinogen and thrombospondin), which contain substances that enhance platelet aggregation. Platelets in contact with Clopidogrel maintain the end of the life of platelets (7 - 10 days).

Unlike Aspirin, Clopidogrel inhibits Cycloxygenase in operation to prevent prostaglandin and thromboxan synthesis a.

When taking daily dose clopidogrel 75 mg, the inhibitory effect of plateletal training appears on the first day of treatment and reaches 40-60% inhibition at a stable level of about 3-7 days. After stopping the drug, platelets and bleeding time return to the original level within 5 days.

Dynamic pharmacokinetics

absorption

Clopidogrel absorbs quickly and not completely through oral, absorbing at least 50% of oral dose. When taking the dose of 75 mg, the clopidogrel concentration in plasma at 2 hours after taken is very low, usually under the quantitative limit (0.00025 mg/liter). The highest concentration of the main metabolites in plasma is 3 mg/liter at 1 hour after drinking.

distribution

Clopidogrel and main metabolites associated with high -ratio plasma proteins (98% and 94%).

transformation

Clopidogrel is a precursor and is metabolized through the liver, mostly into carboxylic acid derivatives that are inactive metabolites. Metabolized by liver by isenzymecytochrom P450. The active metabolite is a thiol conductivity, but it is very unstable if separated from plasma.

Elimination

Clopidogrel and metabolites are eliminated in urine and feces. About 50% of oral doses are eliminated through urine and 46% excreted in feces. The sale time of metabolites is 8 hours after single dose and repeat dose.

The pharmacokinetics research of the main metabolite shows that Clopidogrel's bioavailability is not affected by food.

genetic pharmacology

The polymorphism of the CYP1C19 gene can affect the mundane response to Clopidogrel's dynamic and pharmacokinetics. CYP2C19 is involved in creating both activity and intermediate metabolites 2-olo-clopidogrel. Pharmacokinetics and platelet resistance of metabolites are active of clopidogrel when quantified by experiments to stop platelet exercises from the body varies depending on the genotyps of CYP2C19. The genetic variants of other CYP450 enzymes can also affect the active metabolites of clopidogrel. Alen CYP2C19*1 corresponds to adequate metabolic function, while alleles CYP2C19*2 and CYP2C19*3 have no function. The percentage of people carrying CYP2C19 alenes reduces the function in the general population depends on the race. Most people with poor skin metabolism (85%), Asia (99%) have alleles reducing CYP2C19*2 and CYP2C19*3. Other alleles are less functional and less common.

Notice immediately to the doctor or pharmacist the harmful reactions encountered when using the drug.

Be cautious when using

need to be very careful when taking the drug for patients in the following cases:

Hemorrhage and hematological disorders

Due to the risk of hemorrhage and adverse hematological reactions, the number of blood cells and/or other appropriate tests should be promptly taken at any time when clinical symptoms suggest hemorrhage occurs during treatment. Like other anti-platelets, clopidogrel should be used cautiously in patients who increase the risk of bleeding due to trauma, surgery or other pathological conditions and in patients treated with ASA, heparin, Glycoprotein ilb/Illa inhibitors or nonsteroidal anti-inflammatory drugs (NSAIDs), including Cyclooxygenase-2 or reconciliation drugs (SSRI). Patients must be carefully monitored any signs of bleeding including internal bleeding, especially in the first weeks of treatment and/or after the procedure of heart invasion or surgery. Concomitant use with oral anticoagulant is not recommended as it can increase bleeding.

If a patient undergo surgery, Clopidogrel should stop 7 days before surgery. It is necessary to notify patients to know they are susceptible to bruising and bleeding, prolonged bleeding time during clopidogrel treatment. Patients need to notify the doctor that they are using clopidogrel before they have surgery or other medications. The drug should be used cautiously in patients with damage to the trend of bleeding (especially digestion and intraocularity).

Platelet hemorrhage (within the first 2 weeks of treatment) occurred in some cases leading to death, in the event of a platelet reduced hemorrhage that need to be replaced with an emergency plasma.

In patients with a history of transient or stroke anemia or stroke, there is a risk of recurrence of ischemic anemia if combined with aspirin treatment in combination with clopidogrel increases effectiveness compared to using clopidogrel simply but also increases the risk of large bleeding.

The risk of gastrointestinal bleeding increases when using clopidogrel, so it must be cautious when used for patients with gastrointestinal damage trend of bleeding such as ulcers.

During Clopidogrel treatment also needs to be cautious if using other drugs at risk of gastrointestinal ulcers.

Cytochrom P450 2C19 (CYP2C19)

Genetically: In poor patients with CYP2C19 metabolic enzymes, in the recommended dose, clopidogrel is less metabolized into more active substances and reduces anti -platelet aggregation effects. Test to determine the patient's CYP2C19 genotype.

Clopidogrel is converted into a partially active metabolic substance by CYP2C19, using enzyme inhibitors that can lead to a decrease in the concentration of the active metabolites of clopidogrel. The clinical involvement of this interaction is uncertain. To prevent the recommendation of the strong or medium CYP2C19 inhibitors.

Cross reactions between thienopyridine

Patients need to be evaluated for hypersensitivity to Thienopyridine (such as clopidogrel, ticlopidin, prasugrel) since the cross -reaction between the Thienopyridine has been reported. Thienopyridine can cause mild to severe allergic reactions such as rash, angioedema or cross -hematoid reaction such as platelets and neutrophils. Patients with a history of allergies and/or hematological reactions to a Thienopyridine may increase the risk of reaction to another Thienopyridine.

Recommended monitoring hypersensitivity signs in patients with allergies to Thienopyridine.

Renal failure: The experience of treatment with clopidogrel in patients with renal impairment is limited. So Clopidogrel should be used cautiously in these patients.

Hepatic failure: Experience is limited in patients with average liver disease, who may have organs bleeding. Clopidogrel should be used carefully in these patients.

Autodity warning

This drug contains hydrogenated castor oil that can cause abdominal pain and diarrhea.

Excipients contain erythrosin red, which is at risk for allergic reactions.

The effect of the drug on the ability to drive and operate machinery

drugs do not affect or negatively affect the ability to drive or operate machinery.

Use drugs for women during pregnancy and lactation

Pregnant women

The safety of drugs in pregnant women has not been studied, but should not use clopidogrel for pregnant women.

breastfeeding women

Experiments on animals shows Clopidogrel and metabolites are excreted in milk. So far, no information shows that Clopidogrel has excreted through breast milk or not. Therefore, it is necessary to consider stopping breastfeeding while taking medication or stopping clopidogrel depending on the level of need to use the drug in the nursing mother.

Interactive drug

Oral anti -dynamic drugs: simultaneous use of clopidogrel with anticoagulant drugs are not recommended because it can increase bleeding intensity. Although using Clopidogrel 75 mg/day does not change the pharmacokinetics of s-warfarin or international normalization index (INR) in patients treated with long-term warfarin, simultaneous use of clopidogrel with warfarin increases the risk of bleeding due to independent effects on coagulation.

Glycoprotein IIB/IIIA inhibitors: Clopidogrel should be used cautiously in patients using Glycoprotein Ilb/Illa inhibitors.

Acetylsalicylic Acid (ASA): Asa does not change the inhibition of clopidogrel through the ADP intermediaries causing platelet gathering, but clopidogrel makes ASA capable of acting on collagen causing platelet aggregation. However, simultaneous use of ASA 500 mg twice a day in a day does not significantly increase the extension of bleeding time caused by clopidogrel. The pharmacokinetic interaction between clopidogrel and Asa may occur, resulting in an increased risk of bleeding. Therefore, it is necessary to be cautious when used simultaneously. However, Clopidogrel and ASA are used simultaneously for up to 1 year.

Heparin: In a clinical study conducted in healthy people, no need to change the heparin dose or change the effects of heparin on blood clotting. Simultaneous use with heparin does not affect the inhibition of platelets caused by clopidogrel.

Mobile pharmacokinetic interaction between clopidogrel and heparin may occur, resulting in an increased risk of bleeding. Therefore, be careful when using clopidogrel and heparin simultaneously.

Blood therapy: Safety when used simultaneously clopidogrel, fibrin or non-fibrin and heparin medications are assessed in acute myocardial infarction patients. The clinical significant bleeding rate is similar to the use of thrombosis and heparin in combination with ASA.

Non -steroid anti -inflammatory drugs (NSAIDs): In a clinical study conducted in healthy volunteers, simultaneous use of clopidogrel and Naproxen increased gastrointestinal loss. However, due to the lack of interactive studies with other NSAIDs, it is unclear whether it increases the risk of gastrointestinal bleeding with all NSAIDs. Therefore, NSAIDs include selective inhibitors Cycloxygenase-2 and Clopidogrel should be used cautiously.

SSRIs: SSRIs affect platelet activation and increase the risk of bleeding, simultaneous use of SSRIs with Clopidogrel should be used carefully.

Other simultaneous treatment: Clopidogrel is converted into a partially active metabolic substance by CYP2C19, using enzyme inhibitors that can lead to a reduction in the activity metabolic concentration of clopidogrel. The clinical involvement of uncertain interactions. To be wary, it is not recommended to simultaneously use strong or medium CYP2C19 inhibitors with Clopidogrel. CYP2C19 or medium inhibitors include, for example, omeprazol and esomeprazol, fluvoxamine, fluoxetin, moclobemid, voriconazole, fluconazole, ticlopidine, carbamazepine and efavirenz.

Proton pump inhibitors (PPI): Omeprazol 80 mg once a day use at the same time as clopidogrel or within 12 hours between 2 times of using the drug will reduce the contact of metabolites that are active in 45% (loaded dose) and 20% (maintenance dose). This leads to reduced inhibition of platelet gathering 39% (loaded dose) and 21% (maintenance dose).

Esomeprazol also has similar interactions with clopidogrel.

Data from both observation and clinical studies without heterogeneity of pharmacokinetics (PK)/Pharmacological (PD) on cardiovascular events have been reported. To prevent and use simultaneously with omeprazol or esomeprazol is not recommended.

Reducing the exposure of less obvious metabolites has been observed with Pantoprazol or Lansoprazol.

Plasma concentrations of metabolites have a 20% reduction (loaded dose) and 14% decrease (maintenance dose) when treated simultaneously with Pantoprazol 80 mg once a day.

This leads to reduction in platelet collection inhibitors, equivalent to 15% and 11%. These results show that Clopidogrel can be used simultaneously with Pantoprazol.

There is no evidence that other drug products reduce stomach acid such as Histamine h, or anti -acid anti -acid drugs that prevents plateloon resistant activity of clopidogrel.