Plavix (Clopidogrel). Dosage, Side Effects, Interactions
Plavix (Clopidogrel) belongs to the drug group of platelet aggregation inhibitors and is used to prevent atherothrombotic events. The prodrug exerts its effect only after being metabolised by mainly CYP2C19 into its effective form.
Plavix (Clopidogrel) has the following indications:
- Heart attack (a few days to less than 35 days ago)
- ischemic stroke (7 days to less than 6 months ago)
- peripheral arterial disease
- Non- ST segment elevation acute coronary syndrome (unstable angina or non-Q-wave myocardial infarction), including patients undergoing stenting for percutaneous coronary intervention, in combination with acetylsalicylic acid (ASA)
- ST segment elevation acute myocardial infarction, in combination with ASA, in medically treated patients eligible for thrombolytic therapy
- Prevention of atherothrombotic and thromboembolic events in atrial fibrillation , including stroke, in patients with at least one risk factor for vascular events who cannot receive vitamin K antagonist therapy and who are at low risk of bleeding, in combination with ASA
Clopidogrel is approved for oral use on the market in the form of film-coated tablets and can be taken independently of meals.
How Plavix (Clopidogrel) works
The antiplatelet drug clopidogrel is a prodrug that is first metabolized to its active form, a thiol derivative of clopidogrel, by metabolism primarily by CYP2C19 . The active metabolite selectively blocks the P2Y12 subtype ADP receptor on the surface of platelets and thus irreversibly blocks adenosine diphosphate (ADP)-mediated activation of the glycoprotein IIb/IIIa receptor, which initiates platelet cross-linking via fibrinogen bridges. Adenosine diphosphate (ADP) is the most important endogenous platelet-activating substance.
Clopidogrel is a prodrug that is partially metabolised in the liver via cytochrome P450 2C19 (CYP2C19) before it can exert its biological activity in the prevention of atherothrombotic events.
Clopidogrel is rapidly absorbed after single and repeated dosing. Mean peak plasma levels of unchanged clopidogrel are reached approximately 45 minutes after dosing. The absorption rate is at least 50% based on the clopidogrel metabolites excreted in the urine.
The plasma protein binding of clopidogrel and the main circulating (inactive) metabolite is 98% and 94%, respectively. In vitro, the binding remains unsaturated over a wide range of concentrations.
Clopidogrel is mainly metabolised in the liver. On the one hand, clopidogrel is hydrolyzed by esterases to form the inactive carboxylic acid derivative (85% of circulating metabolites) and on the other hand, clopidogrel is first metabolized to a 2-oxo-clopidogrel intermediate via multiple cytochromes P450 . Subsequent metabolism of the 2-oxo-clopidogrel intermediate results in the formation of the active metabolite (a thiol derivative of clopidogrel). The active metabolite is primarily formed by CYP2C19 with the involvement of several other CYP enzymes including CYP1A2 , CYP2B6 and CYP3A4 .
Cmax is reached approximately 30 to 60 minutes after ingestion.
After administration of an oral dose of 14C-labelled clopidogrel to humans, approximately 50% was excreted in the urine and approximately 46% in the faeces within 120 hours. After a single oral dose of 75 mg, clopidogrel has a half-life of approximately 6 hours. The elimination half-life of the main circulating (inactive) metabolite was 8 hours after both single and repeated dosing.
CYP2C19 is involved in the formation of both the 2-oxo-clopidogrel intermediate and the main metabolite. The pharmacokinetics of the active metabolite of clopidogrel and the antiplatelet effect differ depending on the CYP2C19 genotype.
The CYP2C19*1 allele corresponds to fully functional metabolism, while the CYP2C19*2 and CYP2C19*3 alleles correspond to nonfunctional metabolism.
The CYP2C19*2 and CYP2C19*3 alleles account for the majority of reduced-function alleles in Caucasian (85%) and Asian (99%) poor metabolisers.
Other alleles associated with absent or decreased metabolism are less common and include CYP2C19*4, *5, *6, *7, and *8.
A patient with poor metaboliser status carries two loss-of-function alleles.
Dosage of Plavix (Clopidogrel)
The recommended dosage is generally 75 mg clopidogrel once a day. More detailed information can be found in the respective specialist information.
Side effects of Plavix (Clopidogrel)
The following side effects occurred frequently (≥1/100 to <1/10) with the use of clopidogrel in clinical studies:
- gastrointestinal bleeding
- stomach pain
- bleeding at puncture sites
The following interactions should be considered when using clopidogrel:
- Strong or moderate CYP2C19 inhibitors such as omeprazole and esomeprazole , fluvoxamine , fluoxetine , moclobemide , voriconazole , fluconazole , ticlopidine , carbamazepine and efavirenz : Since clopidogrel is partially metabolised by CYP2C19 to its active metabolite, it is expected that CYP2C19 inhibitors , lead to decreased levels of the active metabolite of clopidogrel.
- Proton Pump Inhibitors (PPIs): Taking clopidogrel-containing medicinal products and PPIs should be avoided as this interaction could lead to a reduction in the clinical activity of clopidogrel.
- Medicinal products with associated risk of bleeding: There is an increased risk of bleeding due to the possible additive effect. The concomitant use of medicinal products with an associated risk of bleeding should be carried out with caution
- Oral anticoagulants : Concomitant use is not recommended as bleeding may be increased. The use of clopidogrel with warfarin increases the risk of bleeding due to independent effects on hemostasis.
- Glycoprotein IIb/IIIa Inhibitors: Clopidogrel should be used with caution in patients being treated concomitantly with glycoprotein IIb/IIIa inhibitors
- Acetylsalicylic acid (ASA): ASA had no effect on clopidogrel-mediated inhibition of ADP-induced platelet aggregation. In contrast, clopidogrel potentiated the effect of ASA on collagen-induced platelet aggregation. Co-administration of ASA 500 mg twice daily for one day resulted in no significant increase in clopidogrel-induced prolongation of bleeding time. Combination therapy should be used with caution.
- Heparin : A pharmacodynamic interaction between clopidogrel and heparin associated with an increased risk of bleeding is possible. Combination therapy should therefore only be carried out with caution
- Thrombolytics: The safety of co-administration of clopidogrel, direct or indirect thrombolytics (fibrin or non-fibrin specific) and heparins has been studied in patients with acute myocardial infarction. The incidence of clinically relevant bleeding was consistent with that seen when thrombolytics and heparin were administered concomitantly with ASA
- NSAIDs : In a clinical trial in volunteers, co-administration of clopidogrel and naproxen resulted in increased occult gastrointestinal blood loss. NSAIDs, including COX-2 inhibitors , and clopidogrel should be co-administered with caution
- SSRI : When SSRIs are used concomitantly with clopidogrel, the risk of bleeding may increase due to the activation of platelets by SSRIs. SSRIs should therefore be administered concomitantly with clopidogrel with caution.
- CYP2C8 substrates (eg, repaglinide , paclitaxel ): Clopidogrel increases repaglinide exposure. The increased repaglinide exposure is due to inhibition of CYP2C8 by the glucuronidated metabolite of clopidogrel.
The active substance clopidogrel must not be used in:
- Hypersensitivity to the active substance
- severe liver dysfunction
- Acute pathological bleeding such as peptic ulcer disease or intracranial bleeding
In the absence of clinical data on the use of clopidogrel during pregnancy, as a precautionary measure, clopidogrel should not be used during pregnancy.
It is not known whether clopidogrel is excreted in human breast milk. Animal studies have shown that clopidogrel passes into breast milk. As a precautionary measure, breast-feeding should be stopped during clopidogrel use.
Clopidogrel has no or negligible influence on the ability to drive and use machines.
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