Aplagrel contains Clopidogrel bisulfate, an inhibitor of ADP-induced platelet aggregation, which acts by direct inhibition of the binding of adenosine diphosphate (ADP) to its receptor, and of subsequent ADP-mediated activation of the GPIIb / IIIa glycoprotein complex. Clopidogrel also inhibits platelet aggregation induced by agonists other than ADP by blocking the expansion of platelet activation by released ADP. Clopidogrel does not inhibit phosphodiesterase activity.
Mechanism of action
Clopidogrel is an inhibitor of platelet aggregation. For various drugs, which act by inhibiting platelet function, it has been shown that they reduce morbid events in patients with established atherosclerotic vascular disease, evidenced by stroke or transient ischemic attacks, unstable angina, myocardial infarction, or need. of a shunt or angioplasty. This indicates that platelets participate in the genesis and / or evolution of these events, the rate of which can be reduced by inhibiting their aggregation.
Clopidogrel works by irreversibly modifying the ADP receptor on platelets. Consequently, platelets exposed to Clopidogrel are affected for the rest of their life span.
Pharmacokinetics and metabolism
After repeated oral 75mg doses of Clopidogrel (base), the plasma concentrations of the primary compound, which has no platelet inhibitory effect, are very low. Clopidogrel is extensively metabolized in the liver. The main circulating metabolite is a carboxylic acid derivative, which also has no effect on platelet aggregation.
Absorption and distribution
Clopidogrel is rapidly absorbed after oral administration of repeated 75mg doses of Clopidogrel (base), with peak plasma levels (3mg /L) of the major circulating metabolite occurring approximately 1 hour after administration. The pharmacokinetics of the major circulating metabolite are linear (plasma concentrations increase in proportion to the dose) in the 50 to 150mg dose range of Clopidogrel. The quantification of the urinary excretion of the metabolites of Clopidogrel has allowed us to know that the absorption is at least 50%.
Clopidogrel and the major circulating metabolite reversibly bind to human plasma proteins (98% and 94% respectively).
Metabolism and elimination
In vitro and in vivo, Clopidogrel undergoes rapid hydrolysis, giving its carboxylic acid derivative. Glucoronide from the carboxylic acid derivative is also observed in plasma and urine.
Following the oral dose of C14-labeled Clopidogrel in humans, approximately 50% was excreted in the urine and approximately 46% in the faeces within 5 days of dosing. The elimination half-life of the major circulating metabolite was 8 hours after single or repeated administrations. The covalent binding of platelets was determined as 2% of the radiolabelled, with a half-life of 11 days.
Administration of Clopidogrel with food does not significantly alter the bioavailability of Clopidogrel.
- Geriatric patients: No dosage adjustment is required for elderly patients.
- Renal impairment patients: After repeated 75mg doses of Clopidogrel per day, plasma levels of the major circulating metabolite were lower in patients with severe renal impairment (creatinine clearance 5 to 15 ml / min) compared to patients with moderate kidney failure (creatinine clearance 30 to 60 ml / min) or with healthy subjects. No dosage adjustment is necessary in patients with renal impairment.
- Gender: No significant difference in plasma levels of the major circulating metabolite was observed between males and females.
- Race: Pharmacokinetic differences that may exist in relation to race have not been studied.
Indications and use
Aplagrel (Clopidogrel bisulfate) is indicated for the reduction of atherothrombotic events: recent AMI, recent stroke or established peripheral arterial disease: In these cases Clopidogrel has been shown to reduce the rate of a combined parameter of new ischemic stroke (fatal or not ) and other vascular events.
Acute coronary syndrome: in patients with an acute coronary syndrome (unstable angina / AMI without Q wave), including patients who have been medically improved and those who have been managed with percutaneous coronary intervention (with or without stent) or CABG, Clopidogrel has been shown to reduce the rate of a parameter of cardiovascular death, AMI, or stroke, as well as the rate of a combined parameter of cardiovascular death. AMI, cerebral stroke or refractory ischemia.
Aplagrel is contraindicated in the following conditions:
Hypersensitivity to the active substance or to any component of the product. Pathological active bleeding such as peptic ulcer or intracranial hemorrhage. Severe liver failure.
Thrombotic thrombocytopenic purpura (PTT): PTT has been reported rarely after using Clopidogrel sometimes, after a short exposure (less than 2 weeks).
- Gastrointestinal: Abdominal pain, dyspepsia, gastritis, vomiting, constipation, and bleeding.
- Neutropenia / Agranulocytosis.
- Urticaria and other skin disorders.
- Nervous system disorders: Syncope, palpitations, cramps, paresthesia, vertigo.
- Others: Anxiety, insomnia, and an increase in enzymes at the liver level.
General: As with other platelet antiaggregants, clopidogrel should be used with caution in patients who may be at risk of bleeding from trauma, surgery, or another pathological condition. If a patient is to undergo elective surgery and the antiplatelet effect is not desired, clopidogrel should be discontinued 5 days before surgery. GI bleeding: Clopidogrel prolongs bleeding time.
Use in patients with liver failure:
There is little experience in patients with severe liver disease who may have bleeding diathesis. Clopidogrel should be used with caution in this type of population.
Each coated tablet contains:
Clopidogrel bisulfate 75 mg
Recent myocardial infarction, ischemic stroke, or established arterial disease, the recommended dose of Aplagrel is 75mg once a day.
Acute coronary syndrome:
For patients with acute coronary syndrome (unstable angina / AMI without Q wave), treatment with Aplagrel should be started with a single attack dose of 300mg, followed by 75mg once daily. Aspirin (75mg – 325mg once daily) should be started and continued in combination with Clopidogrel.
Aplagrel can be administered with or without food. No dosage adjustment is necessary in elderly patients or patients with kidney disease.
Box containing a blister with 10 coated tablets.
Box containing 5 blisters with 10 coated tablets.
Store below 30 °C. Protect from light and moisture.
Aspirin: Aspirin does not modify clopidogrel-mediated inhibition in ADP-induced platelet aggregation. Heparin: Concomitant use with clopidogrel does not alter the effect of heparin on coagulation and no dose modification is necessary. Aines: Concomitant administration of Aines and clopidogrel is associated with a higher rate of GI bleeding. Warfarin: No safety has been established in the co-administration of warfarin with clopidogrel.
No clinically significant drug interactions when clopidogrel is administered with atenolol, nifedipine, phenobarbital, cimetidine, or estrogen, digoxin, or theophylline. At a high in vitro concentration, clopidogrel inhibits cytochrome P450 (2C9). Consequently, Clopidogrel may interfere with the metabolism of phenytoin, tamoxifen, tolbirtamide, warfarin, steroids, but there are no data to predict the magnitude of these interactions. Caution should be exercised when using Clopidogrel concomitantly with any of these drugs. In addition to the above specific interaction studies, patients entering clopidogrel clinical studies received a variety of concomitant medications, including diuretics, beta-blocker agents, angiotensin-converting enzyme inhibitors, calcium, lipid lowering agents, coronary vasodilators, antidiabetic agents (including insulin), antiepileptic agents and hormone replacement therapies, heparin (unfractionated and LMWH) and GPIIb / IIa antagonists, with no evidence of clinically significant adverse interactions.
Use in pregnancy: No known carcinogenesis, mutagenesis, or impairment of fertility. Aplagrel should be used during pregnancy only if strictly necessary.
Lactation: Studies in rats have shown that Clopidogrel and / or its metabolites are excreted in milk. It is not known whether the drug is excreted in human milk. Because many drugs are excreted in human milk, as well as the possibility of serious adverse reactions in infants, the decision must be made to stop breast-feeding or to discontinue the drug, taking into account its importance for the nursing woman.
Pediatric Use: Safety and effectiveness in the pediatric population has not been established.