- ANTITHROMBOTIC DRUGS
- CARDIOVASCULAR DRUGS
- Pharmaceutical Form : Film coated tablets
- Composition : Clopidogel (Bisulfate) 75 mg
- Active Substance : Clopidogel
Clopidogrel is an inhibitor of platelet activation and aggregation through the irreversible binding of its active metabolite to one class ADP receptors on platelets.
Clopidogrel must be metabolized by CYP450 enzymes to produce the active metabolite. The active metabolite of clopidogrel selectively inhibits the binding of adenosine diphosphate (ADP) to its receptor and the subsequent activation of the glycoprotein GPIIb/IIIa complex, thereby inhibiting platelet aggregation for their lifespan. Elderly (≥75 years) and young healthy subjects had similar effects on platelet aggregation.
Absorption: After oral doses, clopidogrel is rapidly absorbed. Absorption is at least 50%, based on urinary excretion of clopidogrel metabolites.
Metabolism : Clopidogrel is a prodrug and it is metabolized by two main metabolic pathways: one leading to an inactive metabolite and one mediated by multiple cytochrome P450 and lead to the formation of the active metabolite, a thiol derivative that binds rapidly and irreversibly to platelet receptors, Cmax occurs approximately 30 to 60 minutes after dosing
Elimination: After a single, oral dose of 75 mg, clopidogrel has a half-life of approximately 6 hours. The half-life of the active metabolite is about 30 minutes
Acute Coronary Syndrome (ACS):
For patients with non-ST-segment elevation ACS [unstable angina /non-ST-elevation myocardial infarction], including patients who are to be managed medically and those who are to be managed with coronary revascularization, clopidogrel bisulfate has been shown to decrease the rate of a combined endpoint of cardiovascular death, myocardial infarction (MI), or stroke as well as the rate of a combined endpoint of cardiovascular death, MI, stroke, or refractory ischemia..
For patients with ST-elevation myocardial infarction, clopidogrel bisulfate has been shown to reduce the rate of death from any cause and the rate of a combined endpoint of death, reinfarction, or stroke. The benefit for patients who undergo primary percutaneous coronary intervention is unknown.
The optimal duration of clopidogrel bisulfate therapy in ACS is unknown.
Recent MI, Recent Stroke, or Established Peripheral Arterial Disease: For patients with a history of recent myocardial infarction (MI), recent stroke, or established peripheral arterial disease, clopidogrel bisulfate has been shown to reduce the rate of a combined endpoint of new ischemic stroke (fatal or not), new MI (fatal or not), and other vascular death.
In patients with active pathological bleeding such as peptic ulcer or intracranial hemorrhage.
In patients with hypersensitivity (e.g., anaphylaxis) to clopidogrel or any component of the product.
Diminished Antiplatelet Activity Due to Impaired CYP2C19 Function:
Clopidogrel is a prodrug. Inhibition of platelet aggregation by clopidogrel is achieved through an active metabolite. The metabolism of clopidogrel to its active metabolite can be impaired by genetic variations in CYP2C19 and by concomitant drugs that interfere (inhibition) with CYP2C19 which results in reduced plasma concentrations of the active metabolite and a reduction in platelet inhibition, Although a higher doses regimen increases antiplatelet response, an appropriate doses regimen has not been established.
General Risk of Bleeding:
Thienopyridines, including clopidogrel, increase the risk of bleeding. If a patient is to undergo surgery and an antiplatelet effect is not desired, discontinue clopidogrel 5 days prior to surgery.
The inhibition of platelet aggregation is for the lifetime of the platelet (7 to 10 days), so withholding a dose will not be useful in managing a bleeding event or the risk of bleeding associated with an invasive procedure. Because the half-life of clopidogrel’s active metabolite is short, it may be possible to restore hemostasis by administering exogenous platelets; however, platelet transfusions within 4 hours of the loading dose or 2 hours of the maintenance dose may be less effective.
Discontinuation of Clopidogrel:
Lapses in therapy should be avoided, and if clopidogrel must be temporarily discontinued, restart as soon as possible. Premature discontinuation may increase the risk of cardiovascular events.
Patients with Recent Transient Is chemic Attack (TIA) or Stroke:
In patients with recent TIA or stroke who are at high risk for recurrent ischemic events, the combination of aspirin and clopidogrel has not been shown to be more effective than clopidogrel alone, but the combination has been shown to increase major bleeding.
Thrombotic Thrombocytopenic Purpura (TTP):
TTP, sometimes fatal, has been reported following use of clopidogrel bisulfate, sometimes after a short exposure (<2 weeks), and it is a serious condition that requires urgent treatment including plasmapheresis (plasma exchange). It is characterized by thrombocytopenia, microangiopathic hemolytic anemia, neurological findings, renal dysfunction, and fever.
Cross -Reactivity among Thienopyridines
Hypersensitivity including rash, angioedema or hematologic reaction have been reported in patients receiving clopidogrel, including patients with a history of hypersensitivity or hematologic reaction to other thienopyridines.
Pregnancy: Category B:
There are no adequate and well-controlled studies in pregnant women. Clopidogrel should be used during pregnancy only if clearly needed.
It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from clopidogrel, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.
Pediatric Use: Safety and effectiveness in pediatric have not been established
Geriatric Use: No dosage adjustment is necessary in elderly patients.
Experience is limited in patients with severe and moderate renal impairment, patients with severe renal impairment (creatinine clearance from 5 to 15 mL/min) and moderate renal impairment (creatinine clearance from 30 to 60 mL/min) showed low (25%) inhibition of ADP-induced platelet aggregation.
No dosage adjustment is necessary in patients with hepatic impairment
Proton Pump Inhibitors (PPI):
Concomitant use with omeprazole or esomeprazole should be avoided, because both significantly reduce the antiplatelet activity of clopidogrel. Consider using another acid-reducing agent with minimal or no CYP2C19 inhibitory effect on the formation of the active metabolite. Dexlansoprazole, lansoprazole and pantoprazole had less effect on the antiplatelet activity of clopidogrel than did omeprazole or esomeprazole
Nonsteroidal Anti-Inflammatory Drugs (NSAIDs):
Coadministration with NSAIDs increases the risk of gastrointestinal bleeding.
Coadministration with warfarin increases the risk of bleeding because of independent effects on hemostasis.
SSRIs and SNRIs:
Since selective serotonin reuptake inhibitors (SSRIs) and serotonin norepinephrine reuptake inhibitors (SNRIs) affect platelet activation, the concomitant administration of these drugs with clopidogrel may increase the risk of bleeding.
Epistaxis, hematuria, bruise, hematoma, Pruritus, jaundice, weakness or tiredness , pale skin, fever, shortness of breath, tachycardia, headache, speech changes, confusion, coma, stroke, seizure, oliguria, abdominal pain, nausea, vomiting, diarrhea, vision changes, gastrointestinal hemorrhage, intracranial hemorrhage.
Dosage and administration:
Clopidogrel tablets can be administered with or without food
Acute Coronary Syndrome:
For patients with non-ST-elevation [ unstable angina/non-ST-elevation myocardial infarction], clopidogrel tablets should be initiated with a single 300 mg loading dose and then continue at 75 mg once daily. Aspirin should be Initiated (75 to 325 mg once daily) and continue in combination with clopidogrel tablets
For patients with ST-elevation myocardial infarction, the recommended dose of clopidogrel is 75 mg once daily, administered in combination with aspirin (75 to 325 mg once daily), with or without thrombolytics. Clopidogrel may be initiated with or without a loading dose.
Recent MI, Recent Stroke, or Established Peripheral Arterial Disease: The recommended daily dose of clopidogrel is 75 mg once daily.
Platelet inhibition by clopidogrel is irreversible and will last for the life of the platelet. Overdose following clopidogrel administration may result in bleeding complications.
Symptoms of acute toxicity were vomiting, prostration, difficult breathing, and gastrointestinal hemorrhage in animals. Based on biological plausibility, platelet transfusion may restore clotting ability
Storage conditions: Don’t store above 30°C.
Pack contains 10 film coated tablets.
Pack contains 30 film coated tablets.