COMPOSITION AND EXCIPIENTS
Active ingredient:
- Each film coated tablet of CLOPIGREL 75 contains Clopidogrel Bisulfate equivalent to 75 mg Clopidogrel base.
- Each film coated tablet of CLOPIGREL 300 contains Clopidogrel Bisulfate equivalent to 300 mg Clopidogrel base.
Inactive ingredients:
- Tablet : Hydroxypropylcellulose, Mannitol, Microcrystalline cellulose, Polyethylene glycol 6000.
- Film coating : Hypromellose, PEG 6000, Talc, Titanium dioxide, Ponceau 4R lake Red
WARNING: DIMINISHED EFFECTIVENESS IN POOR METABOLIZERS
The effectiveness of clopidogrel is dependent on its activation to an active metabolite by the cytochrome P450 (CYP) system, principally CYP2C19. Clopidogrel at recommended doses forms less of that metabolite and has a smaller effect on platelet function in patients who are CYP2C19 poor metabolizers. Poor metabolizers with acute coronary syndrome or undergoing percutaneous coronary intervention treated with clopidogrel at recommended doses exhibit higher cardiovascular event rates than do patients with normal CYP2C19 function. Tests are available to identify a patient’s CYP2C19 genotype; these tests can be used as an aid in determining therapeutic strategy. Consider alternative treatment or treatment strategies in patients identified as CYP2C19 poor metabolizers.
PHARMACOLOGICAL EFFECT
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.
PHARMACOKINETICS
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.
INDICATIONS
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.
CONTRAINDICATIONS
- 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.
WARNINGS
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.
Lactation:
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.
Renal Impairment:
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.
Hepatic Impairment:
No dosage adjustment is necessary in patients with hepatic impairment.
DRUG INTERACTIONS
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.
Warfarin:
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.
SIDE EFFECTS
Epistaxis, hematuria, bruise, hematoma, Pruritus, jaundice, weakness or tirednes, 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
CLOPIGREL tablets can be administered with or without food.
Acute Coronary Syndrome:
- For patients with non-ST-elevation [unstable angina/non-ST-elevation myocardial infarction], CLOPIGREL 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 CLOPIGREL is 75 mg once daily, administered in combination with aspirin (75 to 325 mg once daily), with or without thrombolytics.
Recent MI, Recent Stroke, or Established Peripheral Arterial Disease: The recommended daily dose of CLOPIGREL is 75 mg once daily.
OVERDOSE
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
Store at temperature between 15° – 30 ̊C.
PACKAGING
CLOPIGREL (75 – 300) mg is supplied as blister strips (Aluminum – White P.V.D.C), each strip contains 10 F.C.T and each box contains 1 , 2 or 3 strips (10 , 20 or 30 F.C.T per box).