Clopidogrel

Oral
Prophylaxis of thromboembolic disorders
Adult: For patients with recent MI, recent ischaemic stroke, or established peripheral arterial disease: 75 mg once daily. For patients with atrial fibrillation who have at least 1 risk factor for vascular events, are not suitable for vitamin K antagonist treatment, and have low bleeding risk: In combination with aspirin: 75 mg once daily.
Hepatic impairment: Severe: Contraindicated.

Oral
Acute coronary syndrome
Adult: In the management of acute ST-elevation MI: In combination with aspirin (with or without thrombolytics): ≤75 years 300 mg loading dose, followed by 75 mg once daily. Initiate combined treatment as early as possible after symptoms start and continue for at least 4 weeks. In the management of non-ST-elevation MI or unstable angina, including those undergoing stent placement after percutaneous coronary intervention (PCI): In combination with aspirin: 300 mg loading dose, followed by 75 mg once daily.
Elderly: In the management of acute ST-elevation MI: In combination with aspirin (with or without thrombolytics): ≤75 years Same as adult dose; >75 years 75 mg once daily (without a loading dose). Initiate combined treatment as early as possible after symptoms start and continue for at least 4 weeks.
Hepatic impairment: Severe: Contraindicated.

Special Populations: Pharmacogenomics: Clopidogrel is a prodrug that is metabolised mainly by CYP2C19 into active form. CYP2C19 gene variants are known to be associated with increased or decreased response to clopidogrel. The prevalence of CYP2C19 poor metabolisers has been estimated in 2% of Caucasians, 4% of African Americans, and 14% of Chinese. Genetic testing prior to initiation of therapy is an effective tool to identify if patient is homozygous for functional or non-functional alleles. CYP2C19 Ultrarapid metabolisers Carriers of *17/*17 or *17/*1 allele. These individuals have increased platelet inhibition and decreased residual platelet aggregation. Recommendation: No dose adjustment needed. CYP2C19 Extensive metabolisers Carriers of 2 functional alleles *1/*1. These individuals have normal platelet inhibition and normal residual platelet aggregation. Recommendation: No dose adjustment needed. CYP2C19 Intermediate metabolisers Carriers of functional allele *1 and non-functional allele *2 to *8. These individuals have reduced platelet inhibition, increased residual platelet aggregation and increased risk for adverse cardiovascular events. Recommendation: Alternative antiplatelet therapy, if no contraindication (e.g. prasugrel, ticagrelor). Double clopidogrel dose to 150 mg/day (600 mg loading dose). CYP2C19 Poor metabolisers Carriers of non-functional allele *2 to *8. These individuals have significantly reduced platelet inhibition, increased residual platelet aggregation and an increased risk for adverse cardiovascular events. Recommendation: Alternative antiplatelet therapy (if no contraindication); e.g. prasugrel, ticagrelor. For ACS patients managed medically or with PCI, use an alternative antiplatelet (e.g. prasugrel, ticagrelor) if no contraindication. For other indications, check platelet aggregation inhibition level by clopidogrel and consider an alternative agent.

Clopidogrel: May be taken with or without food.

Active pathological bleeding (e.g. peptic ulcer or intracranial haemorrhage). Severe hepatic impairment.

Patients with platelet disorders, bleeding disorders, or at increased risk for bleeding (e.g. recent trauma or surgery); lesions with a propensity to bleed (e.g. gastrointestinal, intraocular), acute lower gastrointestinal bleeding, coronary artery stents; previous hypersensitivity or haematologic reactions to thienopyridine use (e.g. ticlopidine, prasugrel). CYP2C19 intermediate and poor metabolisers. Patients undergoing CABG or other elective surgical procedures. Temporarily discontinue 5-7 days before elective surgery if antiplatelet effect is not desirable. Renal and moderate hepatic impairment. Elderly. Pregnancy and lactation. Monitoring Parameters Monitor Hb and haematocrit periodically; signs of bleeding including occult bleeding, particularly during the 1st weeks of treatment and following invasive cardiac procedures or surgery.

Significant: Cross-reactive drug hypersensitivity (e.g. rash, angioedema, haematologic reaction) among thienopyridines; prolonged bleeding time. Rarely, acquired haemophilia. Blood and lymphatic system disorders: Thrombocytopenia, leucopenia, eosinophilia, neutropenia. Gastrointestinal disorders: Diarrhoea, abdominal pain, dyspepsia, gastric ulcer, duodenal ulcer, gastritis, vomiting, nausea, constipation, flatulence. General disorders and administration site conditions: Puncture site bleeding. Investigations: Decreased neutrophil and platelet counts. Nervous system disorders: Headache, paraesthesia, dizziness. Renal and urinary disorders: Haematuria. Respiratory, thoracic and mediastinal disorders: Epistaxis. Skin and subcutaneous tissue disorders: Bruising, pruritis. Vascular disorders: Haematoma.
Potentially Fatal: Rarely, thrombotic thrombocytopenic purpura, intracranial bleeding, gastrointestinal and retroperitoneal haemorrhage.

Symptoms: Prolonged bleeding time and subsequent bleeding complications. Management: Consider platelet transfusion if prompt correction of prolonged bleeding time is required.

Increased risk of bleeding with aspirin, anticoagulants, antiplatelets, NSAIDs including cyclooxygenase 2 (COX-2) inhibitors, thrombolytics, glycoprotein IIb/IIIa inhibitors, SSRIs, serotonin norepinephrine reuptake inhibitors. Antiplatelet effect may be reduced when given with moderate or strong CYP2C19 inhibitors (e.g. esomeprazole, omeprazole, fluvoxamine, moclobemide, voriconazole, ticlopidine, carbamazepine, efavirenz). May increase the plasma concentrations of CYP2C8 substrates (e.g. repaglinide, paclitaxel). Absorption may be delayed and reduced by opioid agonists (e.g. morphine).

Grapefruit or grapefruit juice may reduce the antiplatelet effect of clopidogrel.

Clopidogrel selectively and irreversibly inhibits adenosine diphosphate (ADP) from binding to its platelet P2Y₁₂ receptor and subsequent ADP-mediated activation of glycoprotein GPIIb/IIIa complex, thus reducing platelet aggregation.
Absorption: Rapidly but incompletely absorbed from the gastrointestinal tract (approx 50%). Time to peak plasma concentration: Approx 45 minutes.
Distribution: Plasma protein binding: 98% (parent drug); 94% (carboxylic acid derivative).
Metabolism: Extensively metabolised in the liver via hydrolysis by esterases to form inactive carboxylic acid derivative, and via oxidation by multiple CYP450 isoenzymes (primarily CYP2C19) to form active thiol metabolite.
Excretion: Via urine (approx 50%); faeces (approx 46%). Elimination half-life: Approx 6 hours (parent drug); approx 0.5 hours (thiol derivative); approx 8 hours (carboxylic acid derivative).

Oral: Store at 25°C.

Anticoagulants, Antiplatelets & Fibrinolytics (Thrombolytics)

B01AC04 - clopidogrel ; Belongs to the class of platelet aggregation inhibitors excluding heparin. Used in the treatment of thrombosis.