Clopidogrel

Oral
Acute coronary syndrome

Oral
Secondary prevention of atherothrombotic events

Pharmacogenomics:

Clopidogrel, a thienopyridine prodrug, is metabolised in the liver mainly by CYP2C19 isoenzyme to form its active thiol metabolite. The CYP2C19 genotype may impact the formation of clopidogrel's active metabolite, its platelet inhibition effects, and the risk of major CV and cerebrovascular adverse events.

Individuals who are homozygous for non-functional alleles of the CYP2C19 gene, known as CYP2C19 poor metabolisers, have reduced active metabolite concentration, resulting in reduced antiplatelet activity. The prevalence of CYP2C19 poor metabolisers is approx 2% in Whites, 4% in Blacks, and 14% in Chinese. Genetic testing may be considered prior to treatment initiation to guide in drug and dose selection.

Most definitive studies showed the relationship between clopidogrel response and CYP2C19 genotype has been mainly conducted in patients with acute coronary syndrome (almost all underwent PCI). However, there are data that showed a similar relationship between clopidogrel response and CYP2C19 non-functional alleles when used for other indications (e.g. TIA or acute ischaemic stroke). These data, together with strong pharmacokinetic and pharmacodynamic data, support the use of CYP2C19 genotype-guided antiplatelet therapy when considering use of clopidogrel for neurovascular indications.

Clinical Pharmacogenetics Implementation Consortium (CPIC) Guideline as of January 2022:

Antiplatelet treatment recommendations when considering clopidogrel for CV indications:

Phenotype and Genotype	Implications	Therapeutic Recommendations
CYP2C19 likely intermediate metabolisers Individuals carrying 1 normal functional allele and 1 decreased functional allele, or 1 increased functional allele and 1 decreased functional allele, or 2 decreased functional alleles e.g. *1/*9, *9/*17, *9/*9.	Reduced formation of clopidogrel active metabolite, increased on-treatment platelet reactivity, and increased risk for adverse cardiac and cerebrovascular events.	Avoid clopidogrel standard dose (75 mg) if possible; if no contraindication, use prasugrel or ticagrelor at standard dose.
CYP2C19 intermediate metabolisers Individuals carrying 1 normal functional allele and 1 non-functional allele, or 1 increased functional allele and 1 non-functional allele e.g. *1/*2, *1/*3, *2/*17, *3/*17.	Reduced formation of clopidogrel active metabolite, increased on-treatment platelet reactivity, and increased risk for adverse cardiac and cerebrovascular events.	Avoid clopidogrel standard dose (75 mg) if possible; if no contraindication, use prasugrel or ticagrelor at standard dose.
CYP2C19 likely poor metabolisers Individuals carrying 1 decreased functional allele and 1 non-functional allele e.g. *2/*9, *3/*9.	Significantly reduced formation of clopidogrel active metabolite, increased on-treatment platelet reactivity, and increased risk for adverse cardiac and cerebrovascular events.	Avoid clopidogrel if possible; if no contraindication, use prasugrel or ticagrelor at standard dose.
CYP2C19 poor metabolisers Individuals carrying 2 non-functional alleles e.g. *2/*2, *3/*3, *2/*3.	Significantly reduced formation of clopidogrel active metabolite, increased on-treatment platelet reactivity, and increased risk for adverse cardiac and cerebrovascular events.	Avoid clopidogrel if possible; if no contraindication, use prasugrel or ticagrelor at standard dose.

Antiplatelet therapy recommendations when considering clopidogrel for neurovascular indications:

Phenotype and Genotype	Implications	Therapeutic Recommendations
CYP2C19 likely intermediate metabolisers Individuals carrying 1 normal functional allele and 1 decreased functional allele, or 1 increased functional allele and 1 decreased functional allele, or 2 decreased functional alleles e.g. *1/*9, *9/*17, *9/*9.	Reduced formation of clopidogrel active metabolite, increased on-treatment platelet reactivity, and increased risk for adverse cardiac and cerebrovascular events.	If no contraindication and clinically indicated, consider an alternative P2Y12 inhibitor (e.g. ticagrelor, ticlopidine) at standard dose.
CYP2C19 intermediate metabolisers Individuals carrying 1 normal functional allele and 1 non-functional allele, or 1 increased functional allele and 1 non-functional allele e.g. *1/*2, *1/*3, *2/*17, *3/*17.	Reduced formation of clopidogrel active metabolite, increased on-treatment platelet reactivity, and increased risk for adverse cardiac and cerebrovascular events.	If no contraindication and clinically indicated, consider an alternative P2Y12 inhibitor (e.g. ticagrelor, ticlopidine) at standard dose.
CYP2C19 likely poor metabolisers Individuals carrying 1 decreased functional allele and 1 non-functional allele e.g. *2/*9, *3/*9.	Significantly reduced formation of clopidogrel active metabolite, increased on-treatment platelet reactivity, and increased risk for adverse cardiac and cerebrovascular events.	Avoid clopidogrel if possible. If no contraindication and clinically indicated, consider an alternative P2Y12 inhibitor (e.g. ticagrelor, ticlopidine) at standard dose.
CYP2C19 poor metabolisers Individuals carrying 2 non-functional alleles e.g. *2/*2, *3/*3, *2/*3.	Significantly reduced formation of clopidogrel active metabolite, increased on-treatment platelet reactivity, and increased risk for adverse cardiac and cerebrovascular events.	Avoid clopidogrel if possible. If no contraindication and clinically indicated, consider an alternative P2Y12 inhibitor (e.g. ticagrelor, ticlopidine) at standard dose.

The Royal Dutch Pharmacists Association - Pharmacogenetics Working Group (DPWG) Guideline as of November 2018:

Phenotype	Description	Recommendations
CYP2C19 intermediate metabolisers	Increased risk of serious CV and cerebrovascular events, particularly in patients undergoing balloon angioplasty or stent placement (PCI) and in those with TIA or stroke as the genetic variation decreases clopidogrel activation. No negative clinical effects have been observed in other patients.	For PCI, TIA or stroke: Consider choosing an alternative (e.g. prasugrel, ticagrelor, aspirin + dipyridamole) or double the dose to 150 mg daily (600 mg loading dose). For other indications: No action is required.
CYP2C19 poor metabolisers	Increased risk of serious CV and cerebrovascular events, particularly in patients undergoing balloon angioplasty or stent placement (PCI) and those with TIA or stroke as the genetic variation decreases clopidogrel activation. No negative clinical effects have been observed in other patients.	For PCI, TIA or stroke: Avoid clopidogrel; use an alternative (e.g. prasugrel, ticagrelor, aspirin + dipyridamole). For other indications: Check the level of clopidogrel platelet inhibition. Consider an alternative (e.g. prasugrel, ticagrelor) in poor responders.

Severe: Contraindicated.

Clopidogrel May be taken with or without food.
Clopidogrel hydrogen sulfate film-coated tab: May be taken with or without food.

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

Patient with lower gastrointestinal bleed; lesions with a propensity to bleed (e.g. gastrointestinal or intraocular); risk factors for increased bleeding (e.g. trauma, surgery, or other pathological conditions); history of hypersensitivity or haematologic reaction to other thienopyridines (e.g. ticlopidine, prasugrel). Patients undergoing elective surgery; may consider temporary discontinuation of therapy 5-7 days prior to the procedure when antiplatelet effect is not desirable. CYP2C19 intermediate and poor metabolisers. Renal and moderate hepatic impairment. Elderly. Pregnancy and lactation.

Significant: Hypersensitivity reactions, acquired haemophilia.
Blood and lymphatic system disorders: Thrombocytopenia, leucopenia, eosinophilia.
Eye disorders: Eye bleeding (retinal, conjunctival, ocular).
Gastrointestinal disorders: Abdominal pain, dyspepsia, diarrhoea, nausea, vomiting, constipation, flatulence, gastritis, gastrointestinal haemorrhage; gastric or duodenal ulcer.
Hepatobiliary disorders: Rarely, hepatitis, acute liver failure.
Investigations: Prolonged bleeding time; decreased neutrophil and platelet count. Rarely, abnormal LFTs.
Nervous system disorders: Headache, dizziness, paraesthesia.
Renal and urinary disorders: Haematuria.
Respiratory, thoracic and mediastinal disorders: Epistaxis.
Skin and subcutaneous tissue disorders: Bruising, rash, pruritus, skin bleeding (purpura). Rarely, drug reaction with eosinophilia and systemic symptoms, acute generalised exanthematous pustulosis.
Vascular disorders: Haematoma.
Potentially Fatal: Bleeding. Rarely, thrombotic thrombocytopenic purpura.

PO: B

Monitor Hb and haematocrit (periodically). Assess for signs and symptoms of bleeding.

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

Increased risk of bleeding with aspirin, anticoagulants (e.g. heparin, warfarin), NSAIDs including COX-2 inhibitors, thrombolytics, SSRIs, pentoxifylline. Decreased serum concentration of clopidogrel active metabolite with strong or moderate CYP2C19 inhibitors (e.g. esomeprazole, omeprazole, voriconazole, fluconazole, fluvoxamine, fluoxetine, moclobemide, ticlopidine, carbamazepine, efavirenz). Increased serum concentration of clopidogrel active metabolite and increased risk of bleeding with strong CYP2C19 inducers (e.g. rifampicin). May increase the plasma concentrations of rosuvastatin, and agents metabolised by CYP2C8 (e.g. repaglinide, paclitaxel). Diminished antiplatelet effect with ritonavir, morphine and other opioid agonists.

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

Description:
Mechanism of Action: Clopidogrel, a thienopyridine derivative, is a prodrug of the active thiol metabolite which irreversibly and selectively inhibits the binding of adenosine diphosphate (ADP) to platelet P2Y₁₂ receptor and the subsequent activation of the glycoprotein GPIIb/IIIa complex, thereby inhibiting platelet aggregation.
Pharmacokinetics:
Absorption: Rapidly but incompletely absorbed from the gastrointestinal tract. 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 by esterases via hydrolysis to form an inactive carboxylic acid derivative (main inactive circulating metabolite), and by multiple CYP450 (mainly CYP2C19 isoenzyme) via oxidation to form the 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).

Source: National Center for Biotechnology Information. PubChem Compound Summary for CID 60606, Clopidogrel. https://pubchem.ncbi.nlm.nih.gov/compound/Clopidogrel. Accessed Sept. 25, 2024.

Store between 15-30°C.

Anticoagulants, Antiplatelets & Fibrinolytics (Thrombolytics)

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

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Annotation of CPIC Guideline for Clopidogrel and CYP2C19. Pharmacogenomics Knowledgebase (PharmGKB). https://www.pharmgkb.org. Accessed 25/07/2024.

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Clopidogrel 75 mg Film-coated Tablets (Kent Pharma UK Limited). MHRA. https://products.mhra.gov.uk. Accessed 24/07/2024.

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