Oral Secondary prevention of atherothrombotic events
Adult: Available preparations:
Clopidogrel 75 mg and aspirin 75 mg cap
Clopidogrel 75 mg and aspirin 75 mg tab
Clopidogrel 75 mg and aspirin 100 mg tab
As continuation therapy in patients with acute coronary syndrome already initiated with separate clopidogrel and aspirin agents, particularly to reduce the rate of atherothrombotic events (including MI and stroke) in acute ST segment elevation MI in medically treated patients eligible for thrombolytic therapy and in non-ST segment elevation acute coronary syndrome (unstable angina or non-Q wave MI), including patients undergoing a stent placement following percutaneous coronary intervention (PCI): Maintenance: 75 mg clopidogrel/75 mg aspirin or 75 mg clopidogrel/100 mg aspirin once daily. Treatment duration must be based on current clinical practice guidelines.
Special Patient Group
Pharmacogenomics:
Clopidogrel
Clopidogrel, a thienopyridine prodrug, is required to be metabolised in the liver mainly by the CYP2C19 isoenzyme to form its active thiol metabolite. The presence of CYP2C19 genotype may impact the formation of clopidogrel active metabolite, its pharmacokinetics, its antiplatelet effects, and the risk of major CV and cerebrovascular adverse events.
Individuals who have reduced function or non-functional metabolism due to genetic variations of CYP2C19, known as CYP2C19 poor metabolisers, may have diminished antiplatelet response to clopidogrel. The prevalence of CYP2C19 poor metabolisers is approx 2% in Caucasians, 4% in Blacks, and 14% in Chinese ancestry. CYP2C19 gene testing may be considered prior to initiation to serve as an aid in determining therapeutic strategies.
Most definitive studies showed the relationship between clopidogrel response and CYP2C19 genotype in patients with acute coronary syndrome who almost all underwent PCI. However, data accumulated also showed the relationship between CYP2C19 non-functional alleles and clopidogrel response when used for other indications (including therapy of acute ischaemic stroke or TIA). These data along with strong pharmacokinetic and pharmacodynamic data support the use of CYP2C19 genotype-guided antiplatelet treatment when considering clopidogrel for neurovascular indications (e.g. acute ischaemic stroke or TIA, secondary prevention of stroke, prevention of thromboembolic events after neurointerventional procedures).
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 function allele and 1 decreased function allele, or 1 increased function allele and 1 decreased function allele, or 2 decreased function 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 function allele and 1 non-functional allele, or 1 increased function 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 function 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 function allele and 1 decreased function allele, or 1 increased function allele and 1 decreased function allele, or 2 decreased function 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 clinically indicated and no contraindication, consider an alternative P2Y12 inhibitor (e.g. ticagrelor, ticlopidine) at standard dose.
CYP2C19 intermediate metabolisers
Individuals carrying 1 normal function allele and 1 non-functional allele, or 1 increased function 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 clinically indicated and no contraindication, consider an alternative P2Y12 inhibitor (e.g. ticagrelor, ticlopidine) at standard dose.
CYP2C19 likely poor metabolisers
Individuals carrying 1 decreased function 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 clinically indicated and no contraindication, 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, use prasugrel or ticagrelor at standard dose.
Royal Dutch Pharmacists Association - Pharmacogenetics Working Group (DPWG) Guideline as of November 2022:
Phenotype
Description
Recommendation
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 stroke or TIA as the genetic variation decreases clopidogrel activation. No negative clinical effects have been observed in other patients.
For PCI, stroke or TIA: Consider choosing an alternative (e.g. prasugrel, ticagrelor, aspirin + dipyridamole) or double the dose to 150 mg daily (600 mg loading dose). No action is required for other indications.
CYP2C19 poor metabolisers
Increased risk of serious CV and cerebrovascular events, particularly in patients undergoing balloon angioplasty or stent placement (PCI) and in those with stroke or TIA as the genetic variation decreases clopidogrel activation. No negative clinical effects have been observed in other patients.
For PCI, stroke or TIA: 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.
Renal Impairment
Severe: Contraindicated.
Hepatic Impairment
Severe: Contraindicated.
Contraindications
Hypersensitivity to clopidogrel, aspirin, other salicylates, or NSAIDs. Active pathological bleeding, gastrointestinal bleeding, intracranial haemorrhage, haemophilia, or known bleeding disorders; active peptic ulcer or erosive oesophagitis, pre-existing mastocytosis in whom aspirin use may induce severe hypersensitivity reactions; syndrome of asthma with rhinitis and/or nasal polyps. Severe renal and hepatic impairment. Pregnancy (3rd trimester) and lactation.
Special Precautions
Patient with recent TIA or stroke, lacunar stroke within 180 days; history of peptic ulcer, gastroduodenal haemorrhage, or minor upper gastrointestinal symptoms; G6PD deficiency, gout, history of asthma or allergic disorders; hypersensitivity or haematologic reaction to previous thienopyridine use; who have lesions with a propensity to bleed (e.g. gastrointestinal or intraocular lesions), who are at increased risk of bleeding (e.g. trauma, surgery). For elective surgery, consider temporary discontinuation of therapy 7 days prior to the procedure. CYP2C19 likely intermediate, intermediate, likely poor, and poor metabolisers. Mild to moderate renal and hepatic impairment. Pregnancy (1st-2nd trimester).
Adverse Reactions
Significant: Increased risk of bleeding, prolonged bleeding time, increased urate concentrations; renal papillary necrosis and other renal injury (prolonged use), haemolytic anaemia (in patients with G6PD deficiency), hypersensitivity reactions, cross-reactivity among thienopyridine agents (e.g. prasugrel, ticlopidine). Rarely, acquired haemophilia. Blood and lymphatic system disorders: Leucopenia, eosinophilia, thrombocytopenia. Rarely, neutropenia. Cardiac disorders: Kounis syndrome. Ear and labyrinth disorders: Tinnitus, hearing loss. Rarely, vertigo. Eye disorders: Eye bleeding (retinal, conjunctival, ocular). Gastrointestinal disorders: Dyspepsia, abdominal pain, diarrhoea, nausea, constipation, flatulence, gastritis, vomiting; gastric, peptic or duodenal ulcer. Rarely, taste disturbances, ageusia. Hepatobiliary disorders: Acute liver failure, hepatitis. Immune system disorders: Insulin autoimmune syndrome. Rarely, anaphylactoid reactions, serum sickness. Metabolism and nutrition disorders: Hypoglycaemia. Musculoskeletal and connective tissue disorders: Rarely, arthralgia, myalgia, arthritis. Nervous system disorders: Headache, dizziness, paraesthesia. Renal and urinary disorders: Haematuria. Respiratory, thoracic and mediastinal disorders: Epistaxis Skin and subcutaneous tissue disorders: Rash, pruritus, skin bleeding (purpura). Rarely, toxic epidermal necrolysis, Stevens-Johnson syndrome, erythema multiforme. Vascular disorders: Haematoma. Rarely, vasculitis, hypotension. Potentially Fatal: Serious gastrointestinal bleeding, ulceration, and perforation. Rarely, thrombotic thrombocytopenic purpura.
Monitoring Parameters
Obtain blood cell count, Hb, haematocrit, and platelets. Monitor for signs and symptoms of hypersensitivity reaction (particularly in patients with known thienopyridine allergy), gastrointestinal or other bleeding.
Overdosage
Symptoms: Clopidogrel: Prolonged bleeding time and subsequent bleeding complications. Aspirin: Headache, dizziness, nausea, vomiting, gastric pain, tinnitus, confusion, hyperventilation resulting in respiratory alkalosis, metabolic acidosis, hyperthermia, perspiration causing dehydration, hypoglycaemia, restlessness, hallucinations, convulsions, coma, CV collapse and respiratory arrest. Management: Symptomatic treatment. For moderate intoxication, induction of vomiting may be considered; if this fails, gastric lavage may be performed. May administer activated charcoal and Na sulfate. Urine alkalinisation using Na bicarbonate while monitoring the urine pH may be indicated. For severe intoxication, haemodialysis may be performed.
Drug Interactions
Increased risk of bleeding with other antiplatelet agents (e.g. ticlopidine, tirofiban), anticoagulants (e.g. heparin, warfarin), NSAIDs including COX-2 inhibitors, thrombolytics, SSRIs, and pentoxifylline. May increase the risk of renal impairment with ACE inhibitors, thiazide diuretics, and NSAIDs including COX-2 inhibitors.
Clopidogrel: Serum concentrations of the active metabolite of clopidogrel may be decreased by strong or moderate CYP2C19 inhibitors (e.g. esomeprazole, omeprazole, fluvoxamine, fluoxetine, moclobemide, voriconazole, fluconazole, ticlopidine, carbamazepine, efavirenz). Strong CYP2C19 inducers (e.g. rifampicin) may increase the serum concentration of the clopidogrel active metabolite and may increase the risk of bleeding. Antiplatelet effect may be diminished with ritonavir. May increase the plasma concentrations of rosuvastatin, and agents metabolised by CYP2C8 (e.g. repaglinide, paclitaxel).
Aspirin: Metamizole may decrease the effect of aspirin on platelet aggregation. May increase the risk of gastrointestinal ulceration and bleeding with corticosteroids. May inhibit the effects of uricosuric agents (e.g. probenecid, sulfinpyrazone). May result in bone marrow toxicity with methotrexate (doses higher than 20 mg/week). May cause reduced valproic acid protein binding and inhibition of valproic acid metabolism, resulting in increased serum levels of total and free valproic acid. May increase the risk of Reye's syndrome with varicella vaccines. Increased risk of metabolic acidosis with acetazolamide. May increase the risk of severe complications (e.g. gastrointestinal ulceration, perforation or haemorrhage) of nicorandil. Absorption may be reduced and delayed by opioid agonists (e.g. morphine). May enhance the effects of oral hypoglycaemic agents.
Food Interaction
Clopidogrel: Grapefruit or grapefruit juice may substantially reduce the antiplatelet effect of clopidogrel.
Aspirin: Food may decrease the rate but not the extent of absorption. Increased risk of bleeding and enhanced gastric mucosal damage with alcohol.
Lab Interference
Aspirin: May lead to false-negative results for glucose oxidase urinary glucose tests and false-positive reaction when using cupric sulfate method. May cause false-positive result for aldosterone/renin ratio (ARR). May interfere with Gerhardt test, vanillyl mandelic acid (VMA) determination, hydroxyindoleacetic acid (5-HIAA), xylose tolerance test, and T3 and T4.
Action
Description: Mechanism of Action: Clopidogrel is a prodrug of the active thiol metabolite that selectively and irreversibly inhibits the binding of adenosine diphosphate (ADP) to its platelet P2Y12 receptor and the subsequent ADP-mediated activation of glycoprotein IIb/IIIa complex, thus reducing platelet aggregation.
Aspirin is a salicylate that exhibits analgesic, anti-inflammatory, and antipyretic properties. It inhibits platelet aggregation by irreversible inhibition of cyclooxygenase-1 and 2 (COX-1 and 2) enzymes via acetylation which leads to reduced formation of prostaglandin precursors, thus preventing the generation of thromboxane A2 (an inducer of platelet aggregation and vasoconstriction).
Synonym: Aspirin: acetylsalicylic acid. Onset: Aspirin: Platelet inhibition: <1 hour (nonenteric-coated); 3-4 hours (enteric-coated). Duration: Aspirin: 4-6 hours (immediate-release). Pharmacokinetics: Absorption: Rapidly absorbed from the gastrointestinal tract.
Clopidogrel: Time to peak plasma concentration: Approx 45 minutes.
Aspirin: Food may reduce the rate but not the extent of absorption. Bioavailability: 50-75% (immediate-release). Time to peak plasma concentration: Approx 1-2 hours (nonenteric-coated); 3-4 hours (enteric-coated). Distribution: Clopidogrel: Plasma protein binding: 98% (parent drug); 94% (carboxylic acid derivative).
Aspirin: Distributed widely and readily into most body fluids and tissues. Crosses the placenta and enters breastmilk. Volume of distribution: 10 L. Plasma protein binding: Approx 90%, mainly to albumin (<100 mcg/mL concentration). Metabolism: Clopidogrel: Extensively metabolised in the liver via hydrolysis by esterases to form an inactive carboxylic acid derivative (main inactive circulating metabolite), and via oxidation by multiple CYP450 isoenzymes (primarily CYP2C19 isoenzyme) to form the active thiol metabolite.
Aspirin: Hydrolysed by esterases in the gastrointestinal mucosa, RBCs, synovial fluid and blood to form salicylate (active), which is primarily conjugated in the liver into salicyluric acid, salicyl phenolic glucuronide, acyl glucuronide, and other minor metabolites. Excretion: Clopidogrel: Via urine (approx 50%); faeces (approx 46%). Elimination half-life: Approx 6 hours (parent drug); approx 0.5 hours (active thiol derivative); approx 8 hours (carboxylic acid derivative).
Aspirn: Via urine (75% as salicyluric acid, 10% as salicylic acid, 10% as phenolic glucuronide, 5% as acyl glucuronide). Elimination half-life: Parent drug: 15-20 minutes (plasma concentration). Salicylates (dose-dependent): Approx 3 hours (300-600 mg dose); 5- hours (after 1,000 mg); 10 hours (high doses).
Chemical Structure
Clopidogrel Source: National Center for Biotechnology Information. PubChem Compound Summary for CID 60606, Clopidogrel. https://pubchem.ncbi.nlm.nih.gov/compound/Clopidogrel. Accessed Nov. 23, 2022.
Aspirin Source: National Center for Biotechnology Information. PubChem Compound Summary for CID 2244, Aspirin. https://pubchem.ncbi.nlm.nih.gov/compound/Aspirin. Accessed Nov. 23, 2022.
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