Clopidogrel is a medicine that prevents blood clots forming on platelets, used after heart attack, stroke or in patients with stents, almost always in combination with aspirin. It increases the risk of bleeding, so precautions are required before surgery.
Also known as: Plavix
Dual antiplatelet therapy: increases bleeding risk. This association is frequently indicated (e.g. after acute coronary syndrome), but requires bleeding risk assessment.
Aspirin and clopidogrel inhibit platelet aggregation by complementary mechanisms (COX-1 and the P2Y12 receptor), and dual antiplatelet therapy is the standard treatment after acute coronary syndrome and coronary stents, reducing thrombotic events. However, the benefit is accompanied by an increased bleeding risk, particularly digestive, especially in the elderly, with a history of ulcer or bleeding, or with anticoagulants. The duration of dual therapy should be defined by the ischaemic vs bleeding risk (usually 1–12 months depending on the scenario), with gastroprotection (PPI) in at-risk patients and periodic reassessment.
Aspirin + clopidogrel: dual antiplatelet therapy with additive bleeding risk. Use only in approved indications (ACS, stents) and assess the duration.
Aspirin irreversibly inhibits COX-1 and Clopidogrel blocks the P2Y12 receptor — additive platelet inhibition.
Watch for signs of bleeding throughout therapy.
Prolonged bleeding, haematuria, melaena, severe abdominal pain.
Use only under medical prescription within approved indications; assess treatment duration and individual bleeding risk.
DailyMed/FDA (NIH/NLM) — approved Clopidogrel label: https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=c9928956-bb7b-4ec2-bc38-d3c9c4199cae ; approved Aspirin label: https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=3ba0a9f2-062a-401e-82eb-54383a822366
Enoxaparin with clopidogrel increases the risk of major bleeding.
Clopidogrel (a P2Y12 inhibitor) and enoxaparin (a low molecular weight heparin) act on different haemostasis pathways and the bleeding risk is additive: the clopidogrel label states that "P2Y12 inhibitors, including clopidogrel, increase the risk of bleeding" and that the risk increases "with the concomitant use of other drugs that increase the risk of bleeding"; the enoxaparin label warns that the risk of epidural haematomas increases with "the concomitant use of other drugs that affect haemostasis, such as NSAIDs, platelet inhibitors and other anticoagulants" and recommends extreme caution with platelet inhibitors. The combination is used in specific settings (e.g. acute coronary syndromes under intervention, during a short transition period), but requires: monitoring for bleeding (including retroperitoneal and intracranial), blood count monitoring, and respecting the recommended intervals between doses around procedures (e.g. epidural catheter removal 12–24h after the enoxaparin dose).
Clopidogrel + enoxaparina: additive bleeding (antiplatelet + anticoagulant). Watch for bleeding signs; use with extreme caution.
Anticoagulant (LMWH) + antiplatelet (P2Y12), with additive bleeding.
Monitor blood count and clinical signs of bleeding.
Intracranial or GI bleeding; spontaneous bruising.
Use with caution in high bleeding-risk patients; monitor.
DailyMed (FDA) — approved Enoxaparin label: https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=5017a927-2a24-4f27-89f9-27c805bf7d59 ; approved Clopidogrel label: https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=55731d95-0c99-ff61-e063-6394a90a1ab5 — additional reference: Prontuário Terapêutico do INFARMED (11th ed., 2012)
Dabigatran plus clopidogrel increases bleeding risk.
Clopidogrel inhibits platelet aggregation and dabigatran directly inhibits thrombin; the combination adds up the anticoagulant effects and increases the risk of major bleeding, including intracranial and gastrointestinal bleeding. The dabigatran label states that the bleeding risk increases with the concomitant use of "other drugs affecting haemostasis, including antiplatelet agents" and warns about the added risk in elderly patients, with renal impairment or low body weight; the clopidogrel label states that the bleeding risk increases with "the concomitant use of other drugs that increase the risk of bleeding". The combination is avoided in practice (dual/triple therapy in atrial fibrillation is used for short periods and with restricted criteria — e.g. after stenting). If used, monitor for bleeding signs, renal function (dabigatran is renally eliminated) and consider a dabigatran dose reduction.
Clopidogrel + dabigatran: additive bleeding (antiplatelet + anticoagulant). Watch bleeding and renal function.
Combined thrombin and P2Y12 inhibition, with an additive bleeding effect.
Monitor blood count and bleeding signs.
Severe bleeding, melaena, haematemesis.
Use only with a clear indication; adjust the dabigatran dose to renal function.
DailyMed (FDA) — approved Dabigatran label: https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=f7ea7e2c-ca54-4ecc-9fc7-bd3571b0ebc2 ; approved Clopidogrel label: https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=55731d95-0c99-ff61-e063-6394a90a1ab5 — additional reference: Prontuário Terapêutico do INFARMED (11th ed., 2012)
Rivaroxaban plus clopidogrel increases the risk of major bleeding.
Clopidogrel inhibits platelet aggregation and rivaroxaban inhibits factor Xa; the combination adds up the effects on haemostasis and increases the risk of major bleeding. The rivaroxaban label explicitly states that "clopidogrel and chronic NSAID use may increase the risk of bleeding" and recommends caution with the concomitant use of "antiplatelet agents, other antithrombotics, fibrinolytics and NSAIDs"; the clopidogrel label states that the risk increases with "the concomitant use of other drugs that increase the risk of bleeding". Dual therapy rivaroxaban 2.5 mg + aspirin/clopidogrel is approved in specific settings (coronary/peripheral artery disease with CAD/PAD) for defined periods, but the combination with clopidogrel in general should be avoided. Monitor for bleeding signs (including intracranial and GI) and renal function.
Clopidogrel + rivaroxaban: additive bleeding (antiplatelet + anticoagulant). Watch bleeding; short-duration combination in restricted settings.
Combined antithrombotic effect (factor Xa + P2Y12) with additive bleeding.
Monitor for bleeding signs and blood count.
Intracranial, GI or retroperitoneal bleeding.
Reserve for high thrombotic-risk indications; consider a gastroprotectant.
DailyMed (FDA) — approved Rivaroxaban label: https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=481b7802-5093-43e7-bbd9-1532197eb6e6 ; approved Clopidogrel label: https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=55731d95-0c99-ff61-e063-6394a90a1ab5 — additional reference: Prontuário Terapêutico do INFARMED (11th ed., 2012)
Apixaban with clopidogrel raises bleeding risk; the combination is used in selected cases (e.g. post-ACS with AF).
Apixaban inhibits factor Xa and clopidogrel inhibits platelet aggregation: the apixaban label states that "co-administration with antiplatelet agents, fibrinolytics, heparin, aspirin and chronic NSAID use increases the risk of bleeding" and documents a trial with clopidogrel "terminated early due to a higher rate of bleeding with apixaban compared to placebo"; the clopidogrel label states that the risk increases with "the concomitant use of other drugs that increase the risk of bleeding". The combination should only be used in restricted settings (e.g. short duration after acute coronary syndrome with atrial fibrillation) and with close monitoring: watch for bleeding (including GI and intracranial), blood count and renal function, and reassess the duration of the combined therapy.
Apixaban + clopidogrel: additive bleeding (anticoagulant + antiplatelet). Watch bleeding; short-duration combination in restricted settings.
Combined inhibition of factor Xa and platelet aggregation with an additive bleeding risk.
Monitor occult bleeding, bruising and blood count.
GI or intracranial bleeding; extensive spontaneous bruising.
Use only with a clear indication; reduce the apixaban dose according to patient profile.
DailyMed (FDA) — approved Apixaban label: https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=a454cd24-0c6d-46e8-b1e4-197388606175 ; approved Clopidogrel label: https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=55731d95-0c99-ff61-e063-6394a90a1ab5 — additional reference: Prontuário Terapêutico do INFARMED (11th ed., 2012)
Reduced Clopidogrel efficacy. Omeprazole inhibits CYP2C19, reducing pro-drug activation.
Clopidogrel is a prodrug that depends on CYP2C19 to be converted into the active metabolite; omeprazole is a potent inhibitor of this enzyme and reduces the formation of the active metabolite and platelet inhibition, with a documented increased risk of cardiovascular events. The clopidogrel label advises against co-administration with CYP2C19 inhibitors such as omeprazole and esomeprazole. Whenever gastroprotection is needed in patients taking clopidogrel, prefer pantoprazole (less CYP2C19 inhibition) or an H2 antagonist, and avoid the combination.
Clopidogrel + omeprazole: omeprazole inhibits CYP2C19 and reduces clopidogrel activation, decreasing antiplatelet protection. Avoid; prefer pantoprazole or an H2 antagonist.
Clopidogrel requires CYP2C19 for activation; Omeprazole potently inhibits that enzyme.
Watch for thrombotic events (chest pain, neurological symptoms).
New thrombotic events — chest pain, sudden unilateral weakness, speech changes.
Prefer Pantoprazole (less interaction) or another gastric protectant when needed.
DailyMed/FDA (NIH/NLM) — approved Clopidogrel label: https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=c9928956-bb7b-4ec2-bc38-d3c9c4199cae ; approved Omeprazole label: https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=37291cab-e350-d8e3-e063-6294a90a9cb1
Clopidogrel can be taken with or without food, with no relevant food interaction.
May be taken with or without food, consistently.
DailyMed/FDA (NIH/NLM) — approved Clopidogrel label: https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=c9928956-bb7b-4ec2-bc38-d3c9c4199cae
Grapefruit inhibits CYP3A4 (one of the activation pathways of clopidogrel) and may reduce conversion to the active metabolite, decreasing antiplatelet efficacy.
Avoid grapefruit juice during treatment.
DailyMed/FDA (NIH/NLM) — approved Clopidogrel label: https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=c9928956-bb7b-4ec2-bc38-d3c9c4199cae
Clopidogrel increases the risk of GI bleeding in patients with peptic ulcer or recent GI bleeding.
Consider a gastroprotectant (PPI) during treatment; monitor for bleeding signs.
EMC-UK (MHRA) — approved Clopidogrel SmPC: https://www.medicines.org.uk/emc/product/5207/smpc
Clopidogrel is contraindicated in clinically significant active bleeding because of its antiplatelet effect.
Do not use in active bleeding; treat the cause of bleeding.
EMC-UK (MHRA) — approved Clopidogrel SmPC: https://www.medicines.org.uk/emc/product/5207/smpc
Clopidogrel is not recommended in pregnancy unless the benefit outweighs the risk, because of a lack of safety data.
Avoid in pregnancy except for vital indications (e.g. recent stent).
Excretion into breast milk is unknown; avoid during breastfeeding.
In women of childbearing age, rule out pregnancy before starting long-term treatment.
EMC-UK (MHRA) — approved Clopidogrel SmPC: https://www.medicines.org.uk/emc/product/5207/smpc
Clinical and educational support tool. The information does not replace a medical prescription or the opinion of a qualified healthcare professional.
Antiplatelet agent. Inhibition of platelet aggregation is seen 2 hours after the oral dose and reaches steady state between days 3 and 7 with 75 mg/day (mean inhibition of 40 to 60%). Inhibition is irreversible — it lasts for the life of the platelet (7 to 10 days); aggregation and bleeding time return to baseline about 5 days after discontinuation.
Prodrug: the active metabolite irreversibly binds to the platelet P2Y12 class of ADP receptors, inhibiting ADP-mediated activation of the GPIIb/IIIa complex and platelet aggregation; aggregation induced by other agonists is also inhibited by blocking the amplification by released ADP.
Rapid oral absorption (at least 50%, based on urinary excretion of metabolites); active metabolite Cmax about 30 to 60 minutes after dosing. It may be administered with or without food; a meal reduces active metabolite Cmax by 57% without changing AUC.
Extensively metabolised: one pathway by esterases (85% of circulating metabolites, inactive carboxylic acid derivative) and one by several cytochromes; the active metabolite (thiol derivative) is formed mostly by CYP2C19, with contributions from CYP1A2, CYP2B6 and CYP3A. CYP2C19 poor metabolisers have less active metabolite and less platelet inhibition.
Half-life of clopidogrel of about 6 hours (after 75 mg); that of the active metabolite is about 30 minutes. Approximately 50% of the radioactivity is excreted in urine and 46% in faeces within 5 days.
Medicines from the same therapeutic group (ATC classification) or the same pharmacological class.
