Clopidogrel

Clopidogrel is an P2Y12 ADP receptor antagonist on platelets belonging to Antiplatelet Agent / Anticoagulant.

Clopidogrel is an antiplatelet agent used to prevent blood clots in peripheral vascular disease, coronary artery disease, and cerebrovascular disease.

After single and repeated oral doses of 75 mg per day, clopidogrel is rapidly absorbed. Mean peak plasma levels of unchanged clopidogrel (approximately 2.2-2.5 ng/mL after a single 75-mg oral dose) occurred approximately 45 minutes after dosing. Clopidogrel and the main circulating inactive metabolite bind reversibly in vitro to human plasma proteins (98% and 94%, respectively). Clopidogrel is extensively metabolized by the liver. Following an oral dose of 14C-labeled clopidogrel in humans, approximately 50% of total radioactivity was excreted in urine and approximately 46% in feces over the 5 days post-dosing.

Clopidogrel shows common side effects like Excessive tiredness, headache, dizziness, nausea, vomiting, stomach pain, diarrhea, nosebleed, etc.

Clopidogrel is available in the form of Oral Tablets.

Clopidogrel is available in India, the US, the UK, Canada, Russia, Japan, New Zealand, Korea, China, and Australia.

Clopidogrel belonging to the Antiplatelet Agent / Anticoagulant, acts as an P2Y12 ADP receptor antagonist.

Clopidogrel is metabolized to its active form by carboxylesterase-1. The active form is a platelet inhibitor that irreversibly binds to P2Y₁₂ ADP receptors on platelets. This binding prevents ADP binding to P2Y₁₂ receptors, activation of the glycoprotein GPIIb/IIIa complex, and platelet aggregation.

The Onset of action of Clopidogrel is found to be 2 hours.

The Duration of Action of Clopidogrel is approximately 12 hours.

Clopidogrel is available in the form of Oral Tablets.

Clopidogrel tablet is taken orally usually once or twice a day.

Clopidogrel is an anticlotting medicine (blood thinners). It is one of the primarily prescribed medications that prevent clot formation. Clopidogrel helps in reducing the risk of various heart problems such as angina pectoris (chest discomfort/pain caused due to insufficient oxygen supply to the heart muscle), heart attack (blockage of heart muscles due to the formation of plaques), and stroke (decreased blood flow to your brain), etc. Clopidogrel prevents blood clotting and promotes a smooth flow of blood.

Clopidogrel is an P2Y12 ADP receptor antagonist on platelets belonging to Antiplatelet Agent / Anticoagulant.

Clopidogrel selectively and irreversibly inhibits adenosine diphosphate (ADP) from binding to its platelet P2Y₁₂ receptor and subsequent ADP-mediated activation of glycoprotein IIb/IIIa complex, thus reducing platelet aggregation.

Clopidogrel is approved for use in the following clinical indications

• 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 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.

• Acute Coronary Syndrome

For patients with non-ST-segment elevation acute coronary syndrome (unstable angina/non-Q-wave MI) including patients who are to be managed medically and those who are to be managed with percutaneous coronary intervention (with or without stent) or CABG, Clopidogrel has been shown to decrease the rate of a combined endpoint of cardiovascular death, MI, or stroke as well as the rate of a combined endpoint of cardiovascular death, MI, stroke, or refractory ischemia.

For patients with ST-segment elevation acute myocardial infarction, Clopidogrel has been shown to reduce the rate of death from any cause and the rate of a combined endpoint of death, reinfarction, or stroke. This benefit is not known to pertain to patients who receive primary angioplasty.

Although not approved, there have been certain off-label indications. These include

• Percutaneous coronary intervention for stable ischemic heart disease
• Carotid artery atherosclerosis, symptomatic
• Carotid artery stenting
• Coronary artery bypass graft surgery
• Peripheral atherosclerotic disease
• Stable ischemic heart disease
• Transcatheter aortic valve replacement, thromboprophylaxis
• Transcatheter mitral valve repair with MitraClip device, thromboprophylaxis

• Recent MI, Recent Stroke, or Established Peripheral Arterial Disease

Oral:

Initial: 300 mg oral loading dose and then continue at 75 mg once daily.

• Acute Coronary Syndrome

Oral:

Initial: 75 mg once daily orally without a loading dose.

Although not approved, there have been certain off-label indications. These include

• Percutaneous coronary intervention for stable ischemic heart disease (off-label)

Oral:

Initial: 600 mg once, administered ≥2 hours before PCI, ideally ≥24 hours before PCI; followed by 75 mg once daily.

• Carotid artery atherosclerosis, symptomatic (off-label)

Oral: 75 mg once daily.

• Carotid artery stenting (off-label)
• Percutaneous approach

Initial

Initiation ≥48 hours before procedure: Oral: 75 mg twice daily in combination with aspirin.

Initiation <48 hours before procedure: Oral: 450 mg once at least 4 hours before procedure in combination with aspirin.

Maintenance

Oral: 75 mg once daily in combination with aspirin for at least 4 weeks; then discontinue clopidogrel and continue aspirin indefinitely thereafter. In patients with history of neck irradiation, some experts recommend continuing clopidogrel plus aspirin indefinitely.

• Transcarotid approach (off-label)

Initial

Initiation ≥72 hours before procedure: Oral: 75 mg once daily in combination with aspirin.

Initiation <72 hours before procedure: Oral: 450 mg once at least 4 hours before procedure in combination with aspirin.

Maintenance

Oral: 75 mg once daily in combination with aspirin for at least 4 weeks; then discontinue clopidogrel and continue aspirin indefinitely thereafter. In patients with history of neck irradiation, some experts recommend continuing clopidogrel plus aspirin indefinitely.

• Coronary artery bypass graft surgery (off-label)
• Aspirin-allergic or aspirin-intolerant patients: Oral: 75 mg once daily; continue indefinitely. Some experts recommend a loading dose of 300 mg administered 6 hours after surgery, followed by 75 mg once daily.

• Following off-pump coronary artery bypass graft surgery: Oral: 75 mg once daily in combination with aspirin for 1 year, then discontinue clopidogrel and continue aspirin indefinitely.

• Patients with acute coronary syndrome followed by coronary artery bypass graft surgery: Oral: 75 mg once daily in combination with aspirin for 1 year, then discontinue clopidogrel and continue aspirin indefinitely.

• Peripheral atherosclerotic disease (off-label)

Oral: 75 mg once daily.

• Stable ischemic heart disease (off-label)

Oral: 75 mg once daily.

• Transcatheter aortic valve replacement, thromboprophylaxis (off-label)

Oral: 300 mg once prior to valve implantation in combination with aspirin, followed by 75 mg once daily; may be used in combination with aspirin for 3 to 6 months depending on the type of valve implanted. To minimize risk of bleeding complications, may give aspirin or clopidogrel alone and reserve dual antiplatelet therapy during the first 3 to 6 months for patients at high risk of a thrombotic event; for either strategy, continue aspirin indefinitely after the initial 3 to 6 months of therapy.

• Transcatheter mitral valve repair with MitraClip device, thromboprophylaxis (off-label)

Oral

Loading dose: 300 mg once immediately following MitraClip insertion or within 24 hours prior to the procedure; may use as monotherapy or in combination with aspirin.

Maintenance: 75 mg once daily for at least 6 months; may use as monotherapy or in combination with aspirin.

• Antiplatelet effect for pediatric (off-label)

Infants and Children ≤24 months: In the PICOLO trial, a dose of 0.2 mg/kg/dose once daily was found to achieve a mean inhibition of platelet aggregation similar to adults receiving the adult recommended dose.

Children >2 years and Adolescents: Initial dose: 1 mg/kg once daily; in general, do not exceed the adult dose.

Clopidogrel is available in various strengths as 75mg and 300mg.

Clopidogrel is available in the form of Oral Tablets.

• Dosage Adjustment in Kidney Patient

Mild to severe impairment: No dosage adjustment necessary.

Avoid or minimize the consumption of grapefruit or grapefruit juice. It may reduce the antiplatelet effect of Clopidogrel.

Clopidogrel is contraindicated in patients with

• Clopidogrel is contraindicated in patients with active pathological bleeding such as a peptic ulcer or intracranial hemorrhage.
• Clopidogrel is contraindicated in patients with hypersensitivity (e.g., anaphylaxis) to clopidogrel or any component of the product.

• Diminished Antiplatelet Activity in Patients with 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. The metabolism of clopidogrel can also be impaired by drugs that inhibit CYP2C19, such as omeprazole or esomeprazole. Avoid concomitant use of Clopidogrel with omeprazole or esomeprazole because both significantly reduce the antiplatelet activity of Clopidogrel

• General Risk of Bleeding

P2Y12 inhibitors (Thienopyridines), including Clopidogrel, increase the risk of bleeding. P2Y12 inhibitors (Thienopyridines), inhibit platelet aggregation for the lifetime of the platelet (7-10 days). 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. Use of drugs that induce the activity of CYP2C19 would be expected to result in increased drug levels of the active metabolite of clopidogrel and might potentiate the bleeding risk. As a precaution, avoid the concomitant use of strong CYP2C19 inducers.

• Discontinuation Of Clopidogrel

Discontinuation of Clopidogrel increases the risk of cardiovascular events. If Clopidogrel must be temporarily discontinued (e.g., to treat bleeding or for surgery with a major risk of bleeding), restart it as soon as possible. When possible, interrupt therapy with Clopidogrel for five days prior to such surgery. Resume Clopidogrel as soon as hemostasis is achieved.

• Thrombotic Thrombocytopenic Purpura (TTP)

TTP, sometimes fatal, has been reported following the use of Clopidogrel, sometimes after a short exposure (<2 weeks). TTP is a serious condition that requires urgent treatment including plasmapheresis (plasma exchange). It is characterized by thrombocytopenia, microangiopathic hemolytic anemia (schistocytes [fragmented RBCs] seen on peripheral smears), neurological findings, renal dysfunction, and fever.

• Cross-Reactivity Among Thienopyridines

Hypersensitivity including rash, angioedema, or hematologic reaction has been reported in patients receiving Clopidogrel, including patients with a history of hypersensitivity or hematologic reaction to other thienopyridines.

Studies in rats have shown that clopidogrel and/or its metabolites are excreted in the milk. 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, a decision should be made whether to discontinue nursing or to discontinue the drug, considering the importance of the drug to the nursing woman.

Increased risk of major birth defects, miscarriage, or adverse fetal outcomes has not been associated with maternal use of clopidogrel. The user should not be withheld if needed for emergent treatment of stroke or myocardial infarction during pregnancy. Discontinue use 5 to 7 days prior to labor, delivery, or neuraxial blockade if possible due to increased risk of maternal bleeding and hemorrhage.

Avoid or minimize the consumption of grapefruit or grapefruit juice. It may reduce the antiplatelet effect of Clopidogrel.

• Common Adverse effects

Major hemorrhage (life-threatening), minor hemorrhage, Hemorrhagic stroke, intracranial hemorrhage.

• Rare Adverse effects

Hypotension, vasculitis, Acute generalized exanthematous pustulosis, bullous rash, eczema, erythema multiforme, erythematous rash, exfoliative dermatitis, lichen planus, lichenoid eruption, maculopapular rash, pruritus, pustular psoriasis, Stevens-Johnson syndrome, toxic epidermal necrolysis, urticaria, Insulin autoimmune syndrome, Ageusia, colitis, diarrhea, duodenal ulcer, gastric ulcer, pancreatitis, stomatitis, Acquired blood coagulation disorder, agranulocytosis, aplastic anemia, pancytopenia, thrombotic thrombocytopenic purpura, Acute hepatic failure, hepatitis (non-infectious), Angioedema, nonimmune anaphylaxis, serum sickness, Drug reaction with eosinophilia and systemic symptoms, Confusion, hallucination, headache, Arthralgia, arthritis, myalgia, Increased serum creatinine, Bronchospasm, eosinophilic pneumonitis, interstitial pneumonitis, fever.

• CYP2C19 Inducers

Since clopidogrel is metabolized to its active metabolite partly by CYP2C19, the use of drugs that induce the activity of this enzyme would be expected to result in increased drug levels of the active metabolite of clopidogrel. Rifampin strongly induces CYP2C19 resulting in both an increased level of clopidogrel active metabolite and platelet inhibition, which might potentiate the risk of bleeding. As a precaution, avoid the concomitant use of strong CYP2C19 inducers.

• CYP2C19 Inhibitors

Clopidogrel is metabolized to its active metabolite in part by CYP2C19. Concomitant use of drugs that inhibit the activity of this enzyme results in reduced plasma concentrations of the active metabolite of clopidogrel and a reduction in platelet inhibition.

• Omeprazole Or Esomeprazole

Avoid concomitant use of Clopidogrel with omeprazole or esomeprazole. In clinical studies, omeprazole was shown to significantly reduce the antiplatelet activity of Clopidogrel when given concomitantly or 12 hours apart. A similar reduction in antiplatelet activity was observed with esomeprazole when given concomitantly with Clopidogrel. Dexlansoprazole, lansoprazole, and pantoprazole had less effect on the antiplatelet activity of Clopidogrel than did omeprazole or esomeprazole.

• Opioids

As with other oral P2Y12 inhibitors, coadministration of opioid agonists delay and reduces the absorption of clopidogrel, presumably because of slowed gastric emptying, resulting in reduced exposure to its metabolites. Consider the use of a parenteral antiplatelet agent in acute coronary syndrome patients requiring coadministration of morphine or other opioid agonists.

• Nonsteroidal Anti-inflammatory Drugs (NSAIDs)

Coadministration of Clopidogrel and NSAIDs increases the risk of gastrointestinal bleeding.

• Warfarin (CYP2C9 Substrates)

Although the administration of clopidogrel 75 mg per day did not modify the pharmacokinetics of S-warfarin (a CYP2C9 substrate) or INR in patients receiving long-term warfarin therapy, coadministration of Clopidogrel with warfarin increases the risk of bleeding because of independent effects on hemostasis. However, at high concentrations in vitro, clopidogrel inhibits CYP2C9.

• SSRIs And SNRIs

Since selective serotonin reuptake inhibitors (SSRIs) and serotonin-norepinephrine reuptake inhibitors (SNRIs) affect platelet activation, the concomitant administration of SSRIs and SNRIs with clopidogrel may increase the risk of bleeding.

• Repaglinide (CYP2C8 Substrates)

The acyl-β-glucuronide metabolite of clopidogrel is a strong inhibitor of CYP2C8. Clopidogrel can increase systemic exposure to drugs that are primarily cleared by CYP2C8, thereby needing dose adjustment and appropriate monitoring. Clopidogrel increased repaglinide exposures by 3.9-fold to 5.1-fold. Avoid concomitant use of repaglinide with Clopidogrel. If concomitant use cannot be avoided, initiate repaglinide at 0.5 mg before each meal and do not exceed a total daily dose of 4 mg. Increased frequency of glucose monitoring may be required during concomitant use.

The common side effects of Clopidogrel include the following

• Common

Excessive tiredness, headache, dizziness, nausea, vomiting, stomach pain, diarrhea, and nosebleed.

• Rare

Hives, rash, Itching, difficulty breathing or swallowing, swelling of the face, throat, tongue, lips, eyes, hands, feet, ankles, or lower legs, hoarseness, black and tarry stools, red blood in stools, bloody vomit, vomit that looks like coffee grounds, unusual bleeding or bruising, pink or brown urine, slow or difficult speech, weakness or numbness of an arm or a leg, changes in vision, fever, shortness of breath, fast heartbeat, pale skin, purple patches or bleeding under the skin, confusion, yellowing of the skin or eyes, seizures.

• Pregnancy

Pregnancy Category B

Reproduction studies performed in rats and rabbits at doses up to 500 and 300 mg/kg/day (respectively, 65 and 78 times the recommended daily human dose on an mg/m2 basis), revealed no evidence of impaired fertility or fetotoxicity due to clopidogrel. There are, however, no adequate and well-controlled studies in pregnant women. Because animal reproduction studies are not always predictive of human response, Clopidogrel should be used during pregnancy only if clearly needed.

• Nursing Mothers

Studies in rats have shown that clopidogrel and/or its metabolites are excreted in the milk. 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, a decision should be made whether to discontinue nursing or to discontinue the drug, considering the importance of the drug to the nursing woman.

• Pediatric Use

As per FDA, safety and effectiveness in the pediatric population have not been established.

• Geriatric Use

Of the total number of subjects in the CAPRIE, CURE, and CLARITY-controlled clinical studies, approximately 50% of patients treated with Clopidogrel were 65 years of age and older, and 15% were 75 years and older. In COMMIT, approximately 58% of the patients treated with Clopidogrel were 60 years and older, 26% of whom were 70 years and older.

• Overdose following clopidogrel administration may lead to prolonged bleeding time and subsequent bleeding complications. A single oral dose of clopidogrel at 1500 or 2000 mg/kg was lethal to mice and to rats and at 3000 mg/kg to baboons. Symptoms of acute toxicity were vomiting (in baboons), prostration, difficult breathing, and gastrointestinal hemorrhage in all species.

Pharmacodynamic

Clopidogrel is a prodrug of a platelet inhibitor used to reduce the risk of myocardial infarction and stroke. It has a long duration of action as it is taken once daily and a large therapeutic window as it is given in doses of 75-300mg daily.

Pharmacokinetics

• Absorption

After single and repeated oral doses of 75 mg per day, clopidogrel is rapidly absorbed. Mean peak plasma levels of unchanged clopidogrel (approximately 2.2-2.5 ng/mL after a single 75-mg oral dose) occurred approximately 45 minutes after dosing. Absorption is at least 50%, based on urinary excretion of clopidogrel metabolites.

• Distribution

Clopidogrel and the main circulating inactive metabolite bind reversibly in vitro to human plasma proteins (98% and 94%, respectively). The binding is nonsaturable in vitro up to a concentration of 100 mcg/mL.

• Metabolism

Clopidogrel is extensively metabolized by the liver. In vitro and in vivo, clopidogrel is metabolized according to two main metabolic pathways: one mediated by esterases and leading to hydrolysis into its inactive carboxylic acid derivative (85% of circulating metabolites), and one mediated by multiple cytochromes P450. Cytochromes first oxidize clopidogrel to a 2-oxo-clopidogrel intermediate metabolite. Subsequent metabolism of the 2 oxo-clopidogrel intermediate metabolite results in the formation of the active metabolite, a thiol derivative of clopidogrel. In vitro, this metabolic pathway is mediated by CYP3A4, CYP2C19, CYP1A2, and CYP2B6. The active thiol metabolite, which has been isolated in vitro, binds rapidly and irreversibly to platelet receptors, thus inhibiting platelet aggregation.

• Excretion

Following an oral dose of 14C-labeled clopidogrel in humans, approximately 50% of total radioactivity was excreted in urine and approximately 46% in feces over the 5 days postXXX dosing. After a single, oral dose of 75 mg, clopidogrel has a half-life of approximately 6 hours. The elimination half-life of the inactive acid metabolite was 8 hours after single and repeated administration. Covalent binding to platelets accounted for 2% of radiolabel with a half-life of 11 days. In plasma and urine, the glucuronide of the carboxylic acid derivative is also observed.

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