Clopidogrel


Thông tin thuốc gốc
Chỉ định và Liều dùng
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.

Oral
Prophylaxis of thromboembolic disorder
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.
Special Patient Group
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 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.
Hepatic Impairment
Severe: Contraindicated.
Cách dùng
May be taken with or without food.
Chống chỉ định
Active pathological bleeding (e.g. peptic ulcer or intracranial haemorrhage). Severe hepatic impairment.
Thận trọng
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.
Phản ứng phụ
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.
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.
Quá liều
Symptoms: Prolonged bleeding time and subsequent bleeding complications. Management: Consider platelet transfusion if prompt correction of prolonged bleeding time is required.
Tương tác
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).
Food Interaction
Grapefruit or grapefruit juice may reduce the antiplatelet effect of clopidogrel.
Tác dụng
Description: 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.
Pharmacokinetics:
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).
Đặc tính

Chemical Structure Image
Clopidogrel

Source: National Center for Biotechnology Information. PubChem Database. Clopidogrel, CID=60606, https://pubchem.ncbi.nlm.nih.gov/compound/Clopidogrel (accessed on Jan. 21, 2020)

Bảo quản
Store at 25°C.
Phân loại ATC
B01AC04 - clopidogrel ; Belongs to the class of platelet aggregation inhibitors excluding heparin. Used in the treatment of thrombosis.
References
Dean L. Clopidogrel Therapy and CYP2C19 Genotype. Medical Genetics Summaries [Internet]. Bethesda (MD): National Center for Biotechnology Information (US). Accessed 20/09/2018. PMID: 28520346

Scott SA, Sangkuhl K, Gardner EE et al. Clinical Pharmacogenetics Implementation Consortium Guidelines for CYP2C19 Genotype and Clopidogrel Therapy. Clinical Pharmacogenetics Implementation Consortium Guidelines. doi: 10.1038/clpt.2011.132. Accessed 11/09/2018

Annotation of CPIC Guideline for Clopidogrel and CYP2C19. Pharmacogenomics Knowledgebase (PharmGKB). https://www.pharmgkb.org/. Accessed 09/10/2018 .

Annotation of EMA Label for Clopidogrel and CYP2C19. Pharmacogenomics Knowledgebase (PharmGKB). https://www.pharmgkb.org/. Accessed 09/10/2018 .

Annotation of FDA Label for Clopidogrel and CYP2C19. Pharmacogenomics Knowledgebase (PharmGKB). https://www.pharmgkb.org/. Accessed 09/10/2018 .

Annotation of HCSC Label for Clopidogrel and CYP2C19. Pharmacogenomics Knowledgebase (PharmGKB). https://www.pharmgkb.org/. Accessed 09/10/2018 .

Anon. Clopidogrel. AHFS Clinical Drug Information [online]. Bethesda, MD. American Society of Health-System Pharmacists, Inc. https://www.ahfscdi.com. Accessed 04/11/2019.

Anon. Clopidogrel. Lexicomp Online. Hudson, Ohio. Wolters Kluwer Clinical Drug Information, Inc. https://online.lexi.com. Accessed 04/11/2019.

Anon. CYP2C19 - Clopidogrel (Pharmacogenomics). Lexicomp Online. Hudson, Ohio. Wolters Kluwer Clinical Drug Information, Inc. https://online.lexi.com. Accessed 09/10/2018 .

Buckingham R (ed). Clopidogrel. Martindale: The Complete Drug Reference [online]. London. Pharmaceutical Press. https://www.medicinescomplete.com. Accessed 04/11/2019.

Clinical Annotation for CYP2C19*1, CYP2C19*2, CYP2C19*3, CYP2C19*4, CYP2C19*5, CYP2C19*6, CYP2C19*8 Related to Clopidogrel - Efficacy/Toxicity (1A). Pharmacogenomics Knowledgebase (PharmGKB). https://www.pharmgkb.org/. Accessed 11/09/2018.

Clinical Pharmacogenetics Implementation Consortium Guidelines for CYP2C19 Genotype and Clopidogrel Therapy. Clinical Pharmacogenetics Implementation Consortium (CPIC). https://cpicpgx.org/. Accessed 11/09/2018.

Clopidogrel Overview. Pharmacogenomics Knowledgebase (PharmGKB). https://www.pharmgkb.org/. Accessed 09/10/2018 .

Clopidogrel Tablet, Film Coated (Teva Pharmaceuticals USA, Inc.). DailyMed. Source: U.S. National Library of Medicine. https://dailymed.nlm.nih.gov/dailymed/. Accessed 04/11/2019.

Clopivid 75 mg Tablet (HOVID Berhad). National Pharmaceutical Regulatory Agency - Ministry of Health Malaysia. https://www.npra.gov.my/. Accessed 04/11/2019.

Joint Formulary Committee. Clopidogrel. British National Formulary [online]. London. BMJ Group and Pharmaceutical Press. https://www.medicinescomplete.com. Accessed 04/11/2019.

Sanofi-Aventis New Zealand Limited. Plavix 75 mg Film Coated Tablet data sheet 07 January 2019. Medsafe. http://www.medsafe.govt.nz/. Accessed 04/11/2019.

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