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药品详细

Rivaroxaban(利伐沙班)

化学结构式图
中文名
利伐沙班
英文名
Rivaroxaban
分子式
C19H18ClN3O5S
化学名
5-chloro-N-{[(5S)-2-oxo-3-[4-(3-oxomorpholin-4-yl)phenyl]-1,3-oxazolidin-5-yl]methyl}thiophene-2-carboxamide
分子量
Average: 435.881
Monoisotopic: 435.065569098
CAS号
366789-02-8
ATC分类
B01A 抗血栓药
药物类型
small molecule
阶段
approved
商品名
同义名
基本介绍

Rivaroxaban is an anticoagulant and the first orally active direct factor Xa inhibitor. Unlike warfarin, routine lab monitoring of INR is not necessary. However there is no antidote available in the event of a major bleed. Only the 10 mg tablet can be taken without regard to food. The 15 mg and 20 mg tablet should be taken with food. FDA approved on July 1, 2011.

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    封装厂家
    参考
    Synthesis Reference Not Available
    General Reference
    1. Piccini JP, Patel MR, Mahaffey KW, Fox KA, Califf RM: Rivaroxaban, an oral direct factor Xa inhibitor. Expert Opin Investig Drugs. 2008 Jun;17(6):925-37. Pubmed
    2. Alban S: Pharmacological strategies for inhibition of thrombin activity. Curr Pharm Des. 2008;14(12):1152-75. Pubmed
    3. Stevenson M, Scope A, Holmes M, Rees A, Kaltenthaler E: Rivaroxaban for the prevention of venous thromboembolism: a single technology appraisal. Health Technol Assess. 2009 Oct;13 Suppl 3:43-8. Pubmed
    4. Imberti D, Dall’Asta C, Pierfranceschi MG: Oral factor Xa inhibitors for thromboprophylaxis in major orthopedic surgery: a review. Intern Emerg Med. 2009 Dec;4(6):471-7. Pubmed
    5. Alexander D, Jeremias A: Rivaroxaban in the contemporary treatment of acute coronary syndromes. Expert Opin Investig Drugs. 2011 Jun;20(6):849-57. Epub 2011 May 10. Pubmed
    6. Cabral KP: Pharmacology of the new target-specific oral anticoagulants. J Thromb Thrombolysis. 2013 May 5. Pubmed
    剂型
    规格
    化合物类型
    Type small molecule
    Classes Not Available
    Substructures Not Available
    适应症
    药理
    Indication Rivaroxaban is indicated for the prevention of venous thromboembolic events (VTE) in patients who have undergone total hips replacements and total knee replacement surgery; prevention of stroke and systemic embolism in patients with nonvalvular atrial fibrillation; treatment of deep vein thrombosis (DVT) and pulmonary embolism (PE); to reduce risk of recurrent DVT and/or PE. Due to a lack of safety studies, it is not recommended for use in those under 18 years old. Its use is also not recommended in those with severe renal impairment (<30mL/min).
    Pharmacodynamics Rivaroxaban is an anticoagulant which binds directly to factor Xa. Thereafter, it effectively blocks the amplification of the coagulation cascade, preventing the formation of thrombus. Rivaroxaban is a unqiue anticoagulant for two reasons. First of all, it is does not involve antithrombin III (ATIII) to exert its anticoagulant effects. Secondly, it is an oral agent whereas the widely used unfractionated heparin and low molecular weight heparins are for parenteral use only. Although the activated partial thromboplastin time (aPTT) and HepTest (a test developed to assay low molecular weight heparins) are prolonged in a dose-dependant manner, neither test is recommended for the assessment of the pharmacodynamic effects of rivaroxaban. Anti-Xa activity and inhibition of anti-Xa activity monitoring is also not recommended despite being influenced by rivaroxaban.
    Mechanism of action Rivaroxaban competitively inhibits free and clot bound factor Xa. Factor Xa is needed to activate prothrombin (factor II) to thrombin (factor IIa). Thrombin is a serine protease that is required to activate fibrinogen to fibrin, which is the loose meshwork that completes the clotting process. Since one molecule of factor Xa can generate more than 1000 molecules of thrombin, selective inhibitors of factor Xa are profoundly useful in terminating the amplification of thrombin generation. The action of rivaroxaban is irreversible.
    Absorption Following oral administration, rivaroxaban is rapidly absorbed and reaches peak plasma concentration in 2-4 hours. Bioavailability of the 10 mg dose is >80%. However, the 15-20 mg dose have a lower bioavailability if taken in the fasted state and consequently should be taken with food.
    Volume of distribution

    The steady state Vd is 50 L
    Protein binding Plasma protein binding is about 92% to 95%
    Metabolism
    Approximately two-thirds of the dose is metabolized. It is metabolized by CYP3A4, CYP3A5, CYP2J2 and CYP-independant mechanisms
    Route of elimination Approximately two-thirds of rivaroxaban is excreted into urine (via active tubular secretion in which approximately 36% as unchanged drug and 30% as inactive metabolism). The remaining third of the administered dose is excreted via feces in which 7% is in the form of unchanged drug and 21% as inactive metabolites.
    Half life The terminal half life is 5-9 hours in adults and 11-13 hours in the elderly.
    Clearance

    Systemic clearance is approximately 10 L/h, so rivaroxaban is considered a drug with low clearance. Renal clearance is ~3-4 L/h.
    Toxicity Excessive bleeding. Overdosages should be treated using activated charcoal and supportive measures such as mechanical compression and hemodynamic support. If bleeding is not controlled, the following procoagulants can be administered: activated prothrombin complex concentrate, prothrombin complex concentrate and recombinant factor VIIa. There is also a higher chance of post procedural hemorrhage compared to enoxaparin (1.55% vs. 1.39% respectively).
    Affected organisms
    • Humans and other mammals
    Pathways Not Available
    理化性质
    Properties
    State solid
    Experimental Properties Not Available
    Predicted Properties
    Property Value Source
    water solubility 1.00e-02 g/l ALOGPS
    logP 1.74 ALOGPS
    logP 1.9 ChemAxon
    logS -4.6 ALOGPS
    pKa (strongest acidic) 13.6 ChemAxon
    pKa (strongest basic) -1.6 ChemAxon
    physiological charge 0 ChemAxon
    hydrogen acceptor count 5 ChemAxon
    hydrogen donor count 1 ChemAxon
    polar surface area 88.18 ChemAxon
    rotatable bond count 5 ChemAxon
    refractivity 104.74 ChemAxon
    polarizability 43.53 ChemAxon
    药物相互作用
    Drug Interaction
    Apixaban Avoid combination. Otherwise, excessive anticoagulation will likely occur.
    Bivalirudin Anticoagulants may enhance the anticoagulant effect of rivaroxaban. Avoid concurrent use of rivaroxaban with other anticoagulants whenever possible, other than during transition periods, due to the possible increased for bleeding.
    Clopidogrel Antiplatelet agents such as clopidogrel may enhance the anticoagulant effect of rivaroxaban. Avoid concurrent use of clopidogrel with rivaroxaban unless the anticipated benefits outweigh the risks of bleeding. Canadian rivaroxaban labeling recommends avoiding concurrent use with any antiplatelet agent, while the U.S. rivaroxaban labeling recommends caution and increased monitoring if used with any other antiplatelet agent. Any combined use should only be undertaken with increased monitoring for evidence of bleeding.
    Conivaptan CYP3A4 Inhibitors (Strong) may increase the serum concentration of Rivaroxaban. Consider avoiding use of rivaroxaban with any strong CYP3A4 inhibitors as many such agents are inhibitors of both CYP3A4 and P-glycoprotein. Use of rivaroxaban concomitantly with drugs that are strong inhibitors of both CYP3A4 and P-glycoprotein is specifically contraindicated.
    Dabigatran etexilate Using additional anticoagulants such as dabigatran can increase the anticoagulant effect of rivaroxaban. Avoid concurrent use of rivaroxaban with other anticoagulants whenever possible, other than during transition periods, due to the possible increased for bleeding.
    Etravirine Rivaroxaban may experience a decrease in serum concentration. U.S prescribing information recommends avoiding concurrent therapy.
    Ginkgo biloba Additive anticoagulant/antiplatelet effects may increase bleed risk. Concomitant therapy should be avoided.
    Itraconazole Use of rivaroxaban with agents that are strong inhibitors of both CYP3A4 and P-glycoproteins are contraindicated.
    Ketoconazole Use of rivaroxaban with agents that are strong inhibitors of both CYP3A4 and P-glycoproteins are contraindicated.
    Posaconazole Use of rivaroxaban with agents that are strong inhibitors of both CYP3A4 and P-glycoproteins are contraindicated.
    Ritonavir Use of rivaroxaban with agents that are strong inhibitors of both CYP3A4 like ritonavir and P-glycoproteins are contraindicated.
    Tamoxifen Tamoxifen may increase serum concentrations of Rivaroxaban increasing the risk of bleeding. Concomitant therapy should be avoided.
    Telithromycin Telithromycin may reduce clearance of Rivaroxaban. Concomitant therapy is contraindicated.
    Treprostinil The prostacyclin analogue, Treprostinil, increases the risk of bleeding when combined with the anticoagulant, Rivaroxaban. Monitor for increased bleeding during concomitant thearpy.
    Voriconazole Voriconazole, a strong CYP3A4 inhibitor, may increase the serum concentration of rivaroxaban by decreasing its metabolism. Increased bleed risks may occur. Consider alternate therapy.
    食物相互作用
    • Food should be taken with the 15 mg and 20 mg tablet. Food increases the bioavailability of the 20 mg dose.
    • Foods with antiplatelet/anticoagulants properties such as horseradish, gingko, ginger, garlic, feverfew
    • St. John's Wort is a CYP3A4 inducer and will decrease levels of rivaroxaban

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