아픽사반(apixaban), 요양급여

Apixaban Overview (apixaban)

Apixaban is an orally active factor Xa inhibitor with a half-life of approximately 12 hours.

* 반감기 12시간

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Apixaban is used in the prevention and treatment of VTE and in stroke prevention in patients with AF.

* 아픽사반은 VTE 예방, 치료와 AF 환자에서 stroke 예방 위해 사용됩니다.

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Dosing, monitoring, risks (apixaban)

Apixaban is generally given at a fixed dose without monitoring.

The dosing of apixaban differs according to the clinical indication and the patient's age, weight, and renal function.

* 아픽사반은 일반적으로 모니터링 없이 고정된 용량으로 투약합니다.

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Standard dosing of direct oral anticoagulants

Anticoagulant	Nonvalvular AF - stroke prophylaxis*	VTE treatment¶	VTE primary prophylaxisΔ
Dabigatran (Pradaxa)	150 mg twice daily	Parenteral anticoagulation for 5 to 10 days; then dabigatran 150 mg twice daily	110 mg for the first day, then 220 mg once daily
Apixaban (Eliquis, 유한에픽사반)	5 mg twice daily	10 mg twice daily for one week, then 5 mg twice daily	2.5 mg twice daily
Betrixaban (Bevyxxa)			160 mg on the first day, followed by 80 mg once daily, with food
Edoxaban (Savaysa, Lixiana)	60 mg once daily	Parenteral anticoagulation for 5 to 10 days; then edoxaban 60 mg once daily
Rivaroxaban (Xarelto)	20 mg once daily with the evening meal	15 mg twice daily with food for three weeks; then 20 mg once daily with food	10 mg once daily, with or without food

This is a simplified table that lists the most common dosing in individuals with normal renal function, normal weight, and lack of concomitant interacting medications (eg, P-glycoprotein inhibitors or inducers). Refer to UpToDate topics on AF, VTE treatment, VTE prophylaxis, and DOAC dosing for possible changes based on impaired renal function or extremes of weight. Other factors may influence dosing in individual patients.

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AF: atrial fibrillation; VTE: venous thromboembolism, includes deep vein thrombosis and pulmonary embolism; DOAC: direct oral anticoagulant.

* Dosing may be reduced for certain drugs in certain settings (eg, use of dabigatran 110 mg twice daily for individuals who are at increased risk of bleeding; refer to UpToDate topic on anticoagulation for atrial fibrillation for other examples).

¶ Treatment for acute VTE typically refers to the first three to six months of administration; continued treatment beyond six months may be done with a lower dose for some anticoagulants (eg, apixaban, rivaroxaban); the dose is not lowered whten therapy is continued using dabigatran or edoxaban. Refer to the latest prescribing information for each individual anticoagulant.

Δ Prophylaxis refers to primary prophylaxis in settings such as after knee or hip surgery.

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● Venous thromboembolism (VTE) prophylaxis in surgical patients: 2.5 mg twice daily; duration (12 days versus extended to 35 days) depends on the type of surgery, as discussed separately.

● Treatment and secondary prevention of VTE: 10 mg twice daily for seven days, followed by 5 mg twice daily. If therapy continues beyond six months, the dose is reduced to 2.5 mg twice daily.

● Stroke prevention in atrial fibrillation (AF): 5 mg twice daily (CrCl >50 mL/minute); or 2.5 mg twice daily for those with any two of the following: age ≥80 years, body weight ≤60 kg, or serum creatinine ≥1.5 mg/dL.

* 심방세동에서 뇌졸중 예방 위해 사용되는 용량은 5 mg, 하루 2회 또는 [age ≥80 years, body weight ≤60 kg, or serum creatinine ≥1.5 mg/dL]​​ 중 2개 이상인 경우에는 2.5 mg, 하루 2회입니다.

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Apixaban dose reduction is recommended for patients who are also receiving strong dual inhibitors of CYP-3A4 and P-glycoprotein.

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Pharmacokinetics and drug interactions of direct oral anticoagulants

Anticoagulant	Bioavailability	Metabolism and clearance*¶	Half-life	Potential for pharmacokinetic drug interactions*¶
Dabigatran (Pradaxa)	3 to 7% bioavailable Unaffected by food Capsule must be taken intact and requires gastric acidity for absorption	Over 80% renally cleared P-gp substrate*	12 to 17 hours Prolonged in renal impairment and older adults	P-gp inhibitors can increase dabigatran effect P-gp inducers can decrease dabigatran effect Avoidance of some combinations or dose adjustment may be needed
Apixaban (Eliquis)	50% bioavailable Unaffected by food	27% renally cleared Metabolized, primarily by CYP3A4¶ P-gp substrate*	12 hours Prolonged in older adults	Strong CYP3A4 inhibitors and/or strong P-gp inhibitors can increase apixaban effect Strong CYP3A4 inducers and/or strong P-gp inducers can decrease apixaban effect Avoidance of some combinations or dose adjustment may be needed
Betrixaban (Bevyxxa)	34% bioavailable Taken with food at the same time each day. Absorption is increased if taken without food.	Minimal renal clearance (5 to 7%) Undergoes minimal CYP metabolism P-gp substrate* 85% eliminated via hepatobiliary route	19 to 27 hours (effective half-life); peak-to-trough ratio is low and terminal serum half-life is 37 hours, and betrixaban may persist in the circulation for longer than predicted by the effective half-life	P-gp inhibitors can increase betrixaban effect P-gp inducers may decrease betrixaban effect Avoidance of some combinations or dose adjustment may be needed
Edoxaban (Savaysa, Lixiana)	62% bioavailable Unaffected by food	50% renally cleared Reduced efficacy in patients with NVAF and CrCl >95 mL/minute​Δ Undergoes minimal CYP metabolism¶ P-gp substrate*	10 to 14 hours Prolonged in renal impairment	P-gp inhibitors can increase edoxaban effect P-gp inducers can decrease edoxaban effect Avoidance of some combinations or dose adjustment may be needed
Rivaroxaban (Xarelto)	10 mg dose: 80 to 100% bioavailable Unaffected by food ​ 20 mg dose: 66% bioavailable if taken when fasting; increased if taken with food	36% renally cleared Metabolized, primarily by CYP3A4¶ P-gp substrate*	7 to 11 hours[1] Prolonged in renal impairment and older adults	Strong CYP3A4 inhibitors and/or strong P-gp inhibitors can increase rivaroxaban effect Strong CYP3A4 inducers and/or strong P-gp inducers can decrease rivaroxaban effect Avoidance of some combinations or dose adjustment may be needed

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Refer to UpToDate for dosing in specific clinical settings, including nonvalvular AF, VTE treatment, and VTE prophylaxis. Data on clearance may help assess the potential for accumulation in patients with renal impairment. Data on metabolism may help assess potential drug interactions through alteration of CYP3A4 metabolism and/or P-gp-mediated drug efflux. Refer to Lexi-Interact, the drug interactions tool included with UpToDate, for specific drug interactions. Tables of P-gp inhibitors and inducers and CYP3A4 inhibitors and inducers are available separately in UpToDate.

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P-gp: P-glycoprotein drug efflux pump; CYP3A4: cytochrome p450 3A4 isoform; CrCl: creatinine clearance estimated by the Cockcroft-Gault equation; AF: atrial fibrillation; VTE: venous thromboembolism, includes deep vein thrombosis and pulmonary embolism; DOAC: direct oral anticoagulant.

* Examples of P-gp inhibitors that reduce metabolism of DOACs, leading to increased DOAC levels, include clarithromycin, ombitasvir- or ritonavir-containing combinations, and verapamil. Examples of P-gp inducers that increase DOAC metabolism, leading to lower DOAC levels, include phenytoin, rifampin, and St. John's wort.

¶ Examples of strong CYP3A4 inhibitors that reduce metabolism of some DOACs, leading to increased DOAC levels, include clarithromycin and ombitasvir- or ritonavir-containing combinations. Examples of strong CYP3A4 inducers that increase metabolism of some DOACs, leading to lower DOAC levels, include carbamazepine, phenytoin, and rifampin.

Δ Blood levels of edoxaban were reduced and a higher rate of ischemic stroke was observed in patients with AF and CrCl >95 mL/minute who were treated with edoxaban compared with those receiving warfarin. Refer to the UpToDate topic on anticoagulation in AF for additional information.

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Prepared with data from Lexicomp Online. Copyright © 1978-2019 Lexicomp, Inc. All Rights Reserved with additional data from US prescribing information available at https://www.accessdata.fda.gov/scripts/cder/drugsatfda/index.cfm.

Reference:

Rivaroxaban (Xarelto) Health Canada product monograph. Bayer Inc. (revised February 16, 2018) https://pdf.hres.ca/dpd_pm/00043960.PDF.

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Cytochrome P450 3A (including 3A4) inhibitors and inducers

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Strong inhibitors

Atazanavir

Clarithromycin

Cobicistat and cobicistat-containing coformulations

Darunavir

Idelalisib

Indinavir

Itraconazole

Ketoconazole

Lopinavir

Mifepristone

Nefazodone

Nelfinavir

Ombitasvir-paritaprevir-ritonavir

Ombitasvir-paritaprevir-ritonavir plus dasabuvir

Posaconazole

Ritonavir and ritonavir-containing coformulations

Saquinavir

Telithromycin

Voriconazole

Moderate inhibitors

Amiodarone*

Aprepitant

Ceritinib

Cimetidine*

Conivaptan

Crizotinib

Cyclosporine*

Diltiazem

Duvelisib

Dronedarone

Erythromycin

Fluconazole

Fosamprenavir

Fosaprepitant*

Grapefruit juice

Imatinib

Isavuconazole (isavuconazonium sulfate)

Letermovir

Netupitant

Nilotinib

Ribociclib

Schisandra

Verapamil

Strong inducers

Apalutamide

Carbamazepine

Enzalutamide

Fosphenytoin

Lumacaftor

Mitotane

Phenobarbital

Phenytoin

Primidone

Rifampin (rifampicin)

Moderate inducers

Bexarotene

Bosentan

Dabrafenib

Dexamethasone¶

Efavirenz

Eslicarbazepine

Etravirine

Lorlatinib

Modafinil

Nafcillin

Rifabutin​

Rifapentine

St. John's wort

For drug interaction purposes, the inhibitors and inducers of CYP3A metabolism listed above can alter serum concentrations of drugs that are dependent upon the CYP3A subfamily of liver enzymes, including CYP3A4, for elimination or activation.

These classifications are based upon US Food and Drug Administration (FDA) guidance.[1,2] Other sources may use a different classification system resulting in some agents being classified differently.

Data are for systemic drug forms. Degree of inhibition or induction may be altered by dose, method, and timing of administration.

Weak inhibitors and inducers are not listed in this table with exception of a few examples. Clinically significant interactions can occasionally occur due to weak inhibitors and inducers (eg, target drug is highly dependent on CYP3A4 metabolism and has a narrow therapeutic index). Accordingly, specific interactions should be checked using a drug interaction program such as Lexicomp interactions included within UpToDate.

Refer to UpToDate topics on specific agents and indications for further details.

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* Classified as a weak inhibitor of CYP3A4 according to FDA system.[1]

¶ Classified as a weak inducer of CYP3A4 according to FDA system.[1]

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Data from: Lexicomp Online (Lexi-Interact). Copyright © 1978-2019 Lexicomp, Inc. All Rights Reserved.

References:

​US Food & Drug Administration. Clinical drug interaction studies - Study design, data analysis and clinical implications; Guidance for industry (October 24, 2017) available at: https://www.fda.gov/downloads/drugs/guidances/ucm292362.pdf.

US Food & Drug Administration. Drug Development and Drug Interactions: Table of Substrates, Inhibitors and Inducers. Available at: FDA.gov website.

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Inhibitors and inducers of P-glycoprotein (P-gp) drug efflux pump (P-gp multidrug resistance transporter)

Inhibitors of P-gp
Amiodarone	Ledipasvir
Azithromycin (systemic)	Lopinavir-ritonavir
Carvedilol	Neratinib
Clarithromycin	Ombitasvir-paritaprevir-ritonavir (Technivie)¶
Cobicistat and cobicistat-containing coformulations*	Propafenone
Cyclosporine (systemic)	Quinidine
Daclatasvir	Quinine
Dronedarone	Ranolazine
Elagolix	Ritonavir and ritonavir-containing coformulations¶
Eliglustat	Rolapitant
Erythromycin (systemic)	Simeprevir
Flibanserin	Tacrolimus (systemic)*
Fostamatinib	Tamoxifen*
Glecaprevir-pibrentasvir	Telaprevir
Itraconazole	Ticagrelor*
Ivacaftor	Velpatasvir
Ketoconazole (systemic)	Vemurafenib
Lapatinib	Verapamil

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Apixaban has the least dependence on renal clearance of the direct factor Xa inhibitors. Canadian product information states that apixaban is not recommended in individuals with creatinine clearance <15 mL/minute; United States product information recommends dose adjustments based on creatinine clearance, body weight, and age. Creatinine clearance can be estimated from the patient's sex, age, weight, and serum creatinine.

* Apixaban은 27% 콩팥으로 배출되고 betrixaban 다음으로 신장을 통해 배설되는 비율이 낮음

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Laboratory testing prior to initiating apixaban should include platelet count, PT, and aPTT, to assess and document coagulation status before anticoagulation; and measurement of serum creatinine and liver function tests, as a baseline and for potential dose adjustment in the event of renal or hepatic insufficiency.

* 아픽사반 투약 전에 시행해야 하는 검사는 혈소판, PT, aPTT, Cr, liver function test

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Routine monitoring of coagulation times is not required for patients taking apixaban, because drug levels are relatively predictable for a given dose, and there is no established therapeutic range. However, possible improvements in efficacy and/or safety with monitoring have been suggested.

* 투약 용량에 약물 수치가 상대적으로 예견적이므로 아픽사반 복용 중 일상적인 추적 응고 검사는 필요하지 않습니다.

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If there is a concern that apixaban drug levels are abnormally low or abnormally high, it may be appropriate to test for the presence of the drug. A consensus document from the International Council for Standardization in Haematology (ICSH) has provided examples of apixaban drug levels for the 5 mg twice-daily dose, with an expected median peak of approximately 171 to 132 ng/mL (5th to 95th percentile of 59 to 321 ng/mL) and an expected trough of approximately 63 to 103 ng/mL (5th to 95th percentile, 22 to 230 ng/mL). These values are intended to be used as guides to provide evidence of drug absorption, not as therapeutic targets.

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Settings in which coagulation testing for apixaban effect may be helpful include the following:

● Bleeding in a patient receiving apixaban, or with suspected apixaban overdose

● Need for emergency or urgent surgery in a patient receiving apixaban

● Concerns about absorption (eg, altered gastrointestinal anatomy) or drug adherence.

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In such cases, monitoring can be accomplished through the measurement of anti-factor Xa activity.

As with all anticoagulants, apixaban increases bleeding risk and is administered in the setting of increased thromboembolic risk. Product labeling for apixaban has Boxed Warnings regarding the risk of spinal/epidural hematoma in patients undergoing neuraxial anesthesia or spinal puncture and the risk of thrombotic events following premature discontinuation.

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REF. UpToDate 2019.06.29