Apixaban

Last updated

Apixaban
Apixaban.svg
Apixaban ball-and-stick model.png
Clinical data
Trade names Eliquis, others
Other namesBMS-562247-01
AHFS/Drugs.com Monograph
MedlinePlus a613032
License data
Pregnancy
category
Routes of
administration 		By mouth
ATC code
Legal status
Legal status
  • UK: POM (Prescription only) [2]
  • US: WARNING [3] Rx-only [4]
  • EU:Rx-only [5]
  • In general: ℞ (Prescription only)
Pharmacokinetic data
Bioavailability ~50%
Protein binding ~87%
Metabolism CYP3A4, CYP3A5, CYP1A2 and others
Elimination half-life 9–14 h
Excretion Bile duct (75%), kidney (25%)
Identifiers
  • 1-(4-methoxyphenyl)-7-oxo-6-[4-(2-oxopiperidin-1-yl)phenyl]-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxamide
CAS Number
PubChem CID
IUPHAR/BPS
DrugBank
ChemSpider
UNII
KEGG
ChEMBL
CompTox Dashboard (EPA)
ECHA InfoCard 100.167.332 OOjs UI icon edit-ltr-progressive.svg
Chemical and physical data
Formula C25H25N5O4
Molar mass 459.506 g·mol−1
3D model (JSmol)
  • O=C5N(c4ccc(N3C(=O)c1c(c(nn1c2ccc(OC)cc2)C(=O)N)CC3)cc4)CCCC5
  • InChI=1S/C25H25N5O4/c1-34-19-11-9-18(10-12-19)30-23-20(22(27-30)24(26)32)13-15-29(25(23)33)17-7-5-16(6-8-17)28-14-3-2-4-21(28)31/h5-12H,2-4,13-15H2,1H3,(H2,26,32) Yes check.svgY
  • Key:QNZCBYKSOIHPEH-UHFFFAOYSA-N Yes check.svgY
   (verify)

Apixaban, sold under the brand name Eliquis, is an anticoagulant medication used to treat and prevent blood clots and to prevent stroke in people with nonvalvular atrial fibrillation through directly inhibiting factor Xa. [6] [7] [8] It is used as an alternative to warfarin to prevent blood clots following hip or knee replacement and in those with a history of prior clots. [6] [8] and does not require monitoring by blood tests [6] or dietary restrictions. [9] It is taken by mouth. [6]

Contents

Common side effects include bleeding and nausea. [6] [7] Other side effects may include bleeding around the spine and allergic reactions. [6] Use is not recommended during pregnancy or breastfeeding. [1] [7] Use appears to be relatively safe in those with mild kidney problems. [7] Compared to warfarin it has fewer interactions with other medications. [10] It is a direct factor Xa inhibitor. [6]

In 2007, Pfizer and Bristol-Myers Squibb began the development of apixaban as an anticoagulant. [11] Apixaban was approved for medical use in the European Union in May 2011, and in the United States in December 2012. [5] [6] [12] It is on the World Health Organization's List of Essential Medicines. [13] In 2022, it was the 27th most commonly prescribed medication in the United States, with more than 19 million prescriptions. [14] [15] It is available as a generic medication, although not in the United States. [8] [16]

Medical uses

Apixaban is indicated for the following: [4]

In the EU, apixaban is indicated for the prevention of venous thromboembolic events (VTE) in adults who have undergone elective hip or knee replacement surgery, the prevention of stroke and systemic embolism in adults with non-valvular atrial fibrillation (NVAF) with one or more risk factors, for the treatment of deep vein thrombosis (DVT) and pulmonary embolism (PE) in adults, and for the prevention of recurrent DVT and PE in adults. [5]

Atrial fibrillation

Apixaban is recommended by the National Institute for Health and Clinical Excellence for the prevention of stroke and systemic embolism in people with non-valvular atrial fibrillation and at least one of the following risk factors: prior stroke or transient ischemic attack, age 75 years or older, diabetes, or symptomatic heart failure. [17]

Apixaban and other anticoagulants (dabigatran, edoxaban and rivaroxaban) appear equally effective as warfarin in preventing non-hemorrhagic stroke in people with atrial fibrillation and are associated with lower risk of intracranial bleeding. [18] [19]

While apixaban may be used in people with severely decreased kidney function and those on hemodialysis it has not been studied in these groups. [6]

Side effects

Bleeding

Apixaban can increase the risk of bleeding which may be serious and potentially fatal. Concurrent use with other medications that affect blood clotting can further increase this risk. This includes medications such as other anticoagulants, heparin, aspirin, antiplatelet medications, selective serotonin reuptake inhibitors, serotonin norepinephrine reuptake inhibitors, and nonsteroidal anti-inflammatory drugs (NSAIDs). [4] [20] [21] [22]

Andexanet alfa is a US Food and Drug Administration (FDA) approved antidote for apixaban in people with uncontrolled and life-threatening bleeding events. [23] [24]

Spinal puncture

Following spinal anesthesia or puncture, people who are being treated with anti-thrombotic agents are at higher risk for developing a hematoma, which causes long-term or permanent paralysis. The risk of this may be increased by using epidural or intrathecal catheters after a surgical operation or from the concurrent use of medicinal agents that affect hemostasis. [4]

Mechanism of action

Apixaban is a highly selective, orally bioavailable, and reversible direct inhibitor of free and clot-bound factor Xa. Factor Xa catalyzes the conversion of prothrombin to thrombin, the final enzyme in the coagulation cascade that is responsible for fibrin clot formation. [25] Apixaban has no direct effect on platelet aggregation, but by inhibiting factor Xa, it indirectly decreases clot formation induced by thrombin. [4]

History

Apixaban was approved for medical use in the European Union in May 2011. [5]

A new drug application (NDA) for the approval of apixaban was submitted to the US Food and Drug Administration (FDA) by Bristol-Myers Squibb (BMS) and Pfizer jointly after the conclusion of the ARISTOTLE clinical trial in 2011. [26] [12] Apixaban was approved for the prevention of stroke in people with atrial fibrillation in December 2012. [12] [27] In March 2014, it was approved for the additional indication of preventing deep vein thrombosis and pulmonary embolism in people who have recently undergone knee or hip replacement. [28] [29] In August 2014, the FDA approved apixaban for the additional indication of the treatment of recurring deep vein thrombosis and pulmonary embolism. [28] [30] During its development the drug was known as BMS-562247-01. [31] By late 2019, sales of the product by BMS accounted for thirty percent of their quarterly revenue. [32]

Society and culture

Economics

In December 2019, the US FDA approved a generic version of apixaban produced jointly by Mylan and Micro Labs. [33] [32] [8] BMS and Pfizer worked quickly to block generics from being created, and in August 2020, they won a patent infringement lawsuit against Sigmapharm, Sunshine Lake, and Unichem, after previously settling patent cases against 25 other companies. [34] [35] In September 2021, a Federal Circuit Court upheld the ruling. [36] The result is that apixaban generics will most likely not be available in the United States until at least 2026, but possibly 2031. [16]

In July 2022, the Canadian generic drug company, Apotex Inc., obtained approval for marketing of apixaban. [37] [38]

Apixaban is one of ten medications covered by price negotiations in the US under the Inflation Reduction Act. The negotiations, conducted by the Centers for Medicare & Medicaid Services, apply to pricing for Medicare recipients. Bristol Myers Squibb responded to initial reports of the negotiations by highlighting out-of-pocket prices for Eliquis. A senior BMS executive argued in an August 2023 interview that patients already received low out-of-pocket prices, commenting that "seniors on average pay about [US]$55 per month for Eliquis and over half of all Eliquis patients—whether they’re commercial or Medicare—pay [US]$45 or less." [39] The results of the negotiations were announced in August 2024, and Medicare's negotiated price for a 30-day supply of Eliquis is US$231, a 56% decrease from the 2023 list price of US$521. The pricing is set to take effect in 2026. [40] [41]

Related Research Articles

<span class="mw-page-title-main">Anticoagulant</span> Class of drugs

An anticoagulant, commonly known as a blood thinner, is a chemical substance that prevents or reduces the coagulation of blood, prolonging the clotting time. Some occur naturally in blood-eating animals, such as leeches and mosquitoes, which help keep the bite area unclotted long enough for the animal to obtain blood.

<span class="mw-page-title-main">Thrombosis</span> Formation of blood clots inside the blood vessels

Thrombosis is the formation of a blood clot inside a blood vessel, obstructing the flow of blood through the circulatory system. When a blood vessel is injured, the body uses platelets (thrombocytes) and fibrin to form a blood clot to prevent blood loss. Even when a blood vessel is not injured, blood clots may form in the body under certain conditions. A clot, or a piece of the clot, that breaks free and begins to travel around the body is known as an embolus.

<span class="mw-page-title-main">Venous thrombosis</span> Blood clot (thrombus) that forms within a vein

Venous thrombosis is the blockage of a vein caused by a thrombus. A common form of venous thrombosis is deep vein thrombosis (DVT), when a blood clot forms in the deep veins. If a thrombus breaks off (embolizes) and flows to the lungs to lodge there, it becomes a pulmonary embolism (PE), a blood clot in the lungs. The conditions of DVT only, DVT with PE, and PE only, are all captured by the term venous thromboembolism (VTE).

<span class="mw-page-title-main">Warfarin</span> Anticoagulant medication

Warfarin, sold under the brand name Coumadin among others, is an anticoagulant medication. While the drug is described as a "blood thinner", it does not reduce viscosity but rather prevents blood clots (thrombus) from forming (coagulating). Accordingly, it is commonly used to prevent deep vein thrombosis and pulmonary embolism, and to protect against stroke in people who have atrial fibrillation, valvular heart disease, or artificial heart valves. Warfarin may sometimes be prescribed following ST-segment elevation myocardial infarctions (STEMI) and orthopedic surgery. It is usually taken by mouth, but may also be administered intravenously. It is a vitamin K antagonist.

<span class="mw-page-title-main">Prothrombin time</span> Blood test that evaluates clotting

The prothrombin time (PT) – along with its derived measures of prothrombin ratio (PR) and international normalized ratio (INR) – is an assay for evaluating the extrinsic pathway and common pathway of coagulation. This blood test is also called protime INR and PT/INR. They are used to determine the clotting tendency of blood, in such things as the measure of warfarin dosage, liver damage, and vitamin K status. PT measures the following coagulation factors: I (fibrinogen), II (prothrombin), V (proaccelerin), VII (proconvertin), and X.

<span class="mw-page-title-main">Ximelagatran</span> Anticoagulant

Ximelagatran is an anticoagulant that has been investigated extensively as a replacement for warfarin that would overcome the problematic dietary, drug interaction, and monitoring issues associated with warfarin therapy. In 2006, its manufacturer AstraZeneca announced that it would withdraw pending applications for marketing approval after reports of hepatotoxicity during trials, and discontinue its distribution in countries where the drug had been approved.

<span class="mw-page-title-main">Enoxaparin sodium</span> Anticoagulant medication (blood thinner)

Enoxaparin sodium, sold under the brand name Lovenox among others, is an anticoagulant medication. It is used to treat and prevent deep vein thrombosis (DVT) and pulmonary embolism (PE) including during pregnancy and following certain types of surgery. It is also used in those with acute coronary syndrome (ACS) and heart attacks. It is given by injection just under the skin or into a vein. It is also used during hemodialysis.

<span class="mw-page-title-main">Rivaroxaban</span> Anticoagulant drug

Rivaroxaban, sold under the brand name Xarelto among others, is an anticoagulant medication used to treat and prevent blood clots. Specifically it is used to treat deep vein thrombosis and pulmonary emboli and prevent blood clots in atrial fibrillation and following hip or knee surgery. It is taken by mouth.

<span class="mw-page-title-main">Dalteparin sodium</span> Pharmaceutical drug

Dalteparin is a low molecular weight heparin. It is marketed as Fragmin. Like other low molecular weight heparins, dalteparin is used for prophylaxis or treatment of deep vein thrombosis and pulmonary embolism to reduce the risk of a stroke or heart attack. Dalteparin acts by potentiating the activity of antithrombin III, inhibiting formation of both Factor Xa and thrombin. It is normally administered by self-injection.

<span class="mw-page-title-main">Dabigatran</span> Anticoagulant medication

Dabigatran, sold under the brand name Pradaxa among others, is an anticoagulant used to treat and prevent blood clots and to prevent stroke in people with atrial fibrillation. Specifically it is used to prevent blood clots following hip or knee replacement and in those with a history of prior clots. It is used as an alternative to warfarin and does not require monitoring by blood tests. In a meta analysis of 7 different studies, there was no benefit of dabigatran over warfarin in preventing ischemic stroke; however, dabigatran were associated with a lower hazard for intracranial bleeding compared with warfarin, but also had a higher risk of gastrointestinal bleeding relative to warfarin. It is taken by mouth.

Hypercoagulability in pregnancy is the propensity of pregnant women to develop thrombosis. Pregnancy itself is a factor of hypercoagulability, as a physiologically adaptive mechanism to prevent post partum bleeding. However, when combined with an additional underlying hypercoagulable states, the risk of thrombosis or embolism may become substantial.

Direct factor Xa inhibitors (xabans) are anticoagulants, used to both treat and prevent blood clots in veins, and prevent stroke and embolism in people with atrial fibrillation (AF).

<span class="mw-page-title-main">Vitamin K antagonist</span> Group of substances

Vitamin K antagonists (VKA) are a group of substances that reduce blood clotting by reducing the action of vitamin K. The term "vitamin K antagonist" is technically a misnomer, as the drugs do not directly antagonize the action of vitamin K in the pharmacological sense, but rather the recycling of vitamin K. Vitamin K antagonists (VKAs) have been the mainstay of anticoagulation therapy for more than 50 years.

<span class="mw-page-title-main">Left atrial appendage occlusion</span> Medical treatment

Left atrial appendage occlusion (LAAO), also referred to as left atrial appendage closure (LAAC), is a procedure used to reduce the risk of blood clots from the left atrial appendage entering the bloodstream and causing a stroke in those with non-valvular atrial fibrillation.

<span class="mw-page-title-main">Edoxaban</span> Anticoagulant medication

Edoxaban, sold under the brand name Lixiana among others, is an anticoagulant medication and a direct factor Xa inhibitor. It is taken by mouth.

<span class="mw-page-title-main">Betrixaban</span> Chemical compound

Betrixaban is an oral anticoagulant drug which acts as a direct factor Xa inhibitor. Betrixaban is FDA approved for venous thrombosis prevention in adults hospitalized for an acute illness who are at risk for thromboembolic complications. Compared to other directly acting oral anticoagulants betrixaban has relatively low renal excretion and is not metabolized by CYP3A4.

<span class="mw-page-title-main">Darexaban</span> Chemical compound

Darexaban (YM150) is a direct inhibitor of factor Xa created by Astellas Pharma. It is an experimental drug that acts as an anticoagulant and antithrombotic to prevent venous thromboembolism after a major orthopaedic surgery, stroke in patients with atrial fibrillation and possibly ischemic events in acute coronary syndrome. It is used in form of the maleate. The development of darexaban was discontinued in September 2011.

Direct thrombin inhibitors (DTIs) are a class of anticoagulant drugs that can be used to prevent and treat embolisms and blood clots caused by various diseases. They inhibit thrombin, a serine protease which affects the coagulation cascade in many ways. DTIs have undergone rapid development since the 90's. With technological advances in genetic engineering the production of recombinant hirudin was made possible which opened the door to this new group of drugs. Before the use of DTIs the therapy and prophylaxis for anticoagulation had stayed the same for over 50 years with the use of heparin derivatives and warfarin which have some well known disadvantages. DTIs are still under development, but the research focus has shifted towards factor Xa inhibitors, or even dual thrombin and fXa inhibitors that have a broader mechanism of action by both inhibiting factor IIa (thrombin) and Xa. A recent review of patents and literature on thrombin inhibitors has demonstrated that the development of allosteric and multi-mechanism inhibitors might lead the way to a safer anticoagulant.

Four drugs from the class of direct Xa inhibitors are marketed worldwide. Rivaroxaban (Xarelto) was the first approved FXa inhibitor to become commercially available in Europe and Canada in 2008. The second one was apixaban (Eliquis), approved in Europe in 2011 and in the United States in 2012. The third one edoxaban was approved in Japan in 2011 and in Europe and the US in 2015. Betrixaban (Bevyxxa) was approved in the US in 2017.

Portola Pharmaceuticals is an American clinical stage biotechnology company that researches, develops, and commercializes drugs. The company focuses primarily on drugs used in the treatment of thrombosis and hematological malignancies. Founded in 2003 and headquartered in South San Francisco, California, Portola Pharmaceuticals is a member of the NASDAQ Biotechnology Index.

References

  1. 1 2 "Apixaban (Eliquis) Use During Pregnancy". Drugs.com. 21 June 2019. Retrieved 13 August 2020.
  2. ↑ "Eliquis 5 mg film-coated tablets - Summary of Product Characteristics (SmPC)". (emc). 3 May 2022. Retrieved 8 October 2022.
  3. ↑ "FDA-sourced list of all drugs with black box warnings (Use Download Full Results and View Query links.)". nctr-crs.fda.gov. FDA . Retrieved 22 October 2023.
  4. 1 2 3 4 5 "Eliquis- apixaban tablet, film coated Eliquis 30-day starter pack- apixaban kit". DailyMed. 26 November 2019. Retrieved 22 April 2020.
  5. 1 2 3 4 "Eliquis EPAR". European Medicines Agency . 17 September 2018. Retrieved 22 April 2020. Text was copied from this source which is copyright European Medicines Agency. Reproduction is authorized provided the source is acknowledged.
  6. 1 2 3 4 5 6 7 8 9 "Apixaban Monograph for Professionals". Drugs.com. American Society of Health-System Pharmacists. Retrieved 27 March 2019.
  7. 1 2 3 4 British national formulary: BNF 76 (76 ed.). Pharmaceutical Press. 2018. pp. 124–125. ISBN   9780857113382.
  8. 1 2 3 4 "FDA approves first generics of Eliquis". U.S. Food and Drug Administration (FDA). 23 December 2019. Archived from the original on 23 December 2019. Retrieved 23 December 2019.PD-icon.svg This article incorporates text from this source, which is in the public domain .
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  10. ↑ Kiser K (2017). Oral Anticoagulation Therapy: Cases and Clinical Correlation. Springer. p. 11. ISBN   9783319546438.
  11. ↑ "Bristol-Myers Squibb and Pfizer Announce Worldwide Collaboration to Develop and Commercialize Anticoagulant and Metabolic Compounds". Pfizer (Press release). Archived from the original on 10 September 2015. Retrieved 25 December 2021.
  12. 1 2 3 "Drug Approval Package: Eliquis (apixaban) NDA #202155". U.S. Food and Drug Administration (FDA). 13 February 2013. Retrieved 23 December 2019.
  13. ↑ World Health Organization (2023). The selection and use of essential medicines 2023: web annex A: World Health Organization model list of essential medicines: 23rd list (2023). Geneva: World Health Organization. hdl: 10665/371090 . WHO/MHP/HPS/EML/2023.02.
  14. ↑ "The Top 300 of 2022". ClinCalc. Archived from the original on 30 August 2024. Retrieved 30 August 2024.
  15. ↑ "Apixaban Drug Usage Statistics, United States, 2013 - 2022". ClinCalc. Retrieved 30 August 2024.
  16. 1 2 "With Court Win, BMS and Pfizer Stave Off Generic Challengers to Eliquis – For Now". BioSpace. 6 August 2020. Retrieved 29 November 2021.
  17. ↑ "Apixaban for preventing stroke and systemic embolism in people with nonvalvular atrial fibrillation" (PDF). National Institute for Health and Care Excellence. January 2013. Retrieved 26 February 2016.
  18. ↑ Gómez-Outes A, Terleira-Fernández AI, Calvo-Rojas G, Suárez-Gea ML, Vargas-Castrillón E (2013). "Dabigatran, Rivaroxaban, or Apixaban versus Warfarin in Patients with Nonvalvular Atrial Fibrillation: A Systematic Review and Meta-Analysis of Subgroups". Thrombosis. 2013: 640723. doi: 10.1155/2013/640723 . PMC   3885278 . PMID   24455237.
  19. ↑ Lowenstern A, Al-Khatib SM, Sharan L, Chatterjee R, Allen LaPointe NM, Shah B, et al. (December 2018). "Interventions for Preventing Thromboembolic Events in Patients With Atrial Fibrillation: A Systematic Review". Annals of Internal Medicine. 169 (11): 774–787. doi:10.7326/M18-1523. PMC   6825839 . PMID   30383133.
  20. ↑ "Atrial fibrillation and new oral anticoagulant drugs". U.S. Food and Drug Administration (FDA). 2 December 2015. Retrieved 22 April 2020.
  21. ↑ "Atrial fibrillation, oral anticoagulant drugs, and their reversal agents". U.S. Food and Drug Administration. 2 December 2015. Retrieved 22 April 2020.
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  27. ↑ Cada DJ, Levien TL, Baker DE (June 2013). "Apixaban". Hospital Pharmacy. 48 (6): 494–509. doi:10.1310/hpj4806-494. PMC   3839491 . PMID   24421512.
  28. 1 2 "FDA-Approved Drugs: Eliquis (apixaban)". U.S. Food and Drug Administration (FDA). Retrieved 23 December 2019.
  29. ↑ Neale T (14 March 2014). "FDA OKs Apixaban for DVT Prevention". MedPage Today. Retrieved 17 September 2015.
  30. ↑ "U.S. FDA Approves Eliquis (apixaban) for the Treatment of Deep Vein Thrombosis (DVT) and Pulmonary Embolism (PE), and for the Reduction in the Risk of Recurrent DVT and PE Following Initial Therapy" (Press release). Pfizer. 21 August 2014. Retrieved 26 February 2016.
  31. ↑ "Apixaban". PubChem, US National Library of Medicine. 27 August 2022. Retrieved 2 September 2022.
  32. 1 2 "FIRST: Mylan, Micro Labs get USFDA nod for generic version of blood thinner Eliquis". Business Medical Dialogues. New Delhi, India: Minerva Medical Treatment. 24 December 2019. Retrieved 24 December 2019.
  33. ↑ "2019 First Generic Drugs Approvals". U.S. Food and Drug Administration (FDA). 5 August 2020. Archived from the original on 30 June 2023. Retrieved 30 June 2023.
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  37. ↑ Levy S (1 August 2022). "Apotex offers generic Eliquis in Canada". Drugstore News. Retrieved 2 September 2022.
  38. ↑ "First Generic Alternative to Eliquis Now Available in Canada". Apotex (Press release). 20 July 2022. Retrieved 29 June 2023.
  39. ↑ Kansteiner F (29 August 2023). "Drugs from J&J, Merck, Novartis, BMS and more set for first round of Medicare price negotiations: CMS" . Retrieved 31 August 2023.
  40. ↑ Lovelace Jr B (15 August 2024). "Medicare announces lower prices on 10 common, high-cost drugs". NBC News. Retrieved 21 August 2024.
  41. ↑ "Medicare Drug Price Negotiation Program: Medicare Prices Negotiated for 2026 Compared to List and U.S. Market Prices" (PDF). Office of the Assistant Secretary for Planning and Evaluation, U.S. Department of Health and Human Services. 15 August 2024.
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