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Table of Contents
DRUG REVIEW
Year : 2020  |  Volume : 3  |  Issue : 2  |  Page : 264-269

Rivaroxaban: Drug review


1 Department of Medical Oncology, HBCH/MPMMCC, Varanasi, Uttar Pradesh, India
2 Department of Medical Oncology, Tata Memorial Hospital, Homi Bhabha National Institute, Mumbai, Maharashtra, India
3 Department of Surgical Oncology, HBCH/MPMMCC, Varanasi, Uttar Pradesh, India
4 Department of Pharmacy, Amity University, Lucknow, Uttar Pradesh, India
5 Department of Biotechnology, Bangalore University, Bengaluru, Karnataka, India

Date of Submission29-Dec-2019
Date of Decision09-Jan-2020
Date of Acceptance17-Mar-2020
Date of Web Publication19-Jun-2020

Correspondence Address:
Abhishek Kumar Singh
Department of Medical Oncology, HBCH/MPMMCC, Varanasi, Uttar Pradesh
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/CRST.CRST_122_19

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  Abstract 


Cancer-associated thrombosis is a challenging problem when treating patients with cancer. It is recurrent and difficult to treat because of the increased risk of bleeding. Low-molecular-weight heparin is the standard of care for treating cancer-associated venous thromboembolism/pulmonary embolism (VTE/PE). Recently, there have been emerging data favoring the use of direct oral anticoagulants (DOACs) for treating cancer-associated VTE/PE. They are well tolerated because of oral administration and favorable side effect profile. Rivaroxaban was the first DOAC to be approved by the US Food and Drug Administration in 2012. In this comprehensive review, we discuss the history, chemistry, mechanism of action, indications, dose modifications, and drug–drug interactions of rivaroxaban. We also discuss briefly the results of various clinical trials related to DOACs.

Keywords: Anticoagulant therapy, cancer-associated thrombosis, direct oral anticoagulant, pulmonary embolism, venous thromboembolism


How to cite this article:
Singh AK, Noronha V, Gupta A, Singh D, Singh P, Singh A, Singh A. Rivaroxaban: Drug review. Cancer Res Stat Treat 2020;3:264-9

How to cite this URL:
Singh AK, Noronha V, Gupta A, Singh D, Singh P, Singh A, Singh A. Rivaroxaban: Drug review. Cancer Res Stat Treat [serial online] 2020 [cited 2020 Aug 7];3:264-9. Available from: http://www.crstonline.com/text.asp?2020/3/2/264/287201




  Introduction Top


Cancer-associated thrombosis (CAT), which includes deep vein thrombosis (DVT) and pulmonary embolism (PE), is a serious concern in patients with cancer. According to Chew et al., occurrence of CAT is an indicator of poor prognosis and is associated with increased risk of death within 1 year of cancer diagnosis.[1] Certain solid cancers (such as pancreatic, stomach, lung, gynecological, genitourinary, and brain cancers), hematological malignancies, and certain cancer therapies (such as anthracyclines and antimetabolites) are associated with a high risk of CAT. The incidence of CAT is particularly high in the metastatic setting. CAT can be recurrent and more challenging to treat in patients with cancer than in those without cancer, because of the increased risk of bleeding in the former. There is also an increased risk of interaction between chemotherapeutic drugs and drugs for treating CAT. Clinical trials have shown that low-molecular-weight heparins (LMWHs) are superior to Vitamin K antagonists (VKAs), such as warfarin, for treating cancer-associated venous thromboembolism (VTE).[2] Treatment with LMWH should be given for at least 3–6 months. The rate of VTE recurrence and major bleeding with LMWH was approximately 7%–8% and 4%–5%, respectively, across several studies.[2],[3],[4] However, a drawback of using LMWH is poor compliance because of the high cost and troublesome injections. This can be partially overcome with the use of direct oral anticoagulants (DOACs); there is growing evidence of their effectiveness in several trials.


  Overview of Clinical Trials Top


Trials for the use of rivaroxaban in cancer patients

Currently, LMWH is the preferred treatment modality for CAT. It has similar or lower rates of VTE recurrence and bleeding compared to VKAs, with the added advantage of minimal interaction with chemotherapeutic drugs; moreover, it does not rely on gastrointestinal absorption.[2],[4],[5] Various trials have compared LMWHs with VKAs [Table 1] and DOACs with VKAs [Table 2].
Table 1: Comparison of low-molecular-weight heparins with Vitamin K antagonists

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Table 2: Comparison of direct oral anticoagulants with Vitamin K antagonist

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There are two major classes of DOACs:

  1. Direct thrombin inhibitors (such as dabigatran)
  2. Direct factor Xa inhibitors (such as rivaroxaban, apixaban, edoxaban, and betrixaban).


There are various advantages of DOACs over LMWHs, which make them good primary and secondary thromboprophylactic agents. These include:

  1. Oral administration
  2. Fixed dosing schedule
  3. Predictable pharmacokinetics and pharmacodynamics
  4. No need for monitoring with prothrombin time/international normalized ratio (PT/INR) or activated partial thromboplastin time (aPTT).


In the HOKUSAI VTE cancer trial,[12] a lower incidence of recurrent VTE events was noted with edoxaban than with dalteparin (7.9% vs. 11.3%, respectively), whereas the risk of bleeding was higher with edoxaban in patients with cancers of the gastrointestinal tract [Table 2]. In SELECT-D trial by Young et al.,[13] rivaroxaban was compared with dalteparin. A lower incidence of VTE recurrence was observed in the rivaroxaban arm compared to the dalteparin arm (4% vs. 11%, respectively). Even in the SELECT-D trial, most bleeding events were gastrointestinal and urological.

Trials related to the use of rivaroxaban in non-cancer patients

  • ROCKET AF (NCT00403767): This was a multinational, double-blinded randomized controlled trial for stroke prevention in cardiac patients with non-valvular atrial fibrillation. In this trial, rivaroxaban was compared with warfarin. The primary endpoint of the study was time to first incidence of any type of stroke or non-central nervous system (CNS) system embolism. The outcome analysis showed stroke occurrence of 2% for rivaroxaban and 2.2% for warfarin; the occurrence of non-CNS embolism was 0.2% in each arm
  • EINSTEIN DVT/PE trial: This was a multinational, open-label, randomized controlled trial for the treatment of DVT/PE, where rivaroxaban was compared to enoxaparin with VKA. A total of 8281 patients were randomized. The primary endpoint was time to first occurrence of recurrent VTE or PE. This trial concluded rivaroxaban to be noninferior to enoxaparin/VKA (EINSTEIN DVT study – primary composite endpoint was 2.1% for rivaroxaban arm versus 3% for enoxaparin/VKA arm; EINSTEIN PE study – primary composite endpoint was 2.1% rivaroxaban arm versus 1.8% for enoxaparin/VKA arm).



  History Top


Rivaroxaban was initially developed by Bayer and sold under the brand name Xarelto. It was the first DOAC to get approval from the US Food and Drug Administration (FDA) in 2012.


  Chemistry Top


Rivaroxaban has structural similarity to linezolid [Figure 1], a monoamine oxidase inhibitor. Both have an oxazolidinone-derived core structure. Rivaroxaban was initially developed as an antibacterial, but later, it was found that rivaroxaban or its metabolite do not possess any antimicrobial property. Subsequently, its activity as a direct inhibitor of factor Xa was studied; it was then developed and approved by the US FDA as a DOAC.
Figure 1: Structural comparison between rivaroxaban and linezolid- (Source- Jonathan Douxfils, Anne Tamigniau, Bernard Chatelain, Christian Chatelain, Pierre Wallemacq, François Mullier, et al.)

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Chemical name: 5-Chloro-N-({(5S)-2-oxo-3- [4-(3-oxo-4-morpholinyl) phenyl]-1, 3-oxazolidin-5-yl} methyl)-2 thiophene carboxamide

Molecular formula: C19H18ClN3O5S

Molecular weight: 435.89 g/mol

The structural formula is:

Source: Jonathan Douxfils, Anne Tamigniau, Bernard Chatelain, Christian Chatelain, Pierre Wallemacq, François Mullier, et al.


  Physical Properties Top


  • Odorless
  • Non-hygroscopic
  • White to yellowish powder
  • Slightly soluble in organic solvents
  • Insoluble in water and aqueous media.



  Dosage Forms and Strength Top


  • 2.5 mg tablet-round, light yellow
  • 10 and 15 mg tablets-round, light red
  • 20 mg tablet-triangle shaped, dark red.



  Mechanism of Action Top


Pharmacodynamics

Rivaroxaban is a direct-acting, potent oral anticoagulant with a strong selectivity for factor Xa. It inhibits factor Xa in a dose-dependent manner and does not require any cofactor for its action. It has no direct effect on platelet aggregation. Rivaroxaban can cause elevation of PT/INR or aPTT in a dose-dependent manner; for example, if PT/INR or aPTT is measured within 2–4 h of oral administration of rivaroxaban, when it is expected to exert its peak effect, they will be elevated (INR may be elevated in the range of 1.7–2.5 and aPTT may be elevated slightly in the range of 35–40 s). There is no conventional method to reliably monitor the anticoagulant effect of rivaroxaban. Antifactor Xa level testing could be used for this purpose, but the interpretation of the test results would be challenging.

Pharmacokinetics

Bioavailability: The bioavailability of rivaroxaban is dose dependent. The bioavailability of 2.5 and 10 mg tablets is not affected by food, whereas the bioavailability of 15 and 20 mg tablets increases when taken with food.

The maximum concentration of rivaroxaban is achieved between 2 and 4 h of tablet intake. Its pharmacokinetics is not affected by drugs that alter the gastric pH, such as H2 receptor antagonists, antacids, or proton-pump inhibitors. Plasma protein binding (mainly with albumin) is approximately 92%–95%.

Metabolism

Fifty-one percent of the orally administered drug gets metabolized to an inactive form which is excreted in the urine (30%) and feces (21%), whereas 43% is excreted unchanged in urine and feces (36% and 7%, respectively). The half-life of rivaroxaban is 5–9 h.


  Indications, With Recommended Doses Top


  • Treatment of DVT/PE – 15 mg twice daily for 3 weeks followed by 20 mg once daily orally with food
  • Prophylaxis of VTE in patients at risk of thromboembolic events (like patients with cancer) – 10 mg once daily orally with or without food during acute illness phase and after that for at least 4–6 weeks
  • Prophylaxis of VTE in the postoperative period (knee or hip replacement) – 10 mg once daily orally with or without food
  • Risk reduction of recurrence of DVT/PE – 10 mg once daily orally with or without food for at least 6 months
  • Non-valvular atrial fibrillation – 20 mg (if creatinine clearance is >50 ml/min) or 15 mg (if creatinine clearance is ≤ 50 ml/min) once daily with or without food
  • Risk reduction of major cardiovascular complications (cardiovascular death, myocardial infarction, and stroke) in coronary artery disease or peripheral arterial disease – 2.5 mg twice daily with or without food along with aspirin (75–100 mg) once daily.



  Contraindications Top


  • Patients with any severe active bleeding episode
  • Patients who are allergic to rivaroxaban.



  Adverse Drug Reactions Top


The most common adverse effect (>5%) of rivaroxaban is bleeding. The reported incidence of bleeding complications when rivaroxaban is used for various indications is as follows:

  • Atrial fibrillation – 6%
  • DVT prophylaxis – <1%
  • DVT treatment – 1%
  • VTE prophylaxis – 0.7%


Other adverse events (1-10%):

  • Hematoma – <3%
  • Back pain – 2.9%
  • Wound secretion (serous discharge from wound and delayed healing) – 2.8%
  • Abdominal pain – 2.7%
  • Dizziness – 2.2%
  • Pain in extremity – 1.7%
  • Insomnia – 1.6%
  • Fatigue – 1.4%
  • Depression – 1.2%
  • Muscle spasm – 1.2%.



  Warning Top


  • Increased risk of thrombotic events when rivaroxaban is stopped abruptly
  • Increased risk of active pathological bleeding; the risk is more if there is,


    • Concomitant use of other drugs that impair hemostasis, such as aspirin, dual anti-platelet therapy, nonsteroidal anti-inflammatory drug (NSAIDs), and fibrinolytic therapy
    • History of active gastrointestinal bleeding ulcer in the past 3 months
    • History of pulmonary hemorrhage, active pulmonary cavitary lesion, and bronchiectasis.


  • When lumbar puncture for anesthesia or any procedure is planned on a patient who is on rivaroxaban, the risk of hematoma formation and subsequent permanent neurological paralysis is high
  • Rivaroxaban should be avoided in patients with antiphospholipid syndrome because of increased risk of recurrent thromboembolic events.



  Drug Overdose and Reversal Top


An overdosing of rivaroxaban can lead to hemorrhage. In such cases, the drug should be immediately discontinued and activated charcoal should be given to stop further absorption of the drug in the systemic circulation. As rivaroxaban has substantial binding to plasma proteins, dialysis may not help in the elimination of this drug from circulation. Plasma products can be used to reverse the anticoagulant effects.

In 2018, the FDA granted accelerated approval to andexanet alfa, also called the inactivated zhzo, which is a recombinant modified human factor Xa protein. Thus far, this is the only antidote for rivaroxaban. The FDA approval was granted on the basis of demonstration of change in factor Xa levels in healthy volunteers and not on the basis of its effect on hemostasis. It is indicated for use in the reversal of the anticoagulant effect in patients who develop life-threatening or uncontrolled bleeding as a result of rivaroxaban or apixaban. It should be given intravenously, initially as a bolus at the target rate of 30 mg/min, followed by a maintenance infusion over the next 120 min. Two dose regimens have been defined: low-dose (400 mg) and high-dose (800 mg) regimen. The dose regimen to be selected is based on the last dose of rivaroxaban and the time since the last dose. The high-dose regimen is recommended if >10 mg (or unknown dose) of rivaroxaban was administered within the last 8 h (or at an unknown time). The low-dose regimen is recommended if ≤10 mg of rivaroxaban was administered within the last 8 h or if any dose was administered 8 or more hours ago. Andexanet carries a black box warning due to the risk of thromboembolic events, both arterial and venous, ischemic events, cardiac events, and sudden death.


  Drug Interaction Top


  • Rivaroxaban is a substrate of P-glycoprotein and cytochrome P450 3A4. Therefore, its concomitant use with drugs that inhibit cytochrome P450 3A4, such as ketoconazole, ritonavir, and erythromycin, should be avoided
  • Avoid concomitant use of rivaroxaban with drugs that induce P-glycoprotein and Cytochrome P450 3A4, such as carbamazepine, phenytoin, and rifampicin
  • Co-administration of rivaroxaban with enoxaparin, warfarin, aspirin, clopidogrel, and NSAIDs (prolonged use) might increase the risk of bleeding and hence should be avoided.



  Renal Dose Adjustment Top


  • In the treatment of DVT/PE or during prophylaxis for recurrent DVT/PE
  • Patients with creatinine clearance <30 ml/min should be observed closely for any signs and symptoms of DVT/PE. If they are symptomatic, rivaroxaban can be started as long as the creatinine clearance is over 15 ml/min
  • Non-valvular atrial fibrillation
  • 20 mg once daily with or without food if creatinine clearance is >50 ml/min
  • 15 mg once daily with or without food if creatinine clearance is ≤50 ml/min.



  Use in Patients With Hepatic Impairment Top


As no data are available, it is better to avoid the use of rivaroxaban in moderately or severely impaired liver disease (Child–Pugh B and C, respectively) or in liver diseases which severely affect coagulation.


  Use of Rivaroxaban in Pregnant Women Top


It has not been studied in pregnant women. Therefore, it should only be used after proper evaluation of the risk–benefit ratio, provided the benefits outweigh the risks.


  Carcinogenic and Mutagenic Potential Top


Rivaroxaban was not found to be carcinogenic or mutagenic in clinical trials.


  Effect on Fertility Top


Rivaroxaban was not shown to have any effect on fertility in clinical trials.


  Special Instructions and Warnings Top


  • Rivaroxaban should be avoided in hemodynamically compromised patients or in patients who might require thrombolysis or pulmonary embolectomy
  • Rivaroxaban should be stopped a minimum of 24 h before any planned procedure or surgery because of the increased risk of bleeding
  • Any spinal procedure such as lumbar puncture or epidural catheter placement should be performed when its anticoagulant effect is low; however, the exact timing is unknown
  • Any intrathecal or epidural catheter should be removed after stopping rivaroxaban for at least 18 h in young patients aged between 20 and 45 years and for 26 h in older patients
  • No data are available for its use in patients with prosthetic heart valves. Therefore, it is better to avoid its use in such patients
  • If a patient is unable to swallow, the tablet can be crushed and administered, immediately followed by feeding
  • If nasogastric or gastric feeding tube is in situ, the tablets should be crushed and dissolved in 50 ml water and administered via a feeding tube followed by feeding. Avoid drug delivery distal to stomach
  • If a dose is missed, the missed dose should be taken immediately, but do not double the dose in the same day just to make up for the missed dose
  • Premature discontinuation of any oral anticoagulant, including rivaroxaban, will have increased risk of thrombotic events. Therefore, adequate overlap with another anticoagulant is required before it can be discontinued
  • If switching of warfarin to rivaroxaban is planned, it should be done as soon as the INR is below 3.0; for switching from any other anticoagulant (like LMWH or non-warfarin oral anticoagulant) to rivaroxaban, it is advised to start rivaroxaban at the time of or at least within 2 h of the next scheduled dose of anticoagulant therapy
  • For switching from rivaroxaban to a VKA other than warfarin, the VKA can be given at the time of the next scheduled administration of rivaroxaban
  • No data to guide the switching from rivaroxaban to warfarin are available
  • Monitoring with PT, INR, or aPTT is not recommended for rivaroxaban.



  Conclusion Top


CAT is a common and challenging problem when treating patients with cancer. As CAT tends to recur, it requires prolonged treatment with antithrombotic agents. Rivaroxaban is a DOAC and an excellent alternative to LMWHs for treatment and prophylaxis for cancer-associated DVT/PE.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
  References Top

1.
Chew HK, Wun T, Harvey D, Zhou H, White RH. Incidence of venous thromboembolism and its effect on survival among patients with common cancers. Arch Intern Med 2006;166:458-64.  Back to cited text no. 1
    
2.
Lee AY, Levine MN, Baker RI, Bowden C, Kakkar AK, Prins M, et al. Low-molecular-weight heparin versus a coumarin for the prevention of recurrent venous thromboembolism in patients with cancer. N Engl J Med 2003;349:146-53.  Back to cited text no. 2
    
3.
Khorana AA, McCrae KR, Milentijevic D, Fortier J, Nelson WW, Laliberté F, et al. Current practice patterns and patient persistence with anticoagulant treatments for cancer-associated thrombosis. Res Pract Thromb Haemost 2017;1:14-22.  Back to cited text no. 3
    
4.
Lee AY, Kamphuisen PW, Meyer G, Bauersachs R, Janas MS, Jarner MF, et al. Tinzaparin vs. warfarin for treatment of acute venous thromboembolism in patients with active cancer: A randomized clinical trial. JAMA 2015;314:677-86.  Back to cited text no. 4
    
5.
Farge D, Bounameaux H, Brenner B, Cajfinger F, Debourdeau P, Khorana AA, et al. International clinical practice guidelines including guidance for direct oral anticoagulants in the treatment and prophylaxis of venous thromboembolism in patients with cancer. Lancet Oncol 2016;17:e452-66.  Back to cited text no. 5
    
6.
Meyer G, Marjanovic Z, Valcke J, Lorcerie B, Gruel Y, Solal-Celigny P, et al. Comparison of low-molecular-weight heparin and warfarin for the secondary prevention of venous thromboembolism in patients with cancer: A randomized controlled study. Arch Intern Med 2002;162:1729-35.  Back to cited text no. 6
    
7.
Deitcher SR, Kessler CM, Merli G, Rigas JR, Lyons RM, Fareed J, et al. Secondary prevention of venous thromboembolic events in patients with active cancer: Enoxaparin alone versus initial enoxaparin followed by warfarin for a 180-day period. Clin Appl Thromb Hemost 2006;12:389-96.  Back to cited text no. 7
    
8.
Hull RD, Pineo GF, Brant RF, Mah AF, Burke N, Dear R, et al. Long-term low-molecular-weight heparin versus usual care in proximal-vein thrombosis patients with cancer. Am J Med 2006;119:1062-72.  Back to cited text no. 8
    
9.
Schulman S, Goldhaber SZ, Kearon C, Kakkar AK, Schellong S, Eriksson H, et al. Treatment with dabigatran or warfarin in patients with venous thromboembolism and cancer. Thromb Haemost 2015;114:150-7.  Back to cited text no. 9
    
10.
Prins MH, Lensing AW, Brighton TA, Lyons RM, Rehm J, Trajanovic M, et al. Oral rivaroxaban versus enoxaparin with vitamin K antagonist for the treatment of symptomatic venous thromboembolism in patients with cancer (EINSTEIN-DVT and EINSTEIN-PE): A pooled subgroup analysis of two randomised controlled trials. Lancet Haematol 2014;1:e37-46.  Back to cited text no. 10
    
11.
Agnelli G, Buller HR, Cohen A, Gallus AS, Lee TC, Pak R, et al. Oral apixaban for the treatment of venous thromboembolism in cancer patients: Results from the AMPLIFY trial. J Thromb Haemost 2015;13:2187-91.  Back to cited text no. 11
    
12.
Raskob GE, van Es N, Verhamme P, Carrier M, Di Nisio M, Garcia D, et al. Edoxaban for the treatment of cancer-associated venous thromboembolism. N Engl J Med 2018;378:615-24.  Back to cited text no. 12
    
13.
Young AM, Marshall A, Thirlwall J, Chapman O, Lokare A, Hill C, et al. Comparison of an oral factor xa inhibitor with low molecular weight heparin in patients with cancer with venous thromboembolism: Results of a randomized trial (SELECT-D). J Clin Oncol 2018;36:2017-23.  Back to cited text no. 13
    


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    Tables

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  In this article
Abstract
Introduction
Overview of Clin...
History
Chemistry
Physical Properties
Dosage Forms and...
Mechanism of Action
Indications, Wit...
Contraindications
Adverse Drug Rea...
Warning
Drug Overdose an...
Drug Interaction
Renal Dose Adjus...
Use in Patients ...
Use of Rivaroxab...
Carcinogenic and...
Effect on Fertility
Special Instruct...
Conclusion
References
Article Figures
Article Tables

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