Rivaroxaban

RIVAROXABAN (BAY 59-7939), Xarelto® A POSSIBLE REPLACEMENT FOR WARFARIN (Coumadin, Jantoven)

The following was written by Gretchen Kunze, Doctor of Pharmacy Candidate at the University of Colorado at Denver and Health Sciences Center.

It is written in the form that would be used if a hospital were to consider adding it to their formulary (a list of medications used in that hospital). It is current as of October 27, 2007.

PROPRIETY NAME: Xarelto® (Bayer HealthCare, Ortho-McNeil Pharmaceuticals Inc.)

INDICATIONS: Rivaroxaban is currently in Phase III clinical trials and does not have any approved indications at this time. However, Bayer HealthCare, intends to submit for approval for indications in stroke prevention in atrial fibrillation and in the treatment and long-term secondary prevention of venous thromboembolism (VTE). They are also studying the effectiveness of this drug in the management of acute coronary syndrome (ACS).^{8, 1}

CLINICAL PHARMACOLOGY: Rivaroxaban directly inhibits factor Xa therefore prolonging clotting times and reducing the formation of thrombin, an essential component to the development of thrombus formation. The L-shaped structure of rivaroxaban allows it to be highly selective for factor Xa.^{1, 3} This high selectivity allows the drug to inhibit free factor Xa, prothrombinase activity, and clot-associated factor Xa, giving it the ability to not only prevent clots from forming, but to also possibly break down clots already present. This drug does not have significant direct effects on thrombin or antithrombin activity.^{1, 3, 8} The mechanism of action of rivaroxaban is beneficial in the prevention and treatment of thromboembolic diseases.

Peak plasma concentrations are reached 2 to 4 hours after oral administration, and the bioavailability of rivaroxaban ranges from 60-80%.^1,8 The presence of food increased maximum concentration, time to maximum concentration, and AUC. Prothrombin time was also affected depending on if a patient was in a fed or fasting state. Maximum PT was increased by 53% (10mg) and 83% (20mg) if patients were fed compared to 44% (10mg) and 53% (20mg) in the fasting state.¹¹ Maximum inhibition of factor Xa occurred within 1 to 4 hours after administration and ranged from 20-61% for the 5-80mg doses.^{4, 1, 3}

After multiple doses of rivaroxaban, dose-proportional increases in AUC were observed. It was also noted that once the drug reached steady state, there were no significant accumulations of the drug.¹ It appears that body weight influences the volume of distribution, but this change has not been found to be significant.

A study by Kubitza et al. looked at the effects of extreme body weights (≥ 120 kg and ≤ 50 kg) and gender on the PK and PD of rivaroxaban 10mg. Results showed no effects on Cmax in subjects ≥ 120 kg and up to a 24% increase in Cmax in subjects ≤ 50 kg. This increase in Cmax caused a slight increase in prothrombin time, but the investigators concluded that this was not clinically significant. No significant differences were seen between males and females as well. These results suggest that dose adjustments are not needed in patients with extreme body weights or between the different genders.¹⁰

It is unknown whether rivaroxaban is metabolized hepatically or renally. Other direct factor Xa inhibitors are metabolized by the liver, so there is a high probability that rivaroxaban is also metabolized through this route.

Rivaroxaban goes through both renal (66%) and biliary (28%) excretion, and 36% is excreted as unchanged drug in the urine.^{1, 8} In young, healthy subjects, rivaroxaban has a half-life of around 9 hrs, but this number increases in elderly subjects (12 hrs) and patients with renal impairment.⁸ It has not been determined if dose-adjustments are needed in the elderly or renal impairment because of this increased half-life. In Phase III trials, patients with renal impairment received reduced doses of rivaroxaban. Most trials have excluded patients with creatinine clearances below 30 ml/min, but it has not been officially determined if this level of renal impairment required dosage adjustments.

PK parameters correlated closely with the inhibition of factor Xa activity and PT prolongation.⁴

Because of its predictable pharmacokinetics, this drug does not require the routine monitoring like warfarin does.

PHARMACODYNAMICS: Since there is a strong relationship between the pharmacokinetics and pharmacodynamics of rivaroxaban, this drug offers predictable anticoagulation across many different parameters. There are strong correlations between the inhibition of factor Xa and plasma concentrations as well as plasma concentrations and prothrombin time.¹

Table 2: Comparison of the Pharmacokinetic Parameters of Available Anticoagulants

COMPARITIVE EFFICACY: Rivaroxaban has been compared to enoxaparin in Phase II studies looking at its effectiveness of preventing a venous thromboebolism from forming after orthopedic surgeries. This same comparison has been made looking at its effectiveness in treatment of DVTs.

The effects of rivaroxaban were tested in a multicenter, parallel-group, double-blind study (RECORD3) where 621 patients were randomly assigned to receive oral rivaroxaban (2.5, 5, 10, 20, and 30 mg PO BID, starting 6-8 hrs after surgery) or subcutaneous enoxaparin (30 mg SC BID, starting 12-24 hrs after surgery) after elective total knee replacement. These treatments were continued for 5 to 9 days after surgery until mandatory bilateral venography was performed. The primary efficacy endpoint of this study was a composite of any DVT (proximal and/or distal), confirmed non-fatal PE, and all-cause mortality during treatment. Incidence of major, postoperative bleeding during treatment was the primary safety endpoint.⁵ Results are shown below:

Intervention

Primary Efficacy Endpoint

Major, postoperative bleeding

Rivaroxaban

2.5 mg

5 mg

10 mg

20 mg

30 mg

31.7%

40.4%

23.3%

35.1%

25.4%

1.0%

1.9%

3.1%

7.5%

Enoxaparin

30 mg

44. 3%

1.9%

There was not a significant difference between the different strengths of rivaroxaban for the primary endpoint (P=0.29) and these numbers did not differ significantly from the enoxaparin group either. The frequency of bleeding increased with increasing doses of rivaroxaban and these differences were significant (P=0.0007). However, when compared to the frequency of bleeding with enoxaparin, there was not a significant difference. The authors concluded that rivaroxaban at doses of 2.5 to 10 mg PO BID showed similar efficacy and safety as enoxaparin for the prevention of VTE in patients undergoing elective total knee replacement.⁵

A second study looked at rivaroxaban’s ability to treat preexisting clots and act as a long-term anticoagulant. This Phase II trial was a multicenter, partially-blinded, parallel-group study that looked at the treatment of proximal DVT’s. Subjects were given oral rivaroxaban in doses of 10, 20, and 30 mg PO BID , 40 mg PO once daily or enoxaparin 1 mg/kg subcutaneously BID followed by a vitamin K antagonist. These treatments were given for 12 weeks.⁷

The primary outcome of this study was an improvement in thrombotic burden at day 21 (≥ 4 pt. reduction in thrombus score) without confirmed symptomatic extension or recurrence of DVT, PE, or VTE-related death. The percentage of patients meeting the primary efficacy point was similar among the 4 rivaroxaban dose groups (10 mg- 53/100 (53%), 20mg- 58/98 (59.2%), 30mg- 62/109 (56.9%), 40mg- 49/112 (43.8%)) and the enoxaparin/vitamin K antagonist group (50/109 (45.9%)). These numbers improved even further at 3 months, suggesting that rivaroxaban is capable of providing long-term anticoagulation. The primary safety outcome was incidence of major bleeding. Bleeding was observed in the rivaroxaban group, however, there was not a significant trend in the dose-response relationship (10mg- 1.7%, 20mg- 1.7%, 30mg- 3.3%, 40mg- 1.7%). There were no bleeding incidents in the enoxaparin/vitamin K antagonist group. The investigators concluded that this range of doses of rivaroxaban is as effective and safe at treating proximal DVT compared to enoxaparin/vitamin K antagonist and the results support Phase III evaluation.⁷

CONTRAINDICATIONS, WARNINGS, AND PRECAUTIONS: In the trials that have been conducted thus far, rivaroxaban has proven to be safe. Currently there are not any populations of patients where this drug is contraindicated. We can speculate that precautions should be taken in certain patients, however, such as those with active bleeding, intracerebral or gastrointestinal bleeding within the past 6 months, neurosurgery within past 4 weeks, an active peptic ulcer, a known bleeding disorder, prolonged PT/INR, pregnancy, low platelet levels, kidney function impairment (CrCl < 30 ml/min) or certain malignancies.^{7, 5, 6} These different conditions have been included in the exclusion criteria in clinical trials of rivaroxaban and are also similar to the contraindications and precautions that are seen with warfarin and enoxaparin. Until specific recommendations come out, caution should be exercised in patients with these conditions.^{7, 8}

ADVERSE REACTIONS: There have been very minimal side effects associated with Rivaroxaban in clinical trials. The most common adverse affect noted was headache, while some patient’s have experienced mild nausea and vomiting.¹ A small number of subjects had increases in their liver enzymes, however, similar increases were seen in the enoxaparin group as well.^{5,
1} No clinically significant changes were seen in bleeding time, blood pressure, heart rate, electrocardiogram, vital signs, or laboratory parameters (except for clotting tests).^5,1

With any anticoagulant, one of the main concerns is with bleeding. There have not been any reports of significant bleeding with this drug. Bleeding rates have been similar to those of enoxaparin.^{5, 6, 7} However, more bleeding has been associated with twice-daily dosing⁵ (ODIXa-DVT study) compared to once-daily dosing (EINSTEIN-DVT study).

DRUG INTERACTIONS: No significant drug interactions have been found with rivaroxaban, including with aspirin, NSAIDs, antacids, H2 antagonists and digoxin.^{1,
11}

The interaction between rivaroxaban and aspirin was studied in a phase I trial to determine if aspirin influenced the effectiveness and safety of rivaroxaban. This combination was well tolerated in the healthy, male subjects studied. Aspirin did not affect the inhibition of factor Xa activity or prolongation of PT/aPTT by rivaroxaban. In addition, rivaroxaban did not interfere with the inhibitory effects of aspirin on platelet aggregation.²

A phase II study in 2007 looked at the effects of the combination of naproxen and rivaroxaban on safety, tolerability, PK and PD. Patients were given naproxen alone, rivaroxaban alone, or a combination of the two drugs. This study showed no mechanistic interaction between rivaroxaban and naproxen, and the addition of naproxen did not effect the prothrombin time, pTT or platelet aggregation. There was a significant increase in bleeding seen with the combination group, however, this increase was less than that seen with naproxen alone.⁹ Further phase III studies are being conducted to confirm the safety of this combination.

DOSING: There have been several studies that have looked at various dosing ranges of rivaroxaban, from 2.5mg to 40mg, given either twice-daily or once-daily. Most strengths of rivaroxaban have proven to be effective, and no dose-efficacy response has been established. However, twice daily dosing has resulted in significantly more bleeding than once-daily dosing suggesting that dose frequency might influence bleeding risk independently of dose intensity.

Rivaroxaban 20mg once-daily is the strength that is being used in Phase III trials looking at treatment of VTE and prevention of stroke in A. fib. During the RECORD3 study, a phase III trial, it was determined that 10mg of rivaroxaban given once daily was the most effective and safest dose at preventing VTE after orthopedic surgery. This strength is currently being evaluated further in this population.

CONCLUSION: There is a need for a new anticoagulant that is just as effective as warfarin, but without the rigorous monitoring schedule. Once-daily dosing of rivaroxaban has been shown to produce 24 hours of inhibition of factor Xa and thrombin generation, allowing for convenient dosing.⁴ Rivaroxaban offers once-daily dosing, and there may be the potential for no monitoring with this drug.¹ Unlike warfarin that has several different strengths and may need to be taken differently each day, rivaroxaban will be much easier to manage and may increase patient compliance as well.

1. Laux V, Perzborn E, Kubitza D, Misselwitz F. Preclinical and Clinical Characteristics of Rivaroxaban: A Novel, Oral, Direct Factor Xa Inhibitor. Seminars in Thrombosis and Hemostasis 2007;33:515-22.

2. Kubitza D, Becka M, Mueck W, Zuehlsdorf M. Safety, Tolerability, Pharmacodynamics, and Pharmacokinetics or Rivaroxaban-an Oral, Direct Factor Xa Inhibitor-Are Not Affected by Aspirin. J Clin Pharmacol 2006;46:981-90.

3. Kubitza D, Becka M, Voith B, Zuehlsdorf M, Wensing G. Safety, pharmacodynamics, and pharmacokinetics of single doses of BAY 59-7939, an oral, direct factor Xa inhibitor. Clinical Pharmacology and Therapeutics 2005;78:412-21.

4. Graff J, Hentig N, Misselwitz F, Kubitza D, Becka M, Breddin HK, Harder S. Effects of the Oral, Direct Factor Xa Inhibitor Rivaroxaban on Platelet-Induced Thrombin Generation and Prothrombinase Activity. J Clin Pharmacol 2007;1-9.

5. Turpie AG, Fisher WD, Bauer KA, Kwong LM, Irwin MW, Kalebo P, Misselwitz F, Gent M. BAY 59-7939: an oral, direct Factor Xa inhibitor for the prevention of venous thromboembolism in patients after total knee replacement. A phase II dose-ranging study. J of Thrombosis and Haemostatis 2005;3:2479-2486.

6. Erikkson BI, Borris L, Dahl OE, Haas S, Huisman MV, Kakkar AK, Misselwitz F, Kalebo P, ODIXa-Hip study investigators. Oral, direct Factor Xa inhibition with BAY 59-7939 for the prevention of venous thromboembolism after total hip replacement. J Thromb Haemost 2006;4:121-

7. Agnelli G et al. Treatment of Proximal Deep-Vein Thrombosis With the Oral Direct Factor Xa Inhibitor Rivaroxaban (BAY 59-7939): The ODIXa-DVT (Oral Direct Factor Xa Inhibitor BAY 59-7939 in Patients with Acute Symptomatic Deep-Vein Thrombosis) Study. Circulation 2007;116:180-7.

8. Hirsh J, O’Donnell M, Eikelboom JW. Beyond Unfractionated Heparin and Warfarin: Current and Future Advances. Circulation 2207;216:552-60.

9. Kubitza D, Becka M, Mueck W, Zuehlsdorf M. Rivaroxaban (BAY 59-7939)- an oral, direct Factor Xa Inhibitor- has no clinically relevant interaction with naproxen. Brit J Clin Pharmacol 2007; 63: 469-76.

10. Kubitza D, Becka M, Zuehlsdorf M, Mueck W. Body weight has limited influence on the safety, tolerability, pharmacokinetics, and pharmacodynamics or rivaroxaban (BAY 59-7939) in healthy subjects. J Clin Pharmacol 2007; 47:218-26.

11. Kubitza D, Becka M, Zuehlsdorf M, Mueck W. Effects of food, an antacid, and the H2 antagonist ranitidine on the absorption of BAY 59-7939 (rivaroxaban), an oral, direct factor Xa inhibitor, in healthy subjects. J Clin Pharmacol 2006; 46:549-58.

12. Lacy CF, Armstrong LL, Goldman MP, Lance LL. DI Handbook. Lexi-Comp Inc. 13^th edition.2005. 517-20, 1571-74.

13. DRUGDEX® System [internet database]. Greenwood Village, Colorado: Thompson Micromedex. Updated periodically.

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Drug	Trade Name	Company	FDA-Approved Indications
Rivaroxaban	Xarelto®	Bayer, Ortho-McNeil	None at this time
Warfarin	Coumadin® Jantoven®	Many	Prophylaxis and treatment of thromboembolism in PE, VTE, post-MI, prosthetic cardiac valves, and A. Fib.
Enoxaparin	Lovenox®	Sanofi-Aventis	Prophylaxis and treatment of DVT, prophylaxis of post-op DVT (hip, knee, abdominal), unstable angina or non-Q-wave MI

	Rivaroxaban	Enoxaparin	Warfarin
Onset of action	2.5-4 hours	3-5 hours	36-72 hours
Duration of action	24 hrs	12 hrs	2-5 days
Bioavailability	60-80%	92%	100%
Metabolism	Unknown	Hepatic	Hepatic, metabolites
Elimination t ½	5.7-9.2 hours	4.5-7 hours	20-60 hours
Protein binding		80%	~ 99%
Renal excretion	66%	40%, 10% unchanged	92%
Biliary excretion	28%	60%	8%
Dose adjustment in renal dysfunction	N/A	YES	NO
Dose adjustment in hepatic dysfunction	N/A	NO	YES