Rivaroxaban

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Rivaroxaban
Systematic (IUPAC) name
(S)-5-chloro-N-{[2-oxo-3-[4-(3-oxomorpholin-4-yl)
phenyl]oxazolidin-5-yl]methyl} thiophene-2-carboxamide
Clinical data
Trade namesXarelto
AHFS/Drugs.comMicromedex Detailed Consumer Information
Licence dataEMA:LinkUS FDA:link
Pregnancy cat.C (US)
Legal statusPOM (UK) -only (US)
Routesoral
Pharmacokinetic data
Bioavailability80% to 100%; Cmax = 2–4 hours (10 mg oral)[1]
MetabolismCYP3A4 , CYP2J2 and CYP-independent mechanisms[1]
Half-life10 mg oral 7–11 hours[1]
Excretion2/3 metabolized in liver and 1/3 eliminated unchanged[1]
Identifiers
CAS number366789-02-8 N
ATC codeB01AF01
PubChemCID 6433119
DrugBankDB06228
ChemSpider8051086 YesY
UNII9NDF7JZ4M3 YesY
ChEBICHEBI:68579 N
ChEMBLCHEMBL198362 YesY
Chemical data
FormulaC19H18ClN3O5S 
Mol. mass435.882 g/mol
 N (what is this?)  (verify)
 
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Rivaroxaban
Systematic (IUPAC) name
(S)-5-chloro-N-{[2-oxo-3-[4-(3-oxomorpholin-4-yl)
phenyl]oxazolidin-5-yl]methyl} thiophene-2-carboxamide
Clinical data
Trade namesXarelto
AHFS/Drugs.comMicromedex Detailed Consumer Information
Licence dataEMA:LinkUS FDA:link
Pregnancy cat.C (US)
Legal statusPOM (UK) -only (US)
Routesoral
Pharmacokinetic data
Bioavailability80% to 100%; Cmax = 2–4 hours (10 mg oral)[1]
MetabolismCYP3A4 , CYP2J2 and CYP-independent mechanisms[1]
Half-life10 mg oral 7–11 hours[1]
Excretion2/3 metabolized in liver and 1/3 eliminated unchanged[1]
Identifiers
CAS number366789-02-8 N
ATC codeB01AF01
PubChemCID 6433119
DrugBankDB06228
ChemSpider8051086 YesY
UNII9NDF7JZ4M3 YesY
ChEBICHEBI:68579 N
ChEMBLCHEMBL198362 YesY
Chemical data
FormulaC19H18ClN3O5S 
Mol. mass435.882 g/mol
 N (what is this?)  (verify)

Rivaroxaban (BAY 59-7939) is an oral anticoagulant invented and manufactured by Bayer; in a number of countries it is marketed as Xarelto.[1] In the United States, it is marketed by Janssen Pharmaceutica.[2] It is the first available orally active direct factor Xa inhibitor. Rivaroxaban is well absorbed from the gut and maximum inhibition of factor Xa occurs four hours after a dose. The effects lasts 8–12 hours, but factor Xa activity does not return to normal within 24 hours so once-daily dosing is possible.

There is no specific way to reverse the anticoagulant effect of rivaroxaban in the event of a major bleeding event, unlike warfarin.

Medical uses[edit]

Rivaroxaban can be used to prevent strokes in those with atrial fibrillation due to causes other than heart valve disease, and at least one additional risk factor for stroke (congestive heart failure, hypertension, age, diabetes, and prior stroke)

Rivaroxaban can also be used to prevent the formation of blood clots in the veins (deep venous thrombosis) in adults who have had an operation to replace a hip or knee and following an acute deep venous thrombosis in adults.

Rivaroxiban can also be used for treatment of deep venous thrombosis (DVT).

Rivaroxaban is not indicated for prosthetic heart valves or for mitral stenosis.

Rivaroxaban is not indicated as add-on treatment for dual antiplatelet therapy in secundary prevention of coronary incidents. (Triple therapy).[3][4]

Systematic reviews[edit]

Prevention of ischaemic stroke in non-valvular atrial fibrillation[edit]

A systematic review of novel anticoagulants concluded: new oral anticoagulants are a viable option for patients receiving long-term anticoagulation. As for al new oral anticoagulants treatment benefits compared with warfarin are small and vary depending on the control achieved by warfarin treatment.[5]

Treatment and prevention of venous thromboembolism and pulmonary embolism[edit]

In a systematic review compared with vitamin K antagonists (warfarin) in treatment of acute venous thromboembolism, the novel oral anticoagulants had a similar risk of recurrence of acute venous thromboembolism and all cause mortality.[6]

In a systematic review of three trials, novel anticoagulants (rivaroxaban and dabigatran) did not differ for mortality or venous thromboembolism related mortality from warfarin in prevention of venous thromboembolism. Following trials were included: Einstein-DVT and Einstein-PE for rivaroxaban and Re-cover for dabigatran.[5]

Prevention of venous thromboembolism: perioperative[edit]

A systematic review concludes: the new oral anticoagulants are effective for thromboprophylaxis after THR and TKR. Their clinical benefits over LMWH are marginal and offset by increased risk for major bleeding. So there is no evidence that new anticoagulants have a better harm-benefit balance than LMWH. New oral anticoagulants have not been compared with warfarin in this indication.[7]

In a systematic review comparing rivaroxiban, dabigatran and apixaban with enoxaparin after total hip or knee replacement, the higher efficacy of rivaroxiban was associated with a higher bleeding tendency, but the new anticoagulants did not differ significantly for efficacy and safety.[8]

Regulatory approval and indications[edit]

In September 2008, Health Canada granted marketing authorization for rivaroxaban as one 10 mg tablet taken once daily for the prevention of venous thromboembolism (VTE) in patients who have undergone elective total hip replacement or total knee replacement surgery.[9] In September 2008, the European Commission granted marketing authorization of rivaroxaban for the same indication.[10]

In December 2011, rivaroxaban was approved by the European Commission for use in two new indications: prevention of stroke and systemic embolism in adult patients with non-valvular atrial fibrillation (AF) with one or more risk factors, and for treatment of deep venous thromboembolism. It was also approved for prevention of recurrent deep venous thromboembolism and pulmonary embolism (PE) following an acute deep venous thromboembolism in adults.[11]

On July 1, 2011, the U.S. Food and Drug Administration (FDA) approved rivaroxaban for prophylaxis of deep vein thrombosis (DVT), which may lead to pulmonary embolism (PE), in adults undergoing hip and knee replacement surgery.[2] On November 4, 2011, the U.S. FDA approved rivaroxaban for stroke prophylaxis in patients with non-valvular atrial fibrillation. On November 2, 2012, the U.S. Food and Drug Administration (FDA) approved rivaroxaban for the treatment of patients with deep vein thrombosis (DVT) and pulmonary embolism (PE), as well as long-term treatment to prevent recurrence.[12]

Mechanism of action[edit]

Rivaroxaban is an oxazolidinone derivative optimized for inhibiting both free Factor Xa and Factor Xa bound in the prothrombinase complex.[13] It is a highly selective direct Factor Xa inhibitor with oral bioavailability and rapid onset of action. Inhibition of Factor Xa interrupts the intrinsic and extrinsic pathway of the blood coagulation cascade, inhibiting both thrombin formation and development of thrombi. Rivaroxaban does not inhibit thrombin (activated Factor II), and no effects on platelets have been demonstrated.[1]

Rivaroxaban has predictable pharmacokinetics across a wide spectrum of patients (age, gender, weight, race) and has a flat dose response across an eightfold dose range (5–40 mg).[14] Clinical trial data have shown that it allows predictable anticoagulation with no need for dose adjustments and routine coagulation monitoring.[1] However, these trials have excluded patients with liver disease and end-stage renal disease; therefore, the safety of rivaroxaban in these populations is unknown.

Adverse effects[edit]

According to a systematic review, adverse effects of new anticoagulants (dabigatran, rivaroxaban and apixaban) compared with warfarin were lower for fatal bleeding and hemorrhagic stroke, numerically lower for major bleeding, numerically higher for gastrointestinal bleeding, and higher for discontinuation due to adverse events. Bleeding risks may be increased for persons older than 75 years or those receiving warfarin who have good control.[15]

Bleeding risk[edit]

Rivaroxaban increases the risk of bleeding and can cause serious, potentially fatal bleeding. Concomitant use of drugs affecting hemostasis increases the risk of bleeding including aspirin and other anti-platelet agents (clopidogrel), other anticoagulants (warfarin and other new anticoagulants), heparin and LWMH, thrombolytic agents, SSRIs and SNRIs (both antidepressants), and NSAIDs (anti-inflammatory).

Overdose[edit]

There is no established way to reverse the anticoagulant effect of rivaroxaban in cases of serious bleedings or accidents, which can be expected to persist for about 24 hours after the last dose (i.e., about two half-lives). A specific antidote is not available. Prothrombin complex concentrate immediately and completely reversed the anticoagulant effect in a study with 12 healthy subjects[16] but the clinical effectiveness of this treatment has yet to be proven.[17]

Discontinuation[edit]

There is increased risk of stroke with discontinuation of rivaroxaban. Discontinuing apixaban in the absence of adequate alternative anticoagulation increases the risk of thrombotic events. If rivaroxaban must be discontinued for a reason other than pathological bleeding, consider coverage with another anticoagulant. Rivaroxaban has a black-box in the US warning regarding potential thrombosis that may occur if it is discontinued and not replaced by another anticoagulant.

Drug interactions[edit]

Strong dual Inhibitors of CYP3A4 and P-gp (e.g., ketoconazole (Nizoral), itraconazole (Sporanox), ritonavir, or clarithromycin) increase the exposure to rivaroxaban and increase the risk of bleeding . Avoid them.

Strong dual inducers of CYP3A4 and P-gp decrease exposure to rivaroxaban and increase the risk of stroke. Avoid concomitant use of rivaroxaban with rifampin, carbamazepine (Tegretol), phenytoin and St. John’s wort, because such drugs will decrease exposure to rivaroxaban.

Coadministration of antiplatelet agents, fibrinolytics, heparin, aspirin, and chronic NSAID increases the risk of bleeding.

Long term safety[edit]

The safety (and efficacy) of rivaroxaban in the longer term (beyond two years) are uncertain.

Contraindications[edit]

Rivaroxaban must not be used in patients who are actively bleeding, or who have liver disease which leads to problems with blood clotting and an increased risk of bleeding. The medicine must also not be used in patients with conditions putting them at risk of major bleeding, such as an ulcer in the gut, or in patients being treated with other anticoagulant medicines.

Rivaroxaban must not be used in women who are pregnant or breast-feeding due to lack of data and in patients below 18 years of age.

It must not be used in patients who are hypersensitive (allergic) to rivaroxaban or any of the other ingredients.[18]

It is not recommended in patients with severe renal impairment (creatinine clearance <15 ml/min); in patients receiving concomitant systemic treatment with strong concurrent CYP3A4- and P-gp-inhibitors, i.e. azole-antimycotics (Sporanox, Nizoral) or HIV protease inhibitors and in patients concomitantly treated with dronedarone.[1]

Pivotal trials for authorisation[edit]

Prevention of venous thromboembolism: perioperative[edit]

Four clinical studies, the RECORD studies, with a total enrollment of over 12,000 patients have shown that oral rivaroxaban has non-inferior and possibly superior efficacy compared to 40 mg per day of the subcutaneous low molecular weight heparin (LMWH) enoxaparin in preventing venous thromboembolism in adult patients undergoing total hip or knee replacement surgery. However, the risk of bleeding was greater in patients randomized to rivaroxaban (10 mg/day) rather than enoxaparin (40 mg/day) and one patient (out of > 6000) randomized to rivaroxaban died of liver toxicity. [19][20][21][22]

Treatment and prevention of venous thromboembolism and pulmonary embolism[edit]

The EINSTEIN study for treatment and secondary prevention of venous thromboembolism shows that rivaroxaban can be a single-drug approach to the short-term and continued treatment of venous thrombosis and can also improve the benefit-to-risk profile of anticoagulation. The open-label (not blinded), randomized, noninferiority part of the study compared oral rivaroxaban alone (15 mg twice daily for 3 weeks, followed by 20 mg once daily) with subcutaneous enoxaparin followed by a vitamin K antagonist (either warfarin or acenocoumarol) for 3, 6, or 12 months in patients with acute, symptomatic DVT. The study also carried out a double-blind, randomized, event-driven superiority study that compared rivaroxaban alone (20 mg once daily) with placebo for an additional 6 or 12 months in patients who had completed 6 to 12 months of treatment for venous thromboembolism.[23] Rivaroxaban had noninferior efficacy with respect to the primary outcome venous thrombolic events. The principal safety outcome, major bleedings, was not different. Overall, the INR was in the therapeutic range (2.0 to 3.0) for 57.7% of the time. So warfarin treatment was not optimal. In the continued-treatment study, which included 602 patients in the rivaroxaban group and 594 in the placebo group, rivaroxaban had strong efficacy (8 events [1.3%], vs. 42 with placebo [7.1%]; hazard ratio, 0.18; 95% CI, 0.09 to 0.39; P<0.001). Four patients in the rivaroxaban group had nonfatal major bleeding (0.7%), versus none in the placebo group (P=0.11).[23][24]

In the EINSTEIN–Pulmonary Embolism Study, an open label (not blinded) trial rivaroxaban and usual care (enoxaparin and warfarin) had similar rates of recurrent venous thromboembolism and bleeding in symptomatic pulmonary embolism.[25][26]

Prevention of stroke in non-valvular atrial fibrillation[edit]

In the ROCKET-AF trial, a Bayer company based double blind trial, comparing a once-daily, fixed dose (20 mg daily or 15 mg daily in patients with a creatinine clearance of 30 to 49 ml per minute) of rivaroxaban with adjusted-dose warfarin in patients with nonvalvular atrial fibrillation who were at moderate-to-high risk for stroke, rivaroxaban was not inferior to warfarin in the prevention of subsequent stroke or systemic embolism. There were no significant differences in rates of major and clinically relevant nonmajor bleeding between the two study groups. Intracranial and fatal bleeding occurred less frequently in the rivaroxaban group, bleeding from gastrointestinal sites, including upper, lower, and rectal sites, occurred more frequently in the rivaroxaban group, as did bleeding that led to a drop in the hemoglobin level or bleeding that required transfusion.

Among patients in the warfarin group, the proportion of time in which the intensity of anticoagulation was in the therapeutic range TTR (mean, 55%), was lower than in previous studies of other new anticoagulants in patients with atrial fibrillation (range, 64 to 68%).[27][28] Documents from the Food and Drug Administration (FDA) Advisory Committee meeting reported that when warfarin was administered skillfully within the trial, and the TTR was above approximately 68%, there was a relative increase in primary outcome events (stroke and systemic embolism) in the rivaroxaban group. It was noted that the hazard ratio increased sharply as the center TTR rose to above 65%, and at a TTR above 67%, the hazard ratio crossed 1.0. The FDA reviewer concluded: the poor warfarin control, as evidenced by the overall TTR in ROCKET of 55%, biased the study in favor of rivaroxaban. The study results do not convincingly demonstrate the non-inferiority, much less the superiority, of rivaroxaban to warfarin when the latter is used skillfully. TTR in ROCKET varied widely over regions and countries. In general, TTR was higher in Western Europe (especially in the UK and Scandinavia), North America (i.e., Canada and the US), and some areas in the Pacific basin (Australia, New Zealand, Singapore and Hong Kong), and tended to be low in Eastern Europe, South America, and with a few notable exceptions, the Asia-Pacific region.

In the ROCKET AF study 23.7% of the patients in the rivaroxaban group and 36.2% in the warfarin group completed early study treatment and these patients were not recorded anywhere in the various analyses.[29][28]

Other trials[edit]

Prevention of venous thromboembolism: medically ill patients[edit]

The MAGELLAN study was initiated for prevention of venous thrombosis in hospitalized medically ill patients. It shows that taking rivaroxaban 10 mg once daily for 35 days was associated with a reduction in the risk of venous thrombosis, compared with standard 10-day treatment with enoxaparin by subcutaneous injection, in acutely ill hospitalized medical patients. However, bleeding rates were significantly increased with rivaroxaban. At day 10 there were 5 fatal bleedings against 1 for enoxaparin, after 35 days there were 7 fatal bleedings against 1 for enoxaparin.[30][31]

Currently available evidence does not indicate that routine administration of post-discharge extended prophylaxis will be beneficial to the patients admitted for medical illness.[32]

Prevention of recurrent coronary events[edit]

The ATLAS ACS 2 TIMI 51 trial for secondary prevention of major cardiovascular events in patients with acute coronary syndrome shows for the 2.5-mg twice-daily dose of rivaroxaban a reduction in overall (Absolute Risk Decrease 1,6%) and cardiovascular mortality vs placebo, despite an increased risk of major bleeding (Absolute Risk Increase 1,2%), bleeding requiring medical attention and intracranial haemorrhage (ARI 0,5%). There was no increased risk of fatal bleeding. For this low dose there was no effect on myocardial infarctions and stroke. In higher dose rivaroxaban (5 mg twice daily) the benefits on mortality were not observed, but bleeding effects were still higher.[33][34] The studies were hindered by early patients withdrawals and incomplete follow up. In May 2012 missing data lead FDA panel to vote against rivaroxaban for acute coronary syndrome.[35]

A meta-analysis has concluded that new anticoagulants (anti-Xa or direct thrombin inhibitors) give a small benefit when added to dual antiplatelet therapy in acute coronary syndrome, but an unacceptably high rate of bleeding.[36]

Pharmacovigilance[edit]

Dabigatran and warfarin are the most frequently named suspect drugs in direct reports to the FDA in 2012. A third anticoagulant, rivaroxaban (XARELTO), is ranked tenth. [37]

Chemistry[edit]

Chemical structures of linezolid (top) and rivaroxaban (bottom). The shared structure is shown in blue.

Rivaroxaban bears a striking structural similarity to the antibiotic linezolid: both drugs share the same oxazolidinone-derived core structure. Accordingly, rivaroxaban was studied for any possible antimicrobial effects and for the possibility of mitochondrial toxicity, which is a known complication of long-term linezolid use. Studies found that neither rivaroxaban nor its metabolites have any antibiotic effect against Gram-positive bacteria. As for mitochondrial toxicity, in vitro studies found the risk to be low.[38]

Related drugs[edit]

A number of anticoagulants inhibit the activity of Factor Xa. Unfractionated heparin (UFH), low molecular weight heparin (LMWH), and fondaparinux inhibit the activity of factor Xa indirectly by binding to circulating antithrombin (AT III). These agents must be injected. Warfarin, phenprocoumon, and acenocoumarol are orally active vitamin K antagonists (VKA) which decrease hepatic synthesis of a number of coagulation factors, including Factor X. In recent years, a new series of oral, direct acting inhibitors of Factor Xa have entered clinical development. These include rivaroxaban, apixaban, betrixaban, LY517717, darexaban (YM150) and DU-176b edoxaban. Dabigatran is a direct thrombin inhibitor.[39]

References[edit]

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