Rivaroxaban

Articles · Medicine Compliance Aid Stability · Lactation Safety Information · New Medicines ·
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Articles

Safety in Lactation: Drugs for thromboembolic disorders

Additional information relating to breastfeeding To be used in conjunction with individual drug entries for specific information and guidance. Oral anticoagulants The coumarin anticoagulants, warfarin… Abciximab Acenocoumarol Alteplase Apixaban Argatroban Aspirin Cardiovascular system disorders Clopidogrel Dabigatran etexilate Dalteparin Dipyridamole Edoxaban Enoxaparin Epoprostenol Eptifibatide Fondaparinux Heparin Phenindione Prasugrel Rivaroxaban Safety in Lactation Ticagrelor Tinzaparin Urokinase Warfarin

Medicine Compliance Aid Stability

Xarelto · Bayer plc

Bayer plc
Xarelto
Tablets f/c 10mg, 15mg, 20mg
A2 · Amber 2 · No stability data is available, the manufacturer does not, or cannot recommend use in CAs but there are no theoretical concerns with the product.
No special precautions for storage
No special precautions for storage.
9th November 2015

Lactation Safety Information

Warfarin
Direct activated factor X inhibitor
Very limited published evidence of safety indicates small amounts in breast milk
Monitor infant for bleeding and bruising
13th August 2020

New Medicines

Xarelto · Venous thromboembolism (VTE) in children

Information

Xarelto
Licence extension / variation and new formulation
Bayer
Janssen

Development and Regulatory status

Recommended for approval (Positive opinion)
Recommended for approval (Positive opinion)
Phase III Clinical Trials
Nov 20 · Recommended for EU approval by CHMP - the additional indication is "Treatment of venous thromboembolism (VTE) and prevention of VTE recurrence in term neonates, infants and toddlers, children, and adolescents aged less than 18 years after at least 5 days of initial parenteral anticoagulation treatment." An additional dose form, granules for oral suspension 1 mg/ml, has also been licensed [8].
Sep 19 · Filed in EU via centralised procedure [6].

Category

Factor Xa inhibitor
Annual incidence of VTE in children has been estimated at 0.7–1.0 per 100,000 population, with a prevalence of 5.3 per 10,000 hospital admissions according to the Canadian VTE registry, and these figures are in good agreement with more recent national registries [1].
Venous thromboembolism (VTE) in children
Oral

Trial or other data

Nov 19 · PIII EINSTEIN Junior RCT (n=500) reports fewer symptomatic recurrent venous thromboembolism rates with rivaroxaban: 1% of 335 children receiving weight-adjusted rivaroxaban vs 3% of 165 receiving standard anticoagulants (HR 0.40, 95% CI 0.11–1.41), with similar rates of bleeding in both groups [7].
Jul 19 · Positive results from PIII EINSTEIN-Jr study reported at conference: rate of VTE recurrence was 1.2% for rivaroxaban vs 3.0% for standard anticoagulation. Clinically relevant bleeding occurred in 3.0% vs 1.9% respectively [5].
Jan 19 · PIII EINSTEIN Junior trial status changed from recruiting to active, no longer recruiting.[4]
Mar 18 · PIII EINSTEIN Junior trial is still recruiting (NCT02234843). Collection of primary outcome data due to complete Jul 18 [3].
Mar 18 · EINSTEIN Junior PII trial that evaluated the safety and efficacy of oral rivaroxaban in infants and children with VTE completes (EINSTEINJr; NCT02309411). The trial enrolled 47 patients, aged six months to five years [2].
Mar 18 · PII trial investigating the tolerability, efficacy, pharmacodynamics and pharmacokinetics of rivaroxaban versus standard of care therapy (low-molecular weight heparins, fondaparinux sodium and/or vitamin K antagonist) for the prevention and treatment of venous thrombosis, pulmonary embolism and thromboembolism in approximately 50 children and adolescents completes (NCT01684423) [2].
Mar 18 · PIII EINSTEIN Junior to assess the comparative efficacy and safety of rivaroxaban tablets or suspension to standard-of-care in children with acute VTE starts (NCT02234843). The primary endpoint is the composite number of symptomatic recurrent VTE, up to three months. The global trial is intended to enrol approximately 160 patients aged 6 months to 17 years, in the US, Australia, Austria, France, Germany, Israel, Italy, the Netherlands, Russia, Spain, Switzerland and the UK [2].
Mar 18 · The EINSTEIN Junior trials include PI, IIa, IIb and III trials and will evaluate rivaroxaban for treatment and secondary prevention of DVT and/or PE in children. Rivaroxaban will be evaluated according to an age- and body-weight adjusted dosing schedule in 150 patients in 20 countries [2].

Xarelto · Reduction in risk of major thrombotic vascular events in symptomatic PAD patients with a recent lower extremity revascularisation procedure

Information

Xarelto
Licence extension / variation
Bayer
Janssen

Development and Regulatory status

Pre-registration (Filed)
Pre-registration (Filed)
Phase III Clinical Trials
Sep 20 · No longer listed in Bayer pipeline, but J&J pipeline not updated since July. Possibly filed in US. Bayer is no longer seeking a licence extension in the EU, although has submitted VOYAGER-PAD data for consideration by the EMA [10-12].
Jan 20 · US filing planned for 2020; plans for EU filing not stated [8].
Aug 17 · Will be filed via the EU centralised procedure [2].

Category

Factor Xa inhibitor
20% of the UK population aged 55–75 years have evidence of lower extremity PAD, equating to a prevalence of 850,000 people, of whom 5% have symptoms (42,500). Number of people in England admitted to hospital with a main diagnosis of atherosclerosis of arteries of extremities was 12,196 in 2014/15. Assuming all of these have peripheral infra-inguinal revascularisation, and scaling this up to the UK (England pop x 1.19 based on mid pop estimates) = 14,513 eligible population [2].
Reduction in risk of major thrombotic vascular events in symptomatic PAD patients with a recent lower extremity revascularisation procedure
Oral

Trial or other data

Nov 20 · Review of the PIII VOYAGER PAD trial found rivaroxaban plus aspirin reduced the risk of adverse cardiovascular and limb events irrespective of clopidogrel use. Safety was also consistent regardless of clopidogrel, but with a trend for more major bleeding with clopidogrel use >30 days [13].
Mar 20 · PIII VOYAGER study (n=6,564) is published; it found that rivaroxaban plus aspirin was superior to aspirin plus placebo for a composite cardiovascular efficacy outcome (multiple cardiovascular outcomes including cardiovascular death) – 17.3% vs 19.9%, HR 0.85, 95% CI 0.76-0.96)[9].
Jan 20 · PIII VOYAGER study completes [26].
Jan 20 · The phase III VOYAGER PAD study (NCT02504216) is ongoing, but has completed in a number of EU countries [6].
Oct 18 · PIII VOYAGER PAD study primary completion date changed to Oct 19. [5]
Jan 18 · The phase III VOYAGER PAD study (NCT02504216) is ongoing, with an estimated primary completion date of Jan 2019. [4]
Aug 15 · PIII study to investigate the efficacy and safety of rivaroxaban to reduce the risk of major thrombotic vascular events in patients with symptomatic PAD undergoing lower extremity revascularization procedures starts (NCT02504216). Participating countries include UK, Eastern Europe, Western Europe, North America, South America and Asia. Patient population includes patients aged 50 years and older with documented moderate to severe symptomatic lower extremity peripheral artery occlusive disease and technically successful peripheral infra-inguinal revascularization within the last 7 days prior to randomization. tudy. Primary objective is to evaluate whether rivaroxaban added to acetylsalicylic acid (ASA) is superior to ASA alone in reducing the risk of major thrombotic vascular events in symptomatic PAD patients undergoing lower extremity revascularization procedures, and the overall safety and tolerability of rivaroxaban added to ASA compared to ASA alone. Anticipated date of study completion Q1 19 [2,3].

Evidence based evaluations

Xarelto · Venous thromboembolism (VTE) prevention ambulatory cancer patients receiving chemotherapyat high risk for VTE

Information

Xarelto
Licence extension / variation
Bayer
Janssen

Development and Regulatory status

Discontinued
Discontinued
Discontinued
Sep 20 · CHMP scheduled to discuss the final report from the CASSINI study. It is not known yet whether this information will be used to update the EU Xarelto SPC [7].
Apr 20 · No longer listed in company pipeline; assume all development discontinued [6].

Category

Factor Xa inhibitor
Around 110,000 people a year have a stroke in England and it is the third largest cause of death after heart disease and cancer. Ischaemic stroke accounts for 85% of stroke cases. In the UK there are over 53,000 deaths due to stroke each year . Around 20,000 people in the UK will suffer a TIA. Patients who have suffered a stroke remin at an increased risk of a further stroke (30%-40% risk within 5 years). The risk is highest early after stroke or TIA.
Venous thromboembolism (VTE) prevention ambulatory cancer patients receiving chemotherapyat high risk for VTE
Oral

Trial or other data

Dec 18 · New data from the PIII CASSINI study (NCT02555878; EudraCT2015-001630-21; n=843) released at the annual American Society of Hematology meeting. The composite primary endpoint of VTE occurrence did not reach statistical significance, although use of rivaroxaban resulted in a clinically meaningful and nominally significant 60% reduction of VTE events vs placebo during the time patients were actively receiving treatment. In a separate analysis removing the patients who had stopped taking the drug during the trial (approx. 40%), results were “highly significant” [4].