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Small volume intramuscular injections in people taking oral anticoagulants

11 May 2022Advice and a summary of the issues and evidence for healthcare professionals with concerns about use of IM injections in people taking oral anticoagulants

Using oral anticoagulants in breastfeeding women

2 November 2021Thromboembolic disease management whilst breastfeeding is challenging. Warfarin is the preferred choice. Guidance on using DOACs is also provided.

Oral anticoagulant formulations suggested for adults with swallowing difficulties

1 July 2021A range of oral anticoagulants are suitable for adults with swallowing difficulties.

Using COVID-19 vaccines in patients with anticoagulation and bleeding disorders

7 January 2021Information on use of the vaccine in patients who are receiving anticoagulants or have a bleeding disorder is given below.

Non-vitamin K antagonist oral anticoagulants (NOACs): Is it safe to take them with herbal medicines?

26 March 2020There is a lack of scientific evidence of the safety and efficacy of herbal medicines together with an under-reporting and underestimation of adverse effects. Interactions…
Search Articles

Medicine Compliance Aid Stability

XareltoBayer plc

Bayer plc
Xarelto
Tablets f/c 10mg, 15mg, 20mg
A2 · Amber 2No 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.
9 November 2015

Lactation Safety Information

Caution
Warfarin, Dabigatran
Direct activated factor X inhibitor
Very limited published evidence of safety indicates very small amounts in breast milk
Low levels in breast milk also anticipated based on the drug’s properties
Monitor infant for bleeding and bruising
1 November 2021

New Medicines

XareltoVenous thromboembolism (VTE) in children

Information

Xarelto
New formulation and licence extension / variation
Bayer
Janssen

Development and Regulatory status

Launched
Approved (Licensed)
Approved (Licensed)
May 2021
Dec 21Approved for use in the US for treatment of VTE and recurrent VTE prevention in patients from birth to <18yrs post 5 days parenteral anticoagulation and thromboprophylaxis aged ≥2yrs with congenital heart disease & undergone Fontan procedure [13].
Jun 21Filed in US for paediatric VTE/CHD [11].
May 21Xarelto 1mg/mL granules for oral suspension available in the UK. 10mL is £9 and 250mL is £18 [12].
Feb 21Granule formulation yet to be launched in the UK [10].
Feb 21Approved in EU and the UK [9]
Nov 20Recommended 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 19Filed 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 19PIII 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 19Positive 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 19PIII EINSTEIN Junior trial status changed from recruiting to active, no longer recruiting.[4]
Mar 18PIII EINSTEIN Junior trial is still recruiting (NCT02234843). Collection of primary outcome data due to complete Jul 18 [3].
Mar 18EINSTEIN 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 18PII 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 18PIII 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 18The 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].

Evidence based evaluations

XareltoReduction 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

Not approved
Not approved
Launched
Sep 21MHRA also updates the SPC for Xarelto 2.5mg with data from the PIII VOYAGER PAD study but a new indication is not approved [19].
Aug 21Approved in US [16].
Aug 21SPC updated to include data from PIII VOYAGER PAD study. This was not considered sufficient to represent a new indication as patients with PAD are already included in the current indication based on data from COMPASS study [18].
Oct 20Filed in US [14]
Sep 20No 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 20US filing planned for 2020; plans for EU filing not stated [8].
Aug 17Will 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

Apr 22Additional analyses of PIII VOYAGER PAD trial found rivaroxaban plus aspirin reduction in risk of thrombotic hospitalisations for PAD was consistent in those with & without CKD. Benefit in PAD patients on statin treatment for hyperchloesterolaemia was also confirmed [20].
Aug 21Results of PIII VOYAGER PAD trial (n=6564) reported in European Heart Journal [17].
May 21Results of PIII VOYAGER PAD trial (n=6564) reported in JACC [15].
Nov 20Review 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 20PIII 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 20PIII VOYAGER study completes [26].
Jan 20The phase III VOYAGER PAD study (NCT02504216) is ongoing, but has completed in a number of EU countries [6].
Oct 18PIII VOYAGER PAD study primary completion date changed to Oct 19. [5]
Jan 18The phase III VOYAGER PAD study (NCT02504216) is ongoing, with an estimated primary completion date of Jan 2019. [4]
Aug 15PIII 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