Labelling updates to mitigate the risk of bleeding with new oral anticoagulants

HSA would like to highlight recent updates made to the labelling of new oral anticoagulants (NOACs), namely the direct thrombin inhibitor dabigatran and the two direct Factor Xa inhibitors, apixaban and rivaroxaban, related to the known risk of bleeding. Dabigatran (Pradaxa®, Boehringer Ingelheim Singapore Pte Ltd), apixaban (Eliquis®, Bristol-Myers Squibb (Singapore) Pte Ltd) and rivaroxaban (Xarelto®, Bayer (South East Asia) Pte Ltd) have been registered locally since August 2009, December 2012 and November 2008, respectively.

The labelling amendments for Eliquis® were company-initiated. They include contraindication of Eliquis® in patients with a lesion or condition if considered to be a significant risk of major bleeding, as well as those receiving concomitant treatment with any other anticoagulant. HSA has reviewed these information and deemed the amendments necessary to maintain the positive benefit-risk balance of this product. In addition, HSA has assessed that the above contraindications should also be extended to Xarelto® and Pradaxa®.

Background

In 2012, the European Medicines Agency's (EMA's) Committee for Medicinal Products for Human Use (CHMP) conducted a review of available data on the risk of serious or fatal bleeding with Pradaxa®.¹ Although the CHMP concluded that the benefit-risk balance of Pradaxa® remained positive, further updates to the product information would be recommended to provide clearer guidance on how to reduce and manage the risk of bleeding. This includes identifying the types of lesions or conditions and the concomitant medications which predisposed patients to significant risk of major bleeds.

In October 2013, the UK Medicines and Healthcare Products Regulatory Agency (MHRA) further advised that the enhanced contraindications for Pradaxa® should also extend to Eliquis® and Xarelto® for all indications and doses due to similar bleeding risks observed in clinical trials and post-marketing experience.²

Local situation

To date, HSA has received 25 local reports of bleeding associated with NOACs which were classified as ‘serious' by the reporting doctor. The ages of the patients were provided in 19 cases, of which 84% were 60 years and over (range 37-86 years). Gastrointestinal bleeding and intracranial bleeding were reported in 56% and 16% of the cases, respectively.

HSA’s advisory

HSA has reviewed the available information and assessments conducted by the EMA and UK MHRA, taking into account our local reports on serious bleeding associated with NOACs, as well as the company-initiated amendments to the Eliquis® local package insert (PI). HSA's assessment is that the local PIs of all NOACs should be strengthened to include the following shared contraindications:

Lesion or condition at significant risk of major bleeding, such as current or recent gastrointestinal ulceration, presence of malignant neoplasms at high risk of bleeding, recent brain or spinal injury, recent brain, spinal or ophthalmic surgery, recent intracranial haemorrhage, known or suspected oesophageal varices, arteriovenous malformations, vascular aneurysms or major intraspinal or intracerebral vascular abnormalities
Concomitant treatment with any other anticoagulant agent, such as unfractionated heparin (UFH), low molecular weight heparins (enoxaparin, dalteparin, etc.), heparin derivatives (fondaparinux, etc.) or oral anticoagulants (warfarin, etc.), except under the circumstances of switching of therapy to or from the medicine, or when UFH is given at doses necessary to maintain an open central venous or arterial catheter

It should be noted that in addition to these shared contraindications, there are also other contraindications specific to each NOAC described in the PI for each individual drug product.

In view of the risk of haemorrhage associated with all anticoagulants, healthcare professionals are advised to take note of the indications, contraindications, posology/dosage, and warnings/precautions specific to each NOAC, as well as each individual patient's risk factors for bleeding, particularly age, weight and renal function when prescribing NOACs.

Healthcare professionals are encouraged to report any adverse reactions suspected to be related to the use of NOACs to the Vigilance Branch of HSA.

References

Healthcare professional, Industry member, Therapeutic Products

Published: 25 Apr 2014

Safety Alerts