Overview

Non-Vitamin K antagonist Oral Anticoagulants (NOACs) are now increasingly used in patients with non-valvular atrial fibrillation and for the prevention/treatment of venous thromboembolism.¹ NOACs, commonly known as novel oral anticoagulants include dabigatran (direct thrombin inhibitor) and Factor Xa inhibitors such as rivaroxaban, apixaban and edoxaban.^2,3 In Malaysia, there are currently 14 NOAC products registered with the Drug Control Authority (DCA) which are dabigatran (3), rivaroxaban (6), apixaban (2) and edoxaban (3).⁴

 

Abnormal uterine bleeding is a general term that encompasses irregularities in terms of frequency, regularity, duration, and volume of flow in the menstrual cycle. The underlying aetiologies of abnormal uterine bleeding include structural issues (e.g. polyps or adenomyosis) and non-structural issues (e.g. ovulatory dysfunction or iatrogenic).⁵ The intensity of abnormal uterine bleeding can vary such as from discomfort to severe cases, in which some may require blood transfusions or even long-term surgical intervention such as dilation and curettage (D&C), endometrial ablation, uterine artery embolisation, or hysterectomy.^3,6

 

Background of Safety Issue

The National Pharmaceutical Regulatory Agency (NPRA) has received information from the United States Food and Drug Administration (US FDA) on the risk of abnormal uterine bleeding in females of reproductive potential, associated with the use of NOACs.⁷

 

The US FDA has conducted a retrospective cohort study of abnormal uterine bleeding in the FDA's Sentinel System among females aged more than 18 years old who were newly on NOACs or warfarin for the treatment of venous thromboembolism, atrial flutter or atrial fibrillation. The cohort study was initiated following an increase in the number of menorrhagia reports observed for rivaroxaban compared to other oral anticoagulants in the FDA's Adverse Event Reporting System (FAERS) Database.^8-9 It was observed that there was an increased risk of severe abnormal uterine bleeding leading to surgical intervention with rivaroxaban use, as compared to dabigatran (HR 1.19; 95% CI 1.03-1.38), apixaban (HR 1.23; 95% CI 1.04-1.47), and warfarin (HR 1.34; 95% CI 1.22-1.47). Hysteroscopic polypectomy and hysterectomy accounted for more than half of the gynaecological surgeries that were observed in the study.⁸ Nevertheless, US FDA concluded that the risk of severe abnormal uterine bleeding which potentially requires gynaecological surgical interventions is applicable to the whole class of NOACs, hence warranted product information update for all NOAC products to include the new safety information.⁷

 

In Malaysia, abnormal uterine bleeding related terms including urogenital haemorrhage or genitourinary bleeding have been documented in the product information of all NOAC products¹⁰. 

 

Adverse Drug Reaction (ADR) Reports

NPRA has received a total of 720 reports with 1,152 adverse events suspected to be related to NOAC products. There were four (4) reports of menorrhagia following the administration of rivaroxaban (3) and dabigatran (1). To date, none of these reports involved gynaecological surgical interventions.¹¹

 

Advice for Healthcare Professionals

• Be vigilant on the use of NOAC products and the risk of abnormal uterine bleeding among women of reproductive age.
• Many female patients taking oral anticoagulants for venous thromboembolism are of younger age, hence the effect of anticoagulation on menstrual blood loss can be a concern due to the likelihood of a change in the menstrual bleeding intensity. Thus, additional counselling before and during NOACs treatment is needed for this group of patients.
• Please report all suspected adverse events associated with NOAC products to the NPRA.

 

References:

1. Clinical Excellence Commission. Non-Vitamin K Oral Anticoagulant (NOAC) Guidelines Updated July 2017 [Cited 2021 September 6].
2. Chitra P, Mable B, Alfet RA, Krishnakumar K. NOACs: an emerging class of oral anticoagulants-a review article [Internet]. 2020 [Cited 2021 July 16]. Available from https://fjps.springeropen.com/track/pdf/10.1186/s43094-020-00114-1.pdf.
3. Beyer-Westendorf J. DOACS in women: pros and cons. Thrombosis Research [Internet]. 2019 [Cited 2021 July 16]; S19-S22. Available from https://pubmed.ncbi.nlm.nih.gov/31477222/.
4. National Pharmaceutical Regulatory Agency. Malaysian Product Registration Database (Quest 3+) [Internet]. 2021 [Cited 2021 July 16]. Available from https://www.npra.gov.my.
5. Davis E, Sparzak PB. Abnormal uterine bleeding [Internet]. 2021 [Cited 2021 July 16]. Available from: https://www.ncbi.nlm.nih.gov/books/NBK532913/.
6. Wouk, N, Helton M. Abnormal Uterine Bleeding in Premenopausal Women. Am Fam Physician [Internet]. 2019 [Cited 2021 July 16]; 99(7):435-443. Available from https://www.aafp.org/afp/2019/0401/p435.html#afp20190401p435-t1.
7. United States Food and Drug Administration (FDA). January - March 2021 Potential Signals of Serious Risks/New Safety Information Identified by the FDA Adverse Event Reporting System (FAERS) [Internet]. 13 July 2021 [Cited 2021 16 July]. Available from https://www.fda.gov/drugs/questions-and-answers-fdas-adverse-event-reporting-system-faers/january-march-2021-potential-signals-serious-risksnew-safety-information-identified-fda-adverse.
8. United States Food and Drug Administration (FDA). Comparative Risk Assessment of Severe Abnormal Uterine Bleeding associated with Non-Vitamin K Oral Anticoagulants [Internet]. September 2020 [Cited 2021 16 July]. Available from https://www.sentinelinitiative.org/sites/default/files/communications/publications-presentations/Comparative_Risk_Assessment_of_Severe_Abnormal_Uterine_Bleeding.pdf.
9. Eworuke E, Hou L, Zhang R, Wong, HL, Waldron P, Anderson A, Gassman A, Money D, Huang TY. Risk of Severe Abnormal Uterine Bleeding Associated with Rivaroxaban Compared with Apixaban, Dabigatran and Warfarin. Drug Saf [Internet]. 2021 [Cited 2021 July 19]; 44(7):753-763. Available from https://pubmed.ncbi.nlm.nih.gov/34014506/.
10. National Pharmaceutical Regulatory Agency. Malaysian Product Registration Database (Quest 3+). NOACs local package insert [Internet]. 2021 [Cited 2021 July 16]. Available from https://www.npra.gov.my.
11. National Pharmaceutical Regulatory Agency. The Malaysian National ADR Database [Internet]. 2021 [Cited 2021 July 16]. Available from https://www.npra.gov.my. 

 

DISCLAIMER:
This publication is aimed at health professionals. The information is meant to provide updates on medication safety issues, and not as a substitute for clinical judgement. While reasonable care has been taken to verify the accuracy of the information at the time of publication, NPRA shall not be held liable for any loss whatsoever arising from the use of or reliance on this publication.