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.

 

Overview of Product(s)

Enoxaparin is a low molecular weight heparin (LMWH) with antithrombotic and anticoagulant properties. It is used in the prophylaxis of venous thromboembolic disease, prevention of thrombus formation during haemodialysis, as well as treatment of deep vein thrombosis (DVT), pulmonary embolism (PE), and acute coronary syndrome (ACS)—which includes unstable angina, non ST-segment elevation myocardial infarction (NSTEMI), and acute ST-segment elevation myocardial infarction (STEMI).¹ In Malaysia, there are currently 18 enoxaparin-containing injectable products registered with the Drug Control Authority (DCA).²

 

Overview of Safety Concern

Acute Generalised Exanthematous Pustulosis (AGEP) is a rare but severe cutaneous adverse reaction (SCAR) primarily induced by drugs.³ It presents with oedematous erythema, typically in large skin folds, followed by the eruption of non-follicular sterile pustules and characteristic desquamation (peeling skin). Mucosal involvement is generally mild and occurs in around 20% of cases. Cutaneous symptoms are often accompanied by systemic manifestations, including fever and leukocytosis, with potential hepatic, renal, or pulmonary involvement.

Multiple drugs have been associated with inducing AGEP, primarily anti-infective agents.³ Other associated drugs include hydroxychloroquine, anticancer therapies, analgesics and anti-inflammatory drugs, as well as direct oral anticoagulants. In addition, certain infections have been linked to the occurrence of AGEP.

 

Source of Safety Issue

The National Pharmaceutical Regulatory Agency (NPRA) received information from the European Medicines Agency (EMA) on the risk of AGEP associated with enoxaparin use.^4,5

Based on the assessment of the periodic safety update report (PSUR), and taking into account available data from the literature and spontaneous reports, the EMA considered a causal relationship between enoxaparin and AGEP to be at least a reasonable possibility.⁵ This conclusion is supported by three cases that met the World Health Organisation (WHO) criteria for a probable causal relationship, and two cases with a possible AGEP diagnosis based on the EuroSCAR AGEP validation score. Consequently, the EMA concluded that the product information of products containing enoxaparin should be amended to include the risk of AGEP.

 

Background of Safety Issue

AGEP typically has a rapid onset and resolves within a few weeks.^3,6,7 In the three published case of enoxaparin-induced AGEP, the reported time-to-onset ranged from two days to one week.^6,7 All cases documented skin recovery following enoxaparin discontinuation, with one case showing rapid recovery over several days. One case described localised periumbilical pustules at the injection site, while the other two cases involved diffuse febrile erythematous rashes and pustules not specifically at the injection site.

Patch testing and in vitro assays suggest that AGEP is a T-cell-mediated delayed hypersensitivity reaction to specific drugs or triggers.^3,6 Cross-reactivity between heparins have been frequently reported in delayed-type hypersensitivity.^7,8 Specifically, two published cases of enoxaparin-induced AGEP showed positive delayed intradermal test (IDT) results with cross-reactions to other heparins and a prior history of similar reactions.⁷ In addition, a case of AGEP induced by dalteparin (another LMWH) demonstrated cross-reactions to other LMWHs (enoxaparin, certoparin, reviparin, nadroparin), danaparoid, and fondaparinux, based on subcutaneous provocation testing performed six months later.⁸

The mainstay of AGEP management is discontinuing the causative drug.^3,6 As the condition is typically self-limiting, treatment focuses on symptomatic relief using topical steroids, antipyretics, and antihistamines. In more severe cases, oral corticosteroids may be beneficial in reducing hospital stay and morbidity.

 

Local Adverse Drug Reaction Reports⁹

To date, the NPRA has received a total of 548 reports with 861 adverse events suspected to be related to enoxaparin-containing products. The most frequently reported adverse events were pruritus (104 reports), urticaria (45), and rash (42).

Two (2) reports of AGEP following enoxaparin use have been reported to the NPRA. Enoxaparin was the only suspect drug listed in both reports, with one report involving concomitant use of mefenamic acid. The reported times to onset were 2 and 6 days, and both patients had recovered at the time of reporting.

 

Advice for Healthcare Professionals

• While NPRA is still reviewing this safety issue, be aware that AGEP is a severe cutaneous adverse reaction that can occur with enoxaparin use.
• Carefully review patients’ medication and allergy history prior to initiating enoxaparin, as cross-reactions among different LMWHs have been reported in the literature.
• Educate patients to closely watch for early signs and symptoms of AGEP (e.g., red patches with bumps under the skin, blisters, and fever) after starting enoxaparin. Advise them to stop taking the medication and seek immediate medical care if these signs and symptoms occur.
• If enoxaparin-induced AGEP is suspected, discontinue enoxaparin promptly and provide supportive treatment. Careful evaluation with clinical history and skin testing may guide safe alternative anticoagulant selection.
• Report all adverse events suspected to be related to the use of enoxaparin-containing products to the NPRA.

 

References:

1. National Pharmaceutical Regulatory Agency (NPRA). CLEXANE (enoxparin) [Package Insert]. QUEST3+ Product Search. 2023 June [cited 2025 Feb 3]. Available from: http://www.npra.gov.my.
2. National Pharmaceutical Regulatory Agency (NPRA). QUEST3+ Product Search [Internet]. 2025 [cited 2025 March 26]. Available from: https://www.npra.gov.my
3. Parisi R, Shah H, Navarini AA, Muehleisen B, Ziv M, Shear NH, Dodiuk-Gad RP. Acute Generalized Exanthematous Pustulosis: Clinical Features, Differential Diagnosis, and Management. Am J Clin Dermatol. 2023 Jul;24(4):557-575. Available from: https://doi.org/10.1007/s40257-023-00779-3
4. European Medicines Agency (EMA). Pharmacovigilance Risk Assessment Committee (PRAC): Minute of the meeting on 25-28 October 2021 [Internet]. 2022 July 21 [cited 2025 Feb 3]. Available from: https://www.ema.europa.eu/en/documents/minutes/minutes-prac-meeting-25-28-october-2021_en.pdf
5. European Medicines Agency (EMA). Scientific conclusions and grounds for the variation to the terms of the marketing authorisation(s): Enoxaparin [Internet]. 2021 Nov 11 [cited 2025 Feb 3]. Available from: https://www.ema.europa.eu/en/documents/scientific-conclusion/inhixa-h-c-psusa-00010833-202104-epar-scientific-conclusions-and-grounds-variation-terms-marketing-authorisation_en.pdf
6. Mozafari N, Farjami M, Jamali E, Rostami H, Ketabi Y. Acute localized exanthematous pustulosis caused by enoxaparin. Clin Exp Dermatol. 2021 Dec;46(8):1607-1609. Available from: https://doi.org/10.1111/ced.14805
7. Assier H, Gener G, Chosidow O, Wolkenstein P, Ingen-Housz-Oro S. Acute generalized exanthematous pustulosis induced by enoxaparin: 2 cases. Contact Dermatitis. 2021 Apr;84(4):280-282. Available from: https://doi.org/10.1111/cod.13734
8. Komericki P, Grims R, Kränke B, Aberer W. Acute generalized exanthematous pustulosis from dalteparin. J Am Acad Dermatol. 2007 Oct;57(4):718-21. Available from: https://doi.org/10.1016/j.jaad.2007.05.025
9. National Pharmaceutical Regulatory Agency (NPRA). The Malaysian National ADR Database (QUEST) [Internet]. 2025 [cited 2025 Feb 3]. Available from: https://www.npra.gov.my (access restricted)

 

Written by: Wo Wee Kee

Reviewed/Edited by: Choo Sim Mei, Dr Rema Panickar, Noor'ain Shamsuddin, Norleen Mohamed Ali