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)

Aciclovir is an antiviral drug indicated for the treatment of herpes simplex, herpes zoster (shingles), and varicella (chickenpox) infections, and for the prophylaxis of herpes simplex infections.^1,2 Valaciclovir, the L-valine ester prodrug of aciclovir, is rapidly and almost completely converted to aciclovir and valine following oral administration.^3,4 It is indicated for the treatment of herpes simplex and herpes zoster infections, as well as for the prevention of recurrent herpes simplex infections.⁴ Both drugs exert their antiviral activity by inhibiting the viral DNA polymerase enzyme, thereby suppressing viral DNA synthesis and replication.^3,4

In Malaysia, there are currently 31 aciclovir-containing products (oral and injectable dosage forms) and 3 valaciclovir-containing products (oral dosage forms) registered with the Drug Control Authority (DCA).⁵

 

Overview of Safety Concern

Acute generalised exanthematous pustulosis (AGEP) is a severe cutaneous adverse reaction (SCAR) characterised by the rapid onset of widespread, non-follicular sterile pustules arising on an erythematous base, accompanied by fever, leukocytosis, elevated C-reactive protein levels, and neutrophilia.⁶ Mucosal involvement occurs in fewer than 20% of cases, is usually mild, and is generally limited to a single site, most commonly the oral mucosa.

 

Source of Safety Concern

The National Pharmaceutical Regulatory Agency (NPRA) received information from Japan’s Pharmaceuticals and Medical Devices Agency (PMDA) regarding the risk of AGEP associated with the use of aciclovir (oral and injectable dosage forms) and valaciclovir.⁷ The PMDA reviewed relevant AGEP cases reported in Japan’s safety databases as well as cases submitted by the marketing authorisation holder, identifying instances where a causal relationship was considered reasonably possible. Following consultation with expert advisors on causality assessment, the PMDA concluded that revisions to the product information for these systemic formulations were necessary.

 

Background of Safety Issue

Although AGEP may be triggered by bacterial, viral, or parasitic infections, it is most frequently caused by drugs, notably antibiotics.⁶ The overall prognosis is favourable, with a low reported mortality rate of less than 5%.⁸

A World Health Organisation (WHO) newsletter reported that cases of AGEP associated with aciclovir and valaciclovir were disproportionately reported in the WHO global database based on Information Component (IC) analysis, indicating that these drug-reaction pairs were reported more frequently than expected.³ Analysis of AGEP cases reported to the United States Food and Drug Administration (US FDA) Adverse Event Reporting System (FAERS) also showed that both aciclovir and valaciclovir were significantly associated with an increased risk of AGEP.⁹

The exact pathophysiology of AGEP remains unclear. However, it is widely considered a T cell-mediated hypersensitivity reaction with a sterile neutrophilic inflammatory response, most commonly triggered by medications.⁶ This is supported by positive patch tests, positive delayed intradermal tests, and positive in vitro assays in response to the suspected causative drugs.

The time to onset from drug exposure ranges from several hours to 11 days, but typically occurs within 48 hours.⁶ The reported onset ranges up to 3 weeks for aciclovir,^3,10 and up to 6 months for valaciclovir.³ Resolution is usually observed within 15 days.^6,10,11

Early-stage AGEP can mimic an aggressive herpes eruption or, if mucous membranes are involved, Stevens-Johnson syndrome/toxic epidermal necrolysis (SJS/TEN).³ Misdiagnosis as a worsening herpes infection may lead to inappropriate escalation of antiviral therapy, potentially exacerbating the reaction. Histopathological findings may help differentiate AGEP from other SCARs.

 

Local Adverse Drug Reaction Reports¹²

To date, the NPRA has received a total of 517 adverse drug reaction reports involving 888 adverse events suspected to be related to aciclovir-containing products. For valaciclovir, six reports with 14 adverse events were received. The most frequently reported adverse events for aciclovir were pruritus (62), rash (56), and urticaria (47). For valaciclovir, all reported adverse events occurred once each (n=1), including rash, swelling, and insomnia. One case of AGEP associated with oral aciclovir has been reported locally, while no cases have been reported for valaciclovir.

 

Advice for Health Care Professionals

• While NPRA is still reviewing this safety issue, be aware of the risk of AGEP following the use of products containing aciclovir (oral and injectable dosage forms) or valaciclovir.
• Do not confuse AGEP with a worsening herpes eruption. If AGEP is suspected, consider discontinuing the antiviral immediately, as continuing treatment will worsen clinical outcomes.
• Consider histopathology (skin biopsy) if there is diagnostic uncertainty between severe AGEP with mucosal involvement and SJS/TEN.
• Educate patients to seek medical attention immediately if they develop fever, widespread redness of the skin, or small, pus-filled rashes.
• Identification of the causative agent is essential for effective management. Patch testing may be useful in assessing drug causality in AGEP.
• Report all adverse events suspected to be related to the use of aciclovir and valaciclovir to NPRA.

 

References:

1. National Pharmaceutical Regulatory Agency (NPRA). ZOVIRAX DISPERSIBLE TABLET 200MG (aciclovir) [Package Insert]. QUEST3+ Product Search. 2026 July 26 [cited 2026 Apr 3]. Available from: http://www.npra.gov.my
2. National Pharmaceutical Regulatory Agency (NPRA). ZOVIRAX POWDER FOR I.V. INFUSION (aciclovir) [Package Insert]. QUEST3+ Product Search. 2026 Aug 8 [cited 2026 Apr 3]. Available from: http://www.npra.gov.my
3. Westerberg C. Aciclovir or valaciclovir - Acute generalised exanthematous pustulosis [Internet]. WHO Pharmaceuticals Newsletter 2020 No.4. [cited 2026 Apr 3]. Available from: https://iris.who.int/server/api/core/bitstreams/625b5804-54bc-4255-828c-e2944457c47f/content
4. National Pharmaceutical Regulatory Agency (NPRA). VALTREX TABLET (valaciclovir) [Package Insert]. QUEST3+ Product Search. 2022 Sep 28 [cited 2026 Apr 3]. Available from: http://www.npra.gov.my
5. National Pharmaceutical Regulatory Agency (NPRA). QUEST3+ Product Search [Internet]. 2026 [cited 2026 June 3]. Available from: https://www.npra.gov.my
6. De Groot AC. Results of patch testing in acute generalized exanthematous pustulosis (AGEP): A literature review. Contact Dermatitis. 2022 Feb 20;87(2):119-141. Available from: https://doi.org/10.1111/cod.14075
7. Pharmaceuticals and Medical Devices Agency (PMDA). Summary of Investigation Results. Aciclovir (oral dosage form and injection), Valaciclovir hydrochloride [Internet]. 2026 Feb 10 [cited 2026 Apr 3]. Available from: https://www.pmda.go.jp/files/000279126.pdf
8. Tetart F, Walsh S, Milpied B, Gaspar K, Vorobyev A, Tiplica GS, Didona B, Welfringer-Morin A, Kucinskiene V, Bensaid B, Marvanova E, Salavastru C, Brezinova E, Chua SL, Lovgren ML, Hammers CM, Barbaud A, Mortz CG, Horvath B, Meyersburg D, Lebrun-Vignes B, Bodemer C, Brüggen MC, French LE, Ingen-Housz-Oro S. Acute generalized exanthematous pustulosis: European expert consensus for diagnosis and management. J Eur Acad Dermatol Venereol. 2024 Jul 18;38(11):2073-2081. Available from: https://doi.org/10.1111/jdv.20232
9. Que H, Zheng X, Li X, Wang W. Risk Factors for Drug-Induced Acute Generalized Exanthematous Pustulosis(AGEP) from 2004 to 2024: A Real-World Study Based on the FAERS. Clin Cosmet Investig Dermatol. 2025 Oct 28;18:2835-2845. Available from: https://doi.org/10.2147/ccid.s544845
10. Serra D, Ramos L, Brinca A, Gonçalo M. Acute generalized exanthematous pustulosis associated with acyclovir, confirmed by patch testing. Dermatitis. 2012 Apr 1;23(2):99-100. Available from: https://doi.org/10.1097/der.0b013e31824a603d
11. Kubin ME, Jackson P, Riekki R. Acute Generalized Exanthematous Pustulosis Secondary to Acyclovir Confirmed by Positive Patch Testing. Acta Derm Venereol. 2016 Feb 23;96(6):860-861. Available from: https://doi.org/10.2340/00015555-2352
12. National Pharmaceutical Regulatory Agency (NPRA). The Malaysian National ADR Database (QUEST) [Internet]. 2026 [cited 2026 May 14]. Available from: https://www.npra.gov.my (access restricted)

 

Written by: Wo Wee Kee

Reviewed/Edited by: Lim Sze Gee, Dr Rema Panickar, Noor'ain Shamsuddin, Norleen Mohamed Ali