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, the NPRA shall not be held liable for any loss whatsoever arising from the use of or reliance on this publication.

Background

Doxycycline is a broad-spectrum antibiotic that is active against a wide range of gram-positive and gram-negative microorganisms. It is synthetically derived from oxytetracycline and is available as doxycycline hyclate (hydrochloride hemiethanolate hemihydrate). Doxycycline is primarily bacteriostatic and is thought to exert its antimicrobial effect by the inhibition of protein synthesis.¹

Fixed drug eruption (FDE) is a common drug-induced skin allergy where lesions characteristically recur at the same sites upon re-exposure to the causative drug. It is a delayed type IV hypersensitivity reaction mediated by memory CD8+ T-cells within the skin.^2-3

Trigger of the Safety Signal⁴

This signal was triggered from the Central Drugs Standard Control Organization of India, in the (WHO Pharmaceuticals Newsletter No. 3, 2022) which had approved the recommendation to revise the prescribing information leaflet for doxycycline to include fixed drug eruption as an adverse drug reaction. The National Coordination Centre – Pharmacovigilance Programme of India (NCCPvPI), Indian Pharmacopoeia Commission (IPC) reviewed 94 cases with the use of doxycycline, and found a strong causal relationship between the drug and the event.

Disproportionality Analysis^5-6

Disproportionality analysis in spontaneous reporting databases of adverse drug reactions (ADRs) refers to validated quantitative methods used for signal detection in pharmacovigilance. At NPRA, potential signals are detected using the WHO VigiLyze platform and information component (IC), a tool developed by the WHO-UMC (Uppsala Monitoring Centre) to measure the disproportionality in reporting. IC₀₂₅ is the lower end of a 95% credibility interval for the IC. An IC₀₂₅ value greater than zero indicates disproportionality.

Globally, there were approximately 604 cases of FDE associated with the use of doxycycline, with an IC₀₂₅ value of 4.3. Malaysia was the 4^th top country to report FDE, after Thailand, India and Singapore. Based on the cut-off date of 1^st April 2023, there were 21 reports received for FDE suspected to be related with doxycycline-use in Malaysia. The IC₀₂₅ result for this drug-ADR pair was 2.3, which required further assessment. 

A signal assessment into both local and global pharmacovigilance databases, scientific literature, information obtained from the product registration holder, and regulatory actions taken by other regulatory agencies showed the signal was validated and further risk minimisation measures were needed.

Signal Assessment Outcome⁷

The outcome of the review led to an NPRA directive [NPRA.600-1/9/13 (65) Jld 1] issued for product registration holders of doxycycline-containing products to update the local package inserts and consumer medication information leaflets (RiMUPs) to reflect the risk of fixed drug eruption (FDE).

Recommendations for Healthcare Professionals

• Be aware that skin reactions, such as fixed drug eruptions, have been reported rarely in association with the use of doxycycline.
• Educate patients to inform their doctor immediately if they become aware of any round or oval patches of redness and swelling of the skin which reappear at the same site each time doxycycline is taken.
• Report all suspected adverse events associated with doxycycline-containing products to the NPRA.

References:

1. National Pharmaceutical Regulatory Agency (NPRA). VIBRAMYCIN TABLET 100mg (doxycycline hydrochloride) [Package Insert]. QUEST3+ Product Search. 2023 Dec 26 [cited 2025 Jul 30]. Available from: http://www.npra.gov.my.
2. Oakley A. Fixed Drug Eruption [Internet]. DermNet. 2021 Mar [cited 2024 Jan 30] Available from: https://dermnetnz.org/topics/fixed-drug-eruption
3. Shiohara T. Fixed Drug Eruption [Internet]. UpTpDate. 2022 May 23 [cited 2024 Jan 30] Available from: https://www.uptodate.com/contents/fixed-drug-eruption
4. WHO Pharmaceuticals Newsletter No. 3, 2022 [Internet]. Geneva: World Health Organization; 2022 [cited 2023 Jan 30]. Licence: CC BY-NC-SA 3.0 IGO. Available from: https://www.who.int/publications/i/item/9789240057883
5. Uppsala Monitoring Centre (UMC). The WHO Global ICSR Database (VigiLyze) [Internet]. 2023 [cited 2023 Jan 5]. Available from: https://www.vigilyze.who-umc.org(access restricted)
6. Information from the Uppsala Monitoring Centre (UMC). The UMC Measures of Disproportionate Reporting [Internet]. 2016 [cited 2023 Jan 5]. Available from: https://who-umc.org/media/164041/measures-of-disproportionate-reporting_2016.pdf
7. National Pharmaceutical Regulatory Agency (NPRA). 194 MADRAC meeting minutes. 2025 Jun 26 [cited 2025 Jul 30] (access restricted)

Written by: Dr Vidhya Hariraj
Reviewed/Edited by: Dr Rema Panickar, Nora Ashikin Mohd Ali, Norleen Mohamed Ali