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.

Overview

Ethambutol is an antibiotic commonly used in combination with other drugs for the treatment of tuberculosis (TB) and Mycobacterium avium complex (MAC) infections.^1,2 In Malaysia, there are currently 5 ethambutol-containing products (3 single ingredient and 2 combination products) registered with the Drug Control Authority (DCA).³

Drug reaction with eosinophilia and systemic symptoms (DRESS) is a rare but potentially life-threatening adverse reaction characterised by fever, rash, lymphadenopathy, eosinophilia, and internal organ involvement potentially affecting the liver, lungs, and kidneys.^4-8 Symptoms of DRESS typically appear 2 to 8 weeks after starting the offending drug. The aetiology of DRESS is not fully understood but is believed to involve a complex interplay of factors, including delayed-type immunological reactions to drugs, genetic polymorphisms in drug-metabolising enzymes, genetic predisposition linked to human leukocyte antigen (HLA),  herpes virus reactivation, and activated Janus kinase-signal transducer and activator of transcription (JAK-STAT) pathway.^7,8

Background of the Safety Issue

The National Pharmaceutical Regulatory Agency (NPRA) has received updates from the European Medicines Agency (EMA) regarding the risk of DRESS associated with the use of ethambutol.^9-10 After reviewing the available evidence from the European pharmacovigilance database (EudraVigilance), literature, and cumulative analyses provided by the product registration holder (PRH), the EMA concluded a causal relationship between ethambutol and DRESS. Consequently, the EMA has decided that the product information of all ethambutol-containing products, both single and combination products, should be updated to include information about DRESS.

Cases of DRESS in association with ethambutol treatment have been reported during post-market use.^9-10 A Korean retrospective cohort study by Jung et al. (2019) examining antituberculosis (anti-TB) drugs reported a DRESS prevalence of 1.2% (15 cases) in 1,253 adult TB patients, of which ethambutol was the most frequently implicated drug (53.5%, 8 cases) in DRESS cases among first-line anti-TB drugs.⁴ Additionally, several case reports in the literature have identified ethambutol as a causative agent of DRESS, both as in single agent or in combination products.^5-8

According to Jung et al. (2019), the median latency period for DRESS was 37 days from the start of ethambutol treatment.⁴ Among 8 cases where ethambutol was implicated, 3 also involved other causative anti-TB drugs. Six cases improved after sequential rechallenging (which involved stopping all anti-TB drugs and reintroducing them one by one), while 2 improved with sequential dechallenging (which involved removing drugs one by one with monitoring). The median time from DRESS onset to drug discontinuation was 17.5 days in sequential rechallenging and 56.5 days for sequential dechallenging.

Identifying the causative anti-TB drug is often challenging due to the combined use of anti-TB drugs.⁷ Jung et al. (2019) highlighted that dechallenge and rechallenge require a proactive approach, as discontinuing first-line anti-TB drugs and switching to second-line regimens can reduce effectiveness, increase toxicity risks, and extend treatment to up to 2 years.⁴ Considering the long latency period of DRESS, it is recommended to immediately discontinue all anti-TB drugs followed by sequential rechallenging to identify the causative drug.^4,5,7,8 Patch testing with anti-TB drugs may assist in the drug assessment before rechallenge.

Adverse Drug Reaction Reports¹¹

The NPRA has received a total of 778 reports with 1,347 adverse events suspected to be related to ethambutol-containing products. Of these, 38 cases reported DRESS following the use of ethambutol. Four reports listed ethambutol as the single suspected drug, although 2 of these cases also reported concomitant use of other anti-TB drugs. Another 4 cases listed ethambutol as an interacting drug. In the remaining cases where ethambutol was suspected, all patients were simultaneously taking other anti-TB drugs and reported more than 1 suspected drug, including other anti-TB drugs and antibiotics.

The reported time to onset ranged from days to 3 months. Of the 38 cases, 31 cases were reported to be recovering, while 3 had an unknown outcome at the time of reporting. Three cases reported a fatal outcome and 1 case had not recovered at the time of reporting, all involving multiple suspected drugs. 

Advice for Healthcare Professionals

• Be aware that DRESS is a severe skin adverse reaction that can occur with anti-TB drugs, including ethambutol.
• Be vigilant when starting anti-TB therapy, including ethambutol:
  • Remind patients of the long latency period of DRESS (about 2–8 weeks).
  • Educate patients to closely watch for delayed symptoms of DRESS, including generalised rash, fever, and enlarged lymph nodes.
  • Advise patients to stop taking anti-TB drugs and seek immediate medical care if symptoms occur.
• If a patient presents with any signs and symptoms suggestive of DRESS, promptly discontinue anti-TB drugs, including ethambutol, and refer to a dermatologist for DRESS management.
• Sequential rechallenging with monitoring can help identify the causative drug. If ethambutol is identified as the causative drug, withdraw ethambutol and consider alternative treatment (as appropriate).
• Report all suspected adverse events associated with the use of anti-TB products, including ethambutol, to the NPRA.

References:

1. National Pharmaceutical Regulatory Agency (NPRA). Ethol Tablet 400mg (ethambutol) [Package Insert]. QUEST3+ Product Search. 2021 Jan [cited 2024 Jul 18].Available from: http://www.npra.gov.my.
2. National Pharmaceutical Regulatory Agency (NPRA). AkuriT-4 TABLET (rifampicin, isoniazid, pyrazinamide, ethambutol) [Package Insert]. QUEST3+ Product Search. 2020 Jun 4 [cited 2024 Jul 18].Available from: http://www.npra.gov.my.
3. National Pharmaceutical Regulatory Agency (NPRA). QUEST3+ Product Search [Internet]. 2024 [cited 2024 Jul 18]. Available from: https://quest3plus.bpfk.gov.my/pmo2/index.php
4. Jung HY, Park S, Shin B, Lee J-H, Lee SJ, Lee MK, Lee W-Y, Yong SJ, Kim S-H. Prevalence and Clinical Features of Drug Reactions With Eosinophilia and Systemic Symptoms Syndrome Caused by Antituberculosis Drugs: A Retrospective Cohort Study. Allergy Asthma Immunol Res. 2019;11(1):90-103. Available from: https://doi.org/10.4168/aair.2019.11.1.90
5. Jung ES, Choi B, Choi HS, Kim BH, Ha M, Shin D, Park JS, Lee JR, Seo Y-H, Park YS. Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS) Syndrome Induced by Ethambutol and Rifampin. Infect Chemother. 2012; 44(3):197-200. Available from: http://dx.doi.org/10.3947/ic.2012.44.3.197
6. Kaswala DH. Drug Rash with Eosinophilia and Systemic Symptoms Syndrome Due to Anti‑TB Medication. J Family Med Prim Care. 2013; Volume 2 : Issue 1. Available from: https://doi.org/10.4103/2249-4863.109958
7. Kapur A, Rehan HS. Drug Reaction with Eosinophilia and Systemic Symptoms Syndrome Associated with Ethambutol use: A Case Report. Curr Drug Saf. 2019; 14(3), 249-251. Available from: https://doi.org/10.2174/1574886314666190307150757
8. Adhikari YR, Bhattarai M, Baral B, Jha S, Subedi P, Karki R, Baral A, Sharma P, Kharel A, Paudel BS. Drug reaction with eosinophilia and systemic symptoms syndrome secondary to isoniazid and ethambutol: a case report and literature review. Ann Med Surg (Lond). 2023 Apr 18;85(5):2180-2185. Available from: https://doi.org/10.1097/ms9.0000000000000683
9. European Medicines Agency (EMA). PRAC recommendations on signals: Adopted at the 8-11 April 2024 PRAC meeting [Internet]. 2024 May 6 [cited 2024 Jul 17]. Available from: https://www.ema.europa.eu/en/documents/other/prac-recommendations-signals-adopted-8-11-april-2024-prac-meeting_en.pdf
10. European Medicines Agency (EMA). Pharmacovigilance Risk Assessment Committee (PRAC): Minutes of PRAC meeting on 8-11 April 2024 [Internet]. 2024 Jun 11 [cited 2024 Aug 5]. Available from: https://www.ema.europa.eu/en/documents/minutes/minutes-prac-meeting-8-11-april-2024_en.pdf
11. National Pharmaceutical Regulatory Agency (NPRA). The Malaysian National ADR Database (QUEST) [Internet]. 2024 [cited 2024 Oct 18]. Available from: https://www.npra.gov.my (access restricted)

Written by: Nafiza Mohd. Ismail

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