DISCLAIMER: This publication is intended for healthcare professionals. The information provided aims to update on medication safety issues and should not substitute clinical judgment. 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 arising from the use of or reliance on this publication.

Overview of Products

Linezolid is an oxazolidinone antibiotic that is widely used to treat Gram-positive bacterial infections, especially those caused by methicillin-resistant Staphylococcus aureus (MRSA).^1-2 In Malaysia, eight (8) products containing linezolid are currently registered with the Drug Control Authority (DCA) and are available as oral tablets or solution for infusion.³

Linezolid is approved for the treatment of vancomycin-resistant Enterococcus faecium infections, nosocomial pneumonia, community-acquired pneumonia, and certain skin and skin structure infections.⁴ More recently, it has also been approved for the treatment of drug-resistant tuberculosis caused by Mycobacterium tuberculosis in combination with other tuberculosis medicines.⁵

Overview of Safety Concerns

Rhabdomyolysis is a clinical syndrome resulting from the breakdown of skeletal muscle, leading to the release of intracellular contents such as myoglobin, creatine kinase (CK), electrolytes, and sarcoplasmic proteins into the bloodstream.⁶ Patients typically present with muscle pain, weakness, dark-coloured urine due to myoglobinuria, and localised swelling. Diagnosis is largely supported by laboratory findings, particularly markedly elevated serum CK levels, often exceeding five (5) times the upper limit of normal.

Source of Safety Issue

The National Pharmaceutical Regulatory Agency (NPRA) learned from the Japan PMDA about the risk of rhabdomyolysis associated with linezolid use.^7-8 The PMDA reviewed both local and international reports of rhabdomyolysis associated with linezolid. In Japan, three (3) cases have been reported, including one with a plausible causal link, as well as one death for which causality could not be established. Following expert consultation on causality and the need for regulatory action, a revision to the product information was warranted.

Background of the Safety Issue

Linezolid-associated rhabdomyolysis is thought to be linked to mitochondrial dysfunction, as the mitochondrial ribosome closely resembles the bacterial ribosome.¹ In a monitored case, inhibition of mitochondrial protein synthesis was observed, with mitochondrial function declining after starting linezolid and improving upon discontinuation. However, case reports suggest that this reaction may be idiosyncratic rather than dose-dependent.² Two (2) patients developed marked CK elevations and one (1) case occurred despite subtherapeutic linezolid levels. Rhabdomyolysis is a rare adverse effect of linezolid, primarily documented in a handful of case reports rather than large-scale studies. Onset typically occurs within days to months after starting therapy, with CK elevations serving as an early signal.^1-2 Resolution has consistently been reported following drug discontinuation.

Local Adverse Drug Reaction Reports⁹

To date, the NPRA has received 131 reports comprising 194 adverse events suspected to be associated with linezolid-containing products. The most frequently reported events were thrombocytopenia (38), platelet count decreased (16), rash (9), rash maculo-papular (7) and vomiting (6). Of these, no reports were received associated with rhabdomyolysis.

Regulatory Actions

The NPRA has completed a review of the potential risk of rhabdomyolysis associated with linezolid. On 15 January 2026, a directive [NPRA.600-1/9/13(74) Jld 1] was issued for all registration holders of linezolid to update the local package inserts and consumer medication information leaflets (Risalah Maklumat Ubat untuk Pengguna) to reflect this safety information.

Advice for Healthcare Professionals

• Be aware that rhabdomyolysis has been reported with linezolid therapy and should be considered in the differential diagnosis of patients presenting with muscle pain, weakness, dark urine, or unexplained elevations in CK.
• For patients receiving prolonged linezolid treatment, perform periodic assessment of CK levels and monitor for early signs of muscle toxicity.
• For patients at high risk or those demonstrating early adverse effects, consider an alternative antibacterial therapy to prevent complications such as acute renal failure.
• Discontinue linezolid promptly if rhabdomyolysis is suspected, and initiate appropriate supportive management, including adequate hydration and close monitoring of renal function
• Report all suspected adverse events related to linezolid-containing products to the NPRA.

References:

1. Carrell MW, Choi H, Min S, Hwang S, Park H, Song T, et al. Rhabdomyolysis in a Patient Treated with Linezolid for Extensively Drug-Resistant Tuberculosis. Clin Infect Dis. 2012;54(11):1624-1627. Available from: https://doi.org/10.1093/cid/cis293.
2. Lechner AM, Past E, Porsche U, Kern JM, Hoppe U, Pretsch I. Two cases of serious rhabdomyolysis during linezolid treatment. Infection. 2017;45(4):563-566. Available from: https://doi.org/10.1007/s15010-016-0978-8.
3. National Pharmaceutical Regulatory Agency (NPRA). QUEST3+ Product Search [Internet]. 2025 [cited 2025 Dec 19). Available from https://www.npra.gov.my
4. National Pharmaceutical Regulatory Agency (NPRA). ZYVOXE linezolid) [Package Insert]. QUEST3+ Product Search. 2025 Nov [cited 2025 Dec 19]. Available from: https://www.npra.gov.my
5. National Pharmaceutical Regulatory Agency (NPRA). ZOBERIUM (LINEZOLID) [Package Insert]. QUEST3+ Product Search. 2025 Dec [cited 2025 Dec 19]. Available from: https://www.npra.gov.my
6. Rout P, Chippa V, Adigun R. Rhabdomyolysis. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2025 Jan– [updated 2025 Jul 7]. Available from: https://www.ncbi.nlm.nih.gov/books/NBK448168
7. Pharmaceuticals and Medical Devices Agency (PMDA). Summary of investigation results: Linezolid. [Internet] 2024 Feb 15 [cited 2025 Dec 19]. Available from: https://www.pmda.go.jp/files/000266907.pdf
8. Pharmaceuticals and Medical Devices Agency (PMDA). Revision of PRECAUTIONS: Linezolid [Internet] 2024 Feb 15 [cited 2025 Dec 19]. Available from: https://www.pmda.go.jp/files/000266903.pdf
9. National Pharmaceutical Regulatory Agency (NPRA). The Malaysian National ADR Database (QUEST) [Internet]. 2025 [cited 2025 Dec 19]. Available from: https://www.npra.gov.my (access restricted)

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