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

 

Overview of Products

Sunitinib malate is an oral, multi-targeted tyrosine kinase inhibitor that inhibits receptors, including vascular endothelial growth factor (VEGF) receptors and platelet-derived growth factor (PDGF) receptors, which contribute to tumour angiogenesis and cell proliferation.^1,2

In Malaysia, sunitinib is approved for the treatment of gastrointestinal stromal tumour following disease progression or intolerance to imatinib, advanced renal cell carcinoma, and progressive unresectable or metastatic pancreatic neuroendocrine tumours in adult patients.³ To date, a total of 16 sunitinib-containing products in oral dosage form have been registered with the Drug Control Authority (DCA).⁴

 

Overview of Safety Concern                          

Hyperammonaemic encephalopathy is a potentially fatal complication that may be associated with chemotherapy.^1,5 It is characterised by an acute or subacute alteration in mental status, ranging from mild cognitive impairment and sleep–wake disturbances in mild cases, to agitation, psychosis, and coma in moderate to severe cases.⁵ This condition is accompanied by markedly elevated serum ammonia levels and may occur in the absence of underlying liver disease.

Ammonia is a highly neurotoxic compound produced during nitrogen metabolism.^1,6 Under normal physiological conditions, ammonia is primarily detoxified in the liver through the urea cycle, where it is converted to urea and subsequently excreted in the urine.

 

Source of Safety Issue

The National Pharmaceutical Regulatory Agency (NPRA) has received information from the Therapeutic Goods Administration (TGA) in Australia regarding the risk of hyperammonaemic encephalopathy associated with sunitinib.⁷ The TGA has requested updates to the product information to reflect this risk. The warning advises healthcare professionals to monitor serum ammonia levels in patients who develop unexplained lethargy or changes in mental status to initiate appropriate clinical management when necessary.

Prior to the TGA’s regulatory action, the European Medicines Agency (EMA) had assessed the Periodic Safety Update Report (PSUR) for sunitinib.⁸ Based on evidence from published literature and spontaneous safety reports, including cases demonstrating a close temporal relationship, positive dechallenge, and/or rechallenge, the Pharmacovigilance Risk Assessment Committee (PRAC) concluded that a causal relationship between sunitinib and hyperammonaemic encephalopathy is at least a reasonable possibility. Consequently, the PRAC recommended updates to the product information to reflect this risk.

 

Background of Safety Issue

The association between sunitinib and hyperammonaemia has not been fully elucidated, and the underlying mechanism remains unclear.^1,2 One proposed theory is that sunitinib’s anti-angiogenic properties may disrupt vascular permeability, including that of the blood-brain barrier, allowing increased amounts of ammonia to enter the central nervous system.² Additionally, as sunitinib is primarily metabolised by the liver via cytochrome CYP3A4, a reduction in hepatic reserve may further contribute to the development of hyperammonaemia.

Notably, a higher incidence of toxicity associated with sunitinib has been reported in Asian populations compared with Western populations.¹ Ethnic differences and genetic polymorphisms have been proposed as potential contributing factors to this disparity. The majority of reported hyperammonaemic encephalopathy cases occur approximately 10–17 days after initiation of sunitinib therapy, although delayed onset of up to 44 days has been reported.^1,2,6 Symptoms typically resolved within 1–12 days following discontinuation of sunitinib and initiation of supportive treatment.

 

Local Adverse Drug Reaction Reports⁹

To date, the NPRA has received a total of 203 adverse drug reaction reports, comprising 275 adverse events, associated with the use of sunitinib in Malaysia. No reports of hyperammonaemic encephalopathy have been received. Six cases of lethargy were reported. However, these cases did not include any other adverse effects related to patients’ mental status. In addition, no information on serum ammonia levels was available to support an association with hyperammonaemic encephalopathy. 

 

Regulatory Action

NPRA completed a review of this safety issue and a directive [Ruj. Kami: NPRA.600-1/9/13(5) Jld.2] had been issued for all registration holders of products containing sunitinib 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 hyperammonaemic encephalopathy has been reported in association with sunitinib use.
• Measure serum ammonia levels in patients receiving sunitinib who present with unexplained lethargy or changes in mental status.
• If hyperammonaemic encephalopathy is suspected, consider discontinuing sunitinib and initiating appropriate supportive treatment, such as lactulose. Haemodialysis may be considered in selected cases.
• Report all suspected adverse events associated with sunitinib to the NPRA.

 

References

1. Lee NR, Yhim HY, Yim CY, Kwak JY, Song EK. Sunitinib-Induced Hyperammonemic Encephalopathy in Gastrointestinal Stromal Tumors. Ann Pharmacother. 2011 Oct;45:e56. Available from: https://doi.org/10.1345/aph.1Q038
2. Hayakawa T, Funakoshi S, Hamamoto Y, Hirata K, Kanai T. Sunitinib-induced hyperammonemic encephalopathy in metastatic gastrointestinal stromal tumors: A case report. World J Clin Cases. 2023 Nov 6;11(31):7629-7634. Available from: https://doi.org/10.12998/wjcc.v11.i31.7629
3. National Pharmaceutical Regulatory Agency (NPRA). SUTENT (sunitinib) [Package Insert]. QUEST3+ Product Search. 2025 September 30 [cited 2026 January 8]. Available from: https://www.npra.gov.my
4. National Pharmaceutical Regulatory Agency (NPRA). QUEST3+ Product Search [Internet]. 2026 [cited 2026 January 8). Available from https://www.npra.gov.my
5. Briard JN, Lezaic N, Keezer MR. Pearls & Oy-sters: Chemotherapy-associated hyperammonemic encephalopathy. Neurology. 2020;94:e874-e877. Available from: https://doi.org/10.1212/WNL.0000000000009004
6. Haroon S, Ko S, Wong A, Tan PS, Lee E, Lau T. Sunitinib-associated hyperammonemic encephalopathy successfully managed with higher intensity conventional hemodialysis: a case report. Medicine (Baltimore). 2021;100(5):e24313. Available from: https://doi.org/10.1097/MD.0000000000024313
7. Therapeutic Goods Administration (TGA). Product Information safety updates - March 2025 [Internet] 2025 Mac 31 [cited 2026 Jan 12]. Available from: https://www.tga.gov.au/news/safety-updates/product-information-safety-updates-march-2025
8. European Medicines Agency (EMA). Scientific conclusions and grounds for the variation to the terms of the marketing authorisation(s). Active substance: sunitinib [Internet] 2024 Jan 2025 [cited 2026 Jan 12]. Available from: https://www.ema.europa.eu/en/documents/scientific-conclusion/sutent-h-c-psusa-00002833-202304-epar-scientific-conclusions-grounds-variation-terms-marketing-authorisation_en.pdf
9. National Pharmaceutical Regulatory Agency. The Malaysian National ADR Database [Internet]. 2026 [cited 2026 Jan 12. Available from: https://www.npra.gov.my

 

Written by: Noor'ain Shamsuddin

Reviewed/Edited by: Lim Sze Gee, Dr Rema Panickar, Norleen Mohamed Ali