Fimasartan and local reports of liver injury

HSA would like to inform healthcare professionals about local cases of serious liver injury reported in patients who were treated with fimasartan. Fimasartan (Kanarb®, Boryung Pharmaceutical Co., Ltd) is an angiotensin II receptor blocker (ARB) that has been approved in May 2017 by HSA for the treatment of mild to moderate essential hypertension in Singapore.

 

Local cases

In 2019, HSA received four adverse event (AE) reports of liver injury suspected with the use of fimasartan, which were assessed to be serious by the reporting doctors. Three of the patients were hospitalised. The age of the patients ranged from 57 to 85 years old. Three were female and one was male. Other than hypertension, three patients had other underlying medical conditions including diabetes and hyperlipidaemia, and were taking other long term concomitant medicines. Two patients were reported to have taken other ARB in the past without any liver issues. Please refer to Table 1 for details.

All the patients were reviewed by gastroenterologists who assessed that the liver injuries could possibly be drug-induced, after ruling out other possible causes. The liver injuries reported were of varying severity, including two patients with elevated alanine aminotransferase (ALT) exceeding more than 1,000U/L and jaundice. The patterns of liver toxicity were either hepatocellular or mixed (hepatocellular and cholestatic). These cases of possible drug-induced liver injury (DILI) occurred between 51 to 151 days after the initiation of fimasartan.

All patients were reported to have recovered or were recovering after stopping fimasartan.

Table 1. Patients’ profiles and concomitant medicines

Age	Gender	Onset (days)	Took other ARB previously	Concomitant medicines* and duration taken
65	F	132	Yes (olmesartan for 10 years)	None
85	F	151	Not reported	Linagliptin, amlodipine, atorvastatin, clopidogrel & trimetazidine (taken for a long time); Doxazosin (1 and a half months after fimasartan); Ginseng (once/month for a few years)
70	M	51	Yes (olmesartan)	Fenofibrate and atorvastatin (2 - 3 years); Po Chai Pills, a traditional medicine (took for 2 days one month before DILI)
57	F	52	Not reported	Metformin, sitagliptin and atorvastatin (a few years); Traditional Chinese Medicines for gastric discomfort (two weeks before DILI)

 

Overseas cases

From 2012 to January 2020, there were 221 adverse drug reaction (ADR) reports associated with fimasartan captured in the World Health Organisation’s (WHO’s) global pharmacovigilance database describing liver AEs including increased hepatic enzymes such as ALT and aspartate aminotransferase (AST), increased blood bilirubin or gamma glutamyltransferase (GGTP) and hepatitis. The majority of the cases were from South Korea where the drug is primarily marketed. It is not marketed in countries such as the US or the EU.

A literature review of liver injury with fimasartan found one case report involving a 73-year-old man in South Korea reported by DH Park et al.¹ Other factors such as autoimmune diseases and infections were ruled out. Interestingly, the patient did not experience any AE with three other types of ARBs and DILI occurred only ten months after the first dose. Subsequently, the patient accidentally retook fimasartan for one month and the episode recurred. The authors commented that this strongly suggested that the cause of hepatotoxcity was fimasartan. The Roussel Uclaf Causality Assessment Method (RUCAM) scale score was eight for the first episode and 11 with the second episode of liver injury.

 

ARBs and DILI

An increase in hepatic enzymes (increased ALT, increased AST) was reported in the clinical trials of Kanarb® in the frequency of between 0.1% to less than 1%.²

ARBs as a drug-class have been associated with rare instances of acute liver injury, which more commonly presented as hepatocellular but occasionally cholestatic in nature.³ Individual case reports of clinically apparent liver injury with various ARBs have also been published in literature.  Bearing in mind the high volume of ARBs use in Singapore, to date, HSA has received 12 AE reports of liver injury with losartan (5), telmisartan (2), olmesartan (1) and valsartan (4).

 

Conclusion

As HSA continues to monitor reports of liver injury with the use of fimasartan closely, healthcare professionals are advised to take into consideration the above information when prescribing fimasartan. Some signs and symptoms of liver injury include fatigue or excessive tiredness, nausea and vomiting, abdominal pain and jaundice. Healthcare professionals are also encouraged to report any suspected cases of liver injury related to the use of fimasartan to HSA.

 

References

1. Medicine (Baltimore) 2017; 96(47): e8905
2. Singapore package insert for Kanarb® (approved 6 December 2018)
3. LiverTox®. Clinical and Research Information on Drug-Induced Liver Injury. Angiotensin II receptor antagonists (Updated 13 January 2017). Available at: https://www.ncbi.nlm.nih.gov/books/NBK548642/ (last accessed 21 February 2020)

Published: 5 May 2020

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