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LiverTox: Clinical and Research Information on Drug-Induced Liver Injury [Internet]. Bethesda (MD): National Institute of Diabetes and Digestive and Kidney Diseases; 2012-.

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LiverTox: Clinical and Research Information on Drug-Induced Liver Injury [Internet].

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Artesunate

Last Update: August 5, 2024.

OVERVIEW

Introduction

Artesunate for injection is an antimalarial drug used as the initial treatment of severe malaria in both adults and children. Typically, infusions of artesunate are continued for 2 to 7 days until the patient can tolerate oral antimalarial therapy. Artesunate therapy is associated with mild-to-moderate serum aminotransferase elevations during therapy but has not been linked instances of clinically apparent liver injury.

Background

Artesunate (ar tes’ sun ate) is an intravenously administered antimalarial agent that is used in the initiation of treatment for severe malaria and is continued until the patient can tolerate an appropriate effective oral antimalarial therapy. Artesunate is rapidly metabolized to its active ingredient, dihydroartemisinin (DHA), which induces oxidative stress and inhibits protein and nucleic acid synthesis in plasmodium species that cause malaria. Artesunate has been shown to decrease in-hospital mortality of severe malaria by at least 40% and was approved for this indication in the United States in 2020. Artesunate is available in powdered form in single use vials of 110 mg for reconstitution under the name Artesunate. The recommended dose regimen is 2.4 mg per kg body weight intravenously at 0, 12, and 24 hours followed by once daily until oral therapy can be initiated. Artesunate treatment should be followed by an appropriate oral regimen for malaria. In prelicensure trials, serious adverse events included acute renal failure (9%), hemolysis (7%), and jaundice (2.3%). Artesunate can also cause hypersensitivity reactions including rash, urticaria, anaphylaxis, and Stevens Johnson syndrome. Artesunate given intravenously caused fetal harm in rats, but it is recommended to be given in pregnant women because of the greater harm to mother and child of inadequately treated, severe malaria.

Hepatotoxicity

In an open label study of severe malaria in 104 patients in the United States, elevations in ALT occurred in 27% of subjects, AST in 49%, and bilirubin in 17%. These abnormalities, however, were attributable to the hemolysis and liver involvement that are common in patients with acute, severe malaria. None of the elevations were attributed to drug induced liver injury. Since licensure of artesunate for injection and its more widescale clinical use in the United States, there have been no reports of acute liver injury attributed to its use.

Likelihood score: E (unlikely cause of clinically apparent liver injury).

Mechanism of Injury

The causes of liver test abnormalities during artesunate therapy of malaria are not known and are more likely due to the underlying severe infection rather than the infused drug. Artesunate can cause hypersensitivity reactions including Stevens Johnson syndrome, and liver injury might be a part of the immunoallergic reaction.

Outcome and Management

The product label for artesunate does not recommend monitoring of routine liver tests during therapy and the duration of treatment is usually brief, so that there is generally no chance to respond to occurrence of liver abnormalities and jaundice, which are frequent manifestations of acute severe malaria and resolve rapidly with successful therapy.

Drug Class: Antimalarial Agents

Related Artemisinin Derivative: Artemisinin

PRODUCT INFORMATION

REPRESENTATIVE TRADE NAMES

Artesunate – Artesunate®

DRUG CLASS

Antimalarial Agents

COMPLETE LABELING

Product labeling at the Food and Drug Administration

CHEMICAL FORMULA AND STRUCTURE

DRUGCAS REGISTRY NUMBERMOLECULAR FORMULASTRUCTURE
Artesunate 88495-63-0 C19-H28-O8 image 135022215 in the ncbi pubchem database

SELECTED ANNOTATED BIBLIOGRAPHY

References updated: 05 August 2024

  • FDA. Clinical Review. 2020.
  • https://www​.accessdata​.fda.gov/drugsatfda_docs​/nda/2020/213036Orig1s000MultidisciplineR.pdf
    (FDA Summary of the data the safety and efficacy of artesunate for injection, submitted in support of the application for approval as therapy of severe malaria, mentions that in studies of 102 patients with severe malaria treated in the US, ALT elevations arose in 2.9%, AST in 26%, and bilirubin in 13.7%, but AST and bilirubin might have been raised because of hemolytic anemia; nevertheless, one subject died of acute liver failure, no details provided).
  • CDC. Malaria. https://www​.cdc.gov/malaria​/hcp/clinical-guidance/index.html
    (CDC website with information on the prevalence, clinical features, diagnosis, and management of malaria also has information on how to obtain intravenous artesunate for treatment of acute severe malaria).
  • Hess KM, Goad JA, Arguin PM. Intravenous artesunate for the treatment of severe malaria. Ann Pharmacother. 2010;44:1250-8. [PubMed: 20551300]
    (Systematic review of the efficacy and safety of intravenous artesunate as therapy of severe malaria states that “it is considered to be well tolerated”; no mention of ALT elevations or hepatoxicity).
  • Sinclair D, Donegan S, Isba R, Lalloo DG. Artesunate versus quinine for treating severe malaria. Cochrane Database Syst Rev. 2012;2012:CD005967. [PMC free article: PMC6532684] [PubMed: 22696354]
    (Systematic review and meta-analysis of 8 controlled trials of artesunate vs quinine for severe malaria found that artesunate led to lower rates of mortality in both adults [n=1664: 14.7% vs 24%] and children [n=5765: 8% vs 11%] and that “with exception of hypoglycemia and tinnitus, all adverse events could be attributed to malaria”).
  • Twomey PS, Smith BL, McDermott C, Novitt-Moreno A, McCarthy W, Kachur SP, Arguin PM. Intravenous artesunate for the treatment of severe and complicated malaria in the United States: clinical use under an investigational new drug protocol. Ann Intern Med. 2015;163:498-506. [PMC free article: PMC4627466] [PubMed: 26301474]
    (Among 102 adults with acute severe and complicated malaria treated in the US with intravenous artesunate, most patients began to improve within 3 days and the mortality rate was 7%, all patients dying having presented with moderate-to-severe liver injury; the overall adverse event rate was 92% and the major adverse events were anemia [65%], elevations in AST [49%], ALT [27%], and bilirubin [17%], and acute renal failure [10%], the serum enzyme elevations being most likely from hemolytic anemia and the underlying malaria infection).

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