Artesun Adverse Reactions

The most important reported side effect of artesunate is a rare severe allergic reaction (estimated risk approximately 1 in 3000 patients), which has involved urticarial rash as well as other symptoms, including hypotension, pruritus, oedema, and/or dyspnoea. A potentially serious delayed hemolysis (Post-Artesunate Delayed Hemolysis, PADH) has been reported frequently in travelers and in children. See following text.
More common minor side effects associated with IV administration have included dizziness, light-headedness, rash, and taste alteration (metallic/bitter taste). Transient elevation in liver transaminases, nausea, vomiting, anorexia and diarrhea have also been commonly reported, however it is uncertain whether such events have been symptoms of severe malaria.
Adverse events considered at least possibly related to artesunate are listed as follows by body system, organ class and absolute frequency. Frequencies are defined as very common (>1/10), common (1/100-1/10), uncommon (1/1,000-1/100), rare (1/10,000-1/1,000), and very rare (<1/10,000).
Blood and lymphatic systems disorders: Very common: Post-treatment haemolytic anaemia in travelers, mild and transient decrease in reticulocyte count.
Common to very common: Post-treatment haemolytic anaemia in endemic areas.
Uncommon: Neutropenia and anaemia (both occasionally severe), thrombocytopenia, agranulocytosis, reticulocytopenia, erythroblastopenia.
Very rare: Pure red cell aplasia.
Nervous system disorders: Common: Dizziness, light-headedness, headache, insomnia, tinnitus (with or without decrease in auditory function).
Very rare: Peripheral neuropathy (or paraesthesia).
Cardiovascular disorder: Uncommon: Rhythm and conduction disorders. Some cases of cardiac adverse events and particularly rhythm (bradycardia, sinus arrhythmia) and conduction disorders (QTc lengthening, abnormal sinoatrial conduction) have been recently described. One case of cardiac arrest has been reported in a context of severe malaria with multi-organ failure but the causality by Artesunate has not been established. Whether or not cardiovascular events should be attributed to artesunate or to severe malaria is not known, but considering that other artemisinin derivatives (arthemeter, arteether) have been associated with QT prolongation in pre-clinical data, EKG should be monitored before and during treatment, especially in patients with a history of cardiovascular impairment or having risk factors.
Rare: Arterial ischemia, hypertensive retinopathy.
Respiratory disorders: Common: Cough and/or nasal symptoms.
Gastrointestinal disorders: Common: Altered taste, nausea, vomiting, abdominal pain or cramps, diarrhoea.
Rare: Raised serum amylase, pancreatitis.
Hepatobiliary disorders: Uncommon: Transient rise in liver transaminases (AST, ALT).
Rare: Hepatitis, calculous cholecystitis.
Skin and subcutaneous tissue disorders: Common: Rash, alopecia.
Musculoskeletal and connective tissue disorders: Common: Arthralgia, muscle disorders.
General disorders and administration site conditions: Common: Fatigue, malaise, fever, pain at injection site.
Immune system disorders: Uncommon: Hypersensitivity.
*Post-Artesunate Delayed Hemolysis (PADH): A delayed hemolysis was detected in prospective studies with a frequency ranging from 7 to 27% of patients with artesunate. This adverse event has been observed both in travelers (15%) and among young African children (7-22%) in cases of severe malaria. The best-known cases of delayed haemolysis have been reported in travelers (including non-immune tourists and "visiting friends and relatives" persons). The pathophysiology of this phenomenon has not been fully elucidated but may include various combinations of delayed destruction of different subpopulations of erythrocytes and an immune-mediated etiology. All patients treated with parenteral artesunate should be followed for at least 4 weeks to detect signs of hemolysis and enable appropriate treatment.
Impact: PADH and other post-artesunate hemolytic episodes almost invariably resolve in less than a few weeks, often in a few days. Transfusion indication is per current standard of care. Whether long term sequelae occur in a small proportion of patients is not known. The overall risk/benefit remains highly favourable for injectable artesunate, with a large mortality advantage over quinine. WHO strongly recommends continued use of artesunate for severe malaria.
Paediatric population: The safety profile of injectable artesunate is similar in children and adults.