Lethal Dose of Injectable Artesunate
The lethal dose per kilogram of intravenous (IV) artesunate is not established in humans, but the recommended therapeutic dose of 2.4 mg/kg is considered safe and effective with minimal toxicity even at higher doses. 1
Therapeutic Dosing of IV Artesunate
Intravenous artesunate is the first-line treatment for severe malaria with the following dosing regimen:
- Initial dose: 2.4 mg/kg IV at 0 hours
- Follow-up doses: 2.4 mg/kg IV at 12 hours and 24 hours
- Maintenance: 2.4 mg/kg IV once daily until patient can take oral medication or parasite density falls below 1% 1
Safety Profile and Toxicity Considerations
Large inter-individual variability (up to 10-fold) in dihydroartemisinin (DHA, the active metabolite) concentrations has been observed in patients with severe malaria, suggesting that 2.4 mg/kg should be considered the minimum effective dose 2
Pharmacokinetic studies show that artesunate has a short half-life (2.3-4.3 minutes) and is rapidly converted to dihydroartemisinin, which has a half-life of 40-64 minutes 3
No direct toxicity attributable to artesunate has been reported at therapeutic doses 4
The main adverse effect associated with artesunate therapy is post-artesunate delayed hemolysis (PADH), which requires monitoring of hemoglobin, haptoglobin, and lactate dehydrogenase levels at days 7,14,21, and 28 after treatment 1
Administration Routes
IV artesunate is preferred for severe malaria, but intramuscular administration has shown similar efficacy and safety profiles when IV access is challenging 5
Alternative routes such as intranasal administration have shown promise in experimental models but are not currently recommended for clinical use 6
Clinical Monitoring During Treatment
For patients receiving IV artesunate for severe malaria:
- Monitor parasitemia every 12 hours until decline to <1%, then every 24 hours until negative 1
- Monitor cardiocirculatory, pulmonary, renal, and metabolic parameters (glycemia, bicarbonate, lactate) 1
- Watch for hypoglycemia, which is common in severe malaria and can be exacerbated by antimalarial treatment 1
- Monitor for PADH by checking hemoglobin, haptoglobin, and LDH levels at days 7,14,21, and 28 1
Important Considerations
- IV artesunate should be administered as soon as possible in severe malaria cases as it reduces mortality compared to quinine 1
- After 3 doses of IV artesunate and clinical improvement (parasitemia <1%), switch to a complete course of oral artemisinin-based combination therapy (ACT) 1
- In resource-limited settings where IV artesunate is unavailable, alternatives include intramuscular artemether, artesunate suppositories, or IV quinine 1
While the lethal dose is not established, the therapeutic window of artesunate appears to be wide, making it a safe option for treating severe malaria when used at recommended doses.