According to the Expanded Access Investigational New Drug (IND) Protocol for the use of intravenous (IV) artesunate for treating severe malaria in the United States, artesunate is a first-line IV drug for treating severe malaria in the United States. Until stocking of artesunate in pharmacies and hospitals for its immediate use is available, the Centers for Disease Control and Prevention (CDC) will continue to distribute artesunate under its IND protocol for patients in situations where FDA-approved Artesunate for Injection is not yet available ≤ 24 hours of a clinician requesting the drug. To maximize the curative effect of anti-malarial therapy, IV artesunate should be followed by oral treatment with artemether-lumefantrine (Coartem™); atovaquone-proguanil (Malarone); quinine plus either doxycycline or clindamycin; or mefloquine. [1]
Per CDC guidelines for the treatment of malaria, all patients with severe malaria, regardless of infecting species, should be treated with IV artesunate. In cases in which an immediate use of artesunate is unavailable, interim treatment with an effective oral antimalarial should be considered (e.g., artemether-lumefantrine, atovaquone-proguanil, quinine, and mefloquine). If oral intake is restricted, the use of anti-emetics preceding the oral antimalarial or the use of a nasogastric tube for comatose patients may be considered. Upon availability of IV artesunate, immediately discontinue the oral therapy and initiate IV artesunate at a dose of 2.4 mg/kg at 0, 12, and 24 hours. Following the completion of initial IV artesunate therapy, if parasite density is ≤1% and the patient can tolerate oral treatment, a full treatment course with a follow-on regimen must be administered, preferably using artemether-lumefantrine. Other adequate alternatives include atovaquone-proguanil, quinine plus doxycycline or clindamycin, or mefloquine. Mefloquine is reserved for the last due to its severe neuropsychiatric adverse events. [2]
If the patient’s parasite density is >1%, IV artesunate treatment should be continued once a day for an additional 6 days (a maximum of 7 days) until parasite density is ≤1%. A full course of oral follow-on treatment should be initiated as soon as the parasite density ≤1% and the patient can tolerate oral medications. All persons treated for severe malaria with IV artesunate should be monitored weekly for up to four weeks following the treatment initiation for evidence of hemolytic anemia. IV artesunate is considered safe in infants, children, and pregnant women in the second and third trimesters. [2]
The 2023 World Health Organization (WHO) guidelines for malaria recommend treating adults and children with severe malaria (including infants, pregnant women in all trimesters, and lactating women) with IV or intramuscular (IM) artesunate for at least 24 hours and until they can tolerate oral medication. Once a patient has received at least 24 hours of parenteral therapy and can tolerate oral therapy, complete treatment with 3 days of artemisinin-based combination therapy (ACT; strong recommendation; high certainty evidence). Moreover, in both adults and children, parenteral artesunate prevented more deaths than parenteral quinine (high-quality evidence). Artesunate is associated with a small increase in neurological sequelae at the time of hospital discharge (moderate-quality of evidence). The difference is no longer evident on day 28 after discharge (moderate-quality evidence). Parenteral artesunate is recommended as first-line treatment for adults, children, infants, and pregnant women in all trimesters of pregnancy. Although the safety of artesunate in the first trimester of pregnancy has not been firmly established, the proven benefits to the mother outweigh the potential harm to the developing fetus. Furthermore, guidelines strongly recommend that children weighing <20 kg receive a higher dose of artesunate (3 mg/kg body weight per dose) than larger children and adults (2.4 mg/kg per dose) to ensure equivalent exposure to the drug. [3]
A 2012 Cochrane review of the literature analyzed eight randomized controlled trials (RCTs) enrolling 1,664 adults (from 5 studies) and 5,765 children (from 4 studies) to assess the comparative safety and efficacy of artesunate versus quinine for treating severe malaria in patients who were unable to take oral medication. Based on the findings of this review, artesunate significantly reduced mortality risk in both adults (risk ratio [RR] 0.61, 95% confidence interval [CI] 0.50 to 0.75) and children (RR 0.76, 95% CI 0.65 to 0.90). Although artesunate was associated with a transient increase in the incidence of neurological sequelae at hospital discharge in children, no significant differences between treatments were observed in later follow-ups. This review supports the superiority of parenteral artesunate over quinine for treating severe malaria in both adults and children across different regions. However, variations in study design and the need for further research in special populations like pregnant women and repeated dosing may affect generalizability. [4]
A 2017 systematic review included available literature (12 retrospective studies, one prospective study, and seven case reports; N= 624) to assess the efficacy and safety of artesunate in treating severe malaria in travelers and to provide practical implications for its use, with a focus on post-artesunate delayed hemolysis (PADH). With a follow-up duration ranging from 7 days to 6 months, 23 out of 574 patients (4%) with reported outcomes died, but no death was attributed to artesunate toxicity. Non-hematological side effects were uncommon and mild. PADH occurred in 15% of treated patients, with no deaths or sequelae reported. Overall, non-hematological adverse events included mild hepatitis and neurological, renal, cutaneous, and cardiac issues. PADH was the most common hematological side effect, occurring in 15% of patients and requiring blood transfusion in 50% of those cases. Although the lack of prospective randomized controlled trials in travelers limits the generalizability of the findings, this review demonstrated artesunate is highly effective and well-tolerated in travelers with severe malaria. The frequency of PADH necessitates regular hematological follow-up for one-month post-treatment. [5]
A 2004 meta-analysis based on 16 RCTs (N= 5,948; 12 studies in Africa, three in Thailand, and one in Peru; 12 placebo-controlled and double-blinded trials) examined the effects of the addition of artesunate to standard treatment of plasmodium falciparum malaria. The background drugs were chloroquine (three trials), amodiaquine (three), sulfadoxine-pyrimethamine (seven), and mefloquine (three). The study finding showed a significantly lower parasitological failure with 3 days of artesunate at day 14 (OR 0.20, 95% CI 0.17-0.25, n= 4,504) and at day 28 (excluding new infections, 0.23, 0.19-0.28, n= 2,908; including re-infections, 0.30, 0.26-0.35, n= 4,332), as well as a significantly faster parasite clearance (rate ratio 1.98, 95% CI 1.85-2.12, n= 3,517) with artesunate. In subjects with no gametocytes at baseline, artesunate reduced gametocyte count on day 7 (OR 0.11, 95% CI 0.09–0.15, n= 2,734), with larger effects shown on days 14 and 28. Adding artesunate for 1 day (six trials) was associated with fewer failures by day 14 (0.61, 0.48–0.77, n= 1,980) and day 28 (adjusted to exclude new infections 0.68, 0.53– 0.89, n= 1,205; unadjusted including reinfections 0.77, 0.63–0.95, n= 1,958). Potential confounding factors such as age (younger than 10 years, 10 years, and older than 10 years), the intensity of malaria transmission (seasonal or perennial), and packed cell volume did not yield any significant effects on the effect size of artesunate. No significant differences were observed in the occurrence of serious adverse events between artesunate and placebo. Based on these findings, the authors concluded that the addition of 3 days of artesunate to standard antimalarial treatments substantially reduces treatment failure, recrudescence, and gametocyte carriage. [6]
A 2018 review analyzed available data on the use of artesunate and artemisinin derivates in humans for non-malarial indications. A total of 19 studies, including four randomized controlled trials and one meta-analysis, were included for review. Findings indicated that artesunate combined with praziquantel was effective against schistosomiasis (p= 0.003), although artesunate monotherapy was less effective (p<0.001). Additionally, artesunate showed potential as a chemoprophylactic drug against schistosomiasis (p<0.001). Furthermore, while preliminary data suggested possible benefits in treating multidrug-resistant cytomegalovirus infections, the results were largely inconclusive. Moreover, the review did not confirm the efficacy of artesunate and artemisinin derivatives in treating cancers such as cervix, breast, colorectal and lung cancers. Overall, further robust research is necessary to fully understand the therapeutic potential of artesunate in non-malarial diseases and make a definitive conclusion in regards to its place in therapy. [7]