Artesunate: A Comprehensive Reference
1. Identity: Chemical Name, Natural Source, and Common Forms
Chemical and Botanical Identity
Artesunate is a small molecule, a hydrophilic derivative of artemisinin β a sesquiterpene trioxane lactone peroxide. It is an artemisinin derivative; artemisinin itself is extracted from the plant Artemisia annua. Artesunate corresponds to the compound dihydroartemisinin hemisuccinate and its salts, especially its sodium salt. Also known as dihydroartemisinin-12-Ξ±-succinate, artesunate is a potent, semisynthetic antimalarial compound derived from its parent compound, artemisinin, in a two-step reaction involving reduction and esterification using diisobutylaluminum hydride (DIBAL) and succinic anhydride, respectively.
Artesunate has a chemical formula of C24H39O8 and a molecular weight of 455.56 g/mol. Its CAS number is 88495-63-0 (for the free acid form). The parent compound, artemisinin, is a highly oxygenated sesquiterpene containing a unique 1,2,4-trioxane ring structure, which is responsible for the antimalarial activity of this natural product. The essential endoperoxide pharmacophore is common to artemisinin and all its derivatives; the C-10 position moiety is unique to each individual derivative and determines its water and lipid solubility, and therefore some of its pharmacokinetic properties.
Artesunate is a water-soluble derivative of artemisinin, distinguishing it from the lipophilic artemether and other derivatives. The artesunate has an advantage of a hydrophilic group over other artemisinins which makes it a more potent drug.
Natural Source: Artemisia annua
Artemisia annua L. is one of the famous traditional Chinese medicines commonly known as "Qing Hao." It has been used in China for more than 2,000 years to treat many disorders. Naturally derived artemisinin is usually extracted from dried A. annua leaves, also known as sweet wormwood, a plant in the Asteraceae family. Originally from Asia's temperate regions, particularly China, it is now grown worldwide for its medicinal uses. Artemisinin content varies by species and plant part but is generally under 2%, with leaves having the highest concentration.
A large variety of compounds have been extracted from A. annua, such as sesquiterpenoids, flavonoids, coumarins, lipids, phenolics, purines, steroids, triterpenoids, aliphatics, and artemisinin. Artesunate itself is not found preformed in the plant; it is produced semi-synthetically from extracted artemisinin. When extracting from the plant, the yield of artemisinin is very low, hence there is a need for synthetic or semi-synthetic pathways for its industrial-scale production.
Common Forms and Preparations
Artesunate is a semisynthetic derivative of artemisinin whose water solubility facilitates absorption and provides an advantage over other artemisinins because it can be formulated as oral, rectal, intramuscular, and intravenous preparations. These chemically derived compounds have been formulated for oral, rectal, and parenteral modes of administration as a drug. For parenteral administration of these derivatives, sodium salts of artesunate are used extensively.
- Intravenous (IV) injection: The primary formulation for severe malaria, administered as a slow bolus. Artesunate, an artemisinin derivative, is highly effective at treating severe malaria as it is the only artemisinin derivative that can be given via intravenous injection.
- Intramuscular (IM) injection: Used when IV access is not possible; the water-soluble hemisuccinate artesunate can be given intravenously and is absorbed reliably and rapidly following intramuscular injection.
- Oral tablets: Used for uncomplicated malaria and in clinical investigations of other conditions, including cancer trials where doses of 200 mg/day have been studied.
- Rectal suppositories: Used particularly for pre-referral treatment in resource-limited field settings; dose formulations as suppositories of 50 mg and 200 mg have been studied.
Artesunate is the only artemisinin analogue that can be administered intravenously, and the World Health Organization (WHO) guidelines recommend intravenous artesunate as first-line therapy for severe malaria.
2. Traditional and Historical Use
Ancient Chinese Herbal Medicine
The herb Artemisia annua has been used for many centuries in Chinese traditional medicine as a treatment for fever and malaria. Medicinal use of the Chinese herb qinghao appears in several standard Chinese Materia Medica texts as a treatment for febrile illnesses. The herb was specifically recommended for fevers in the Zhou Hou Bei Ji Fang (The Handbook of Prescriptions for Emergencies), written by Ge Heng and published in 341 AD. The most detailed description appears in the Compendium of Materia Medica β Ben Cao Gang Mu, compiled in 1596, and is still printed in China today.
In China, Artemisia annua is traditionally used for the treatment of fever (especially malaria) and hemorrhoids. The plant was prepared by steeping or decocting the fresh or dried aerial parts in water for use as a fever-reducing remedy. It is also used in the crafting of aromatic wreaths, as a flavoring for spirits such as vermouth, and as a source of essential oils for the perfume industry.
Modern Rediscovery and Development of Artesunate
Chinese scientist Professor Youyou Tu and her team first isolated artemisinin in 1972 from the Artemisia annua plant, known as 'Qinghao' in Chinese herbal medicine for over two millennia and commonly used to treat fever. Tu and her colleagues searched ancient Chinese medical texts for references to herbs and recipes that might have been used to fight malaria-type symptoms such as fever, rigors, and headache. They systematically screened well-documented texts and sifted through more than 2,000 herb preparations of traditional Chinese herbs, from which they identified 380 herb extracts and tested them on mice infected by malaria parasites.
Through a collaborative effort collectively referred to as 'Project 523', the Chinese prepared dihydroartemisinin (DHA), artemether, and artesunate in the 1970s. Due to its rapid onset, high efficiency, and low toxicity, artesunate was approved as a new antimalarial drug by the Chinese Ministry of Health in 1987. It was discovered in 1972 by Tu Youyou, who shared the 2015 Nobel Prize in Physiology or Medicine for this discovery.
Artesunate itself is a modern semi-synthetic derivative; it does not have a traditional use separate from the parent plant A. annua. Its traditional lineage derives entirely from qinghao (sweet wormwood), whose use as a febrifuge spans more than two millennia. The isolated and semi-synthesized compound artesunate represents the pharmaceutical refinement of that traditional knowledge.
3. Key Constituents and Active Compounds
Structural Pharmacophore
The 1,2,4-endoperoxide bridge of artemisinins is responsible for the drug's antimalarial activity. Chemically, artemisinin is a sesquiterpene lactone having the pharmacologically significant 1,2,4-trioxane structure with a peroxide bridge that is actively responsible for its mechanism of action. All derivatives, including artesunate, preserve this critical endoperoxide moiety. Artemisinin does not dissolve in oil or water; therefore, to increase its efficacy it is used as a parent compound for its semisynthetic derivatives that have been modified at the C-10 position to produce dihydroartemisinin, artemether, arteether, and artesunate.
Active Metabolite: Dihydroartemisinin (DHA)
In the body, both artemisinin and artesunate are converted to dihydroartemisinin (DHA, also called artesol), which is the actual schizonticidal active substance. Artemisinin and artesunate can therefore be regarded as prodrugs for dihydroartemisinin. Artesunate is rapidly hydrolyzed to dihydroartemisinin, which is the most active schizonticidal metabolite. They are quickly metabolized by fast oxidative metabolism, hydrolytic cleavage, and glucuronidation.
4. Mechanisms of Action
Antimalarial Mechanism: Iron-Mediated Free Radical Generation
The active moiety of artemisinin is a sesquiterpene lactone containing an endoperoxide bridge whose cleavage in the presence of ferrous iron in a Fenton-type reaction results in the generation of reactive oxygen species (ROS) such as hydroxyl radicals, superoxide anions, and carbon-centered free radicals. Intraparasitic heme iron, which is acquired as a result of hemoglobin digestion by the parasite, reacts with the endoperoxide bridge (active moiety) of artemisinin and mediates the production of free radicals.
ROS inhibit the survival of malaria parasites by attacking and destroying lipids, proteins, and nucleic acids. Artesunate induces DNA double-strand breaks in P. falciparum in a physiologically relevant dose- and time-dependent manner, accompanied by an increase in the intracellular ROS level in the parasites. Mannitol, a ROS scavenger, reversed the cytotoxic effect of artesunate and reduced DNA damage, and modulation of glutathione (GSH) levels was found to impact ROS and DNA damage induced by artesunate.
Artemisinin has been reported to accumulate in neutral lipids, inducing oxidative damage. The inhibition of heme polymerization leads to the accumulation of heme, which also induces ROS generation. This life-saving benefit of artesunate for severe malaria derives from its rapid ability to kill the parasite across all its life stages, unlike quinine, which is slower and stage-specific, mainly affecting the mature blood stage.
Anticancer Mechanisms
Artesunate exerts its anticancer effects through multiple pathways, including ROS-mediated programmed cell death, ferroptosis induction, mitochondrial dysfunction, the inhibition of proliferation, and the disruption of key signaling networks such as NF-ΞΊB, STAT3, and Wnt/Ξ²-catenin cascades. In addition to antimalarial activity, artesunate has potential anticancer effects; proposed mechanisms include induction of apoptosis, inhibition of angiogenesis, inhibition of hypoxia-inducible factor-1Ξ± (HIF-1Ξ±) activation, and direct DNA injury.
Artesunate promotes cell apoptosis by triggering reactive oxygen species (ROS) production and increasing expression of the pro-apoptotic protein Bim. Transferrin receptor 1 (TFRC)-mediated regulation of intracellular iron homeostasis also plays an essential role in AML cell differentiation induced by artesunate.
Immunomodulatory Mechanisms
Artesunate has an immunomodulatory effect on various immune cells and cytokines of the immune system, but it shows different regulatory effects in different immune states. Artesunate inhibits the overactive immune response in autoimmune diseases, while it enhances the killing effect in other immune states. Emerging evidence suggests that artesunate possesses an immunomodulatory effect during innate and adaptive immune responses in a cell-type and context-dependent manner.
Artemisinin and its derivatives inhibit numerous receptor-coupled signaling pathways and ultimately result in the suppression of transcription factor nuclear factor ΞΊB (NF-ΞΊB), thereby regulating cytokines, chemokines, and immune receptors. Artesunate can inhibit pathological B cells generating autoantibodies.
5. Scientific Evidence by Area of Use
5.1 Severe Malaria (Plasmodium falciparum)
Regulatory status and strength of evidence: Very strong; multiple large Phase III RCTs; WHO first-line recommendation.
The primary sources of evidence to support the efficacy and safety of artesunate for the treatment of patients with severe malaria were two pivotal, multicenter, open-label Phase 3 trials: the Southeast Asian Quinine and Artesunate Malaria Trial (SEAQUAMAT) and the African Quinine and Artesunate Malaria Trial (AQUAMAT).
SEAQUAMAT (2005): SEAQUAMAT was conducted in Asia in 1,461 patients. In both trials, artesunate was associated with a significant and substantial reduction in mortality compared to quinine β a 34.7% relative reduction in deaths in SEAQUAMAT. The SEAQUAMAT was a multicenter, randomized, open-label study comparing artesunate with quinine showing that parenteral artesunate was associated with a 35% reduction in the risk of mortality compared to quinine, and it is now the recommended treatment by the WHO for severe and complicated malaria in low-transmission areas and in the second and third trimesters of pregnancy, with almost all the benefit reported in those with high parasite counts.
AQUAMAT (2010): The African Quinine Artesunate Malaria Trial (AQUAMAT) compared parenteral treatment with either artesunate or quinine in African children with severe malaria. This was a multicentre, open-label trial undertaken between October 3, 2005, and July 14, 2010. AQUAMAT was conducted in Africa in 5,425 children. In AQUAMAT, artesunate was associated with a 22.5% relative reduction in deaths compared to quinine. This large multicentre trial shows that artesunate substantially reduces the overall mortality of African children diagnosed with severe malaria.
The mortality rate among quinine-treated patients was 22% and 10.9% in the SEAQUAMAT and AQUAMAT studies respectively; for artesunate this was 15% and 8.5%, a significant reduction of 35% and 22.5%, respectively. These findings resulted in a change of the WHO-recommended first-line antimalarial therapy for severe malaria in all endemic settings. Artesunate for Injection was approved by the FDA in May 2020 and is commercially available in the United States.
In one clinical trial conducted in Thailand for 113 clinically severe falciparum malaria patients, artesunate had a lower mortality rate than quinine (12% vs. 22%). Plasma lactate level, Glasgow Coma Scale score, and total serum bilirubin level were found to be independent risk factors for death. During artesunate therapy, fewer patients became hypoglycemic than with quinine (10% vs. 28%, p = 0.03).
5.2 Uncomplicated Malaria and Artemisinin-Based Combination Therapies (ACTs)
Strength of evidence: Very strong; ACTs are WHO standard of care.
Artemisinin-based combination therapies (ACTs) have become standard treatment worldwide for P. falciparum malaria as well as malaria due to other species of Plasmodium. Such artemisinin-based combination therapy is recommended for treatment of uncomplicated malaria caused by the parasite Plasmodium falciparum. Artesunate is commonly paired with lumefantrine, amodiaquine, or sulfadoxine-pyrimethamine, among others, in these combinations.
There is the emergence of artemisinin resistance in Plasmodium falciparum, and evidence suggests that it is mainly due to mutation at the Kelch13 protein of P. falciparum. Resistance monitoring, particularly in Southeast Asia, represents an ongoing public health challenge.
5.3 Anticancer Applications
Strength of evidence: Predominantly preclinical (in vitro and animal); limited, preliminary, and inconclusive human clinical data. Not an approved cancer treatment.
Due to its demonstrated anticancer properties, artesunate has gained increasing attention as a promising candidate for oncological applications. A systematic review provides a comprehensive evaluation of artesunate's therapeutic potential by examining its anticancer efficacy, underlying molecular mechanisms, synergistic capacity, and pharmacological toxicity.
Evidence from in vitro and in vivo studies confirms artesunate's broad efficacy against a range of malignancies, including hematological cancers such as lymphoma, acute myeloid leukemia, and multiple myeloma, and various solid tumors such as lung, pancreatic, colorectal, hepatocellular, breast, and ovarian cancers. However, these findings are largely preclinical.
Colorectal Cancer: A single-centre, randomised, double-blind, placebo-controlled trial randomized 23 patients planned for curative resection of biopsy-confirmed colorectal cancer to receive preoperatively either 14 daily doses of oral artesunate (200 mg) or placebo. Apoptosis in >7% of cells was seen in 67% and 55% of patients in the artesunate and placebo groups, respectively. During a median follow-up period of 42 months, a single patient in the artesunate group developed recurrent disease compared to six patients in the placebo group, though the small sample size limits interpretation. In addition to preclinical evidence in a range of cancers, this recently completed randomised blinded trial in colorectal cancer has provided a positive signal for further clinical investigation. Used perioperatively, artesunate appears to reduce the rate of disease recurrence.
Non-Small Cell Lung Cancer (NSCLC): Artesunate has been clinically investigated in combination with cisplatin and vinorelbine in patients with advanced NSCLC. In a small study, both the disease control rate and the time to tumor progression were significantly improved for the artesunate and chemotherapy group when compared to the chemotherapy alone group, with no significant differences in toxicity. This finding is preliminary and must be confirmed in larger controlled trials.
Cervical Intraepithelial Neoplasia (CIN): Artesunate is reported to be effective, safe, and well tolerated for the treatment of cervical intraepithelial neoplasia 2/3 (CIN2/3). Phase I clinical trials evaluated artesunate suppositories as effective in treating HPV-infected cells with cytotoxic effects while having minimal effects on healthy cells.
Synergistic potential: Artesunate has been shown to enhance the efficacy of conventional chemotherapeutic agents like cisplatin and gemcitabine while also reducing associated toxicities and overcoming drug resistance. These findings remain largely in vitro or in early-phase trials.
Artesunate shows evidence of anti-microbial, anti-cancer, anti-inflammatory, and anti-fibrotic effects in preclinical models. Aside from malaria, benefits in clinical trials have been modest, but well tolerated.
5.4 Immunological and Autoimmune Diseases
Strength of evidence: Primarily preclinical animal models; very limited human data.
Artesunate exhibits a range of pharmacological effects, including antimalarial, antiviral, anti-inflammatory, antitumor, and immunomodulatory properties. The anti-malarial drug artesunate has immunosuppressive effects on several autoimmune diseases, including systemic lupus erythematosus (SLE), rheumatoid arthritis (RA), and colitis.
Systemic Lupus Erythematosus (SLE): In a systemic lupus erythematosus (SLE) model, artesunate was found to effectively reduce Tfh levels in the spleen of SLE mice, increase Tfr levels, maintain the Tfr/Tfh ratio, reduce SLE severity, and prolong survival. Artesunate alleviates lupus nephritis symptoms by decreasing kidney inflammation, inhibiting B cell activation, and down-regulating the major pro-inflammatory cytokine MCP-1. These results are from animal models; human clinical evidence is currently lacking.
Rheumatoid Arthritis: Studies have shown that artesunate suppressed the production of ROS via activating p62/Nrf2 signaling, thus inhibiting the migration and invasion of fibroblast-like synoviocytes from RA patients. Artesunate prevented the development of arthritis in young K/BxN mice by inhibiting differentiation of germinal center B cells and production of autoantibodies.
Inflammatory demyelinating disease: Administration of artesunate attenuated the clinical signs and symptoms of experimental autoimmune encephalomyelitis (EAE) via preventing migration of pathogenic T cells to the central nervous system. This is an animal model of multiple sclerosis; human data are absent.
5.5 Antiviral Activity
Strength of evidence: Primarily preclinical; clinical data very limited and generally inconclusive.
Recent studies have shown that artesunate has broad biological activities beyond antimalarial activity, ranging from anticancer, antivirus, and treatment of inflammatory and immune diseases to other parasite-related infections (e.g., Schistosoma japonicum and toxoplasma) and antifungal effects. Antiviral activity has been demonstrated in vitro against cytomegalovirus (CMV), hepatitis B and C viruses, and herpes viruses, but clinical translation has been limited. The anti-malaria drug artesunate has been shown to inhibit replication of cytomegalovirus in vitro and in vivo (Antiviral Research, 2006).
5.6 Antiparasitic Activity Beyond Malaria
Artesunate has demonstrated activity against other parasitic infections beyond malaria, including Schistosoma japonicum and toxoplasma. Preclinical and some early clinical evidence supports its use in schistosomiasis, though it is not a standard treatment for these conditions.
6. Pharmacokinetics: Absorption, Distribution, Metabolism, and Elimination
General Pharmacokinetic Profile
Given the therapeutic significance of artesunate and the necessity of appropriate dosing, substantial research has been performed investigating the pharmacokinetics of artesunate and its active metabolite dihydroartemisinin (DHA) following administration by the intravenous (IV), intramuscular (IM), oral, or rectal routes.
Intravenous Administration
Intravenous artesunate is associated with high initial concentrations which subsequently decline rapidly, with typical artesunate half-life estimates of less than 15 minutes. Artesunate clearance and volume estimates average 2β3 L/kg/hr and 0.1β0.3 L/kg, respectively. DHA concentrations peak within 25 minutes post-dose, and DHA is eliminated with a half-life of 30β60 minutes. DHA clearance and volume average 0.5β1.5 L/kg/hr and 0.5β1.0 L/kg, respectively.
After intravenous injection, parent drug rapidly declines and is converted to dihydroartemisinin (DHA) with overall mean elimination half-lives ranging 0.15β0.23 hours for artesunate and 1.23β1.63 hours for DHA, but the peak concentration (Cmax) of artesunate is much higher than that of DHA, with a range of 3.08β3.78-fold.
Intramuscular Administration
Compared to IV administration, IM administration produces lower peaks, longer half-life values, and higher volumes of distribution for artesunate, as well as delayed peaks for DHA; other parameters are generally similar due to the high bioavailability, assessed by exposure to DHA, associated with IM artesunate administration (>86%).
Oral Administration
Similarly high bioavailability of DHA (>80%) is associated with oral administration. Following oral artesunate, peak concentrations are achieved within one hour, and artesunate is eliminated with a half-life of 20β45 minutes. DHA Cmax values are observed within two hours post-dose; DHA half-life values average 0.5β1.5 hours. AUC values reported for artesunate are often substantially lower than those reported for DHA following oral administration.
Rectal Administration
Rectal artesunate administration yields pharmacokinetic results similar to those obtained from oral administration, with the exceptions of delayed artesunate Cmax and longer artesunate half-life.
Artesunate is rapidly hydrolyzed in vivo to DHA, and this conversion contributes the majority of antimalarial activity. Dihydroartemisinin (DHA), a metabolite of artesunate, is a substrate of UDP-glucuronosyltransferase (UGT) 1A9 or 2B7.
7. Dosage Forms and Doses Reported in Studies
Severe Malaria (IV)
The recommended dosage of artesunate for injection is 2.4 mg/kg administered intravenously at 0 hours, 12 hours, and 24 hours, and thereafter, administered once daily until the patient is able to tolerate oral antimalarial therapy.
Phase 1 Clinical Pharmacology
Tolerability and pharmacokinetics of intravenous artesunate were evaluated after ascending multiple doses of 2, 4, and 8 mg/kg daily for three days with 2-minute infusions in 24 healthy subjects divided into three groups. Results showed that there were no dose-dependent increases in any adverse events. Drug concentrations showed no accumulation and no decline of the drug during the three days of treatment.
Rectal (Pre-referral) Dosing
In population pharmacokinetic studies, patients received the nearest approximation to 10 mg/kg intra-rectal artesunate as a single dose. Dose formulations were suppositories of 50 mg and 200 mg.
Oral Cancer Trials
In a randomised controlled trial of oral artesunate in colorectal cancer, patients received oral artesunate at 200 mg per day, or placebo, for 14 days prior to resection. In related oncology investigations, patients were treated with oral artesunate at a dose of 200 mg per day for 14 days prior to surgical resection.
Maximum Tolerated Dose in Oncology
One oncology study determined the maximum tolerated dose to be as high as 18 mg/kg using a D1/D8, 3-week cycle of administration (108 mg/kg total dose), which is higher than maximum recommended doses to treat severe malaria (IV: 4 mg/kg/dose; rectal: 10 mg/kg). 19% of patients receiving 42 mg/kg became neutropenic within 14 days during that study.
Duration of IV Therapy
Artesunate for injection is 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.
8. Body Systems Associated with Artesunate
- Hematopoietic / Blood: Primary site of antimalarial action (parasitized erythrocytes); also implicated in hemolytic adverse effects and in AML research.
- Immune System: Modulates B and T cell populations, NF-ΞΊB signaling, cytokine production, and germinal center responses; studied in SLE, RA, and inflammatory bowel disease models.
- Cardiovascular: The parasitic action occurs within red blood cells circulating throughout the cardiovascular system; angiogenesis inhibition has been proposed as an anticancer mechanism.
- Gastrointestinal / Liver: Artesunate therapy is associated with mild-to-moderate serum aminotransferase elevations during therapy but has not been linked to instances of clinically apparent liver injury.
- Renal: The most common adverse reactions reported with artesunate for injection in clinical trials of severe malaria include acute renal failure requiring dialysis, hemoglobinuria, and jaundice.
- Oncological / Cell Proliferation: Studied preclinically and in early clinical trials for numerous solid and hematological malignancies, largely through ROS and iron-dependent mechanisms.
- Neurological: Preclinical studies suggest artesunate protects against neural injury within a low dose range, but high doses could be neurotoxic. Cognitive benefits have not yet been seen in small trials for indications other than malaria.
9. Safety Considerations and Drug Interactions
General Tolerability
Intravenous artesunate is a safe and effective drug with infrequent adverse events. Artesunate-based regimens are less likely to cause vomiting and tinnitus than quinine plus anti-malarial antibiotic therapy. Injectable artesunate during severe malaria was proven to be associated with a low incidence of adverse events, including post-artemisinin delayed hemolysis (PADH).
Post-Artesunate Delayed Hemolysis (PADH)
Post-treatment hemolysis is characterized by decreased hemoglobin with laboratory evidence of hemolysis (such as decreased haptoglobin and increased lactate dehydrogenase) occurring at least 7 days after initiating artesunate treatment. Cases of post-treatment hemolytic anemia severe enough to require transfusion have been reported. PADH, the most commonly reported adverse event associated with the use of intravenous artesunate, remains infrequent and self-limiting in many cases. However, some studies have reported as many as 85% of PADH cases requiring a transfusion; therefore, weekly monitoring of hemoglobin and hemolytic markers (reticulocyte count, haptoglobin, LDH, and total bilirubin) for 4 weeks after the initial dose is recommended.
Adverse Reactions from Clinical Trials
The most common adverse reactions in the CDC expanded access protocol were anemia (65%), transaminase increase (27%), thrombocytopenia (18%), hyperbilirubinemia (14%), acute renal failure (10%), leukocytosis (10%), acute respiratory distress syndrome (8%), lymphopenia (7%), neutropenia (5%), disseminated intravascular coagulation (3%), elevated creatinine (3%), pneumonia (3%), pulmonary edema (3%), and diarrhea (3%). These rates, however, largely reflect the severity of the underlying disease (severe malaria) rather than the drug alone.
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.
The best recognized adverse effect of the artemisinins is that they lower reticulocyte counts, which is not usually of clinical relevance.
Hypersensitivity
Serious hypersensitivity reactions including anaphylaxis have been reported. Artesunate should be discontinued if signs of serious hypersensitivity occur. Known contraindications include a previous severe allergic reaction to artesunate.
Drug Interactions
Ritonavir, nevirapine, or strong UGT inducers may reduce artesunate efficacy. Strong UGT inhibitors may increase DHA-associated adverse reactions. No formal clinical drug-drug interaction studies have been conducted with artesunate.
Pregnancy and Pediatric Use
Artesunate given intravenously caused fetal harm in rats, but it is recommended to be given to pregnant women because of the greater harm to mother and child of inadequately treated, severe malaria. Extensive experience with oral artesunate and other artemisinin class drugs in pregnant women has not identified a drug-associated risk of major birth defects, miscarriage, or adverse maternal or fetal outcomes. The safety and effectiveness of artesunate for injection for the treatment of severe malaria have been established in pediatric patients.
Animal Toxicology Note
When administered to humans, only a few side effects and no significant toxicity have been observed, although neurotoxicity has occurred in animals. Neurotoxicity noted in animal studies at high doses has not been reproduced as a clinically significant finding in human malaria treatment trials to date.
Overdose
Experience of acute overdose with artesunate is limited. A case has been documented in a 5-year-old child inadvertently administered rectal artesunate at a dose of 88 mg/kg/day (approximately 18 times the maximum recommended daily dose for artesunate for injection) for 4 days; artesunate for injection is not approved for rectal administration. The overdose was associated with pancytopenia, melena, seizures, multiorgan failure, and death.
References
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