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On May 26, 2020, the U.S. Food and Drug Administration (FDA) approved Artesunate for Injection for the initial treatment of severe malaria in adult and pediatric patients. Treatment of severe malaria with Artesunate for Injection should always be followed by a complete treatment course of an appropriate oral antimalarial regimen. Artesunate for Injection does not treat the hypnozoite liver stage forms of Plasmodium and will therefore not prevent relapses of malaria due to Plasmodium vivax or Plasmodium ovale. Concomitant therapy with an antimalarial agent such as an 8-aminoquinoline drug is necessary for the treatment of severe malaria due to P. vivax or P. ovale.
The approved recommended dosage of Artesunate for Injection is 2.4 mg/kg administered intravenously, as a slow bolus over 1 minute to 2 minutes, at 0 hours, 12 hours, and 24 hours, and thereafter, administered once daily until the patient is able to tolerate oral antimalarial therapy. Do NOT administer Artesunate for Injection via continuous intravenous infusion. Additional information regarding dosage and administration as well as important warnings and precautions about post-treatment hemolysis, hypersensitivity, or embryo-fetal toxicity can be found in the full prescribing information linked below.
Mechanism of Action (MOA) and Pharmacokinetics (PK)
MOA: Artesunate is an antimalarial drug.
General PK: Following administration of Artesunate for Injection, artesunate is rapidly converted to its active dihydroartemisinin (DHA) metabolite. The median (range) Cmax of artesunate and DHA was 3.3 mcg/mL and 3.1 mcg/mL (1.7-9.5), respectively. The median (range) AUC of artesunate and DHA was 0.7 mcg-h/mL (0.3-111.3) and 3.5 mcg-h/mL (2.2-6.3), respectively.
Distribution: The median (range) volume of distribution of artesunate and DHA was 68.5 L (0.2-818) and 59.7 L (26-117), respectively. Protein binding was approximately 93%.
Elimination: The median (range) half-life of artesunate and DHA was 0.3 hours (0.1-1.8) and 1.3 hours (0.9-2.9), respectively. The median (range) clearance of artesunate and DHA was 180 L/h (1-652) and 32.3 L/h (16-55).
Metabolism: Artesunate is primarily metabolized via blood esterases to form its DHA metabolite. DHA is primarily metabolized via glucuronidation to form α-DHA-β-glucuronide.
Drug Interactions
Ritonavir, Nevirapine or Strong UDP-Glucuronosyltransferase (UGT) Inducers: If Artesunate for Injection is co-administered with ritonavir, nevirapine, or strong UGT inducers (e.g., rifampin, carbamazepine, phenytoin), monitor for possible reduced antimalarial efficacy of Artesunate for Injection. Concomitant use of Artesunate for Injection with oral ritonavir, nevirapine, or UGT inducers may decrease the AUC and Cmax of DHA, which may reduce the efficacy of Artesunate for Injection.
Strong UGT Inhibitors: Monitor for adverse reactions when co-administering Artesunate for Injection with strong UGT inhibitors (e.g., axitinib, vandetanib, imatinib, diclofenac). Concomitant use of Artesunate for Injection with UGT inhibitors may increase the AUC and Cmax of DHA, which may increase DHA associated adverse reactions.
Use in Specific Populations
No specific dosage adjustments are needed for patients with renal or hepatic impairment. No specific PK studies have been carried out in patients with renal or hepatic impairment.
Pregnancy: Based on animal data, Artesunate for Injection may cause fetal harm. However, administration of Artesunate for Injection for the treatment of severe malaria may be lifesaving for the pregnant woman and fetus. Treatment should not be delayed due to pregnancy. In a published PK study involving 20 pregnant women with acute uncomplicated malaria administered artesunate 4 mg/kg intravenously, systemic exposures (Cmax and AUC) of artesunate and DHA were comparable between the pregnant acute malaria patients and the 3-months post-partum healthy patients. Therefore, no dose adjustment is necessary.
Lactation: Consider the developmental and health benefits of breastfeeding along with the mother’s clinical need for Artesunate for Injection and any potential adverse effects on the breastfed child from Artesunate for Injection or from the underlying maternal condition. DHA, a metabolite of artesunate, is present in human milk. There are no data on the effects of artesunate or DHA on the breastfed infant or on milk production.
Pediatric: For pediatric patients younger than 6 months of age, a pharmacokinetic (PK) extrapolation approach using modeling and simulation indicated comparable or higher predicted PK steady-state AUC of DHA between this age group and older children or adults at the recommended 2.4 mg/kg dose regimen of Artesunate for Injection. No notable safety issues were identified in limited published safety and outcome data for Artesunate for Injection in pediatric patients younger than 6 months of age with severe malaria who received the 2.4 mg/kg dose regimen. No dose adjustment is necessary for pediatric patients regardless of age or bodyweight.
Efficacy and Safety
The efficacy of intravenous artesunate for the treatment of severe malaria was evaluated in a randomized active-controlled trial in Asia that enrolled patients with severe malaria and in a supportive published randomized active-controlled trial in Africa that enrolled pediatric patients (< 15 years of age) with severe malaria. Additional information regarding the efficacy trials can be found in the full prescribing information linked below.
The most common adverse reactions (incidence of 2% or greater) reported with Artesunate for Injection in clinical trials of severe malaria include acute renal failure requiring dialysis, hemoglobinuria, and jaundice.
Full prescribing information is available at https://go.usa.gov/xw457.
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This communication was prepared by Office of Clinical Pharmacology, Office of Translational Sciences, CDER, FDA.
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