Artesunate (Monograph)

Drug class: Antimalarials

Medically reviewed by Drugs.com on Nov 10, 2024. Written by ASHP.

Introduction

Artesunate, a semi-synthetic artemisinin derivative, is an antimalarial drug.

Uses for Artesunate

Artesunate has the following uses:

Artesunate for injection is indicated for the initial treatment of severe malaria in adult and pediatric patients. Treatment of severe malaria with artesunate should always be followed by a complete treatment course of an appropriate oral antimalarial regimen.

Artesunate 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.

Artesunate Dosage and Administration

General

Artesunate is available in the following dosage form(s) and strength(s):

For Injection: 110 mg of artesunate as a powder in a single-dose vial for constitution with the supplied sterile diluent.

Dosage

Adults and Pediatric Patients

Dosage and Administration

The recommended dosage of artesunate is 2.4 mg/kg administered IV at 0 hours, 12 hours, and 24 hours, and thereafter administered once daily until the patient is able to tolerate oral antimalarial therapy.
Artesunate for Injection must be constituted with the supplied diluent prior to administration.
Administer constituted artesunate IV as a slow bolus over 1 to 2 minutes.
Do NOT administer artesunate via continuous IV infusion.
See the full prescribing information for instructions on preparation and administration.

Cautions for Artesunate

Contraindications

Known serious hypersensitivity to artesunate, such as anaphylaxis.

Warnings/Precautions

Post-Treatment Hemolysis

Post-artesunate delayed 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. Monitor patients for 4 weeks after artesunate treatment for evidence of hemolytic anemia. Since a subset of patients with delayed hemolysis after artesunate therapy have evidence of immune-mediated hemolysis, consider performing a direct antiglobulin test to determine if therapy (e.g., corticosteroids) is necessary.

Hypersensitivity

Hypersensitivity to artesunate including cases of anaphylaxis have been reported during the use of parenteral artesunate. If hypotension, dyspnea, urticaria, or generalized rash occurs during administration of artesunate, consider discontinuing administration and continuing therapy with another antimalarial drug.

Embryo-Fetal Toxicity in Animals

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. Animal reproduction studies show that a single IV administration of artesunate to rats early in gestation results in embryolethality and oral administration (not an approved route of administration) of artesunate in rats, rabbits, and monkeys induces a dose-dependent increase in embryolethality and fetal malformations. However, the clinical relevance of these data is uncertain. Delaying treatment of severe malaria in pregnancy may result in serious morbidity and mortality to the mother and fetus.

Specific Populations

Pregnancy

There are serious risks to the mother and fetus associated with untreated severe malaria during pregnancy; delaying treatment of severe malaria in pregnancy may result in serious morbidity and mortality to the mother and fetus. Pregnancy outcomes reported from a prospective surveillance study with IV artesunate are insufficient to identify a drug-associated risk of major birth defects, miscarriage, or fetal death. Experience with oral artesunate (not an approved route of administration) and other artemisinin class drugs (via various routes of administration) in pregnant women over several decades, based on published literature from randomized controlled trials and cohort studies, have not identified a drug-associated risk of major birth defects, miscarriage, or adverse maternal or fetal outcomes. The bioavailability of oral artesunate is expected to be significantly lower than IV artesunate; therefore, the clinical relevance of studies involving oral exposure to artesunate and other artemisinin class drugs is uncertain.

Animal reproduction studies show that a single IV administration of artesunate to rats early in gestation results in embryolethality. Oral administration of artesunate during organogenesis in rats, rabbits, and monkeys induces a dose-dependent increase in embryolethality and fetal malformations (e.g., cardiovascular, brain, and/or skeletal) at 0.3- to 1.6-times the clinical dose based on body surface area (BSA) comparisons. Although animal reproduction studies in several species have demonstrated fetal harm from oral and intravenously administered artesunate and other artemisinin class drugs, the clinical relevance of the animal data is uncertain.

The estimated background risk of miscarriage and maternal and fetal death for the indicated population is higher than the general population. The estimated background risk of major birth defects for the indicated population is unknown. All pregnancies have a background risk of birth defects, loss or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively. There is a pregnancy safety study for artesunate. If artesunate is administered during pregnancy, healthcare providers should report artesunate exposure by contacting Amivas LLC at 1-855-526-4827 (1-855-5AMIVAS) or [Web].

Malaria during pregnancy increases the risk for adverse pregnancy outcomes, including maternal anemia, severe malaria, spontaneous abortion, stillbirth, preterm delivery, low birth weight, intrauterine growth restriction, congenital malaria, and maternal and neonatal mortality.

Lactation

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. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for artesunate and any potential adverse effects on the breastfed child from the drug or from the underlying maternal condition.

Pediatric Use

The safety and effectiveness of artesunate for the treatment of severe malaria have been established in pediatric patients. Use of artesunate for this indication is supported by evidence from adequate and well-controlled studies in adults and pediatric patients with additional pharmacokinetic and safety data in pediatric patients 6 months of age and older.

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. No notable safety issues were identified in limited published safety and outcome data for artesunate in pediatric patients younger than 6 months of age with severe malaria. No dose adjustment is necessary for pediatric patients regardless of age or bodyweight.

Geriatric Use

Clinical studies of artesunate did not include sufficient numbers of patients 65 years of age and older to determine whether they respond differently than younger patients.

Hepatic Impairment

No specific PK studies have been carried out in patients with hepatic impairment. Most patients with severe malaria present with some degree of related hepatic impairment. No specific dose adjustments are needed for patients with hepatic impairment.

Renal Impairment

No specific PK studies have been carried out in patients with renal impairment. Most patients with severe malaria present with some degree of related renal impairment. No specific dosage adjustments are needed for patients with renal impairment.

Common Adverse Effects

The most common adverse reactions (incidence of 2% or greater) reported with IV artesunate in clinical trials of severe malaria include acute renal failure requiring dialysis, hemoglobinuria, and jaundice.

Drug Interactions

Specific Drugs

It is essential that the manufacturer's labeling be consulted for more detailed information on interactions with this drug, including possible dosage adjustments.

Interaction highlights:

Ritonavir, Nevirapine or Strong UDP-Glucuronosyltransferase (UGT) Inducers:

Published clinical reports or in vitro reports indicate that concomitant use of IV artesunate with oral ritonavir, nevirapine, or UGT inducers may decrease dihydroartemisinin (DHA) AUC and C_max, which may reduce the efficacy of artesunate. If artesunate is co-administered with ritonavir, nevirapine or strong UGT inducers (e.g., rifampin, carbamazepine, phenytoin), monitor for possible reduced antimalarial efficacy of artesunate.

Strong UGT Inhibitors

Published reports of in vitro data indicate that concomitant use of IV artesunate with UGT inhibitors may increase DHA AUC and C_max, which may increase DHA associated adverse reactions. Monitor for adverse reactions when co-administering artesunate with strong UGT inhibitors (e.g., axitinib, vandetanib, imatinib, diclofenac).

Actions

Mechanism of Action

Artesunate is an antimalarial drug.

Artesunate is rapidly metabolized into an active metabolite DHA. Artesunate and DHA, like other artemisinins contain an endoperoxide bridge that is activated by heme iron leading to oxidative stress, inhibition of protein and nucleic acid synthesis, ultrastructural changes as well as a decrease in parasite growth and survival. Both artesunate and DHA are active against the different asexual forms of the Plasmodium parasites and clear parasitemia within 48 to 72 hours. Artesunate and DHA are active against the blood-stage asexual parasites and gametocytes of Plasmodium species including the chloroquine resistant strains. However, artesunate and DHA are not active against the hypnozoite liver stage forms of P. vivax and P. ovale. There is a potential for development of resistance to artesunate and DHA. Strains of P. falciparum with a decrease in sensitivity to artesunate can be selected in vitro or in vivo. Alterations in some genetic regions of P. falciparum genes such as multidrug resistant 1 (pfmdr1), chloroquine resistance transporter (pfcrt), and kelch13 (K13) have been reported based on in vitro testing and/or identification of isolates in endemic areas where artemisinin therapy has been used. Nonclinical studies in vitro and in malaria animal models suggest a potential for development of cross-resistance with quinine, halofantrine, and amodiaquine. However, the clinical significance of these findings is not known.

Advice to Patients

Advise patients of the need to complete appropriate oral antimalarial therapy after treatment with artesunate.
Advise patients of the need to take an additional antimalarial agent such as an 8-aminoquinoline drug during or after treatment with artesunate for P. vivax/P. ovale malaria to prevent relapse.
Advise patients of the need for regular blood tests for the 4-week period following completion of artesunate to monitor for post-treatment delayed hemolysis.
Inform patients that hypersensitivity reactions, including anaphylaxis, have occurred with administration of artesunate. Inform patients of the signs and symptoms of hypersensitivity reactions and anaphylaxis and instruct patients to seek immediate medical care if they experience such symptoms during or following administration of artesunate.
Advise pregnant patients and patients who could be pregnant of the potential drug-related embryo-fetal toxicity based on animal studies and the serious risks to mother and fetus of delaying treatment for severe malaria. Instruct patients to inform their healthcare provider of a known or suspected pregnancy.
Advise women who are exposed to artesunate during pregnancy that there is a pregnancy safety study that monitors pregnancy outcomes. Encourage these patients to report their pregnancy to Amivas LLC at 1-855-526-4827 (1-855-5AMIVAS) or [Web].

Additional Information

AHFSfirstRelease™. For additional information until a more detailed monograph is developed and published, the manufacturer's labeling should be consulted. It is essential that the manufacturer's labeling be consulted for more detailed information on usual uses, dosage and administration, cautions, precautions, contraindications, potential drug interactions, laboratory test interferences, and acute toxicity.

Preparations

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.