Artesunate (Monograph)

Drug class: Antimalarials

Introduction

Semi-synthetic artemisinin derivative; antimalarial drug.

Uses for Artesunate

Malaria

Used IV for initial treatment of severe malaria in adult and pediatric patients. Follow with a complete treatment course of an appropriate oral antimalarial regimen.

Artesunate does not treat the hypnozoite liver stage forms of Plasmodiumand will therefore not prevent relapses of malaria due to Plasmodium vivaxor 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.

CDC and WHO provide guidance for treatment of severe malaria. CDC states that patients (including infants, children, and pregnant women) with any manifestations of severe malaria should be treated promptly with IV antimalarial therapy regardless of the species of malaria on blood smear. IV artesunate is the only IV antimalarial medication currently available in the US; if a facility does not have IV artesunate in stock, the drug should be obtained as soon as possible and an oral treatment administered in the interim. Artemether-lumefantrine is the preferred oral treatment if IV artesunate is not available. When IV artesunate is available, immediately discontinue oral medication and start IV artesunate. Oral antimalarial treatment can be started 4–24 hours after the last dose of IV artesunate.

Artesunate Dosage and Administration

General

Patient Monitoring

Monitor hemoglobulin concentration, reticulocyte count, haptoglobin, lactase dehydrogenase, and total bilirubin weekly.
Monitor patients for 4 weeks after treatment for evidence of hemolytic anemia.
After treatment, if concerned for immune-mediated hemolysis, perform a direct antiglobulin test to determine if therapy (e.g., corticosteroids) is necessary.
Monitor for hypotension, dyspnea, urticaria, or generalized rash during administration.

Administration

Administer as a slow IV bolus dose.

Do not administer via continuous IV infusion.

Has been administered IM^{† [off-label]} in clinical studies and is included as an alternate route of administration in WHO guidelines for treatment of severe malaria in adults and children.

Commercially available powder must be constituted with the supplied diluent prior to administration.

After constitution, administer the solution IV (through an established IV line or needle).

IV Administration

Reconstitution

Constitute the powder using supplied diluent (consisting of 12 mL of sterile 0.3 M pH 8.0 sodium phosphate buffer).

Withdraw 11 mL of diluent with a needle and syringe and inject into artesunate vial to provide a final concentration of 10 mg/mL.

Swirl gently (do not shake) for up to 5 to 6 minutes until powder is fully dissolved and no visible particles remain.

Inspect vial visually for particulate matter and discoloration prior to administration. Do not administer if particulate matter and/or discoloration is observed.

Administer within 1.5 hours of constitution.

Discard vial and any unused portion of the drug after use.

Rate of Administration

Administer as a slow bolus over 1 to 2 minutes.

Dosage

Pediatric Patients

Malaria

IV

2.4 mg/kg administered IV at 0, 12, and 24 hours; thereafter, administer once daily for a maximum of 7 days until parasite density is ≤1% and patient is able to tolerate oral antimalarial therapy.

After initial course of IV artesunate is completed, if parasite density is ≤1% (assessed on a thin blood smear collected 4 hours after last dose of IV artesunate) and patient can tolerate oral treatment, administer full treatment course with an oral regimen; start oral regimen 4–24 hours after last dose of IV artesunate.

Adults

Malaria

IV

2.4 mg/kg administered IV at 0, 12, and 24 hours; thereafter, administer once daily for a maximum of 7 days until parasite density is ≤1% and patient is able to tolerate oral antimalarial therapy.

After initial course of IV artesunate is completed, if parasite density is ≤1% (assessed on a thin blood smear collected 4 hours after last dose of IV artesunate) and patient can tolerate oral treatment, administer a full treatment course with an oral regimen; start oral regimen 4–24 hours after last dose of IV artesunate.

Special Populations

Hepatic Impairment

No specific dosage recommendations.

Renal Impairment

No specific dosage recommendations.

Geriatric Patients

No specific dosage recommendations.

Cautions for Artesunate

Contraindications

Known serious hypersensitivity to artesunate, such as anaphylaxis.

Warnings/Precautions

Post-Treatment Hemolysis

Hemolysis may occur at least 7 days after initiating artesunate treatment. Monitor patients for 4 weeks after treatment for evidence of hemolytic anemia. If concern for immune-mediated hemolysis, consider performing a direct antiglobulin test to determine if therapy (e.g., corticosteroids) is necessary.

Hypersensitivity

Hypersensitivity, including anaphylaxis, reported. Consider discontinuing administration if hypotension, dyspnea, urticaria, or generalized rash occurs, and continuing therapy with another antimalarial drug.

Fetal/Neonatal Morbidity and Mortality

Extensive experience with oral artesunate^{† [off-label]} and other artemisinin class drugs in pregnant women has not identified a drug-associated risk of adverse maternal or fetal outcomes. Embryolethality and fetal malformations have been observed in animal reproduction studies with IV or oral administration of artesunate; however, the clinical relevance of data from animal reproduction studies is uncertain.

Specific Populations

Pregnancy

Delayed treatment of severe malaria in pregnancy may result in serious morbidity and mortality to mother and fetus. Data are insufficient to identify a drug-associated risk of major birth defects, miscarriage, or fetal death.

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].

Lactation

Dihydroartemisinin (DHA), a metabolite of artesunate, is present in human milk. No data on the effects of artesunate or DHA on the breastfed infant or on milk production. Consider benefits of breastfeeding along with the mother's clinical need for artesunate and any potential adverse effects on the breastfed child from the drug or underlying maternal condition.

Pediatric Use

Use of artesunate for severe malaria is supported by studies in adults and pediatric patients including pharmacokinetic and safety data in pediatric patients 6 months of age and older. No dose adjustment is necessary for pediatric patients regardless of age or bodyweight.

Geriatric Use

Insufficient number of patients ≥65 years of age were included in studies of artesunate to determine whether they respond differently than younger patients.

Hepatic Impairment

No specific pharmacokinetic studies carried out in patients with hepatic impairment. No specific dose adjustments are needed for patients with hepatic impairment.

Renal Impairment

No specific pharmacokinetic studies carried out in patients with renal impairment. No specific dosage adjustments are needed for patients with renal impairment.

Common Adverse Effects

Most common adverse reactions (incidence of ≥2%): acute renal failure requiring dialysis, hemoglobinuria, jaundice.

Drug Interactions

Artesunate and its metabolite (DHA) are not metabolized by CYP1A2, 2D6, 2C19, 2A6, 2E1, or 3A. Artesunate is not an inhibitor of CYP1A2, 2B6, 2C9, 2C19, 2D6, or 3A4/5. DHA is a weak inhibitor of CYP1A2 and 2C19.

DHA is a substrate of UDP-glucuronosyltransferase (UGT) 1A9 and UGT2B7. DHA is not a substrate or inhibitor of P-glycoprotein (P-gp) or breast cancer resistance protein (BCRP). Artesunate is a substrate of BCRP and P-gp. Artesunate is a weak inhibitor of organic anion transporting polypeptide (OATP) 1B1 and organic anion transporter (OAT) 3.

Drugs Affecting or Metabolized by Hepatic Microsomal Enzymes

Inducers and inhibitors of CYP1A2, 2D6, 2C19, 2A6, 2E1, or 3A: No dosage adjustments are needed when administered concomitantly with artesunate.

Drugs Affecting or Metabolized by Transport Proteins

Strong UGT inducers: Concomitant use of artesunate with UGT inducers may reduce efficacy of artesunate. If artesunate is co-administered with a strong UGT inducer (e.g., rifampin, carbamazepine, phenytoin), monitor for reduced antimalarial efficacy of artesunate.

Strong UGT inhibitors: Concomitant use of artesunate with UGT inhibitors may increase DHA-associated adverse reactions. Monitor for adverse reactions when co-administering artesunate with strong UGT inhibitors (e.g., axitinib, vandetanib, imatinib, diclofenac).

Specific Drugs

Drug(s)

Interaction

Comment

Nevirapine

Co-administration with IV artesunate may result in decreased maximum concentration and AUC of DHA

Manufacturer states if IV artesunate is co-administered with nevirapine, monitor for possible reduced antimalarial efficacy of IV artesunate

Other clinicians recommend that co-administration of IV artesunate with nevirapine should be avoided

Ritonavir

Co-administration with IV artesunate may result in decreased maximum concentration and AUC of DHA

Manufacturer states if IV artesunate is co-administered with ritonavir, monitor for possible reduced antimalarial efficacy of IV artesunate

Other clinicians recommend that co-administration of IV artesunate with ritonavir should be avoided

Other antimalarials

No clinically significant drug interactions reported with co-administration of oral artesunate^{† [off-label]} with atovaquone/proguanil, mefloquine, amodiaquine, and sulfadoxine/pyrimethamine

Artesunate Pharmacokinetics

Distribution

Plasma Protein Binding

73 and 93% for artesunate and DHA, respectively.

Elimination

Metabolism

Artesunate is rapidly hydrolyzed to DHA by plasma esterases.

DHA is not metabolized by CYP450 oxidation or by cytosolic sulfotransferases.

A glucuronide metabolite, alpha-DHA-G, is a major metabolite of DHA in humans and its formation is catalyzed by UGT1A9 and UGT2B7.

Elimination Route

Unknown.

Half-life

0.2 and 1.2 hours for artesunate and DHA, respectively.

Stability

Storage

Parenteral

Injection, for IV Infusion

Store vial of artesunate for injection and sterile diluent in the carton at ≤30°C. Do not freeze. Avoid exposure to heat. Protect from light. Do not use beyond the expiration date.

Actions

Antimalarial drug that is a water-soluble hemisuccinate derivative of artemisinin.
Rapidly metabolized to its active metabolite, DHA, following IV administration. Both artesunate and DHA contain an endoperoxide bridge that is activated by heme iron; produces free radicals and alkylating intermediates that cause oxidative stress, inhibition of protein and nucleic acid synthesis, ultrastructural changes, and decreased parasite growth and survival.
Artesunate and DHA are active against the blood-stage asexual parasites and gametocytes of Plasmodium species including the chloroquine resistant strains.
Alterations in genetic regions of P. falciparum genes such as multidrug resistant 1 (pfmdr1), chloroquine resistance transporter (pfcrt), and kelch13 (K13) have been reported.
Potential for development of cross-resistance with quinine, halofantrine, and amodiaquine.
Cross-resistance may be due to changes in pfmdr1 gene. However, clinical significance unknown.

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. ovalemalaria 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 patients to inform their clinician if they are or plan to become pregnant or plan to breast-feed. 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 patients 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].
Advise patients to inform their clinician of existing or contemplated concomitant therapy, including prescription and OTC drugs and dietary or herbal supplements, as well as any concomitant illnesses.
Inform patients of other important precautionary information.

Additional Information

The American Society of Health-System Pharmacists, Inc. represents that the information provided in the accompanying monograph was formulated with a reasonable standard of care, and in conformity with professional standards in the field. Readers are advised that decisions regarding use of drugs are complex medical decisions requiring the independent, informed decision of an appropriate health care professional, and that the information contained in the monograph is provided for informational purposes only. The manufacturer’s labeling should be consulted for more detailed information. The American Society of Health-System Pharmacists, Inc. does not endorse or recommend the use of any drug. The information contained in the monograph is not a substitute for medical care.

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.