Malaria (severe), treatment:
Note: Patients with severe malaria due to P. vivax or P. ovale should also receive an antimalarial agent active against the hypnozoite liver stage forms of Plasmodium (eg, primaquine) (CDC 2020).
IV: 2.4 mg/kg/dose at 0 hours, 12 hours, and 24 hours. Assess parasite density at least 4 hours after last dose of artesunate and proceed with therapy as follows, based on parasite density (CDC 2020):
If parasitemia ≤1% and patient able to tolerate oral therapy: Transition to full treatment course with oral regimen.
If parasitemia ≤1% and patient unable to tolerate oral therapy: Continue with artesunate 2.4 mg/kg/dose once daily for up to 6 additional days. After 7 total days of IV therapy, proceed with full treatment course with an oral regimen.
If parasitemia >1%: Continue with artesunate 2.4 mg/kg/dose once daily until parasitemia ≤1% (maximum of 7 days IV treatment). Proceed with full treatment course with an oral regimen as soon as parasitemia ≤1% and patient is able to tolerate oral therapy.
Dosage adjustment for concomitant therapy: Significant drug interactions exist, requiring dose/frequency adjustment or avoidance. Consult drug interactions database for more information.
No dosage adjustment necessary.
No dosage adjustment necessary.
(For additional information see "Artesunate: Pediatric drug information")
Malaria (severe), treatment: Limited data available: Note: Patients with Plasmodium vivax or Plasmodium ovale should receive concomitant therapy with an antimalarial agent active against Plasmodium liver hypnozoites (eg, primaquine).
Infants, Children, and Adolescents: IM, IV: 2.4 mg/kg/dose initially, followed by 2.4 mg/kg/dose at 12 hours and 24 hours (CDC 2020; manufacturer's labeling). Administer additional doses once daily. Note: Previously, higher doses of 3 mg/kg/dose were recommended in patients <20 kg; however, current recommendations are based on unpublished FDA pharmacokinetic modeling studies that suggest the 2.4 mg/kg/dose results in adequate exposure for all weight ranges (CDC 2020).
Duration:Assess parasite density 4 hours after third dose of artesunate and proceed with therapy based on result as follows (CDC 2020):
If parasitemia ≤1% and patient able to tolerate oral therapy: Transition to oral; administer a complete oral regimen.
If parasitemia ≤1% and patient unable to tolerate oral therapy: Continue with artesunate once daily for up to 6 additional days, followed by a complete oral regimen when patient can tolerate oral therapy.
If parasitemia >1%: Continue with artesunate once daily until parasitemia ≤1%; transition to oral regimen as soon as parasitemia ≤1% and patient able to tolerate oral therapy; administer a complete oral regimen.
Dosage adjustment for concomitant therapy: Significant drug interactions exist, requiring dose/frequency adjustment or avoidance. Consult drug interactions database for more information.
Infants, Children, and Adolescents: No dosage adjustment necessary (Rosenthal 2008; manufacturer's labeling).
Infants, Children, and Adolescents: No dosage adjustment necessary (Rosenthal 2008; manufacturer's labeling).
Refer to adult dosing.
Excipient information presented when available (limited, particularly for generics); consult specific product labeling. [DSC] = Discontinued product
Solution Reconstituted, Intravenous:
Generic: 110 mg (1 ea)
Solution Reconstituted, Intravenous [preservative free]:
Generic: 110 mg (1 ea [DSC])
Yes
Artesunate is available for purchase in the United States from Amerisource Bergen, Cardinal, and McKesson (https://amivas.com/our-products/). Hospital pharmacies that do not have artesunate in stock when it is needed to treat a patient with severe malaria should contact their drug distributor to request an emergency procurement. If the drug distributor is unable to provide artesunate within 24 hours, health care providers should call the CDC Malaria Hotline (770-488-7788) to obtain artesunate.
IV: Administer via IV bolus slowly over 1 to 2 minutes.
IM: Administer by IM injection into the anterior thigh (WHO 2015).
IV: Administer IV over 1 to 2 minutes.
Malaria (severe), treatment: Initial treatment of severe malaria in adult and pediatric patients.
Limitations of use: 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 following adverse drug reactions and incidences are derived from product labeling unless otherwise specified.
1% to 10%:
Genitourinary: Hemoglobinuria (7%)
Hepatic: Jaundice (2%)
Nervous system: Neurological signs and symptoms (1%)
Renal: Acute renal failure (9%)
Frequency not defined:
Nervous system: Ataxia, balance impairment, confusion, paresis, restlessness
Neuromuscular & skeletal: Asthenia, tremor
Postmarketing:
Hematologic & oncologic: Autoimmune hemolytic anemia, hemolysis, hemolytic anemia
Hypersensitivity: Anaphylaxis, hypersensitivity reaction
Hypersensitivity (eg, anaphylaxis) to artesunate or any component of the formulation.
Concerns related to adverse effects:
• Hemolysis: Postartemisinin delayed hemolysis is characterized by a decrease in Hb with laboratory evidence of hemolysis (eg, decreased haptoglobin, increased lactate dehydrogenase) occurring ≥7 days after initiation of artesunate. Patients with higher parasite density may have a higher likelihood of delayed hemolytic anemia after treatment (CDC 2020). Cases of posttreatment hemolytic anemia severe enough to require transfusion have been reported. A subset of patients has evidence of immune-mediated hemolysis. Monitor patient for 4 weeks after treatment for evidence of hemolytic anemia; consider a direct antiglobulin test to determine if therapy for immune-mediated hemolysis is necessary.
• Hypersensitivity: Hypersensitivity, including anaphylaxis, has been reported. Monitor for signs of hypersensitivity and consider discontinuation of treatment if a reaction occurs.
Substrate of BCRP/ABCG2, CYP2A6 (minor), P-glycoprotein/ABCB1 (minor), UGT1A9, UGT2B7; Note: Assignment of Major/Minor substrate status based on clinically relevant drug interaction potential
Note: Interacting drugs may not be individually listed below if they are part of a group interaction (eg, individual drugs within “CYP3A4 Inducers [Strong]” are NOT listed). For a complete list of drug interactions by individual drug name and detailed management recommendations, use the Lexicomp drug interactions program by clicking on the “Launch drug interactions program” link above.
Artemether and Lumefantrine: Antimalarial Agents may enhance the adverse/toxic effect of Artemether and Lumefantrine. Management: Artemether/lumefantrine (combination product) should not be used with other antimalarials unless there is no other treatment option. If combined, monitor patients for increased toxicities of both agents, including QTc interval prolongation. Risk D: Consider therapy modification
Axitinib: May increase serum concentrations of the active metabolite(s) of Artesunate. Risk C: Monitor therapy
CarBAMazepine: May decrease serum concentrations of the active metabolite(s) of Artesunate. Risk C: Monitor therapy
ChlorproMAZINE: Antimalarial Agents may increase the serum concentration of ChlorproMAZINE. Risk C: Monitor therapy
Dapsone (Systemic): Antimalarial Agents may enhance the adverse/toxic effect of Dapsone (Systemic). Specifically, concomitant use of antimalarial agents with dapsone may increase the risk of hemolytic reactions. Dapsone (Systemic) may enhance the adverse/toxic effect of Antimalarial Agents. Specifically, concomitant use of dapsone with antimalarial agents may increase the risk for hemolytic reactions. Management: Closely monitor patients for signs/symptoms of hemolytic reactions with concomitant use of dapsone and antimalarial agents, particularly in patients deficient in glucose-6-phosphate dehydrogenase (G6PD), methemoglobin reductase, or with hemoglobin M. Risk D: Consider therapy modification
Dapsone (Topical): Antimalarial Agents may enhance the adverse/toxic effect of Dapsone (Topical). Specifically, the risk of hemolytic reactions may be increased. Management: Closely monitor for signs/symptoms of hemolytic reactions with concomitant use of topical dapsone and antimalarial agents. Patients with glucose-6-phosphate dehydrogenase deficiency may be at particularly high risk for adverse hematologic effects. Risk D: Consider therapy modification
Diclofenac (Systemic): May increase serum concentrations of the active metabolite(s) of Artesunate. Risk C: Monitor therapy
Fosphenytoin-Phenytoin: May decrease serum concentrations of the active metabolite(s) of Artesunate. Risk C: Monitor therapy
Imatinib: May increase serum concentrations of the active metabolite(s) of Artesunate. Risk C: Monitor therapy
Nevirapine: May decrease serum concentrations of the active metabolite(s) of Artesunate. Nevirapine may increase the serum concentration of Artesunate. Risk C: Monitor therapy
Nirmatrelvir and Ritonavir: May decrease serum concentrations of the active metabolite(s) of Artesunate. Nirmatrelvir and Ritonavir may increase the serum concentration of Artesunate. Risk C: Monitor therapy
Primaquine: Artesunate may enhance the QTc-prolonging effect of Primaquine. Artesunate may increase the serum concentration of Primaquine. Risk C: Monitor therapy
RifAMPin: May decrease serum concentrations of the active metabolite(s) of Artesunate. Risk C: Monitor therapy
Ritonavir: May decrease serum concentrations of the active metabolite(s) of Artesunate. Ritonavir may increase the serum concentration of Artesunate. Risk C: Monitor therapy
Vandetanib: May increase serum concentrations of the active metabolite(s) of Artesunate. Risk C: Monitor therapy
An increased risk of adverse pregnancy outcomes has not been observed following maternal use of artesunate.
Malaria infection in pregnant women may be more severe than in nonpregnant women and has a high risk of maternal and perinatal morbidity and mortality. Malaria infection during pregnancy can lead to miscarriage, premature delivery, low birth weight, congenital infection, and/or perinatal death. Therefore, pregnant women and women who are likely to become pregnant are advised to avoid travel to malaria-risk areas. When travel is unavoidable, pregnant women should take precautions to avoid mosquito bites and use effective prophylactic medications (CDC 2020; CDC Yellow Book 2020).
Artesunate is recommended for the treatment of severe malaria during pregnancy (CDC 2020; WHO 2015). Severe malaria is life threatening to the mother and fetus; when otherwise indicated, treatment should not be withheld because of fears of teratogenicity.
Data collection to monitor pregnancy and infant outcomes following exposure to artesunate is ongoing. Health care providers are encouraged to enroll females exposed to artesunate during pregnancy in the pregnancy safety study (1-855-526-4827).
Dihydroartemisinin (DHA), the active metabolite of artesunate, can be detected in breast milk. A study (published in abstract) collected breast milk samples over 10 hours following a single maternal dose of artesunate 200 mg (postpartum age and number of samples obtained not reported). Artesunate was not measurable in breast milk (limit of detection 5 ng/mL). DHA was detected within 1 hour after the maternal dose with the highest concentration observed at 90 minutes. DHA was no longer detected 6 hours after the maternal dose. Adverse events in the breastfeeding infant would not be expected (Jansen 2006).
Artesunate is recommended for the treatment of severe malaria in breastfeeding women (WHO 2015). According to the manufacturer, the decision to breastfeed during therapy should consider the risk of infant exposure, the benefits of breastfeeding to the infant, and the benefits of treatment to the mother.
Signs/symptoms of hypersensitivity; Hb, reticulocyte count, haptoglobin, lactate dehydrogenase, and total bilirubin once weekly for up to 4 weeks after artesunate initiation (CDC 2020).
Artesunate, a semisynthetic derivative of artemisinin, is a prodrug that is rapidly metabolized to the active metabolite, dihydroartemisinin (DHA). Artesunate and DHA contain an endoperoxide bridge that is activated by heme iron binding, resulting in oxidative stress, inhibition of protein and nucleic acid synthesis, ultrastructural changes, and a decrease in parasite growth and survival. Both are active against the blood-stage asexual parasites and gametocytes of Plasmodium species (including chloroquine-resistant strains) but not active against the hypnozoite liver stage forms of P. vivax and P. ovale.
Distribution: Vd: Artesunate: 68.5 L; dihydroartemisinin (DHA): 59.7 L.
Protein binding: ~93%.
Metabolism: Artesunate (prodrug) is rapidly hydrolyzed by plasma esterases to an active metabolite, DHA. DHA undergoes glucuronidation.
Half-life elimination: Artesunate: 0.3 hours; DHA: 1.3 hours.
Time to peak: DHA: Adults infected with severe malaria: Within 15 minutes (Newton 2006).
Excretion: Urine.
Clearance: Artesunate: 180 L/hour; DHA: 32.3 L/hour.
Solution (reconstituted) (Artesunate Intravenous)
110 mg (per each): $5,976.00
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