artesunate (Rx)

Brand and Other Names:
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Dosing & Uses

AdultPediatric

Dosage Forms & Strengths

injection, lyophilized powder for reconstitution

  • 110mg/vial

Malaria

Indicated for initial treatment of severe malaria; should always be followed by a complete treatment course of an appropriate PO antimalarial regimen

2.4 mg/kg IV at 0, 12, and 24 hr, THEN qDay until able to tolerate PO antimalarial therapy  

Administer with an antimalarial agent that is active against the hypnozoite liver-stage forms of Plasmodium (eg, 8-aminoquinoline drug) to patients with severe malaria caused by P vivax or P ovale

Dosage Modifications

Renal or hepatic impairment

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

Dosing Considerations

Limitations of use

  • Does not treat hypnozoite liver-stage forms of Plasmodium and therefore does not prevent relapses of malaria caused by P vivax or P ovale
  • Concomitant therapy with an antimalarial agent (eg, 8-aminoquinoline drug) is necessary for the treatment of severe malaria caused by P vivax or P ovale

Dosage Forms & Strengths

injection, lyophilized powder for reconstitution

  • 110mg/vial

Malaria

Indicated for initial treatment of severe malaria; should always be followed by a complete treatment course of an appropriate PO antimalarial regimen

2.4 mg/kg IV at 0, 12, and 24 hr, THEN qDay until able to tolerate PO antimalarial therapy  

Administer with an antimalarial agent that is active against the hypnozoite liver-stage forms of Plasmodium (eg, 8-aminoquinoline drug) to patients with severe malaria caused by P vivax or P ovale

Dosage Modifications

Renal or hepatic impairment

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

Dosing Considerations

Limitations of use

  • Does not treat hypnozoite liver-stage forms of Plasmodium and therefore does not prevent relapses of malaria caused by P vivax or P ovale
  • Concomitant therapy with an antimalarial agent (eg, 8-aminoquinoline drug) is necessary for the treatment of severe malaria caused by P vivax or P ovale
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Interactions

Interaction Checker

and artesunate

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    Contraindicated

      Serious - Use Alternative

        Significant - Monitor Closely

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            Contraindicated (0)

              Serious - Use Alternative (3)

              • dapsone topical

                artesunate, dapsone topical. unspecified interaction mechanism. Avoid or Use Alternate Drug. Avoid coadministration of dapsone topical with oral dapsone or antimalarial medications because of the potential for hemolytic reactions.

              • sotorasib

                sotorasib will decrease the level or effect of artesunate by P-glycoprotein (MDR1) efflux transporter. Avoid or Use Alternate Drug. If use is unavoidable, refer to the prescribing information of the P-gp substrate for dosage modifications.

              • tepotinib

                tepotinib will increase the level or effect of artesunate by P-glycoprotein (MDR1) efflux transporter. Avoid or Use Alternate Drug. If concomitant use unavoidable, reduce the P-gp substrate dosage if recommended in its approved product labeling.

              Monitor Closely (19)

              • axitinib

                axitinib will increase the level or effect of artesunate by decreasing metabolism. Use Caution/Monitor. Coadministration may increase active artesunate metabolite (DHA) by inhibiting UGT. Monitor for increased adverse effects.

              • berotralstat

                berotralstat will increase the level or effect of artesunate by P-glycoprotein (MDR1) efflux transporter. Use Caution/Monitor. Monitor or titrate P-gp substrate dose if coadministered.

              • bupivacaine implant

                artesunate, bupivacaine implant. Either increases effects of the other by Other (see comment). Use Caution/Monitor. Comment: Local anesthetics may increase the risk of developing methemoglobinemia when concurrently exposed to drugs that also cause methemoglobinemia.

              • carbamazepine

                carbamazepine will decrease the level or effect of artesunate by increasing metabolism. Use Caution/Monitor. Coadministration may decrease AUC and peak plasma concentration of active artesunate metabolite (DHA) by inducing UGT. Monitor for decreased efficacy.

              • deferasirox

                deferasirox will increase the level or effect of artesunate by decreasing metabolism. Use Caution/Monitor. Coadministration may increase active artesunate metabolite (DHA) by inhibiting UGT. Monitor for increased adverse effects.

              • diclofenac

                diclofenac will increase the level or effect of artesunate by decreasing metabolism. Use Caution/Monitor. Coadministration may increase active artesunate metabolite (DHA) by inhibiting UGT. Monitor for increased adverse effects.

              • diflunisal

                diflunisal will increase the level or effect of artesunate by decreasing metabolism. Use Caution/Monitor. Coadministration may increase active artesunate metabolite (DHA) by inhibiting UGT. Monitor for increased adverse effects.

              • eltrombopag

                eltrombopag will increase the level or effect of artesunate by decreasing metabolism. Use Caution/Monitor. Coadministration may increase active artesunate metabolite (DHA) by inhibiting UGT. Monitor for increased adverse effects.

              • imatinib

                imatinib will increase the level or effect of artesunate by decreasing metabolism. Use Caution/Monitor. Coadministration may increase active artesunate metabolite (DHA) by inhibiting UGT. Monitor for increased adverse effects.

              • methylene blue

                methylene blue will increase the level or effect of artesunate by decreasing metabolism. Use Caution/Monitor. Coadministration may increase active artesunate metabolite (DHA) by inhibiting UGT. Monitor for increased adverse effects.

              • nevirapine

                nevirapine will decrease the level or effect of artesunate by increasing metabolism. Use Caution/Monitor. Coadministration may decrease AUC and peak plasma concentration of active artesunate metabolite (DHA). Monitor for decreased efficacy.

              • phenobarbital

                phenobarbital will decrease the level or effect of artesunate by increasing metabolism. Use Caution/Monitor. Coadministration may decrease AUC and peak plasma concentration of active artesunate metabolite (DHA) by inducing UGT. Monitor for decreased efficacy.

              • phenytoin

                phenytoin will decrease the level or effect of artesunate by increasing metabolism. Use Caution/Monitor. Coadministration may decrease AUC and peak plasma concentration of active artesunate metabolite (DHA) by inducing UGT. Monitor for decreased efficacy.

              • regorafenib

                regorafenib will increase the level or effect of artesunate by decreasing metabolism. Use Caution/Monitor. Coadministration may increase active artesunate metabolite (DHA) by inhibiting UGT. Monitor for increased adverse effects.

              • rifampin

                rifampin will decrease the level or effect of artesunate by increasing metabolism. Use Caution/Monitor. Coadministration may decrease AUC and peak plasma concentration of active artesunate metabolite (DHA) by inducing UGT. Monitor for decreased efficacy.

              • ritonavir

                ritonavir will decrease the level or effect of artesunate by increasing metabolism. Use Caution/Monitor. Coadministration may decrease AUC and peak plasma concentration of active artesunate metabolite (DHA). Monitor for decreased efficacy.

              • sorafenib

                sorafenib will increase the level or effect of artesunate by decreasing metabolism. Use Caution/Monitor. Coadministration may increase active artesunate metabolite (DHA) by inhibiting UGT. Monitor for increased adverse effects.

              • tucatinib

                tucatinib will increase the level or effect of artesunate by P-glycoprotein (MDR1) efflux transporter. Use Caution/Monitor. Consider reducing the dosage of P-gp substrates, where minimal concentration changes may lead to serious or life-threatening toxicities.

              • vandetanib

                vandetanib will increase the level or effect of artesunate by decreasing metabolism. Use Caution/Monitor. Coadministration may increase active artesunate metabolite (DHA) by inhibiting UGT. Monitor for increased adverse effects.

              Minor (0)

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                Adverse Effects

                >10%

                Anemia (65%)

                Increased transaminase (27%)

                Thrombocytopenia (18%)

                Hyperbilirubinemia (14%)

                1-10%

                Leukocytosis (10%)

                Acute renal failure requiring dialysis (8.9-10%)

                ARDS (8%)

                Lymphopenia (7%)

                Hemoglobinuria (6.7%)

                Neutropenia (5%)

                DIC (3%)

                Elevated creatinine (3%)

                Pneumonia (3%)

                Pulmonary edema (3%)

                Diarrhea (3%)

                Jaundice (2.3%)

                Neurologic sequelae (1%)

                Postmarketing Reports

                Blood and lymphatic system disorders: Delayed hemolysis, immune hemolytic anemia

                Gastrointestinal disorders: Pancreatitis

                Immune system disorders: Hypersensitivity, anaphylaxis

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                Warnings

                Contraindications

                Known serious hypersensitivity (eg, anaphylaxis)

                Cautions

                Hypersensitivity, including anaphylaxis, reported; consider discontinuing if hypotension, dyspnea, urticaria, or generalized rash occurs

                A single IV artesunate dose is associated with embryofetal toxicity in animals; extensive experience with PO artesunate (not available) and other artemisinin drugs in pregnant women has not identified teratogenicity; delayed treatment of severe malaria is associated with serious morbidity and mortality to mother and fetus

                Posttreatment hemolysis

                • Post-artesunate delayed hemolysis is characterized by decreased hemoglobin with laboratory evidence of hemolysis (eg, decreased haptoglobin and increased lactate dehydrogenase) occurring at least 7 days after initiating
                • Cases of posttreatment hemolytic anemia severe enough to require transfusion reported
                • Monitor for 4 weeks after treatment for evidence of hemolytic anemia
                • Since a subset of patients with delayed hemolysis have evidence of immune-mediated hemolysis, consider performing a direct antiglobulin test to determine if therapy (eg, corticosteroids) is necessary

                Drug interaction overview

                • Dihydroartemisinin (DHA), a metabolite of artesunate, is a substrate of UDP-glucuronosyltransferase (UGT) 1A9 or 2B7
                • Ritonavir, nevirapine, or strong UGT inducers may reduce artesunate efficacy
                • Strong UGT inhibitors may increase DHA-associated adverse reactions
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                Pregnancy & Lactation

                Pregnancy

                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

                Randomized controlled trials and cohort studies have not identified a drug-associated risk of major birth defects, miscarriage, or adverse maternal or fetal outcomes with PO artesunate (not an approved route of administration) and other artemisinin class drugs (via various routes of administration) in pregnant females over several decades

                PO bioavailability is expected to be significantly lower than IV; therefore, the clinical relevance of studies involving PO exposure to artesunate and other artemisinin class drugs is uncertain

                If administered during pregnancy, healthcare providers should report drug exposure by contacting Amivas LLC at 1-855-526-4827 (1-855-5AMIVAS) or www.amivas.com/our-products

                Clinical considerations

                • Untreated malaria during pregnancy poses serious risks to the mother and fetus

                • Delaying treatment of severe malaria in pregnancy may result in serious morbidity and mortality to the mother and fetus

                • 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

                Animal studies

                • A single IV administration to rats early in gestation results in embryolethality; PO administration during organogenesis in rats, rabbits, and monkeys induces a dose-dependent increase in embryolethality and fetal malformations (eg, cardiovascular, brain, skeletal) at 0.3-1.6 times the clinical dose based on BSA comparisons
                • Although animal reproduction studies in several species have demonstrated fetal harm from PO and IV artesunate and other artemisinin class drugs, the clinical relevance is uncertain

                Lactation

                Dihydroartemisinin (DHA), a metabolite of artesunate, is present in human milk

                There are no data on the effects of artesunate or DHA on breastfed infants or milk production

                Pregnancy Categories

                A: Generally acceptable. Controlled studies in pregnant women show no evidence of fetal risk.

                B: May be acceptable. Either animal studies show no risk but human studies not available or animal studies showed minor risks and human studies done and showed no risk.

                C: Use with caution if benefits outweigh risks. Animal studies show risk and human studies not available or neither animal nor human studies done.

                D: Use in LIFE-THREATENING emergencies when no safer drug available. Positive evidence of human fetal risk.

                X: Do not use in pregnancy. Risks involved outweigh potential benefits. Safer alternatives exist.

                NA: Information not available.

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                Pharmacology

                Mechanism of Action

                Artemisinin derivative; rapidly metabolized to active metabolite, dihydroartemisinin (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, 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

                Absorption

                Peak plasma concentration

                • Artesunate: 3.3 mcg/mL
                • DHA: 3.1 mcg/mL

                AUC

                • Artesunate: 0.7 mcg⋅h/mL
                • DHA: 3.5 mcg⋅h/mL

                Distribution

                Protein bound: ~93%

                Vd

                • Artesunate: 68.5 L
                • DHA: 59.7 L

                Metabolism

                Primary pathway

                • Artesunate: Blood esterases
                • DHA: Glucuronidation

                Metabolite

                • Artesunate: DHA
                • DHA: alpha-DHA-beta-glucuronide

                Elimination

                Excretion: Unknown

                Half-life

                • Artesunate: 0.3 hr
                • DHA: 1.3 hr

                Clearance

                • Artesunate: 180 L/hr
                • DHA: 32.3 L/hr
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                Administration

                IV Preparation

                Reconstitute vial contents with supplied diluent before administration

                Supplied diluent consists of 12 mL of sterile 0.3 M pH 8.0 sodium phosphate buffer

                Withdraw 11 mL of this diluent with a needle and syringe and inject into the artesunate vial (when constituted the final concentration of artesunate is 10 mg/mL)

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

                Inspect visually for particulate matter and discoloration; do not administer if particulate matter and/or discoloration observed

                Administer within 1.5 hr of reconstitution

                IV Administration

                Administer as slow IV bolus over 1-2 minutes

                Do not administer via continuous IV infusion

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

                Storage

                Unopened vial

                • Store drug and sterile diluent in the carton at 20-25ºC (68-77ºF); excursions permitted to 15-30ºC (59-86ºF)
                • Do not freeze
                • Avoid exposure to heat
                • Keep protected from light

                Reconstituted solution

                • Administer within 1.5 hr following reconstitution
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                Images

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                Patient Handout

                A Patient Handout is not currently available for this monograph.
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                Formulary

                FormularyPatient Discounts

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                The above information is provided for general informational and educational purposes only. Individual plans may vary and formulary information changes. Contact the applicable plan provider for the most current information.

                Tier Description
                1 This drug is available at the lowest co-pay. Most commonly, these are generic drugs.
                2 This drug is available at a middle level co-pay. Most commonly, these are "preferred" (on formulary) brand drugs.
                3 This drug is available at a higher level co-pay. Most commonly, these are "non-preferred" brand drugs.
                4 This drug is available at a higher level co-pay. Most commonly, these are "non-preferred" brand drugs or specialty prescription products.
                5 This drug is available at a higher level co-pay. Most commonly, these are "non-preferred" brand drugs or specialty prescription products.
                6 This drug is available at a higher level co-pay. Most commonly, these are "non-preferred" brand drugs or specialty prescription products.
                NC NOT COVERED – Drugs that are not covered by the plan.
                Code Definition
                PA Prior Authorization
                Drugs that require prior authorization. This restriction requires that specific clinical criteria be met prior to the approval of the prescription.
                QL Quantity Limits
                Drugs that have quantity limits associated with each prescription. This restriction typically limits the quantity of the drug that will be covered.
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                Drugs that have step therapy associated with each prescription. This restriction typically requires that certain criteria be met prior to approval for the prescription.
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                Medscape prescription drug monographs are based on FDA-approved labeling information, unless otherwise noted, combined with additional data derived from primary medical literature.