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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      Serious - Use Alternative

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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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            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.
            ST Step Therapy
            Drugs that have step therapy associated with each prescription. This restriction typically requires that certain criteria be met prior to approval for the prescription.
            OR Other Restrictions
            Drugs that have restrictions other than prior authorization, quantity limits, and step therapy associated with each 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.