Intravenous Artesunate for Treatment of Severe Malaria in the United States

What if my hospital doesn’t stock Artesunate for Injection^TM?

• Severe malaria can progress rapidly to death if not treated right away. There are several options to acquire Artesunate for Injection^TM, and the option that allows for the patient to be treated as quickly as possible should be selected.
  1. The hospital pharmacist should call +1-855-5AMIVAS (+1-855-526-4827) to identify the closest distributor of Artesunate for Injection^TM for a patient emergency. This number operates 24/7/365. If prompted, the hospital pharmacist should leave a voice message with a call back phone number. All voice messages with a contact phone number will receive a call back within 30 minutes.
  2. Another option is to call the emergency line for the hospital’s affiliated distributor. Information and emergency phone numbers for distributors that carry Artesunate for Injection^TM can be found here. *Make sure to emphasize that this is an emergency procurement for a critically ill patient.
  3. If it is not possible to obtain drug from a distributor immediately, consider obtaining drug from a nearby hospital that has it in stock (this can be facilitated by a prearranged agreement), or transferring the patient to a hospital where artesunate is stocked or can be procured more quickly.Options for procuring Artesunate for Injection^TM  include:
• Severe malaria can progress rapidly, therefore it is reasonable to administer an oral antimalarial while waiting for IV artesunate.
  • For patients unable to tolerate an oral antimalarial, healthcare providers will need to decide the most feasible route to administer the drug. Options may include administration of an anti-emetic prior to the antimalarial or use of a nasogastric tube.
  • Artemether-lumefantrine (Coartem®) can be administered while waiting for IV artesunate and is the first choice. If not available, other options include atovaquone-proguanil (Malarone^TM) or quinine. For children <5kg, quinine is the first choice.
• If hospitals do not stock Artesunate for Injection^TM
  • Have a plan for emergency procurement of drug or transfer patient to a facility with Artesunate for Injection^TM in stock.
  • Stock artemether-lumefantrine (Coartem®) as an interim treatment while acquiring Artesunate for Injection^TM or awaiting transfer. Atovaquone-proguanil (Malarone^TM) and quinine are second-line options. For children <5kg, quinine is the first choice.

Can IV artesunate be used in children and in pregnant and lactating women?

IV artesunate is safe for use in children, pregnant women in the second and third trimesters, and during lactation. The benefits of treatment with IV artesunate in the first trimester outweigh the risks given that severe malaria represents a substantial risk for pregnant women and their fetuses, that limited clinical data on women taking IV artesunate in the first trimester of pregnancy have not found harmful effects, and that there are limited treatment options for severe malaria in the United States.

Why is Artesunate for Injection^TM not available at my hospital?

Hospitals can purchase Artesunate for Injection^TM  major drug distributors. If hospitals choose not to stock Artesunate for Injection^TM, options for emergency procurement can be found here. Timely access to IV artesunate is important because patients with severe malaria could die if not treated as soon as possible.

Where can Artesunate for Injection^TM be purchased?

Artesunate for Injection^TM can be purchased from major drug distributors. This link has up-to-date information on how to acquire Artesunate for Injection^TM.

What can I treat my patient with while waiting for Artesunate for Injection^TM  to arrive?

Ideally, having IV artesunate in stock will allow for immediate treatment of patients diagnosed with severe malaria. If there will be a delay in the availability of the IV artesunate, it is important to start patients on oral antimalarials in the interim as severe malaria can progress rapidly. For patients unable to tolerate an oral antimalarial, healthcare providers should consider administration of an anti-emetic prior to the antimalarial or use of a nasogastric tube. Specific recommendations in these cases are part of CDC’s malaria treatment guidelines.

Appropriate interim treatment options include artemether-lumefantrine (Coartem®) (preferred), atovaquone-proguanil (Malarone^TM), or quinine. If none of these options are available and the healthcare provider judges that immediate treatment is needed prior to the arrival of IV artesunate, mefloquine can be used. Note that there is a risk of severe neuropsychiatric effects at treatment dose of mefloquine. IV or oral clindamycin and tetracyclines, such as doxycycline, are not recommended for interim treatment. These drugs are slow-acting antimalarials that would not take effect until well after 24 hours and are not effective antimalarials for treatment of severe malaria when used alone.

What is the definition of severe malaria?

The criteria for severe malaria include a positive blood smear and any one or more of the following:

• High percent parasitemia (≥5%)
• Impaired consciousness
• Seizures
• Circulatory collapse/shock
• Pulmonary edema or acute respiratory distress syndrome (ARDS)
• Acidosis
• Acute renal failure
• Abnormal bleeding or disseminated intravascular coagulation (DIC)
• Jaundice (usually presents with at least one other severe criteria)
• Severe anemia (Hb < 7 g/dL)

IV artesunate can also be used for patients with a positive blood smear, that otherwise do not meet the criteria for severe malaria (uncomplicated malaria), who are unable to tolerate oral medication despite attempts to administer an oral drug.

In exceptional cases, IV artesunate can be used in a patient with a strong clinical suspicion of severe malaria (including history of recent travel to a malaria-endemic area, or recent blood transfusion), for whom timely, reliable microscopy results are not available.

What if my hospital doesn’t stock Artesunate for Injection^TM?

• Severe malaria can progress rapidly to death if not treated right away. There are several options to acquire Artesunate for Injection^TM, and the option that allows for the patient to be treated as quickly as possible should be selected.
  1. The hospital pharmacist should call +1-855-5AMIVAS (+1-855-526-4827) to identify the closest distributor of Artesunate for Injection^TM for a patient emergency. This number operates 24/7/365. If prompted, the hospital pharmacist should leave a voice message with a call back phone number. All voice messages with a contact phone number will receive a call back within 30 minutes.
  2. Another option is to call the emergency line for the hospital’s affiliated distributor. Information and emergency phone numbers for distributors that carry Artesunate for Injection^TM can be found here. *Make sure to emphasize that this is an emergency procurement for a critically ill patient.
  3. If it is not possible to obtain drug from a distributor immediately, consider obtaining drug from a nearby hospital that has it in stock (this can be facilitated by a prearranged agreement), or transferring the patient to a hospital where artesunate is stocked or can be procured more quickly.Options for procuring Artesunate for Injection^TM  include:
• Severe malaria can progress rapidly, therefore it is reasonable to administer an oral antimalarial while waiting for IV artesunate.
  • For patients unable to tolerate an oral antimalarial, healthcare providers will need to decide the most feasible route to administer the drug. Options may include administration of an anti-emetic prior to the antimalarial or use of a nasogastric tube.
  • Artemether-lumefantrine (Coartem®) can be administered while waiting for IV artesunate and is the first choice. If not available, other options include atovaquone-proguanil (Malarone^TM) or quinine. For children <5kg, quinine is the first choice.
• If hospitals do not stock Artesunate for Injection^TM
  • Have a plan for emergency procurement of drug or transfer patient to a facility with Artesunate for Injection^TM in stock.
  • Stock artemether-lumefantrine (Coartem®) as an interim treatment while acquiring Artesunate for Injection^TM or awaiting transfer. Atovaquone-proguanil (Malarone^TM) and quinine are second-line options. For children <5kg, quinine is the first choice.

Treatment regimen for severe malaria

Severe malaria can progress rapidly, so its treatment should be initiated as soon as possible. Healthcare providers should consider treating the patient with an oral treatment if IV artesunate is not immediately available.

Artemether-lumefantrine (Coartem®) is the preferred antimalarial for interim treatment because of its fast onset of action. Other oral options include atovaquone-proguanil (Malarone^TM), quinine, or as a last resort, mefloquine. Because of a higher risk of severe neuropsychatric adverse events at treatment doses, mefloquine should only be used if the other antimalarials are not available.

Of note, exclusive use of IV or oral clindamycin and tetracyclines, such as doxycycline, is not recommended. These drugs are slow-acting antimalarials that would not take effect until well after 24 hours and are not effective antimalarials for treatment of severe malaria when used alone.

Healthcare providers will need to decide the most feasible alternative to administer oral medicines while awaiting IV artesunate. For example, if this intolerance is due to nausea and vomiting, an anti-emetic preceding the antimalarial may help, and, for comatose patients, a nasogastric tube can be considered.

When IV artesunate arrives, discontinue the oral medication. Per WHO guidelines, three doses of IV artesunate, administered intravenously over 1–2 minutes, at 12-hour intervals (0, 12, and 24 hours) is recommended for treatment of severe malaria. The dosing of IV artesunate is the following:

• 2.4 mg/kg at 0, 12, and 24 hours and can be continued daily for up to a total of seven days, if needed.

Patients should have one set of blood smears (thick and thin smear) taken every 12 or 24 hours until a negative (0% parasite density) result is reported.

After the course of IV artesunate is completed, and asexual parasite density is ≤1% (assessed on a blood smear collected four hours after the last artesunate dose) and patient can tolerate oral treatment, a full treatment course with a follow-on drug must be administered and can be started 4 to 24 hours after the last dose of IV artesunate. Options include artemether-lumefantrine (Coartem®) (preferred), atovaquone/proguanil (Malarone^TM), quinine plus doxycycline or clindamycin or, if no other options, mefloquine. Because of risk of severe neuropsychiatric adverse events at treatment doses, mefloquine should only be used if other options are not available. Dosing of these medications can be found in the treatment table. Even if patient received oral interim treatment doses, a full course of one of these alternatives is needed as follow-on treatment.

If after the third IV artesunate dose, the patient’s parasite density is >1% (assessed on a blood smear collected four hours after the last artesunate dose), IV treatment with artesunate should continue with the recommended daily dose for a maximum of seven days. Doses given at 0, 12, and 24 hours count as one day, which means up to six additional days. Healthcare providers should proceed with full-dose oral follow-on treatment 4-24 hours after the last dose of IV artesunate when parasitemia ≤1% and the patient is able to tolerate oral medications. CDC Malaria Branch clinicians may be consulted for specific clinical guidance.

Patients with parasite density ≤1% but who still cannot tolerate oral medications after completing three doses of IV artesunate treatment can continue IV artesunate, at the same dose, daily for up to six more days until the patient is able to take oral therapy.

Once the patient can tolerate oral medications, switch to an oral follow-on treatment starting 4-24 hours after the last dose of IV artesunate. Placement of a nasogastric tube or use of antiemetics should be considered to facilitate administration of oral treatment.

Use in children and pregnant women

IV artesunate is safe for use in infants, children, and pregnant women in the second and third trimesters. The benefits of treatment with IV artesunate in the first trimester outweigh the risks given that severe malaria represents a substantial risk for pregnant women and their fetuses, that limited clinical data on women taking IV artesunate in the first trimester of pregnancy have not found harmful effects, and that there are limited treatment options for severe malaria in the United States.

Contraindications and possible adverse events

The only contraindication to IV artesunate is known allergy to IV artemisinins. In addition, IV artesunate is well tolerated. While rare, delayed post-artemisinin hemolytic anemia has been noted in published case reports following treatment of severe malaria with IV artesunate. Persons with higher parasite density may have a higher likelihood of delayed hemolytic anemia after treatment with IV artesunate. Persons treated for severe malaria with IV artesunate should be monitored weekly for up to four weeks after that treatment for evidence of hemolytic anemia. Weekly laboratory evaluation should include hemoglobin, reticulocyte count, haptoglobin, lactate dehydrogenase (LDH), and total bilirubin. Depending on the amount of hemolysis, blood transfusion may be needed.