Availability of Intravenous Artesunate for Treatment of Severe Malaria in the United States

There are approximately 300 cases of severe malaria in the United States each year, most of them acquired from travel to countries with malaria. Severe malaria should be treated with intravenous (IV) antimalarial medications. The only U.S. Food and Drug Administration (FDA)-approved IV antimalarial in the United States, IV quinidine, has been discontinued, and is no longer available. CDC is providing IV artesunate for the treatment of severe malaria.

IV artesunate is the first-line, WHO-recommended treatment for severe malaria but is neither FDA-approved nor commercially available in the United States. It is unknown when IV artesunate will be FDA approved, as the approval process requires a drug company to submit a new drug application to FDA. The Walter Reed Army Institute of Research (WRAIR) and the U.S. Army Medical Materiel Development Activity have worked together to develop IV artesunate for the United States.

Since 2007, CDC has made IV artesunate, supplied by the U.S. Army Medical Research and Materiel Command (USAMRMC), available under an expanded access investigational new drug (IND) protocol in cases where quinidine is not available, not tolerated, or not working. With the discontinuation of IV quinidine, IV artesunate is now the first-line drug for treatment of severe malaria in the United States.

Clinicians treating patients with severe malaria should call CDC to obtain IV artesunate. The CDC Malaria Hotline (770-488-7788) is available Monday–Friday, 9am–5pm, Eastern time. Outside these hours, providers should call 770-488-7100 and ask to speak with a CDC Malaria Branch expert.

IV artesunate is prepositioned throughout the United States and sent free of charge to the major airport closest to the requesting hospital. We anticipate that hospitals can expect timely delivery of IV artesunate, but delivery times will vary depending on the requesting hospital’s proximity to one of the storage sites. Since severe malaria can progress rapidly, CDC has guidance on interim treatment while waiting for IV artesunate to arrive.

Why is IV artesunate not FDA approved or commercially available in the United States? When will artesunate be FDA approved?

The approval process requires a pharmaceutical company to submit a New Drug Application (NDA) to FDA for approval. CDC does not have authority over NDAs or approval of new drugs. It is unknown when artesunate will be FDA-approved.

Why is artesunate not available at my hospital?

Artesunate is neither FDA approved nor commercially available for hospitals to purchase and keep in stock. CDC has made IV artesunate available through an expanded use investigational new drug protocol (IND), an FDA regulatory mechanism.

Why is artesunate only made available through the expanded use investigational new drug (IND) protocol? (What is an expanded use IND protocol?)

  • When availability of quinidine ends in March 2019, there will be no other FDA-approved intravenous antimalarial available in the United States. Artesunate is not FDA approved for use in the United States at this time, but it has been approved by other countries and is recommended by WHO as first-line treatment for treatment of severe malaria.
  • The expanded use IND is an FDA regulatory mechanism. With the unavailability of an FDA-approved intravenous antimalarial, this IND for IV artesunate allows an effective antimalarial to be available through CDC for treatment of severe malaria in the United States.

Will approval through a local institutional review board (IRB) be necessary?

  • This IND protocol is approved by CDC’s IRB that serves as a central IRB, consistent with FDA regulations and guidance, allowing institutions to rely on CDC’s IRB. Therefore, implementation of the treatment protocol may proceed immediately.
  • Hospitals that are precluded by local law or institutional policy to rely on another IRB, or that decide to perform their own IRB review, should consider the following factors:
    • The purpose of the protocol is to provide treatment with investigational artesunate for patients with severe malaria and is subject to FDA regulations. CDC IRB has determined that the use of investigational artesunate in this IND protocol does not constitute human subjects research as defined in 45 CFR 46.102(d). Therefore, this IND protocol does not need to be reviewed for compliance with 45 CFR 46.
    • This protocol may be used for the administration of IV artesunate to all patients with severe malaria, including vulnerable populations. Vulnerable populations including but not limited to children, pregnant and nursing women, and prisoners may be treated under this IND protocol.
  • As this protocol allows for administration of IV artesunate solely for treatment purposes and for non-research purposes, a Federalwide Assurance (FWA) is not required. The CDC IRB approval meets FDA regulatory requirements for IRB review.

What paperwork is involved for the artesunate release?

  • There is little paperwork needed prior to administration of the IV artesunate. Two documents requiring only signatures are required: 1) signed consent form, and 2) signed FDA form.
  • Release of the artesunate from CDC occurs as soon as possible; it does not depend on completion of the documents.
  • There are follow-up reporting forms to be returned to CDC after treatment is complete to fulfill FDA reporting requirements.

What are the criteria for a patient to be eligible for intravenous artesunate?

  • IV artesunate is indicated in a patient with a positive blood smear and severe malaria as defined by certain criteria, that is one or more of the following:
    • Hyperparasitemia (>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 and 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 strong clinical suspicion of severe malaria, for whom a timely, reliable microscopic diagnosis is not available. This indication requires consultation with a CDC malaria expert.

How do I obtain artesunate from CDC?
Clinicians with patients with severe malaria (or patients with malaria unable to tolerate oral medications) should call CDC to obtain IV artesunate. The CDC Malaria Hotline (770-488-7788) is available Monday–Friday, 9 a.m.–5 p.m., Eastern time. Outside these hours, providers should call 770-488-7100 and ask to speak with a CDC malaria expert.

Will there be delays in obtaining IV artesunate from CDC?

CDC will deliver approved artesunate releases to the airport closest to the requesting hospital. Depending on the hospital’s proximity to one of the 10 quarantine stations where artesunate is stored and timing of request, delivery times will vary. In some cases, delivery time could take up to 24 hours.

What should I do for my patient while waiting for the artesunate?

Timely delivery of artesunate is anticipated; however, severe malaria can progress rapidly. Therefore it is reasonable to administer an oral antimalarial until the artesunate arrives. For patients unable to tolerate an oral antimalarial, health care 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.

  • One dose of artemether-lumefantrine (Coartem®), atovaquone-proguanil or quinine can be administered.
  • If artemether-lumefantrine (Coartem ®), atovaquone-proguanil, or quinine are not available, and the health-care provider judges that immediate treatment is needed prior to the arrival of artesunate, mefloquine can be used. Note that there is a risk of severe neuropsychiatric effects at treatment doses of mefloquine.
  • IV clindamycin and IV tetracyclines such as doxycycline are 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.

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

Artesunate is safe for use in children, pregnant women in the second and third trimesters, and during lactation.

  • Limited clinical data on women taking artesunate in the first trimester of pregnancy have not found harmful effects. Given that severe malaria represents a substantial risk for pregnant women and their fetuses including death, and the lack of other treatment options for severe malaria in the United States, the benefits of treatment with artesunate outweigh the risks.

How will artesunate be distributed?

IV artesunate will be prepositioned at 10 quarantine stations across the United States. These quarantine stations are located at major airports based on proximity or interconnectedness to cities from where requests are most likely to originate. If, after consultation with a CDC expert, it is determined that IV artesunate is indicated, CDC will send artesunate free of charge from the quarantine station to the major airport nearest to the requesting hospital. When artesunate is sent, the requesting hospital will receive information regarding where the artesunate is coming from and time of arrival at the nearest major airport. Delivery times will vary depending on the requesting hospital’s proximity to one of the quarantine stations and flight availability.

Where will the artesunate be prepositioned? (similar questions: How is prepositioning determined?
Why only “select” quarantine stations and not all quarantine stations?)

Intravenous artesunate will be prepositioned at 10 quarantine stations across the United States. Quarantine stations are strategically selected based on their location at major airports and based on proximity and interconnectedness to cities around the country.

How long will it take for artesunate to get to my hospital?

Delivery times will vary depending on the requesting hospital’s proximity to one of the quarantine stations.

When to consider IV artesunate

IV artesunate is indicated in the following situations:

  • Patient has a positive blood smear AND severe malaria as defined by one or more of the following:
    • Hyperparasitemia (>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)
  • Patient has a positive blood smear AND is unable to tolerate oral medications regardless of severity of malaria.
  • In exceptional cases, IV artesunate can be empirically used, e.g., a patient with strong clinical suspicion of severe malaria (see criteria for severe malaria above), for whom a timely, reliable microscopic diagnosis is not available. This requires consultation with a CDC malaria expert.

How to obtain IV artesunate

Clinicians with patients with severe malaria (or patient with malaria unable to tolerate oral medications) should call CDC to obtain IV artesunate. The CDC Malaria Hotline (770-488-7788) is available Monday–Friday, 9am–5pm, Eastern time. Outside these hours, providers should call 770-488-7100 and ask to speak with a CDC malaria expert.

IV artesunate will be prepositioned at select quarantine stations across the United States. These quarantine stations are located at major airports. If, after consultation with a CDC expert, it is determined that IV artesunate is indicated, then CDC will release IV artesunate free of charge from the quarantine station to the major airport nearest to the requesting hospital. When IV artesunate is released, the requesting hospital will receive information regarding where the IV artesunate is coming from, and time of arrival at the nearest major airport. Delivery times will vary depending on the requesting hospital’s proximity to one of the storage sites. The requesting hospital will need to arrange for pick-up from the destination airport or releasing quarantine station (if local delivery) and the transport of any drug release to the hospital lies with the requester.

Treatment regimen for severe malaria

Severe malaria can progress rapidly and must be treated as soon as possible. While timely delivery of IV artesunate is anticipated, health-care providers can consider treating the patient with an oral antimalarial while waiting for the IV artesunate to arrive. Health-care providers will need to decide the most feasible route to administer the drug for patients unable to tolerate an oral antimalarial. For example, if this intolerance is due to nausea and vomiting, an anti-emetic preceding the antimalarial may help. For comatose patients, a nasogastric tube can be considered.

One of the antimalarials listed below can be administered. IV clindamycin and IV tetracyclines such as doxycycline are also not recommended. These drugs are slow-acting antimalarials that would not take effect until well after 24 hours, and they are not effective antimalarials for treatment of severe malaria when used alone.

  • Artemether/lumefantrine (Coartem®): 1 tablet=20 mg artemether and 120 mg lumefantrine. Give initial dose, then if still needed, follow with second dose 8 hours later.
    • 5–14 kg:       1 tablet per dose
    • 15–24 kg:    2 tablets per dose
    • 25–34 kg:    3 tablets per dose
    • ≥ 35–kg:       4 tablets per dose
  • Atovaquone/proguanil (Malarone®): Adult (250 mg atovaquone/100 mg proguanil) and pediatric (62.5 mg atovaquone/25 mg proguanil) formulations are available.
    • Adults: 4 adult tablets as 1 dose
    • Children (≥ 5 kg only): Dosing based on weight:
      • 5–8  kg:          2 peds tabs
      • 9–10 kg:         3 peds tabs
      • 11–20 kg:      1 adult tab
      • 21–30 kg:      2 adult tabs
      • 31–40 kg:      3 adult tabs
      • > 40 kg:          4 adult tabs
  • Quinine: Adults: 650 mg (salt) every 8 hours. Children: 10 mg (salt)/kg every 8 hours.
  • Mefloquine (because of a risk of severe neuropsychiatric adverse events at treatment doses, mefloquine should only be used if atovaquone/proguanil or quinine is not available, and based on health-care provider judgement, treatment is needed prior to the arrival of IV artesunate): Adults: 750 mg salt, initially, then if needed, 500 mg salt 6–12 hours after initial dose. Children: 15 mg salt/kg, initially, then if needed, 10 mg salt/kg 6–12 hours after initial dose.

When IV artesunate arrives, discontinue the oral medication. The dosing of IV artesunate is as follows:

  • Adults and children ≥ 20 kg: 2.4 mg/kg at 0 hour, 12 hours, and 24 hours; and 48 hours
  • Children < 20 kg: 3.0 mg/kg at 0 hour, 12 hours, and 24 hours; and 48 hours

After the course of IV artesunate is completed, a follow-on drug must be administered. Options include the following:

  • Artemether/lumefantrine (Coartem®): 1 tablet=20 mg artemether and 120 mg lumefantrine. A 3-day treatment schedule with a total of 6 oral doses as follows: initial dose, second dose 8 hours later, then 1 dose twice a day for the following 2 days. Dosing as above.
  • Atovaquone/proguanil (Malarone®): One dose daily for 3 days. Dosing as above.
  • Doxycycline:
    • Adults: 100 mg twice a day for 7 days.
    • Children (8 years or older): 2 mg/kg twice a day for 7 days.
    • Children under 8 years of age or pregnant women should instead receive clindamycin 20 mg base/kg/day divided 3 times a day for 7 days.
  • Mefloquine (because of a risk of severe neuropsychiatric adverse events at treatment doses, mefloquine should only be used if other options are not available):
    • Adults: 750 mg salt, initially, then 500 mg salt 6–12 hours after initial dose.
    • Children: 15 mg salt/kg, initially, 10 mg salt/kg 6–12 hours after initial dose.

For those patients who still cannot tolerate oral medications after completing artesunate treatment, several treatment options are available, depending on the patient’s clinical and parasitological status. The most suitable course of treatment should be selected by the attending clinicians in consultation with CDC. Potential options include the following:

  • Continue IV artesunate, 1 dose daily (see above for dosing) not to exceed a total course of 7 days.
  • Switch to treatment with IV doxycycline (7 days) or IV clindamycin (7 days), dosing as above.

Use in children and pregnant women

IV artesunate is safe in infants, children, and pregnant women in the second and third trimesters. There are limited clinical data on women taking IV artesunate in the first trimester of pregnancy; no harmful effects have been observed. Given that severe malaria is life threatening for pregnant women and their fetuses, and the lack of other treatment options for severe malaria in the United States, the benefits of treatment with IV artesunate outweigh the risks and IV artesunate should not be withheld.

Contraindications and possible adverse events

The only contraindication to IV artesunate is known allergy to IV artemisinins.

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 in other non-endemic countries. Persons treated for severe malaria with IV artesunate should be monitored for up to 4 weeks after that treatment for evidence of hemolytic anemia. Persons with higher parasitemias seem to have a higher likelihood of delayed hemolytic anemia after treatment with IV artesunate. Depending on the amount of hemolysis, transfusion may be needed.

Documentation and follow up

Release of the IV artesunate from CDC occurs as soon as possible; it is not dependent on these documents being completed first.

Prior to administration of the IV artesunate, only two documents with signatures are required: 1) signed consent form, and 2) signed FDA form. If the patient is incapacitated, and next of kin is not available to provide consent, the clinician can sign the form stating the medical necessity of administering the medication. As this drug is being made available under an IND protocol, and reporting is required to FDA on its use and safety, additional details of the patient’s hospital course including adverse events and outcomes should be reported to CDC.

This IND protocol is approved by CDC’s Institutional Review Board (IRB). CDC’s IRB serves as a central IRB, consistent with FDA regulations and guidance, allowing institutions to rely on CDC’s IRB. Therefore, implementation of the protocol may proceed immediately, and no local IRB approval is needed unless hospitals are precluded by local laws or institutional policy to rely on another IRB or decide to perform their own IRB review. Note that CDC’s IRB determined that the purpose of this IND protocol is to provide IV artesunate for treatment, not research purposes; therefore, Federalwide Assurance is not needed.

 

Page last reviewed: March 28, 2019