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 malaria-endemic countries. 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. As a result, CDC is providing IV artesunate for the treatment of all severe malaria cases. With the discontinuation of IV quinidine, IV artesunate is now the first-line drug for treatment of severe malaria in the United States.

IV artesunate is the recommended World Health Organization (WHO) first-line treatment for severe malaria but is neither FDA-approved nor commercially available in the United States. It is unknown when IV artesunate will receive FDA approval, as this process requires an interested drug company to submit a new drug application to FDA.

IV artesunate is available from CDC under an expanded-access investigational new drug (IND) protocol for patients with severe malaria and patients with uncomplicated malaria who are unable to take oral medications in the United States. The use of this drug under the IND protocol requires the following criteria to be met:

  • Malaria confirmation by microscopy. In exceptional cases and after discussion with a CDC Malaria Branch clinician, microscopic diagnosis might be waived. Those include a patient with strong clinical suspicion of malaria for whom a timely, reliable microscopic diagnosis is not available; AND
  • Parenteral treatment required due to one or more of the following reasons:
    • Severe malaria based on at least one of the following:
      • High parasite density (≥5%)
      • Impaired consciousness
      • Seizures
      • Circulatory collapse/shock
      • Pulmonary edema or acute respiratory distress syndrome (ARDS)
      • Acidosis
      • Acute kidney injury
      • Abnormal bleeding or disseminated intravascular coagulation (DIC)
      • Jaundice (must be accompanied by at least one other sign)
      • Severe anemia (Hb <7 g/dL)
    • Inability to take oral medications despite attempt after an oral antiemetic

Healthcare providers treating patients with severe malaria should call CDC to obtain IV artesunate. The CDC Malaria Hotline (770-488-7788) is available Monday–Friday, 9 am–5 pm EST. Outside these hours, providers should call 770-488-7100 and ask to speak with a CDC Malaria Branch clinician. When calling, please have the following information available:

  1. Patient’s information (name, date of birth, sex, weight, medical record number)
  2. Patient’s detailed clinical and laboratory information
  3. Hospital name and address
  4. Treating physician’s contact information (name, phone number, email address)
  5. Pharmacist’s contact information (name, phone number, email address)

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

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

Patients are required to meet criteria to allow for IV artesunate use:

  • Malaria confirmation by microscopy. In exceptional cases and after discussion with a CDC Malaria Branch clinician, microscopic diagnosis might be waived. Those include a patient with strong clinical suspicion of malaria for whom a timely, reliable microscopic diagnosis is not available; AND
  • Parenteral treatment required due to one or more of the following reasons:
    • Severe malaria based on at least one of the following:
      • High parasite density (≥5%)
      • Impaired consciousness
      • Seizures
      • Circulatory collapse/shock
      • Pulmonary edema or acute respiratory distress syndrome (ARDS)
      • Acidosis
      • Acute kidney injury
      • Abnormal bleeding or disseminated intravascular coagulation (DIC)
      • Jaundice (must be accompanied by at least one other sign)
      • Severe anemia (Hb <7 g/dL)
    • Inability to take oral medications despite attempt after an oral antiemetic

How do I obtain IV artesunate from CDC?

Healthcare providers with patients who meet the criteria to receive IV artesunate should call CDC to obtain IV artesunate. The CDC Malaria Hotline (770-488-7788) is available Monday–Friday, 9 am–5 pm EST. Outside these hours, providers should call 770-488-7100 and ask to speak with a CDC Malaria Branch clinician on call.

Please have the following information ready to provide to the CDC Malaria Branch clinician:

  1. Patient’s information (name, date of birth, sex, weight, medical record number)
  2. Patient’s detailed clinical and laboratory information
  3. Hospital name and address
  4. Treating physician’s contact information (name, phone number, email address)
  5. Pharmacist’s contact information (name, phone number, email address)

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

Timely delivery of IV artesunate is anticipated but severe malaria can progress rapidly while awaiting artesunate delivery. Therefore, healthcare providers should consider administering interim treatment with an oral antimalarial until the IV artesunate arrives. 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 treatments options include artemether-lumefantrine (Coartem®) (preferred), atovaquone-proguanil, 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.

Why is IV artesunate not available at my hospital?

Since IV artesunate is neither FDA approved nor commercially available in the United States, hospitals cannot purchase and keep it in stock. As an alternative, CDC has made IV artesunate available through an expanded-use investigational new drug (IND) protocol, an FDA regulatory mechanism, to provide this lifesaving treatment to patients with severe malaria.

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

The approval process requires a pharmaceutical company to initiate the process and submit a New Drug Application (NDA) to FDA for approval. It is unknown when IV artesunate will be FDA approved for use in the United States. Of note, CDC does not have authority over NDAs or approval of new drugs.

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

In late 2017, the manufacturer of IV quinidine ceased production and remaining product stocks expired in late March 2019. Therefore, since April 2019 there are no other FDA-approved IV antimalarials commercially available to treat severe malaria in the United States. Although IV artesunate is not FDA approved at this time, it has been approved by other countries and is recommended by WHO as the first-line treatment for severe malaria.

The expanded-use IND is an FDA regulatory mechanism to allow for use of IV artesunate in the United States. With the unavailability of any FDA-approved drug for treatment of severe malaria, IND for IV artesunate becomes the only viable option to offer an effective treatment for severe malaria in the United States.

How is IV artesunate distributed?

At this moment, IV artesunate is prepositioned at 18 CDC quarantine stations across the United States. These quarantine stations are located at major airports and were selected based on proximity or interconnectedness to cities from where artesunate requests are most likely to originate.

If, after consultation with a CDC Malaria Branch clinician, it is determined that IV artesunate is indicated, CDC will send IV artesunate free of charge from these points of distribution to the major commercial airport nearest to the requesting hospital. At the time of artesunate shipment, the requesting hospital will receive information regarding which one of the two products is being sent, where the IV artesunate is coming from, and time of arrival at the destination airport. Delivery times will vary depending on the requesting hospital’s proximity to one of the quarantine stations and flight availability. CDC understands the emergency of artesunate requests and works expeditiously to minimize delivery times.

Where will IV artesunate be prepositioned? How were these points of distribution selected?

At this moment, IV artesunate is prepositioned at 18 CDC quarantine stations across the United States. The selected quarantine stations were strategically chosen based on their location at major airports, interconnectedness to cities around the country, and flight volume.

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

Delivery times will vary depending on the requesting hospital’s proximity to one of the points of distribution, time of request, and availability of flights.

Will there be delays in obtaining IV artesunate from CDC?

CDC will deliver IV artesunate to the closest commercial airport to the requesting hospital. Delivery times will vary depending on the hospital’s proximity to one of the locations where IV artesunate is stored and timing of request. Timely delivery of this lifesaving drug to patients is a priority. CDC is monitoring the distribution of artesunate and working to make improvements in its delivery system on an ongoing basis.

Why are there two types of artesunate products and what are the differences between the Walter Reed Army Institute of Research (WRAIR) Department of Defense (DOD) and Guilin (Fosun Pharma) IV products?

To ensure adequate IV artesunate supply, CDC has sourced IV artesunate from two providers, WRAIR (DoD) and Guilin (Fosun Pharma). Although treatment doses and schedule are the same for both products, there are differences between them. The main differences are outlined in the table below.

Note: There are separate protocols for the WRAIR and Guilin artesunate products; please refer to the protocol for each in the Protocol and Resources section below.

Table. Differences in WRAIR (DOD) and Guilin (Fosun Pharma) artesunate products.

artesunate products

 

Is the dosing for the WRAIR (DOD) and Guilin (Fosun Pharma) artesunate products different?

No. The dosing for both the WRAIR and Guilin artesunate products is the same. The following weight-based dosing and treatment schedule should be used to calculate the correct dose for administration:

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

The higher dose for children <20 kg is related to the higher volume of distribution in this patient group.

Will approval through the treating health facility institutional review board (IRB) be necessary?

CDC IRB serves as the central IRB for review of the IND protocols to help reduce the administrative burden on local IRBs and allow timely use of IV artesunate; therefore, hospitals may rely on CDC IRB’s approval of these protocols. CDC IRB determined that use of IV artesunate as described in protocols #5032 (WRAIR product) and #7171 (Guilin product) does not constitute human subjects research because it is provided for treatment purposes only. IRB review for compliance with 45 CFR 46 is not needed (45 CFR 46.102(d)). Following is a summary of CDC’s IRB review:

  • CDC’s Office for Human Research Protections has determined that administration of investigational drugs that CDC provides solely for treatment, non-research purposes due to lack of comparable FDA-approved alternatives does not require a Federalwide Assurance (FWA). Therefore, implementation of the protocol may proceed immediately.
  • Each hospital that receives IV artesunate for treatment of severe malaria under FDA IND #76,725 may use the CDC IRB approval to meet FDA’s regulatory requirements for IRB review.
  • Due to the volume of the hospitals that may be involved in administration of IV artesunate for compassionate treatment use under FDA IND #76,725, it is not feasible for CDC IRB to provide formal IRB authorization agreements.
  • Hospitals that choose to perform their own IRB review rather than utilizing the central IRB review mechanism should be aware that CDC is unable to accommodate requests for changes to IND protocols #5032 (WRAIR product) and #7171 (Guilin product).

What paperwork is involved for the IV artesunate release?

To comply with the requirements of the FDA IND protocol, there is paperwork associated with administration of the IV artesunate. The following two documents require signatures: 1) signed consent form (Appendix V of protocol) by the patient or his/her representative and a witness, which can be a healthcare provider; and 2) signed FDA form (form FDA 1572) by the attending clinician, who will serve as collaborating investigator. Release of IV artesunate from CDC occurs as soon as possible; it does not depend on completion of these documents.

There are also follow-up reporting forms to be returned to CDC after treatment is complete to fulfill FDA reporting requirements (Appendices I through III and VI, if applicable). Details on completion of these forms are described in the respective protocols, whose links are available under the Protocols and Resources tab below.

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. Limited clinical data on women taking IV 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 IV artesunate outweigh the risks.

Comparison of Walter Reed Army Institute of Research (WRAIR) from the U.S. Department of Defense (DOD) and Guilin (Fosun Pharma, China) artesunate products

There are two IV artesunate IND products, the Walter Reed Army Institute of Research (WRAIR) product identified by a yellow label and the Guilin (Fosun Pharma) product identified by a pink label. The dosing for both the WRAIR and Guilin products is the same: adults and children ≥20 kg should receive 2.4 mg/kg at 0, 12, and 24 hours; children <20 kg should receive 3.0 mg/kg at 0, 12, and 24 hours. This difference in dosing is due to a larger volume of distribution in children <20 kg.

The decision of which product to release depends on availability at the point of distribution associated with the location of the health facility requesting the artesunate. CDC staff will share which product is being shipped at the time of release.

There are differences in the two products; a comparison of the products is shown below.

Figure. Comparison of WRAIR (DOD) and Guilin (Fosun Pharma) products.

Comparison of WRAIR (DOD) and Guilin (Fosun Pharma) products

 

Comparison of WRAIR (DOD) and Guilin (Fosun Pharma) products

 

How to obtain IV artesunate

Healthcare providers treating with patients with severe malaria or who cannot tolerate oral medications should call CDC to obtain IV artesunate. The CDC Malaria Hotline (770-488-7788) is available Monday–Friday, 9 am–5 pm EST. Outside these hours, providers should call 770-488-7100 and ask to speak with the CDC Malaria Branch clinician on call.

Please have the following information ready to provide to the CDC Malaria Branch clinician:

  1. Patient’s information (name, date of birth, sex, weight, medical record number)
  2. Patient’s detailed clinical and laboratory information
  3. Hospital name and address
  4. Treating physician’s contact information (name, phone number, email address)
  5. Pharmacist’s contact information (name, phone number, email address)

IV artesunate will be prepositioned at select CDC points of distribution across the United States. These distribution sites are located at major airports. If, after consultation with a CDC Malaria Branch clinician, it is determined that IV artesunate is indicated, then CDC will release IV artesunate free of charge from the points of distribution to the major commercial airport nearest to the requesting hospital. When IV artesunate is released, the requesting hospital will receive information regarding which one of the two products is being sent, where the artesunate is coming from, and time of arrival at the destination airport.

Delivery times will vary depending on the requesting hospital’s proximity to one of the points of distribution. The requesting hospital is responsible for arranging for pick up from the destination airport or point of distribution. The hospital is responsible for these costs. A list of courierspdf icon that operate near CDC Quarantine Stations is provided for convenience as a reference and is not intended to be an inclusive list, nor constitute any endorsement or recommendation by CDC.

Treatment regimen for severe malaria

Severe malaria can progress rapidly, so its treatment should be initiated as soon as possible. While timely delivery of IV artesunate is anticipated, healthcare providers should consider treating the patient with an oral treatment while waiting for IV artesunate to arrive.

Artemether/lumefantrine (Coartem ®) is the preferred antimalarial for interim treatment because of its fast onset of action. Other oral options include atovaquone-proguanil (Malarone ®), quinine, or 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, 3 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 as follows:

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

The slightly higher dose in children <20 kg is in line with the WHO recommendations based on the larger volume of distribution in children of this weight. 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 4 hours after the last artesunate dose) and patient can tolerate oral treatment, a full treatment course with a follow-on drug must be administered. Options include artemether-lumefantrine (Coartem™) (preferred), atovaquone/proguanil (Malarone™), quinine plus doxycycline or clindamycin, or 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 tablepdf icon. 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 4 hours after the last artesunate dose), IV treatment with artesunate should continue with the recommended daily dose for a maximum of 7 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 as above as soon as parasitemia ≤1% and the patient is able to tolerate oral medications. CDC Malaria Branch clinicians should be consulted for specific clinical guidance.

For patients with parasite density ≤1% but who still cannot tolerate oral medications after completing IV artesunate treatment, potential options as listed below:

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

Once patient can tolerate oral medications, switch to an oral follow-on treatment. Placement of 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 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, but 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. 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 seem to 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.

Documentation and follow-up

Release of the IV artesunate from CDC occurs as soon as possible and is not dependent on any documents being sent to CDC.

Prior to administration of the IV artesunate, the following two documents with signatures are required: signed consent form (Appendix V of artesunate protocol), and signed investigator participant form (FDA Form 1572pdf icon). If the patient is incapacitated, and next of kin is not available to provide consent, the treating 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 using the case report form (Appendixes I thru III and VI, if applicable).

Ethical review

CDC’ Institutional Review Board (IRB) serves as the central IRB for review of the IND protocols to help reduce the administrative burden on local IRBs and allow timely use of IV artesunate; therefore, hospitals may rely on CDC IRB’s approval of these protocols. 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.

CDC IRB determined that use of IV artesunate as described in Protocols #5032, WRAIR (DOD) product, and #7171 Guilin (Fosun Pharma) product, does not constitute human subjects research because it is provided for treatment purposes only. IRB review for compliance with 45 CFR 46 is not needed (45 CFR 46.102(d)). Following is a summary of CDC’s IRB review:

  • CDC’s Office for Human Research Protections has determined that administration of investigational drugs that CDC provides solely for treatment, non-research purposes due to lack of comparable FDA-approved alternatives does not require a Federalwide Assurance (FWA). Therefore, implementation of the protocol may proceed immediately.
  • Each hospital that receives IV artesunate for treatment of severe malaria under FDA IND #76,725 may use the CDC IRB approval to meet FDA’s regulatory requirements for IRB review.
  • Due to the volume of the hospitals that may be involved in administration of IV artesunate for compassionate, treatment use under FDA IND #76,725, it is not feasible for CDC IRB to provide formal IRB authorization agreements.
  • Hospitals that choose to perform their own IRB review rather than utilizing the central IRB review mechanism should be aware that CDC is unable to accommodate requests for changes to IND protocols #5032 and #7171.

FDA Form 1572 filling instructions

The attending physician will serve as the “Investigator” at the hospital for the purposes of IV artesunate treatment protocol. Items 1 and 3 pertain to information on the attending physician and his/her respective hospital. The physician should complete items 1 and 3, then sign and date (items 10 and 11). Fields 2, 5, 7, and 8 have been filled (or will be filled) by CDC. Items 4 and 6 can be left blank. A copy of the attending physician’s CV should also be forwarded to CDC together with the protocol documentation.

Page last reviewed: December 11, 2019