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

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

Hospitals can purchase Artesunate for Injection^TM from specialty pharmacies of major drug distributors. If hospitals choose not to stock Artesunate for Injection^TM, other options can be found hereexternal icon. Timely access to intravenous 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 the specialty pharmacies of the following major drug distributors: Amerisource Bergen, Cardinal, McKesson. This linkexternal icon has up to date information on how to acquire Artesunate for Injection^TM.

If artesunate is commercially available, why is artesunate still made available through the expanded use investigational new drug (IND) protocol?

To ensure continued and timely availability of IV artesunate for critically ill patients, CDC will continue to distribute artesunate under an IND protocol until the distribution of Artesunate for Injection^TM expands nationwide and is sufficiently stocked in the states where the most cases of malaria are found.

How do I obtain IV artesunate from CDC?

Healthcare providers with patients who meet the criteria to receive IV artesunate and are unable to obtain commercially available IV artesunate within 24 hours 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 are the criteria for a patient to be eligible for IV artesunate from CDC?

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;

AND

• Inability to obtain commercially available IV artesunate within 24 hours

What should I do for my patient while waiting for Artesunate for Injection^TM or IV artesunate from the CDC to arrive?

Ideally, having intravenous 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 intravenous artesunate, whether Artesunate for Injection^TM or IV artesunate from the CDC, 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, 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.

How is IV artesunate distributed through the expanded-use IND protocol?

Intravenous artesunate is prepositioned at points of distribution across the United States. These points of distribution 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 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 points of distribution and flight availability. CDC understands the emergency of artesunate requests and works expeditiously to minimize delivery times.

Where is CDC’s IV artesunate prepositioned? How were these points of distribution selected?

Intravenous artesunate is prepositioned at points of distribution across the United States. The selected points of distribution were strategically chosen based on location of previous cases of severe malaria, location at major airports, interconnectedness to cities around the country, and flight volume.

How long will it take for IV artesunate from CDC 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. If the requesting hospital is located in the same city as the prepositioning location, a courier may be used to pick up the drug. 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.

Will approval of the IND protocol 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 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 the IND protocol.

What paperwork is involved for the IV artesunate release through the IND protocol?

To comply with the requirements of the 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 deaths and th lack of other treatment options for severe malaria in the United States, the benefits of treatment with IV artesunate outweigh the risks.

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:

• 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, 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
• Other options for acquiring Artesunate for Injection^TM are hereexternal icon.
  • Order from a specialty pharmacy
  • Call AMIVAS call center
  • Transfer patient to a hospital where artesunate is stocked
• If Artesunate for Injection^TM is not going to be available from the distributor or drug company within 24 hours of a clinician’s request, and it is not possible to transfer the patient to a hospital with artesunate, call CDC for IV artesunate. Malaria Hotline: Monday-Friday 9am-5pm EST 770-488-7788. Emergency Operations Center: afterhours and weekends 770-488-7100
• CDC will continue to distribute artesunate under its investigational new drug (IND) protocol for patients in situations where FDA-approved Artesunate for Injection^TM is not yet available within 24 hours of a clinician requesting the drug. When the distribution of Artesunate for Injection^TM expands nationwide and is stocked in the states where the most cases of malaria are found, CDC will discontinue its distribution of intravenous artesunate. CDC will monitor the availability of Artesunate for Injection^TM closely, and will provide additional communications prior to the discontinuation of its IND program for artesunate.
• 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, 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 ®) can be administered while waiting for IV artesunate and is the first choice. If not available, other options include: atovaquone-proguanil or quinine.

What are the differences between IV artesunate available from CDC and the commercially available Artesunate for Injection^TM?

• Each box of IV artesunate from CDC has a vial with 60mg of drug, and one ampule of sodium bicarbonate. The IND protocol has instructions for reconstituting the drug.
• Each box of commercially available Artesunate for Injection^TM has one vial of 110 mg of drug, and one vial of phosphate buffer. The package insert has instructions for reconstituting the drug.
• The dosing regimen is the same for both drugs. Each dose is 2.4 mg/kg. One dose is given at 0, 12, and 24 hours. Full treatment guidelines can be found here.
  • If after the 24-hour dose >1% of red blood cells are infected with parasite, one dose (2.4 mg/kg) of artesunate can be given daily until:
    § ≤1% of red blood cells are infected, and the patient is able to tolerate oral medications. Switch to a full course of oral antimalarials. Artemether-lumefantrine (Coartem ^®) is the first choice drug. Other options, if more readily available can be given and include atovaquone-proguanil, or quinine plus doxycycline.
  • § If after the 24-hour dose ≤1% of the red blood cells are infected with parasite, and the patient is able to tolerate oral medications, switch to a full oral course of antimalarials. Artemether-lumefantrine (Coartem ^®) is the first-choice drug. Other options, if more readily available can be given and include atovaquone-proguanil, or quinine plus doxycycline.
  • § If patient continues to not tolerate oral medications, artesunate can be given daily for a total course of 7 days maximum until no parasites are seen on the thick malaria blood smear.

How to obtain IV artesunate from the CDC (expanded-use IND protocol)

Healthcare providers treating patients with severe malaria or who cannot tolerate oral medications, and who are at a hospital where it would not be feasible to obtain commercially available IV artesunate within 24 hours 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 is prepositioned at select CDC points of distribution across the United States. 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 or via courier. When IV artesunate is released, the requesting hospital will receive information regarding where the artesunate is coming from and, when applicable, 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:

• 2.4 mg/kg at 0, 12, and 24 hours and can be continued daily for up to a total of 7 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 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.

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 6 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. 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. 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 under CDC IND

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’s 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, 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 the IND protocol.

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.