213036Orig1s000

CENTER FOR DRUG EVALUATION AND RESEARCH

APPLICATION NUMBER:

213036Orig1s000

OTHER REVIEW(S) MEMORANDUM REVIEW OF REVISED LABEL AND LABELING Division of Medication Error Prevention and Analysis (DMEPA) Office of Medication Error Prevention and Risk Management (OMEPRM) Office of Surveillance and Epidemiology (OSE) Center for Drug Evaluation and Research (CDER)

Date of This Memorandum: May 19, 2020 Requesting Office or Division: Division of Anti-Infectives (DAI) Application Type and Number: NDA 213036 Product Name and Strength: Artesunate for Injection, 110 mg per vial Applicant/Sponsor Name: Amivas, LLC OSE RCM #: 2019-1722-3 DMEPA Safety Evaluator: Deborah Myers, RPh, MBA DMEPA Team Leader: Otto L. Townsend, PharmD

1 PURPOSE OF MEMORANDUM The Applicant submitted their revised container label and carton labeling received on May 19, 2020 for Artesunate. The Division of Anti-Infectives (DAI) requested that we review the revised container label and carton labeling for Artesunate (Appendix A) to determine if they are acceptable from a medication error perspective. The revisions are in response to recommendations that we made during a previous label and labeling reviewa, as well recommendations made by the Office of Pharmaceutical Quality included in Labeling Revisions communicated to the Applicant.b

2 CONCLUSION The Applicant implemented all of our recommendations and we have no additional recommendations at this time.

a Myers, D. Label and Labeling Review Memo for Artesunate (NDA 213036). Silver Spring (MD): FDA, CDER, OSE, DMEPA (US); 2020 MAY 14. RCM No.: 2019-1722-2. b DiBernardo, G. FDA Communication: FDA Labeling Revisions for Artesunate. Silver Spring (MD): FDA, CDER, OSE, DMEPA (US); 2020 MAY 15. NDA 213036. Available from: https://darrts.fda.gov/darrts/ViewDocument?documentId=090140af80564c55. 1

Reference ID: 4610973 APPENDIX A. IMAGES OF LABEL AND LABELING RECEIVED ON MAY 19, 2020

Revised Prescribing Information available at the following links:  Track changes version is available at the following link: \\cdsesub1\evsprod\nda213036\0057\m1\us\draft-labeling-text-tracked-changes.docx.  Clean draft version is available at the following link: \\cdsesub1\evsprod\nda213036\0057\m1\us\draft-labeling-text.docx.

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DEBORAH E MYERS 05/19/2020 12:59:16 PM

OTTO L TOWNSEND 05/19/2020 01:19:41 PM

Reference ID: 4610973 MEMORANDUM REVIEW OF REVISED LABEL AND LABELING Division of Medication Error Prevention and Analysis (DMEPA) Office of Medication Error Prevention and Risk Management (OMEPRM) Office of Surveillance and Epidemiology (OSE) Center for Drug Evaluation and Research (CDER)

Date of This Memorandum: May 14, 2020 Requesting Office or Division: Division of Anti-Infectives (DAI) Application Type and Number: NDA 213036 Product Name and Strength: Artesunate for Injection, 110 mg per vial Applicant/Sponsor Name: Amivas, LLC OSE RCM #: 2019-1722-2 DMEPA Safety Evaluator: Deborah Myers, RPh, MBA DMEPA Team Leader: Otto L. Townsend, PharmD

1 PURPOSE OF MEMORANDUM The Applicant submitted revised prescribing information (PI), container labels, and carton labeling, including proposed carton labeling for a new packaging configuration, received on May 14, 2020 for Artesunate. The PI revisions are in response to the Agency’s recommendations dated May 7, 2020, as well as the addition of language to Section 16, How Supplied/Storage and Handling, regarding the newly proposed packaging configuration (i.e., 2 vials of Artesunate for Injection and 2 vials of diluent). The Division of Anti-Infectives (DAI) requested that we review the revised PI, container labels, and carton labeling, for Artesunate (Appendix A) to determine if they are acceptable from a medication error perspective.

2 FINDINGS AND ASSESSMENT Amivas now proposes the addition of a 2 x 2 packaging configuration which will include 2 vials of Artesunate for Injection and 2 vials of diluent. Amivas states this will provide more flexibility for prescribers. We do not object to this proposal. The Office of Pharmaceutical Quality (OPQ) intends to recommend that the Applicant “Update the product name and strength on the cartons and vials from (b) (4) ” to “Artesunate for Injection 110 mg/vial” and we concur with this recommendation.

Reference ID: 4608930 Section 16 How Supplied/Storage and Handling could be revised for clarity and completeness. We provide recommendations below.

3 CONCLUSION AND RECOMMENDATIONS We concur with OPQ’s recommendation to “Update the product name and strength on the cartons and vials from (b) (4) ” to “Artesunate for Injection 110 mg/vial”. The Office of Pharmaceutical Quality intends to recommend that the Applicant “Update the product name and strength on the cartons and vials from (b) (4) ” to “Artesunate for Injection 110 mg/vial” and we concur with this recommendation.

Additionally, for DAI’s consideration we have provided our recommendations to Section 16, How Supplied/Storage and Handling, of the PI on SharePoint. Section 16 is incomplete and lacks clarity. To provide clarity and completeness, we recommend replacing the Applicant’s proposed “How Supplied” text with the following “How Supplied” text:

Artesunate for Injection, is supplied as follows:  110 mg, white or almost white, sterile, fine crystalline powder for constitution in single-dose, clear glass vials sealed with a rubber stopper (not made with natural rubber latex) and an aluminum overseal  clear glass vials of a sterile diluent for constitution are sealed with a rubber stopper (not made with natural rubber latex) and an aluminum overseal.

Artesunate for Injection single-dose vial: NDC 73607-001-01

Sterile Diluent for Constitution single-dose vial: NDC 73607-001-02

Packages of 4 total vials (2 vials of Artesunate for Injection, 110 mg and 2 vials sterile diluent for Artesunate For Injection): NDC 73607-001-11

Packages of 8 total vials (4 vials of Artesunate for Injection, 110 mg and 4 vials sterile diluent for Artesunate for Injection): NDC 73607-001-10

For DAI’s consideration, we have incorporated the above recommendations into Section 16, of the PI on SharePoint.

Reference ID: 4608930 APPENDIX A. IMAGES OF LABEL AND LABELING RECEIVED ON MAY 14, 2020

Prescribing Information is available at the following link:  Track changes version is available at the following link: \\cdsesub1\evsprod\nda213036\0055\m1\us\draft-labeling-text-tracked-changes.docx  Clean draft version is available at the following link: \\cdsesub1\evsprod\nda213036\0055\m1\us\draft-labeling-text.docx

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DEBORAH E MYERS 05/14/2020 05:39:49 PM

OTTO L TOWNSEND 05/14/2020 06:22:35 PM

Reference ID: 4608930 FOOD AND DRUG ADMINISTRATION Center for Drug Evaluation and Research Office of Prescription Drug Promotion ****Pre-decisional Agency Information****

Memorandum

Date: April 20, 2020

To: Leslie Ball, M.D. Division of Anti-Infective Products (DAIP)

Gregory DiBernardo, Regulatory Project Manager, DAIP

Abimbola Adebowale, Associate Director for Labeling, DAIP

From: David Foss, Regulatory Review Officer Office of Prescription Drug Promotion (OPDP)

CC: Jim Dvorsky, Team Leader, OPDP

Subject: OPDP Labeling Comments for ARTESUNATE for injection, for intravenous use

NDA: 213036

In response to DAIP’s consult request dated November 12, 2019, OPDP has reviewed the proposed product labeling (PI) and carton and container labeling for the original NDA submission for Artesunate.

PI: OPDP’s comments on the proposed labeling are based on the draft PI received by electronic mail from DAIP on April 10, 2020, and are provided below.

Carton and Container Labeling: OPDP has reviewed the attached proposed carton and container labeling submitted by the Sponsor to the electronic document room on March 11, 2020, and we do not have any comments.

Thank you for your consult. If you have any questions, please contact David Foss at (240) 402-7112 or [email protected].

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DAVID F FOSS 04/20/2020 04:17:48 PM

Reference ID: 4595052 MEMORANDUM REVIEW OF REVISED LABEL AND LABELING Division of Medication Error Prevention and Analysis (DMEPA) Office of Medication Error Prevention and Risk Management (OMEPRM) Office of Surveillance and Epidemiology (OSE) Center for Drug Evaluation and Research (CDER)

Date of This Memorandum: March 12, 2020 Requesting Office or Division: Division of Anti-Infectives (DAI) Application Type and Number: NDA 213036 Product Name and Strength: Artesunate for Injection, 110 mg per vial Applicant/Sponsor Name: Amivas, LLC OSE RCM #: 2019-1722-1 DMEPA Safety Evaluator: Deborah Myers, RPh, MBA DMEPA Team Leader: Otto L. Townsend, PharmD

1 PURPOSE OF MEMORANDUM The Applicant submitted revised prescribing information (PI), container labels, and carton labeling, received on March 11, 2020, for Artesunate. The Division of Anti-Infectives (DAI) requested that we review the revised PI, container labels, and carton labeling for Artesunate (Appendix A) to determine if they are acceptable from a medication error perspective. The revisions are in response to recommendations that we made during a previous label and labeling review.a

2 CONCLUSION The revised container labels and carton labeling are acceptable from a medication error perspective. Additionally, in Section 3 below, we provide a recommendation to the Division of Anti- Infectives (DAI) to add the national drug code (NDC) for the carton to Section 16, How Supplied/Storage and Handling, of the PI.

3 RECOMMENDATIONS FOR THE DIVISION

a Myers D. Label and Labeling Review for Artesunate (NDA 213036). Silver Spring (MD): FDA, CDER, OSE, DMEPA (US); 2020 FEB 07. RCM No.: 2019-1722. 1

Reference ID: 4574546 We note that the revised prescribing information, submitted on March 11, 2020, does not include the national drug code (NDC) for the carton in Section 16, How Supplied/Storage and Handling. We recommend adding the carton NDC {73607-001-10) to Section 16 of the Pl (see screen shot below):

16 HOW SUPPLIED/STORAGE AND HANDLING (bf(4J

A Myers, Oeboroh ...... ···· 1 ~ DMEPA MCOOUlleim die addit;oo. of th&<:atton NOC.

Reference ID 4574546 APPENDIX A. IMAGES OF LABEL AND LABELING RECEIVED ON MARCH 11, 2020

Prescribing Information is available at the following link:  Track changes version is available at the following link: \\cdsesub1\evsprod\nda213036\0044\m1\us\draft-labeling-text-tracked-changes.docx  Clean draft version is available at the following link: \\cdsesub1\evsprod\nda213036\0044\m1\us\draft-labeling-text.docx

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DEBORAH E MYERS 03/12/2020 04:26:39 PM

OTTO L TOWNSEND 03/12/2020 04:46:17 PM

Reference ID: 4574546 DEPARTMENT OF HEALTH & HUMAN SERVICES Public Health Service

Division of Pediati·ic and Maternal Health Office of New Drngs Center for Drng Evaluation and Research Food and Drng Administi·ation Silver Spring, MD 20993 Tel 301-796-2200 FAX 301-796-9744

Division of Pediatric and Maternal Health Review

Date: 02/28/2020 Date consulted: 11107/2019

From: Wenjie Sun, MD, Medical Officer, Maternal Health Division of Pediati·ic and Maternal Health

Through: Miriam Dinatale, DO, Team Leader, Maternal Health Division of Pediati·ic and Maternal Health

Lynne P. Yao, MD, OND, Division Director Division of Pediati·ic and Maternal Health (DPMH)

To: Division of Anti-infective Products (DAIP)

Drug: Artesunate for injection

NDA: 213036

Applicant: Amivas, LLC

Subject: Pregnancy and Lactation Labeling Recoilllllendations

Proposed Indication: for the treatment of severe malaria

Materials Reviewed: • Applicant's submitted background package and proposed labeling for NDA 213036 • DAIP consult fo1m for DPMH, DARRTS Reference ID 4517102 • DPMH review of Coartem NDA 22068 on April 16, 2019, DARRTS Reference ID 44199371

1 The Coartem consult review was pa1t of the materials reviewed but was not a source relied upon for the labeling recommendations in this consult review.

Reference ID 4568389

Consult Question: - DAIP is seeking assistance from DPMH in developing Sections 8.1 and 8.2 of the product labeling to provide a clear risk summary for IV artesunate use in pregnancy and lactation that will accurately convey the current data and avoid confusion that could lead to critical treatment delays. Specific questions: o How should the apparent discrepancies between the nonclinical and clinical data on safety in pregnancy be addressed in the labeling? Does the accumulating clinical data allow for inclusion of a statement about differences in observations between animal and human exposures such as the statement added to the revised Coartem® PI (“the relevance of the findings from the animal reproductive studies to human risk is unclear”)? o What statements can be made regarding the safety of IV artesunate in pregnancy based on the published clinical data? Is a qualification needed regarding use in the first trimester of pregnancy?” - DAIP also seeks assistance from DPMH in developing Section 12.3 of the product labeling based on the applicants use of the following PK studies in pregnant woman. Specific question: o Is it reasonable to use comparative analysis between post-partum and ante-partum states to infer pregnancy effects on drug (or metabolite) exposures? If yes, is the 3-month time to return to an apparent normal or “baseline” state acceptable? Some key physiological factors relevant for maternal PK of artesunate and DHA may be blood hematocrit, liver blood flow, cytochrome P-450 enzymes (in particular CYP3A, 2B6 at gastrointestinal and hepatic sites) and UDP- glucuronosyltransferases (in particular UGT1A9 and UGT2B7 at gastrointestinal and hepatic sites).

INTRODUCTION AND BACKGROUND On August 12, 2019, the applicant (Amivas) submitted a new original NDA for artesunate injection for approval. The Division of Anti-infective Products (DAIP) consulted the Division of Pediatric and Maternal Health (DPMH) on November 7, 2019, to assist with the Pregnancy and Lactation subsections of labeling.

Regulatory History (b) • Artesunate for injection has a proposed indication of: “the initial treatment of severe (4) (b) (4) malaria in adults and children.” • Artesunate is not approved for use in U.S. Artesunate is registered in China, Myanmar, Thailand, Malaysia, Indonesia, Madagascar and many countries in Africa. • With the discontinuation of intravenous (IV) quinidine, which was indicated for the treatment of life-threatening Plasmodium falciparum malaria, in March 2019, there is currently no approved parenteral antimalarial drug available for patients in the US with severe malaria. • Artesunate is currently available in the US from the Centers for Disease Control and Prevention (CDC) under an expanded-access Investigational New Drug (IND) protocol for patients with severe malaria. • IV artesunate was granted Orphan Drug Designation March 28, 2006.

Reference ID: 4568389 • The US Army entered into a cooperative research and development agreement in 2017 (b) with Amivas to commercialize IV artesunate for treatment of patients with severe (4) malaria in the USA and other jurisdictions. In 2017, the US Army also entered into an exclusive license agreement for IV artesunate for the treatment of severe (b) (4) malaria. • The product is a defense priority product under FDA Reauthorization Act which became Public Law 115-92 and was enacted December 12, 2017. • The US Army Medical Material Development Activity received Breakthrough Therapy Designation on September 11, 2018. It also received Fast Track Designations by the FDA. • Amivas requested priority review and requested that they be granted a Tropical Disease Priority Review Voucher (PRV). • Amivas transferred Orphan Drug Designation with the agreement of the US Army effective April 22, 2019. • Amivas submitted artesunate for injection for treatment of severe malaria as a 505(b) application and relies upon a clinical and non-clinical study conducted by the applicant with artesunate as well as published literature on artesunate.

Drug Characteristics Drug Class Endoperoxide antimalarial (It is a semisynthetic derivative of artemisinin, which is a sesquiterpene lactone produced by Chinese medicinal herb Artemisia annua) Mechanism of action Artesunate (AS) contains an endoperoxide bridge that is activated by heme iron, resulting in the generation of free radicals that alkylate parasite proteins and ultimately lead to cell death. Dihydroartemisinin (DHA, also known as artenimol), the active metabolite of artesunate, was found to specifically increase oxidative stress in P. falciparum-infected erythrocytes but not uninfected cells, by reduction of antioxidants. Metabolism Cytochrome 2A5 in liver convert AS to DHA, 50% of AS is hydrolyzed in blood by esterase. Excretion in urine. Molecular weight 384.43 g/mol Half life 2-15 min (for its metabolite DHA 8-64 min) Protein Binding DHA is 93% bound Bioavailability 100% Serious Adverse Reactions Hypersensitivity reaction, post artesunate delayed hemolysis; other reactions which are common include: anemia, abnormal liver function, thrombocytopenia, hyperbilirubinemia, acute renal failure, acute respiratory distress syndrome, leukocytosis, lymphopenia, and neutropenia.

Reference ID: 4568389 REVIEW PREGNANCY Malaria and Pregnancy2,3 - Incidence: o “An estimated 54.7 million pregnancies occurred in areas of stable Plasmodium falciparum malaria transmission4, and an additional 70.5 million pregnancies occurred in areas of low transmission or areas with only Plasmodium vivax malaria in 2007. Malaria in pregnancy is associated with higher rates of parasitemia, severe anemia, hypoglycemia, and acute pulmonary edema than malaria in non-pregnant women. Malaria in pregnancy is a major contributor to morbidity and mortality, resulting in an estimated 100,000 neonatal deaths and 10,000 maternal deaths annually5.”

o There are approximately 1,700 cases of malaria each year in the United States. Approximately 37% of these cases occur in women, including 5% 6 who are pregnant at the time of infection. - Pregnancy complications of malaria (P. falciparum and vivax): o First-trimester falciparum malaria is strongly associated with miscarriage, especially after recurrence. Recurrence of vivax malaria is also associated with miscarriage. o In addition, malaria is also related to maternal death, severe maternal anemia, placental malaria, low birth weight, congenital malaria, and neonatal mortality. 6,7 8 o According to the CDC , malaria infection in pregnant women can be more severe than in non-pregnant women with high risk of illness and death in both the mother and fetus. Malaria increases the risk for adverse pregnancy outcomes, including prematurity, spontaneous abortion, and stillbirth. For these reasons, women who are pregnant or likely to become pregnant should be advised to avoid travel to areas with malaria transmission, if possible. If travel to a malaria endemic area cannot be deferred, use of an effective chemoprophylaxis regimen is essential. - Risk factor: travel or live in endemic area - Treatment guidelines for malaria (WHO 2015)9 o Uncomplicated malaria . First trimester- 7 days of oral quinine + clindamycin

2 April 16, 2019, DPMH review Coartem, Carrie Ceresa, Pharm D., MPH, Clinical Analyst, DARRTS Reference ID 4419937. 3 The Coartem review was part of the materials reviewed but not a source relied upon for the labeling recommendations below. 4 Areas of Stable Plasmodium falciparum malaria transmission: African Regions (81%), South East Asia (13%) and Eastern Mediterranean Region (5%) 5 Korvacs SD, et. al. Treating severe malaria in pregnancy: a review of the evidence. Drug Saf 2015; 38: 165-181. 6 World Health Organization. Guidelines for the treatment of malaria. 3rd ed. Geneva, Switzerland: World Health Organization; 2015. 7 Nambozi M, et. al. 2019 8 CDC, Pregnant Travelers, https://wwwnc.cdc.gov/travel/yellowbook/2018/advising-travelers-with-specific- needs/pregnant-travelers, accessed 21 February 2019. 9 World Health Organization: Guidelines for the treatment of malaria. Third edition. April 2015.

Reference ID: 4568389 . Second and third trimester- 3 days of one of the following oral combinations below • Artemether + lumefantrine • Artesunate +amodiaquine • Artesunate + mefloquine • Dihydroartemisinin + piperaquine • Artesunate + sulfadoxine-pyrimethamine o Severe malaria: . Treat adults and children with severe malaria (including infants, pregnant women in all trimesters and lactating women) with IV or IM artesunate for at least 24 hours and until they can tolerate oral medication. Complete treatment with 3 days of artemisinin combination therapy (ACT). Add single dose primaquine in areas of low transmission. o Prophylaxis for pregnancy and breastfeeding: . Weekly chloroquine until delivery and breastfeeding are complete then primaquine (based on G6PD status) to prevent future relapse. . In malaria endemic areas in Africa, provide intermittent preventive treatment with sulfadoxine-pyrimethamine (SP) to all women in their first or second pregnancy as part of antenatal care. Dosing should start in the second trimester and does should be given at least 1 month apart with objective of ensuring that at least 3 doses are received.

See Table 1 below for a comparison of IV versus oral artesunate:

IV Artesunate Oral Artesunate Approved for severe Yes. No. malaria? Women with severe malaria in all trimesters, including the first trimester, are treated with IV artesunate. Used for uncomplicated No. Yes. malaria? If so, when? In uncomplicated malaria, oral artesunate is only for 2nd and 3rd trimester. Women who have uncomplicated malaria in the first trimester receive quinine. WHO 2015 recommended 2.4-3mg/kg/dose at 0, 12, 24, and 48 hours then 4 mg/kg/day artesunate with another agent for 3 days dose daily for 7 days or until tolerating po for 7 days -children < 20 kg: 3mg/kg per dose -larger children and adults: 2.4 mg/kg/dose

Nonclinical Experience Pregnant rats, administered a single dose of IV artesunate at approximately 0.1-times the clinical dose based on body surface area (BSA) comparisons early during organogenesis on gestation day (GD) 11, had complete postimplantation loss. Pregnant rats dosed orally during organogenesis (GD 7 through 17) at artesunate doses approximately 0.4 to 1-times the clinical dose based on BSA comparisons showed dose- dependent post-implantation losses, with surviving fetuses displaying cardiovascular (ventricular

Reference ID: 4568389 septal defects, retro-esophageal right subclavian artery arising from the descending aorta) and skeletal (e.g., fused ribs, bent, shortened and/or curved ulna, humerus and scapula) malformations in the absence of maternal toxicity. Oral dosing in pregnant rabbits during organogenesis (GD 7 through GD 19) at artesunate doses of 0.7 to 1.6-times the clinical dose based on BSA comparisons resulted in cardiovascular (e.g., retro-esophageal right subclavian artery arising from descending aorta), skeletal (e.g., shortened/displaced ribs, flexed joints and/or bent scapula) and brain (dilated ventricles, absent pons) malformations in the absence of maternal toxicity. Additionally, administration of artesunate at 12 mg/kg/day to pregnant rabbits during organogenesis resulted in abortions, postimplantation loss and increased intrauterine deaths. Oral administration of artesunate to pregnant cynomolgus monkeys during organogenesis (GD 20 to GD 50) at approximately 1.6-times the clinical dose based on BSA comparisons resulted in increased embryonic death with skeletal malformations (i.e., decrease in absolute length of the ulna) observed in surviving fetuses. The reader is referred to the full Pharmacology/Toxicology review by Kelly Brant, Ph.D. and Terry Miller, Ph.D.

Review of Clinical Trials Amivas Pharma submitted several studies which includes: Phase 1 studies: study ID 1128 and study ID 1142 Phase 2 studies: study ID 1168, study ID1253ab, study EDCTP-MMV01-01 (legacy data) Phase 3 study: study ID R-CDC-060, study SEAQUAMAT (legacy data)

Study CDC-060 is prospective study conducted by US Center for Disease Control under IND: 76725 in which all patients received IV artesunate at a dosage of 2.4 mg/kg at 0, 12, 24, 48 hours. The dose may be modified later to a simpler daily administration for 3 days. The US Army also did a separate retrospective data abstraction to support this filing. This study represents the US intensive care unit experience and accompanying diagnostic procedure and standards for supportive case in pediatric, adult and geriatric patients with severe malaria.

There were three pregnant patients in Study CDC-060 from the period of 2007 to 2010. One delivered her child before artesunate was administered. The two women who received artesunate during pregnancy are listed below. They both delivered healthy infants.

Table 2 Pregnancy outcomes for Protocol CDC-060 Patient number Time of All AE Maternal Neonatal outcome exposure outcome (b) (6) No 35-36 weeks Anemia Spontaneous Healthy infant, Apgars of 8 vaginal delivery and 9, no malformations. (SVD) 6 days after treatment (b) (6) No 34-35 weeks Elevated AST SVD 4 weeks Normal breastfeeding. No after treatment other documented outcome.

Reference ID: 4568389 ill addition, based on info1mation from CDC Malaria surveillance Summaries from 2011 to 2015, 169 pregnant women had malaria; however, it is unclear if they received artesunate for treatment except for one pregnant patient who was diagnosed with P ovale and was treated with IV aitesunate in 201 5; that patient survived, but the outcome of her pregnancy is unknown.

SEAQUAMAT trial is an open label trial in Asia designed for efficacy compai·ing IV aitesunate (n=730) to IV quinine (n=73 1) for the treatment of malai1a, with prima1y end point of death from severe malai·ia. Overall mo1tality of ait esunate recipients was 15% compared to 22% in quinine recipient. There were total of 49 pregnant women in the trial.

There ai·e total of 10 fetal deaths in SEAQUAMAT trial, including five fetal deaths in the aitesunate group and five fetal deaths in the quinine group. One fetal death in the ait esunate group was a result of maternal death. Table 2 below shows a compai·ison of fetal loss between the ait esunate group versus the quinine group. The overall rate of still bi1t h or spontaneous abo1tion ai·e similai· between the aitesunate (5/23, 21.7%) and the quinine group (5/26, 19.2%). Of the 23 pregnant women in the ait esunate group. 2 maternal deaths occmTed. No additional info1m ation was given.

Table 2: SEAQUAMAP0 - Pregnancies, Gestational Age, and Still Biiths/Spontaneous Abo1tions Artesunate Quinine Totals n=730 n=731 n=1461 Pre=ant Flag - 23 (3.2%) 26 (3.6%) 49 (3.4%) Estimated Gestation Time Weeks count subjects with data 23 26 49 mean and standard deviation 24.35 f6.46l 27.38 f7 .94l 25.96 f7.37l median 0 0 0 range 8-36 8-40 8-40 Clinical Event -- Still birth or spontaneous abortion 5 (0.7%) 5 (0.7%) 10 (0.7%) Source: DAIP Consult request fonn12

Reviewer's Comment: The data above is a legacy data set which the applicant acquiredfr om the investigator, no additional clinical data can be obtained.

Review of Literatme Applicant's Review ofLiterature A literature seai·ch was perfo1med for aitesunate by the applicant; five aiticles were reviewed. See Appendix A for the a1ticles reviewed by the applicant.

10 SEAQUAMAT StudyRepo1t: Table 14.1.9.1, Table 14.2.4

Reference ID 4568389 The applicant concluded the following: “In contrast to the embryotoxicity seen in animals, observational studies show that artesunate is well-tolerated in pregnant women with malaria, including those treated during the first trimester period of organogenesis. This disparity between artesunate’s evident embryotoxicity in animal models and its clinical safety in pregnant women has been attributed in the literature to at least 2 possible factors: 1) differences in placentation and the presence of a visceral yolk sac in rats and rabbits versus humans that could result in different levels of embryonic exposure to artesunate; and 2) differences in relative exposure, in that the typical 3-day clinical dosing regimen for artesunate in pregnant women is relatively brief when compared to the full 3-month period of organogenesis in humans.”

“Malaria is life-threatening for both the pregnant woman and her fetus, it was reasoned that IV AS should not be withheld if quinidine was unavailable, contraindicated, ineffective, and/or not tolerated.”

DPMH’s Review of Literature DPMH conducted a literature review in Embase, Pubmed, Micromedex11, and ReproTox12.

Embase and Pubmed were searched for “artesunate” and “pregnancy,” “artesunate” and “fetal malformations/congenital malformations/birth defects/stillbirth/spontaneous abortion/miscarriage.” See APPENDIX B for list of additional articles reviewed.

Artemisinin is extracted from the leaves of the A. annua L. and has been used in China for 2000 years as an antipyretic, referred to as qinghao. It was discovered and purified in 1972. Artemisinin is a sesquiterpene lactone containing an endoperoxide bridge, which is believed to be necessary for antimalarial activity. Artemisinin is poorly soluble and has low bioavailability. After discovery of artemisinin, several semisynthetic derivatives were identified including dihydroartemisinin (DHA), artesunate, artelinate, artemether and arteeth13. There derivatives are all metabolized into DHA. The antimalarial effect results mainly from DHA, which disappears from plasma in one hour16. Due to its short half-life, monotherapy with artemisinin is not recommended to avoid the development of drug resistance16.

IV artesunate Intravenous artesunate is expected to have a significantly higher bioavailability than oral artesunate. There is a published prospective hospital-based surveillance study (Proespoprod et al.), that described the effects of intravenous artesunate use in the first trimester in 10 women. There were no increased rates of miscarriage in these women. 14

11 Truven Health Analytics information, http://www.micromedexsolutions.com/. Accessed 11/19/2019 12 Reprotox Website: www.Reprotox.org. REPROTOX dydtem was developed as an adjunct information source for clinicians, scientists, and government agencies. Accessed 11/19/2019. 13 Gomes et al. 14 Poespoprodjo JR, et al. Dihydroartemisinin-piperaquine treatment of multidrug resistant falciparum and vivax malaria in pregnancy, PLoS One 9 (2014) e84976.

Reference ID: 4568389 Oral artesunate There are < 300 cases of oral artesunate use in the first trimester that have been described in the literature, which include studies from McGready et al. (1998)15, Deen et al. (2001)16, McGready et al. (2001)17, McGready et al. (2003)18, McGready et al. (2012)19, and Moore et al. (2016)20. Please see Appendix D for the tabulated list of all studies with first trimester exposure of artesunate. A brief description of these studies is provided below.

• McGready et al. reported on 15 cases of oral artesunate exposure in the first trimester; spontaneous abortions (SABs) occurred in 20% (3/15) of the pregnancies, which is similar to the background rate of SABs in the general population. Eight infants were followed and were normal until one year of life.18 • In a double-blind placebo controlled randomized trial, Deen et al. reported on 50 pregnant women exposed to a single dose of oral artesunate for malaria prevention in the first trimester and found no major congenital anomalies, spontaneous loss, stillbirths or infant deaths related to treatment. Among the exposed infants (117 pregnant women were exposed in any trimester), there was one report of an infant with an umbilical hernia and one report of an infant with undescended testis.19 • McGready et al. reported on 42 cases of first trimester exposure to either oral artesunate, IV artesunate (n=2) or artemether, and found that the overall SAB rate was 18.9%, which was within the community range (12.3%). All infants who were born live were phenotypically and neurologically normal.20 • McGready et al. reported on 3 cases of first trimester exposure to oral artesunate. There were no reports of congenital abnormalities or increases in maternal adverse effects related to treatment.21 • McGready et al. reported on 64 cases of first trimester exposure to oral artesunate for the treatment of uncomplicated malaria. There were 24 miscarriages (31%) in the group, which was not different from quinine or chloroquine treatment arms. No other adverse effect was related to treatment.22 • Moore et al. reports on 322 cases of first trimester to oral artesunate, dihydroartemisinin, or artemether. This study did not show any increased risk of miscarriage. There was also no increased risk of any major congenital malformations in comparison to quinine.23

15 McGready R., Cho T., Cho J.J., Simpson J.A., Luxemburger C., Dubowitz L., Looareesuwan S., White N.J., Nosten F. Artemisinin derivatives in the treatment of falciparum malaria in pregnancy. Transactions of the Royal Society of Tropical Medicine and Hygiene 1998 92:4 (430-433). 16 Deen, L. et al. The safety of the combination artesunate and pyrimethamine-sulfadoxine given during pregnancy, Trans. R. Soc. Trop. Med. Hyg. 95 (2001) 424–428. 17 McGready R, Cho T, Keo NK, Thwai KL, Villegas L, Looareesuwan S, et al. Artemisinin antimalarials in pregnancy: a prospective treatment study of 539 episodes of multidrug-resistant Plasmodium falciparum. Clin Infect Dis. 2001b;33(12):2009-2016. 18 McGready R, et al. Artesunate-atovaquone-proguanil rescue treatment of multidrug-resistant Plasmodium falciparum malaria in pregnancy: a preliminary report, Trans. R. Soc. Trop. Med. Hyg. 97 (2003) 592–594. 19 McGready R, et al. Adverse effects of falciparum and vivax malaria and the safety of antimalarial treatment in early pregnancy: a population-based study, Lancet Infect. Dis. 12 (2012) 388–396. 20 Moore KA, et al. Safety of artemisinins in ﬁrst trimester of prospectively followed pregnancies: an observational study, Lancet Infect. Dis. 16 (2016) 576–583.

Reference ID: 4568389 Reviewer’s comments: DPMH discussed the difference between IV and oral artesunate with the Clinical Pharmacology team who noted that the Cmax and area-under-the curve (AUC) estimates for artesunate and DHA are not similar following oral artesunate versus IV artesunate for the same given dose; therefore, the Clinical Pharmacology team expects that the bioavailability of oral artesunate is expected to be significantly lower than intravenous artesunate.

Artemisinin Class Drugs There are a total of 1373 first trimester exposures to artemisinin derivatives (oral, intramuscular (IM) or IV) in humans, which did not identify a drug-associated increase in miscarriage, stillbirth and major congenital anomalies.21 In addition, over 6500 pregnancy exposures to artemisinin in the second and third trimesters of pregnancy have not identified any adverse effects of artemisinin on pregnancy or on the health of fetuses or neonates.22,23

Artesunate Exposure During Pregnancy: Human Data versus Animal Data Artesunate is a teratogen in animals, but based on currently available literature, there is a difference in pregnancy outcomes when artesunate and artemisinin products are used in humans compared to animals. Gomes et al. offers two hypotheses for this disparity between human and animal data.24 1) The mechanism of embryotoxicity by artemisinin derivatives is related to depletion of circulating embryonic primitive erythroblasts. In mammals, primitive erythroblasts are formed in the blood islands of the yolk sac and are the ﬁrst red blood cell produced by the embryo. These sensitive progenitor cells in rodents are present in the yolk sac at around 48 hours, and the primitive erythroblasts are released into circulation, where they proliferate by cell division until the liver starts deﬁnitive erythropoiesis. In humans, the primitive erythroblasts are formed by the yolk sac between 3–6 weeks of gestation and are circulating in the embryo around 4–9 weeks of gestation. This sensitive period is longer than the sensitive period in rodents. This is longer than the typical treatment period of 3–7 days. In theory, the longer period allows the damaged cells to be replaced, thus no teratology was present in humans. 2) Non-clinical trials use healthy laboratory test animals, while clinical trials recruit malaria infected human subjects. Malaria has protective effects toward artesunate toxicity. Clark25 demonstrated the reduction on reticulocytes caused by artemisinin derivatives was lower in malaria patients than their healthy counterpart. In theory, the sicker human subjects may experience less embryotoxic effects than healthy laboratory animals.

21 Gomes A, et al. Clinical and non-clinical safety of artemisinin derivatives in pregnancy. Reproductive Toxicology. 2016; 65:194-203. 22 WHO Guidelines for the treatment of malaria 2015. 23 Nambozi M, et. al. Artemisinin-based combination therapy during pregnancy: outcome of pregnancy and infant mortality: a cohort study. Malaria Journal. March 2019; 18:1. 24 Gomes A, et. al. Clinical and non-clinical safety of artemisinin derivatives in pregnancy. Reproductive Toxicology. 2016; 65:194-203. 25 R.L. Clark, Effects of artemisinins on reticulocyte count and relationship to possible embryotoxicity in conﬁrmed and unconﬁrmed malarial patients, Birth Defects Res. A: Clin. Mol. Teratol. 2012; 94: 61–75.

Reference ID: 4568389 Artesunate and Pharmacokinetic Studies A pharmacokinetic study by McGready et al.26 demonstrated no significant differences in artesunate or dihydroartemisinin pharmacokinetics between pregnant women with malaria compared with the same women restudied postpartum in a healthy state after intravenous administration of artesunate. DPMH discussed this finding with DAIP Clinical Pharmacology team, who agreed that dose adjustment of intravenous artesunate is not necessary in pregnant women.

Micromedex- Martindale27 notes the following: - “Artesunate or artemether was used to treat multidrug-resistant falciparum malaria in 83 pregnant women in Thailand; of 73 pregnancies resulting in live births none showed evidence of any congenital abnormality. Sixteen of the women were given artesunate during the first trimester; of these, 12 had normal deliveries, 1 was lost to follow-up, and 3 had spontaneous abortions28. - No undue adverse effects on the neonates occurred in a study29 involving 45 women treated for multidrug-resistant malaria during their second or third trimester of pregnancy with either artemether or artemether plus mefloquine. - Intramuscular artemether was also used to treat chloroquine/quinine-resistant falciparum malaria in 28 pregnant women in eastern Sudan. Artemether was given to 1 woman during the first trimester, to 12 during the second trimester, and to 15 during the third trimester. One baby was delivered at 32 weeks but died 6 hours later; all the other babies were delivered at full term and there were no reports of congenital abnormalities30. - WHO31 recommends that, where available, artesunate is the first option, and artemether is the second, for the parenteral treatment of severe falciparum malaria during the second and third trimesters. In the first trimester, until more evidence becomes available, artesunate may be considered as an option.”

ReproTox32 notes the following: “Qinghaosu (artemisinin) and dihydroartemisinin and their derivatives are toxic to the early embryo in experimental animals. Artemisinin and dihydroartemisin derivatives with antimalarial activity include artesunate, artemether, and arteether. Use of artesunate or

26 McGready R, Phyo AP, Rijken MJ, Tarning J, Lindegardh N, Hanpithakpon W, et al. Artesunate/dihydroartemisinin pharmacokinetics in acute falciparum malaria in pregnancy: absorption, bioavailability, disposition and disease effects. Br J Clin Pharmacol. 2012;73(3):467-477.

27 Martindale- The complete Drug Reference, The Royal Pharmaceutical Society of Great Britain 2019. Accessed 11/19/2019 Truven Health Analytics information, http://www.micromedexsolutions.com/ 28 McGready R, et al. Artemisinin derivatives in the treatment of falciparum malaria in pregnancy. Trans R Soc Trop Med Hyg 1998; 92: 430-3. 29 Sowunmi A, et al. Randomized trial of artemether versus artemether and mefloquine for the treatment of chloroquine/sulfadoxine[sic]-pyrimethamine-resistant falciparum malaria during pregnancy. J Obstet Gynaecol 1998; 18: 322-7. 30 Adam I, et al. Artemether in the treatment of falciparum malaria during pregnancy in eastern Sudan. Trans R Soc Trop Med Hyg 2004; 98: 509-13. 31 WHO. International travel and health. 2011 ed. Available at: http://www.who.int/ith/en. 32 Reprotox. Accessed 11/18/19.

Reference ID: 4568389 artemether in several hundred human pregnancies was not associated with adverse outcomes. Most of the treatments were in the second or third trimesters.”

“Following oral administration, artemether and dihydroartemisinin (measured after artesunate administration) plasma concentrations were lower in pregnant women than in nonpregnant individuals, reflecting the short half-life and increased volume of distribution of these agents during pregnancy…”

Shepard33 notes the following: “Artesunate is in a group of artemisinin drugs used to treat multidrug-resistant malaria. - Clark34 reviewed clinical studies published between 1998-2011 that reported on a total of 1700 cases of artemisinin exposure during pregnancy for treatment of uncomplicated malaria, including 250 cases that occurred during the first trimester. The rates of adverse pregnancy outcomes reported in these studies, including congenital anomalies, were found to be similar to those expected in the general population. - Similarly, the frequencies of abortions, stillbirths, infant deaths or congenital anomalies were not significantly increased among the pregnancies of 287 Gambian women who received a single dose of artesunate in combination with pyrimethamine- sulfadoxine during pregnancy. Thirty-five of the women received treatment during the first trimester.35 - In a small prospective clinical series, no congenital anomalies were observed among 27 liveborn infants whose mothers had been treated for three days during pregnancy with a combination of artesunate-atovaquone-proguanil for multidrug- resistant P. falciparum malaria.36 - Congenital anomalies were observed in two (5.9%) of 34 infants born to women who had been treated for malaria with artesunate-atovaquone-proguanil during the second or third trimester of pregnancy in a randomized clinical trial; but (according to the authors) the anomalies were not considered to be drug related.37”

Reviewer comment: Overall, the applicant provided an adequate review of published literature and of their clinical trial database regarding artesunate and use in pregnant women. The reader is referred to the Discussion and Conclusion section at the end of this review for DPMH’s opinion of the data, submission and recommendations.

33 Shepard’s Catalog. Accessed 11/19/19. 34 Clark, R.L.: Effects of artemisinins on reticulocyte count and relationship to possible embryotoxicity in confirmed and unconfirmed malarial patients. Birth Defects Res. A Clin. Mol. Teratol. 94:61-75, 2012. 35 Deen, J.L., et. al. The safety of the combination artesunate and pyrimethamine-sulfadoxine given during pregnancy. Trans. R. Soc. Trop. Med. Hyg. 95(4):424-428, 2001. 36 McGready, R.; Keo, N.K.; Villegas, L.; White, N.J.; Looareesuwan, S. and Nosten, F. Artesunate-atovaquone- proguanil rescue treatment of multidrug-resistant Plasmodium falciparum malaria in pregnancy: a preliminary report. Trans. R Soc. Trop. Med. Hyg. 97(5):592-594, 2003. 37 McGready, R.; Ashley, E.A.; Moo, E.; Cho, T.; Barends, M.; Hutagalung, R.; Looareesuwan, S.; White, N.J. and Nosten, F.: A randomized comparison of artesunate-atovaquone-proguanil versus quinine in treatment for uncomplicated falciparum malaria during pregnancy. J. Infect. Dis. 192(5):846-853, 2005.

Reference ID: 4568389 LACTATION Nonclinical Experience No animal data are available.

Review of Clinical Trials There were no lactating women participating in any of the clinical trials and lactation studies have not been conducted.

Review of Literature Applicant’s Review of Literature The applicant performed a search of literature and found no published data describing excretion of artesunate or dihydroartemisinin in human milk or effects on the nursing infant are available. The applicant did note that WHO (2010) has supported the use of artemisinin- based combination therapy (ACT) for the treatment of uncomplicated P. falciform malaria in lactating women, while noting that relatively small amounts of antimalarials enter breast milk.

DPMH’s Review of Literature DPMH conducted a search using the sources noted below, and the following findings were retrieved:

A search in PubMed and Embase was performed using the search terms “artesunate” AND “lactation” and “artesunate” AND “breastfeeding,” and two additional articles were found.

Author Type Timin Set up Outcome g Jansen PK Matur Artesunate and DHA was studied in Artesunate was undetectable in breastmilk (<5 mcg/L) at any time. FH, et study e milk milk after giving a single dose of 200 The active metabolite, dihydroartemisinin, reached a peak al.38 mg oral artesunate to lactating women concentration in breastmilk of about 35 mcg/L at 90 minutes after (2006) (# not specified) that had just stopped the dose, and was undetectable (<2.5 mcg/L) 6 hours after the dose. Belgium breastfeeding. Milk was collected at 1, The Authors concluded that the active metabolite of artesunate is 2, 4, 6, and 10 hours after the dose. present at low levels in breastmilk. The authors stated that the drug Abstract levels are not expected to cause any adverse effects in breastfed only Number of subjects was not disclosed. infants. WHO39 Guide The amount of antimalarial drugs that enter milk and are consumed 2015 line by breastfeeding infants are relatively small.

Artesunate is currently recommended for the treatment of severe malaria in lactating women.

Reviewer’s comments: DPMH notes that the study by Jansen FH et al only describes oral administration of artesunate administered as a single dose. This is different than the typical treatment with IV artesunate that lasts a minimum of three days. In addition, the number of subjects was not disclosed. It is

38 Jansen FH, Jansen-Luts A, Ameye C, Penali L. Is Artesunate or Its Active Metabolite Dihydroartemisinin Being Excreted in the Milk of Lactating Mothers? The American Journal of Tropical Medicine and Hygiene. 2006;75(5). 39 WHO Guidelines for the treatment of malaria 2015.

Reference ID: 4568389 difficult to say that the drug is not expected to cause any adverse effects in infants, when use in the clinical setting is longer.

Lactmed40 notes the following: “Limited information indicates that a maternal dose of (artesunate) 200 mg orally produced low levels in milk and would not be expected to cause any adverse effects in breastfed infants, especially if the infant is older than 2 months. Withholding breastfeeding for 6 hours after a dose should markedly reduce the dose the infant receives. In general, small amounts of antimalarial drugs are excreted in the breast milk of lactating women. Because the quantity of antimalarial drugs transferred in breast milk is insufficient to provide adequate protection against malaria, infants who require chemoprophylaxis must receive the recommended dosages of antimalarial drugs.”

Hale41 notes the following: “L3-limited data-probably compatible. - Following an oral dose of (artesunate) 200 mg to breastfeeding mothers, artesunate was undetectable in breastmilk at levels less than 5 µg/L any time during the study. Its active metabolite (DHA) reached a peak of approximately 35 µg at 90 minutes following dose and was totally undetectable at 6 hours. It is unlikely levels in milk will produce significant risk to a breastfed infant.”

Reviewer’s comments: Overall, the applicant provided an adequate review of published literature and of their clinical trial database regarding artesunate and use in lactating women. The reader is referred to the Discussion and Conclusion section at the end of this review for DPMH’s opinion of the data submission and recommendations.

FEMALES AND MALES OF REPRODUCTIVE POTENTIAL Nonclinical Experience No formal reproductive and development studies have been conducted with artesunate in animals. A 28-day repeat dose study (IV) in 5 to 7-month-old Beagle dogs did not display any abnormalities in a histopathological assessment of reproductive organs when given daily IV artesunate at doses of 15, 30, or 40 mg/kg/day.

The reader is referred to the full Pharmacology/Toxicology review by Kelly Brant, Ph.D. and Terry Miller, Ph.D.

Review of Clinical Trials There were no cases of infertility/sterility reported in any of the clinical trials.

40 http;//toxnet nlm nih.gov/newtoxnet/lactmed htm. The LactMed database is a National Library of Medicine (NLM) database with information on drugs and lactation geared toward healthcare practitioners and nursing women. The LactMed data base provides information when available on maternal levels in breast milk, infant blood levels, any potential effects in the breastfeeding infants if known, alternative drugs that can be considered and the American Academy of Pediatrics category indicating the level of compatibility 41 Hale, Thomas. Hale’s Medications and Mother’s Milk 2019. Springer Publishing Company, New York, NY.

Reference ID: 4568389 Review of Literature Applicant’s Review of Literature No literature was submitted by the applicant that suggests a relationship between artesunate and infertility/sterility.

The applicant’s proposed labeling under section 7 Drug Interactions states: (b) (4)

DPMH’s Review of Literature A search was performed using the sources noted below, and the following findings were retrieved:

A search was performed in PubMed and Embase using term “artesunate” and “fertility”, “artesunate” AND “reproduction”, “artesunate” AND “contraception.” No relevant articles were retrieved.

Reprotox42 states: “A study reviewed in abstract form only, suggests that subclinical artesunate exposure of male guinea pigs caused decreases in total sperm count and sperm motility and an increase in abnormal sperm cells. A study of artesunate administered to male rats daily for 6 weeks noted testicular and epididymal lesions, although these lesions did not affect fertility. The lesions were reversible after cessation of treatment. A study in male mice given artesunate as a single dose found a reduction in epididymal sperm count and an increased frequency of sperm with abnormal morphology. Given once daily for three days to male mice, artesunate increased sperm DNA strand breaks. We did not locate reproductive data from human studies.”

Reviewer’s comments: Overall, the applicant provided an adequate review of published literature and of their clinical trial database regarding artesunate use in females and males of reproductive potential. The reader is referred to the Discussion and Conclusion section at the end of this review for DPMH’s opinion of the data, submission and recommendations.

DISCUSSION AND CONCLUSIONS Pregnancy Although artesunate and artemisinin derivatives are teratogens in animals, studies in humans using IV and oral artesunate and other artemisinin drugs have not identified a drug-associated risk of congenital malformations, miscarriage or other adverse pregnancy or fetal outcomes.

Since untreated severe malaria is fatal and there are no other IV options for the treatment of severe malaria, labeling will include language in 8.1, Risk Summary and Clinical Considerations to provide the risk/benefit considerations for the prescriber.

42 Reprotox. Accessed 11/20/2019.

Reference ID: 4568389 Literature on the use of IV artesunate in first trimester of pregnancy is limited to one prospective surveillance study that specifically evaluated fetal loss. In that study (Proespoprod et al.), which consisted of 10 pregnant women exposed to IV artesunate in the first trimester, there were no SABs. Congenital malformations were not reported in this study.

There are < 300 cases of oral artesunate use in the first trimester in the literature. These studies did not identify an association with oral artesunate use in the first trimester of pregnancy and an increased risk of congenital malformation, miscarriage or adverse pregnancy and fetal outcomes.

When looking at first trimester exposure of artemisinin class drugs, published data from 14 studies, including prospective cohort studies and retrospective population based open label designs, have not identified an association with artemisinin class drugs and use during pregnancy and major birth defects, miscarriage, or adverse maternal or fetal outcomes. The literature comprised of a total of > 1300 women exposed to artemisinin class drugs in their first trimester of pregnancy and > 6500 women exposed in the second and third trimesters of pregnancy.

DPMH discussed the difference between IV and oral exposure of artesunate with the Clinical Pharmacology team who noted that the Cmax and AUC estimates for artesunate and DHA are not similar following oral artesunate versus IV artesunate for the same given dose; therefore, the Clinical Pharmacology team expects that the bioavailability of oral artesunate is expected to be significantly lower than intravenous artesunate. Therefore, the clinical relevance of studies involving oral exposure to artesunate and other artemisinin class drugs is uncertain.

Regarding the question about artesunate dosing in pregnancy, DPMH discussed the Pharmacokinetic study by McGready et al.29 with the DAIP Clinical Pharmacology team, who agreed that there should not be any IV artesunate dose changes during pregnancy. Information from the McGready study will be included in section 12 of IV artesunate labeling.

The reported cases of intravenous artesunate use in the first trimester are limited in published literature. Although malaria is common in females of reproductive potential, severe malaria requiring a product, such as IV artesunate, would be less common. Therefore, since there is a lack of information regarding the use of intravenous artesunate during pregnancy, DPMH recommends issuing a postmarketing requirement (PMR) for a Single-Arm Pregnancy Safety Study. The reader is referred to the FDA draft Guidance for Industry Post approval Pregnancy Safety Studies: Considerations for Study Design, published May 2019, for further details.

Lactation Based on results from a small study evaluating the presence of artesunate and DHA in human milk after a single dose of artesunate, DHA was present in human milk in low levels. DHA reached a peak concentration in breastmilk of 35 mcg/L at 90 minutes after the dose and was undetectable (<2.5 mcg/L) 6 hours after the dose. There are no data on the effects of artesunate on breastfed infants or on milk production. DPMH recommend using the standard risk/benefit language in subsection 8.2 of artesunate labeling.

DPMH does not recommend a lactation study as a postmarketing requirement. Artesunate IV is indicated for use in patients with severe malaria. Based on discussion with the DAIP Clinical Team, patients with severe malaria are typically very sick and in the intensive care unit. They

Reference ID: 4568389 will not be in any condition to breastfeed. A lactation study would not be feasible in these patients. Although published studies have demonstrated the presence of artesunate’s metabolite, DHA, in human milk in small amounts, artesunate is also indicated to treat malaria in infants. No additional lactation study is needed at the current time.

Females and Males of Reproductive Potential There are no data on artesunate and the effects of fertility in humans. There is no formal reproduction study conducted in animals.

Artesunate does not appear to have any interactions with hormonal contraceptives.

Due to findings in animal fertility studies and lack of interaction with hormonal contraceptives, subsection 8.3 Females and Males of Reproductive Potential will be omitted in the labeling.

LABELING RECOMMENDATIONS DPMH revised subsections 8.1, 8.2 and 8.3 of labeling for compliance with the PLLR (see below). DPMH discussed our labeling recommendations with DAIP. DPMH recommendations are below and reflect the discussions with DAIP. DPMH refers to the final NDA action for final labeling.

DPMH Proposed Pregnancy and Lactation Labeling

FULL PRESCRIBING INFORMATION 8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Risk Summary There are serious risks to the mother and fetus associated with untreated severe malaria during pregnancy; therefore, treatment of severe malaria in pregnant women should not be delayed (see Clinical Considerations). Pregnancy outcomes reported from a prospective surveillance study with intravenous artesunate are insufficient to identify a drug-associated risk of major births defect, miscarriage and fetal death. Prolonged experience with oral artesunate and other artemisinin class drugs in pregnant women over several decades, based on published literature from randomized controlled trials and cohort studies, have not identified a drug-associated risk of major birth defects, miscarriage, or adverse maternal or fetal outcomes (see Data).The bioavailability of oral artesunate is expected to be significantly lower than intravenous artesunate; therefore, the clinical relevance of studies involving oral exposure to artesunate and other artemisinin class drugs is uncertain.

Animal reproduction studies show a single intravenous administration of artesunate to rats early in gestation results in embryolethality. Oral administration of artesunate during organogenesis in rats, rabbits, and monkeys induces a dose-dependent increase in embryolethality and fetal malformations (e.g., cardiovascular, brain, and/or skeletal) at 0.3- to 1.6-times the clinical dose based on body surface area (BSA) comparisons (see Data). Although animal reproduction studies in several species have demonstrated fetal harm from oral and intravenously administered artesunate and other artemisinin class drugs, the clinical relevance of the animal data is uncertain.

Reference ID: 4568389

The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively.

Clinical Considerations Disease-Associated Maternal and/or Embryo/Fetal Risk Malaria during pregnancy increases the risk for adverse pregnancy and neonatal outcomes, including maternal anemia, severe malaria, spontaneous abortion, stillbirths, preterm delivery, low birth weight, intrauterine growth restriction, congenital malaria, and maternal and neonatal mortality.

Data Human Data Although there are rare reports of first trimester use of intravenous artesunate, published randomized control trials, observational studies and cohort studies on over 1300 women exposed to oral artesunate and other artemisinin class drugs (via oral, intravenous or intramuscular administration) in the first trimester of pregnancy and over 6500 women exposed to oral artesunate and other artemisinin class drugs (via oral, intravenous or intramuscular administration) in the second and third trimester of pregnancy have not demonstrated and increase in major birth defects, miscarriage, or adverse maternal or fetal outcomes. The bioavailability of intravenous artesunate is expected to be significantly higher than oral artesunate. Published epidemiologic studies have important methodological limitations which hinder interpretation of data, including inability to control for confounders, such as the severity of malaria infection, other underlying maternal diseases, and maternal use of concomitant medications and missing information on the route of administration, dose and duration of use.

Animal Data Pregnant rats administered a single dose of intravenous artesunate at 1.5 mg/kg (approximately 0.1 times the clinical dose based on body surface area (BSA) comparisons) early during organogenesis on gestation day (GD) 11 resulted in complete postimplantation loss. A mass balance study conducted in pregnant rats administered a single dose of 5 mg/kg intravenous 14C- artesunate on GD 11 (corresponding to 0.3 times the recommended clinical dose based on BSA comparisons) showed distribution of radiolabeled artesunate (approximately 7 percent of detected radioactivity) to feto-placental tissues.

Pregnant rats dosed orally during organogenesis (GD 7 through 17) with 6, 10 and 16.7 mg/kg/day artesunate (approximately 0.4- to 1-times the clinical dose based on BSA comparisons) showed dose-dependent post-implantation losses, with surviving fetuses displaying cardiovascular (ventricular septal defects, retro-esophageal right subclavian artery arising from the descending aorta) and skeletal (e.g., fused ribs, bent, shortened and/or curved ulna, humerus and scapula) malformations in the absence of maternal toxicity. Oral dosing in pregnant rabbits during organogenesis (GD 7 through GD 19) at doses of 5, 7, and 12 mg/kg/day artesunate (0.7- to 1.6-times the clinical dose based on BSA comparisons) resulted in cardiovascular (e.g., retro-

Reference ID: 4568389 esophageal right subclavian artery arising from descending aorta), skeletal (e.g., shortened/displaced ribs, flexed joints and/or bent scapula) and brain (dilated ventricles, absent pons) malformations in the absence of maternal toxicity. Additionally, administration of artesunate at 12 mg/kg/day to pregnant rabbits during organogenesis resulted in abortions, postimplantation loss and increased intrauterine deaths. Oral administration of artesunate to pregnant cynomolgus monkeys during organogenesis (GD 20 to GD 50) at 12 mg/kg/day (approximately 1.6-times the clinical dose based on BSA comparisons) resulted in increased embryonic death with skeletal malformations (i.e., decrease in absolute length of the ulna) observed in surviving fetuses.

8.2 Lactation Risk Summary Dihydroartemisinin, a metabolite of artesunate, is present in human milk. There are no data on the effects of artesunate or dihydroartemisinin on the breastfed infant or on milk production. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for Artesunate and any potential adverse effects on the breastfed child from Artesunate or from the underlying maternal condition.

12 CLINICAL PHARMACOLOGY 12.3 Pharmacokinetics Specific Populations Pregnant Women No pharmacokinetic studies were carried out on pregnant women with severe malaria following IV administration of artesunate, however, multiple studies evaluated pharmacokinetics of artesunate and DHA following oral artesunate treatment of pregnant women with acute uncomplicated falciparum malaria. Results consistently showed no significant differences in the pharmacokinetics between pregnant and non-pregnant women.

13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility Carcinogenesis Carcinogenicity studies have not been conducted with ARTESUNATE

Mutagenesis Artesunate was negative in an in vitro bacterial reverse mutation assay, an in vitro Chinese hamster ovary chromosome aberration assay, and an in vivo mouse bone marrow micronucleus assay when administered orally. However, in published literature artesunate was positive in an in vivo mouse bone marrow micronucleus assay and induced micronuclei formation in human lymphocytes and for DNA damage (Comet assay) in human lymphocytes and Hep2G cells in vitro. No in vivo genetic toxicology studies have been conducted with intravenously administered artesunate.

Fertility Fertility studies in animals have not been conducted with intravenously administered ARTESUNATE.

Reference ID: 4568389 No significant changes in reproductive organs (i.e., gross, microscopic or histologic lesions or organ weights) or sperm motility, counts or morphology were observed in rats and dogs following 28 days of repeated dosing with intravenously administered ARTESUNATE. However, in the published literature, rats and mice administered oral or intraperitoneal artesunate as a single dose or repeated dosing (3 days to 6 weeks) displayed histopathological changes of the seminiferous tubules and altered spermatogenesis (increased percentage of abnormal sperm and/or decreased sperm motility and viability) at doses ranging from approximately 0.2- to 1.3- times the clinical dose based on BSA comparisons. Given the conflicting findings, in the absence of fertility study(ies) conducted with intravenously administered artesunate, the clinical relevance of the animal data on human fertility is uncertain.

Reference ID: 4568389

APPENDIX A: Applicant’s Review of Literature on Artesunate and Pregnancy

Publication Type N Timing Exposure Outcome Moore K, et Observational 1179 1st 55636 pregnancy reports between 1994 and 2013 were No difference was noted in miscarriage in the first-line falciparum treatments with artemisinin (n=183) versus quinine al.43 retrospective pregnant trimester collected from antenatal clinics on the Thai-Myanmar (n=843; HR 0.78, 95% CI 0.45-1.34; p=0.36) or in risk of major congenital malformations (2 of 109, 2%, 95% CI 0.22- (2016) women border. These pregnancy reports were then analyzed for 6.47) vs 8 of 641, 1%, 95% CI 0.54-2.44). Thailand first trimester malaria diagnosis; 2558 (10%) 183 women pregnancies were affected. 1179 pregnancies with ≥1 P exposed to falciparum infection in first trimester were included; 971 artemisinin received quinine or quinine plus clindamycin; 25 first line received mefloquine;183 received artemisinin. (artesunate, dihydroartemisinin, or artemether) as first 129 exposed line treatment. 129 of 1179 received first-line quinine to treatment followed by artemisinin. artemisinin second line Literature review was also performed for exposure of No randomized controlled trials of first-trimester artemisinin treatment were identified. Only one study reports an artemisinin in first trimester pregnancy. association between recurrent first-trimester malaria and miscarriage. Ten observational studies of first-trimester artemisinin treatment were identified total of 935 documented treatments, and a systematic review published in 2007. These studies showed no evidence of an increased risk of miscarriage or major congenital malformations associated with first-trimester artemisinin treatment (95% CI 0.54-2.44).

Nambozi M, Multicenter Between ACT when administered during pregnancy was carried Results not published in this article. et al.44 (2015) randomized 16-37 out in 4 African countries: Burkina Faso, Ghana, Africa controlled trial weeks Malawi and Zambia. This is a four-arm trial using a (phase 3, balanced incomplete block design. Pregnant women noninferiority) diagnosed with malaria are randomized to receive either amodiaquine-artesunate (AQ-AS), dihydroartemisinin- piperaquine (DHA-PQ), artemether-lumefantrine (AL), or mefloquine-artesunate (MQAS). They are actively followed up until day 63 post-treatment and then monthly until 4–6 weeks post-delivery. Kovacs SD, Review article all A systematic review by Visser et al. (2014) identiﬁed ten studies reporting outcomes of pregnant women treated with et al.45 artesunate. Artesunate is associated with higher cure rates, lower gametocyte carriage, and lower treatment failure than (2015) quinine-based therapies for the treatment of uncomplicated malaria in pregnancy. USA

43 Moore K, et. al. Safety of artemisinins in first trimester of prospectively followed pregnancies: an observational study. Lancet Infect Dis 2016; 16:576-83. 44 Nambozi M, et. al. Safe and efficacious artemisinin-based combination treatments for African pregnant women with malaria: a multicentre randomized control trial. Reproductive Health 2015; 12:5 45 Korvacs S, et al. Treating severe malaria in pregnancy: a review of the evidence. Drug Saf 2015; 38: 165-181.

Reference ID: 4568389

There were two additional studies presenting data on artesunate to treat severe malaria in pregnancy. Poespoprodjo et al. found no statistically significant increased risk of poor maternal or fetal outcomes associated with artesunate compared with quinine and noted than none of the ten women exposed to intravenous artesunate in the ﬁrst trimester had a miscarriage. McGready et al. noted that, although miscarriage rates were very high for women with severe malaria in the ﬁrst trimester (58 %), there was no difference in the rates between pregnant women treated with artesunate or quinine.

WHO46 Guideline “Safety assessment from published prospective data on 700 women exposed in the first trimester of pregnancy has not 2015 indicated any adverse effects of artemisinin-derivatives on pregnancy or on the health of the fetus or neonate.”

Current available data are only sufficient to exclude a >=4.2-fold increase in risk of any major defect detectable at birth defect detectable at birth (background prevalence assumed to 0.9 %), if half the exposures occur during the embryo- sensitive period (4-9 weeks post-conception).

The safest treatment regimen for pregnant women in the 1st trimester with uncomplicated falciparum malaria is quinine + clindamycin or oral artesunate and clindamycin. Artesunate is recommend for treatment of uncomplicated malaria in 2nd and 3rd trimester.

Artesunate is currently recommended for the treatment of severe malaria in pregnant women during all trimesters.

46 WHO Guidelines for the treatment of malaria 2015.

Reference ID: 4568389

Appendix B: DPMH Review of Literature on Artesunate and Pregnancy Table 1: Review articles on artemisinin derivatives and Pregnancy

Publication Type N Timing Exposure Outcome Sridhara K, Review, A literature search carried out in Medline, Cochrane The pooled estimates revealed significantly lower risks of abortion with quinine and artemisinin-lumefantrine compared to et. al.47 meta- CENTRAL and Google Scholar. A total of 1242 papers were dihydroartemisinin-piperaquine, artesunate with mefloquine and artesunate with amodiaquine. (2019) analysis obtained with the search strategy, of which seven studies But when a cohort study that was conducted in the first trimester of pregnancy was excluded, no significant differences were Bahrain evaluating 10 treatment arms (5510 participants) were observed in the risk of abortion between the anti-malarial drugs. included in the present meta-analysis. No significant differences in the risk of either stillbirths or neonatal deaths were observed with any of the drugs. The quality of evidence was found to be very low due to serious limitations in both the precision and indirectness. Korvacs SD, Review all A systematic review by Visser et al. (2014) identified ten studies reporting outcomes of pregnant women treated with et. al.48 article artesunate. Artesunate is associated with higher cure rates, lower gametocyte carriage, and lower treatment failure than (2015) quinine-based therapies for the treatment of uncomplicated malaria in pregnancy. USA Two additional studies presenting data on artesunate to treat severe malaria in pregnancy. Poespoprodjo et al. found no statistically significant increased risk of poor maternal or fetal outcomes associated with artesunate compared with quinine and noted than none of the ten women exposed to intravenous artesunate in the first trimester had a miscarriage. McGready et al. noted that, although miscarriage rates were very high for women with severe malaria in the first trimester (58 %), there was no difference in the rates between pregnant women treated with artesunate or quinine.

Artesunate is generally associated with better tolerability than quinine. The most important reported side effect of artesunate is anaphylaxis, with an estimated risk of approximately 1 in 3,000 patients. Additional common minor side effects associated with intravenous administration include dizziness, light-headedness, rash, and taste alterations. Nausea, vomiting, and diarrhea have been reported, but it is unclear whether these are associated with artesunate or are symptoms of severe malaria. Cardiotoxicity has been observed after administration of high doses of artesunate. Multiple studies in adults and children suggest that up to 25 % of patients treated with intravenous artesunate for severe malaria developed delayed hemolytic anemia 7–31 days after treatment, but the etiology is unknown. Korvacs S. Meta- 20 studies 2nd and 3rd A systematic review and meta-analysis of the occurrence of ORs comparing artemisinin to quinine were et. al.49 analysis (11 cohorts trimester adverse pregnancy outcomes among women treated with stillbirth, 0.49 (95% CI 0.24–0.97, I2 = 0%, 3 studies); (2016) USA and 9 RTC) artemisinins monotherapy or as artemisinin-bases fetal loss, 0.58 (95% CI 0.31–1.16, I2 = 0%, 6 studies); combination therapy during pregnancy relative to women congenital anomalies 1.00 (95% CI 0.27–3.75, I2 = 0%, 3 studies) who received non-artemisinin antimalarials or none at all. ORs comparing artemisinin users to pregnant women who received no antimalarial were miscarriage, 1.13 (95% CI 0.77–1.66, I2 = 86.7%, 3 studies);

47 Sridharan K., Sivaramakrishnan G., Kanters S. Adverse pregnancy outcomes between the anti-malarial drugs: Is there a difference between the drugs recommended by World Health Organization? Results of a mixed treatment comparison analysis of randomized clinical trials and cohort studies. International Journal of Risk and Safety in Medicine 2019 30; 2: 73-89. 48 Korvacs S, et al. Treating severe malaria in pregnancy: a review of the evidence. Drug Saf 2015; 38: 165-181. 49 Kovacs SD, van Eijk AM, Sevene E, Dellicour S, Weiss NS, et al. (2016) The Safety of Artemisinin Derivatives for the Treatment of Malaria in the 2nd or 3rd Trimester of Pregnancy: A Systematic Review and Meta-Analysis. Published: November 8, 2016, https://doi.org/10.1371/journal.pone.0164963

Reference ID: 4568389

Data contains 3,707 women receiving an artemisinin, 1,951 a stillbirth 1.10 (95% CI 0.79–1.54, I2 = 0%, 4 studies); non-artemisinin antimalarial, and 13,714 no antimalarial. congenital anomalies respectively 0.79 (95% CI 0.37–1.67, I2 = 0%, 3 studies)

Treatment with artemisinin in 2nd and 3rd trimester was not associated with increased risks of congenital malformations or miscarriage and may be was associated with a reduced risk of stillbirths compared to quinine.

See APPENDIX C for pooled data of second and third trimester exposure. Gomes C, Review Review of published literature on artemisinin derivatives and Artemisinin derivatives mechanisms of embryotoxicity are related to depletion of circulating embryonic primitive et. al.50 pregnancy in nonclinical and clinical studies. erythroblasts. There is no evidence about embryo toxic effects of artesunate in humans. (2016) This difference can be explained by following specie difference and testing differences: Brazil 1. In mammals, primitive erythroblasts are formed in the blood islands of the yolk sac and are the first red blood cell produced by the embryo. These sensitive progenitor cells in rodents are present is the yolk sac around 48 hours and the primitive erythroblasts are released into circulation where they proliferate by cell division until the liver starts definitive. In humans, cells are formed over a longer period of time. Primitive erythroblasts are formed by the yolk sac between 3–6 weeks of gestation and are circulating in the embryo around 4–9 weeks of gestation. Thus, if these sensitive cells are formed over a longer period than the typical treatment period (3–7 days), then damaged cells would be replaced by newly formed cells, thus no teratology was seen in humans. 2. “It was demonstrated less toxicity of artesunate in infected than in non-infected animals. As reviewed by Clark51 the reduction on reticulocytes caused by artemisinin derivatives was also lower in malaria patients. All developmental non-clinical studies with artemisinin derivatives until now have been conducted in non-infected animals. Meanwhile, almost all clinical studies have been conducted in malaria infected pregnant women or unconfirmed cases of women exposed without knowing their pregnancy.”

See APPENDIX D for pooled data of 1st trimester exposure.

Visser BJ, Review Methods of the search strategy and inclusion and exclusion Human data suggest that ACTs are safe in the first trimester, so the use of ACTs for the treatment of first trimester malaria in et. al.52 criteria were specified in advance and documented in a RCTs appears to be justifiable, as obtaining high-quality data from a controlled trial appears to be superior than collecting (2014) protocol. Recommendations made by the Preferred evidence from retrospective analysis of possibly insufficiently documented anecdotal evidence. So far, women in their first Reporting Items for Systematic Reviews and Meta-Analyses trimester of pregnancy remain excluded. (PRISMA) group were followed where appropriate. The electronic databases Medline/PubMed, Embase, Cochrane Central Register of Controlled Trials (The Cochrane Library), Biosis Previews and the African Index Medicus were searched in order to identify studies published up to June 2014.

50 Gomes A, et. al. Clinical and non-clinical safety of artemisinin derivatives in pregnancy. Reproductive Toxicology. 2016; 65:194-203. 51 R.L. Clark, Effects of artemisinins on reticulocyte count and relationship to possible embryotoxicity in conﬁrmed and unconﬁrmed malarial patients, Birth Defects Res. A: Clin. Mol. Teratol. 2012; 94: 61–75. 52 Visser B.J., Van Vugt M., Grobusch M.P. Malaria: An update on current chemotherapy. Expert Opinion on Pharmacotherapy 2014 15:15 (2219-2254).

Reference ID: 4568389

Morris C, et. Review 9 studies Review of artesunate PK studies in literature. Oral AS administration in pregnancy is altered. Exposure of DHA is substantially lower in pregnant women than the non- al.53 article on pregnant subjects. Pregnancy was associated with a significant increase in DHA CL/F, as well as a trend toward increased PK volume distribution. (2md and 3rd trimester) (2011)

Table 2 Randomized controlled trials and other studies on Artemisinin and Pregnancy Publication Type N Timing Exposure Outcome Nambozi M, RTC 3127 2nd and 3rd PREGAC study of pregnant women with malaria in 4 Prevalence of placental malaria and low birth weight were 28.0% (738/2646) and 16.0% (480/2999), respectively, with no et. al.54 trimester countries (Burkin Faso, Ghana, Malawi and Zambia) were significant differences between treatment arms. (2019) treated with one of 4 groups: Africa No differences in congenital malformations (p = 0.35), perinatal mortality (p = 0.77), neonatal mortality (p = 0.21), and N= 822 Artemether-lumefantrine infant mortality (p = 0.96). N= 775 Amodiaquine-artesunate N= 765 Melfloquine-artesunate N= 765 Dihydroartemisinin-piperaquine

3127 new born were follow up until one year of age. Anvikar R, RTC 248 2nd and 3rd Pregnant women with P falciform mono-infection were Comparable outcomes. et. al.55 trimester randomized to receive: Low birth weight overall (22.4%), preterm delivery 16.6%, and still birth 1.7%, and they are comparable to prior study by (2018) India N= 125 oral artesunate 200mg daily for 3 days + sulfadoxine Jharkhand 2009. (1500mg)-pyrimethamine (75mg) on day 1 N-= 123 oral artesunate 200mg + mefloquine 440mg for 3 days They are followed until delivery and then 42 days postpartum. Osarfo J, et. RTC non- 417 2nd and 3rd 417 pregnant women between the gestational age of 15-31 DHA-PPQ was non-inferior to ASAQ for treatment. al56. (2017) inferiority trimester weeks randomized to receive either dihydroartemisinin- No maternal mortality was recorded. Ghana trial piperaquine (DHA-PPQ, n=212) or artesunate-amodiaquine Birth outcomes are similar. (ASAQ, n=205)) over 3 days. They are followed until 6 Same weeks postpartum. DHA arm has 1 cases of severe anemia, pregnancy induced hypertension (PIH) and antepartum hemorrhage due to population abruption and severe diarrhea. In ASAQ arm there were 3 cases of severe diarrhea and suspected appendicitis. 2 cases of Nasmbozi neonatal death and still birth was recorded in DHA-PPQ arm and one case of still birth was recorded in ASAQ arm. 3 cases M.

53 Morris C.A., Duparc S., Borghini-Fuhrer I., Jung D., Shin C.-S., Fleckenstein L. Review of the clinical pharmacokinetics of artesunate and its active metabolite dihydroartemisinin following intravenous, intramuscular, oral or rectal administration. Malaria Journal 2011 10 Article Number 263 54 Nambozi M, et. al. Artemisinin-based combination therapy during pregnancy: outcome of pregnancy and infant mortality: a cohort study. Malaria Journal. March 2019; 18:1. 55 Anvikar R, et. al. Efficacy of two artemisinin-based combinations for the treatment of malaria in pregnancy in India: A randomized controlled trial. Malaria Journal 2018 17:1. 56 Osarfo J., Tagbor H., Cairns M., Alifrangis M., Magnussen P. Dihydroartemisinin-piperaquine versus artesunate-amodiaquine for treatment of malaria infection in pregnancy in Ghana: an open-label, randomised, non-inferiority trial. Tropical Medicine and International Health 2017. 22; 8:1043-1052.

Reference ID: 4568389

of polydactyly and one cases of gum swelling observed in DHA-PPQ arm. No reported congenital anomaly in the ASAQ arm. Poespoprodj Prospective 363 all From April 2004-June 2009, a prospective hospital-based Those treated with DHP in the second and third trimester were more likely to be discharged with an ongoing pregnancy o et. al.57 hospital- artesunate surveillance screened all pregnant women for malaria and compared to those treated with a non-ACT regimen (Odds Ratio OR = 2.48 [1.26-4.86]); p = 0.006. (2014) based plus 486 documented maternal and neonatal outcomes. Data were Indonesia surveillanc DHP available on 6519 pregnant women admitted to hospital; 63% (5/8) of women treated with oral DHP in the first trimester miscarried compared to 2.6% (1/38) of those receiving oral e 1217 women with documented malaria and delivery included quinine; p<0.001. in the study. They are categorized to: CQ +/- SP (n=97) Of the 847 women admitted for delivery those reporting a history of malaria during their pregnancy who had been treated Oral or IV Quinine hydrochloride (n=271) with quinine-based regimens rather than DHP had a higher risk of malaria at delivery (adjusted OR = 1.56 (95%CI 0.97-2.5), IV artesunate +/- Dihydroartemisinin and piperaquine DHP p = 0.068) and perinatal mortality (adjusted OR = 3.17 [95%CI: 1.17-8.60]; p = 0.023). (n=363) DHP (n=486)

Mosha D, et. cohort 172 <20 weeks 2167 pregnant women were recruited and 1783 (82.3%) Quinine exposure in first trimester was associated with an increased risk of miscarriage/stillbirth (OR 2.5; 1.3-5.1) and al. 58 (2014) exposed completed the study until delivery. premature birth (OR 2.6; 1.3-5.3) compared AL (miscarriage/stillbirth- OR 1.4; 0.8-2.5; preterm birth- OR 0.9; 0.5-1.8. Tanzania 319 (17.9%) used anti-malarial in first trimester. Congenital anomalies were identified in 4 exposure groups namely N=164 AL, N=1, AL N= 70 quinine (Qn) N=1 quinine N= 8 (AL+Qn) N=2 SP N= 66 sulphadoxine-pyrimethamine (SP) N= 19 no-anti-malarial exposure group (19/1464). N=11 amodiaquine. N= 1464 No anti-malarial Tarning J, et PK 48 2nd and 3rd DHA and PPQ The main pharmacokinetic finding was an unaltered total exposure to PPQ but reduced exposure to DHA in pregnant al.59 (2012) trimester 48 Subjects compared to nonpregnant women. The shorter terminal elimination half-life of PPQ and lower exposure to DHA will Thailand N=24 pregnant, infected shorten the posttreatment prophylactic effect and might affect cure rates N=24 nonpregnant, infected PK parameters measured Tarning J, et PK 21 2nd and 3rd 21 pregnant women with uncomplicated P. falciform malaria The treatment was well tolerated, and there were no cases of recurrent malaria. Artemether and DHA exposures were lower al.60 (2012) trimester received the fixed oral combination of 80 mg artemether and than that reported in nonpregnant populations Uganda 480 mg lumefantrine twice daily for three days. Artemether (A) and dihydroartemisinin plasma concentrations after the last dose administration were measured. A separate modeling approach and a non-

57 Poespoprodjo JR, Fobia W, Kenangalem E, Lampah D, Sugiarto P, Tjitra E, et al. Dihydroartemisinin- piperaquine treatment of multidrug resistant falciparum and vivax malaria in pregnancy. PLoS One. 2014; 9: e84976. doi: 10.1371/journal.pone.0084976 PMID: 24465458 58 Mosha D, et. al. Safety of artemether-lumefantrine exposure in first trimester of pregnancy: an observational cohort. Malar J. 2014 May 27; 13:197. 59 Tarning J, Rijken MJ, McGready R, et al. Population pharmacokinetics of dihydroartemisinin and piperaquine in pregnant and nonpregnant women with uncomplicated malaria. Antimicrob Agents Chemother 2012; 56:1997-2007. 60 Tarning J, Kloprogge F, Piola P, et al. Population pharmacokinetics of Artemether and dihydroartemisinin in pregnant women with uncomplicated Plasmodium falciparum malaria in Uganda. Malar J 2012; 11:293.

Reference ID: 4568389

compartmental analysis (NCA) were also performed to enable a comparison with literature values and different modeling strategies. Ishag EM, cohort 62 exposed 1st Between June 2006 and October 2008, the safety of N=2 miscarriage (both given artemether injections) one at 20 weeks of gestation and the other at 22 weeks, each while et. al.61 trimester artemisinins during early human pregnancy was assessed in receiving quinine infusions for a second attack of malaria. (2012) and 2nd Sudan. Each was asked if they had had malaria in the first Sudan trimester trimester of the index pregnancy and, if so, what treatment N=60 delivered apparently healthy babies at full term. they had received. The women who had received Eisihag EE62 artemisinins were then followed-up until delivery and their No congenital malformations were detected; there was no preterm labor. No maternal deaths were recorded during the (2012) babies were followed-up until they were 1-year-old. Overall, follow-up, and there were no infant deaths reported in the first year of life. 62 of the pregnant women reported receiving artemisinins. Medical records were available for 51 (82%) of these 62 women. N=48, artemether injections, N=11 artesunate plus sulfadoxine-pyrimethamine N=3 artemether plus lumefantrine

McGready Retrospecti 945 1st All records of women (48426) in the 1st trimester of The odds of miscarriage increased in women with asymptomatic malaria (adjusted odds ratio 2·70, 95% CI 2·04–3·59) and R, et al.63 ve pregnant trimester pregnancy attending Shoklo Malaria Research Unit from symptomatic malaria (3·99, 3·10–5·13), and were similar for Plasmodium falciparum and Plasmodium vivax. (2012) Thai- population- women 1986-2010 were reviewed. Women with malaria in first Burmese based study with one trimester of pregnancy (single episode) were compared with In women with malaria, additional risk factors for miscarriage included severe or hyperparasitemic malaria (adjusted odds boarder episode of those without. ratio 3·63, 95% CI 1·15–11·46) and parasitemia (1·49, 1·25–1·78 for each ten-fold increase in parasitemia). malaria in 17612 women met inclusion criteria 1st trimester 16668 had no malaria in the first trimester Higher gestational age at the time of infection was protective (adjusted odds ratio 0·86, 95% CI 0·81–0·91). 945 had a single episode in the first trimester. The risk of miscarriage was similar for women treated with chloroquine (92 [26%] of 354), quinine (95 [27%) of 355), or artesunate (20 [31%] of 64; p=0·71). Adverse effects related to antimalarial treatment were not observed.

McGready PK study 20 2nd and 3rd 20 pregnant women receiving either oral or IV artesunate in No drug related AE reported. R, et al.64 with cross trimester pregnancy for malaria. No fetal or maternal toxicity observed. (2012) over design - Group1 IV Artesunate 4mg/kg on day 0 3 women were lost to follow up. Thailand followed by oral artesunate 4 mg/kg orally for 17 women delivered live, singleton babies. 2 were premature. 6 days (n=10) No congenital abnormalities were detected. 12 infants follow up to one year had normal developmental milestones. and

61 Ishag E.M., Ahmed I.A., Ahmed G.K. Safety of artemisinins during early pregnancy, assessed in 62 sudanese women. American Journal of Tropical Medicine and Hygiene 2012 87:5 SUPPL. 1 (95-) 62 Eisihag E.E. Safety of artemisinins during early pregnancy, assessed in 62 Sudanese women. Tropical Medicine and International Health 2012 17 SUPPL. 1 (50- ). 63 McGready R, et. al. Adverse effects of falciparum and vivax malaria and the safety of antimalarial treatment in early pregnancy: a population-based study. The Lancet. May 2012. 12: 5: 388-396. 64 McGready R, Phyo AP, Rijken MJ, Tarning J, Lindegardh N, Hanpithakpon W, et al. Artesunate/dihydroartemisinin pharmacokinetics in acute falciparum malaria in pregnancy: absorption, bioavailability, disposition and disease effects. Br J Clin Pharmacol. 2012;73(3):467-477.

Reference ID: 4568389

- Group 2 oral artesunate 4mg/kg on day 0 Malaria increased the absolute oral bioavailability of artesunate by 87% presumably by inhibiting first pass effect, whereas Kloprogge followed by IV artesunate 4mg/kg on day 1 pregnancy decreased oral bioavailability by 23%. F, et. al.65 followed by oral artesunate 4mg/kg for 5 days. (2015) (n=10) There were no signiﬁcant differences in artesunate or DHA pharmacokinetics between pregnant women with malaria (same Same women were evaluated 3 months postpartum. compared with the same women restudied postpartum in a healthy state after IV administration of artesunate. population) Onyamboko PK study 26 2nd and 3rd PK study single oral dose of artesunate (200mg) in 26 No congenital abnormalities found in all neonates. Normal physical and neurological development in 26 babies followed to M, et. al.66 with cross trimester asymptomatic pregnant women with P. falciparum infection. 1 year old. (2011) over design Comparison was made in the same women 3 months Congo postpartum and in parallel to infected nonpregnant control Rapid elimination of AS was observed in all three groups. The 90% CI for the pregnancy: postpartum ratio of geometric group. means for total and free AUC fell within the pre-specified 0.66 - 1.50 therapeutic equivalence interval. However, more N=25 (infected women, not pregnant) pronounced pharmacokinetic differences were observed between the pregnancy and control subjects, with the 90% CI for Morris C, et. N=13 (22-26 weeks gestation) the pregnancy: control ratio of geometric means for both total 0.68 (90% CI 0.57-0.81) and free AUC 0.78 (90% CI 0.63- al.67 (2011) N=13 (32-36 weeks gestation) 0.95) not fully contained within the 0.66 - 1.50 interval.

Same All subjects cleared parasites rapidly, and there was no difference in the percentage of women who has parasitemia 12 hours population after dosing. Moore KA, Observatio 183 women 1st 55636 pregnancies between 1994 and 2013 collected from et. al.68 nal exposed to trimester antenatal clinics on the Thai-Myanmar border then analysis (2016) prospective artemisinin for first trimester malaria, 2558 (10%) was affected. 1179 Thailand cohort pregnancies with ≥1 P falciparum infection in first trimester included; 971 received quinine or quinine plus clindamycin; 25 received mefloquine;183 received artemisinin.

Literature review was also performed for exposure of artemisinin in first trimester pregnancy. Jaureguiberr Prospective 4 varies Review of surveillance program in France, 4 pregnant One pregnancy ended in SAB with hemorrhage and resulted in a transfusion. No other outcome given. y S, et. al.69 patients were included, and all received IV artesunate. (2015) One was found to be pregnant during treatment. One France received IV artesunate in second trimester and tolerated it well.

65 Kloprogge F, McGready R, Phyo AP, Rijken MJ, Hanpithakpon W, Than HH, et al. Opposite malaria and pregnancy effect on oral bioavailability of artesunate - a population pharmacokinetic evaluation. Br J Clin Pharmacol. 2015;80(4):642-653. 66 Onyamboko MA, Meshnick SR, Fleckenstein L, Koch MA, Atibu J, Lokomba V, et al. Pharmacokinetics and pharmacodynamics of artesunate and dihydroartemisinin following oral treatment in pregnant women with asymptomatic Plasmodium falciparum infections in Kinshasa DRC. Malar J. 2011; 10:49. 67 Morris CA, Onyamboko MA, Capparelli E, Koch MA, Atibu J, Lokomba V, et al. Population pharmacokinetics of artesunate and dihydroartemisinin in pregnant and non-pregnant women with malaria. Malar J. 2011b; 10:114. 68 Moore KA, et. al. Safety of artemisinins in first trimester of prospectively followed pregnancies: an observational study. Lancet Infect Dis 2016; 16:576-83. 69 Jaureguiberry S, Thellier M, Ndour PA, Ader F, Roussel C, Sonneville R, et al. Delayed-onset hemolytic anemia in patients with travel-associated severe malaria treated with artesunate, France, 2011-2013. Emerg Infect Dis. 2015;21(5):804-812.

Reference ID: 4568389

One received IV artesunate in third trimester and tolerated it well. One received IV artesunate in labor and tolerated it well. Twomey PS, Retrospecti 2 3rd 102 patients with severe and complicated malaria in US were Delivery of healthy infants vaginally. et. al.70 ve case trimester reviewed. 2 pregnant women received IV artesunate for (2015) USA review treatment. Ndiaya JL, RTC 28 exposed 2nd and 3rd An open label trial with one treatment arm was conducted in No infant presented either a positive blood smear at birth and during follow up or had any clinical abnormalities et. al.71 trimester the Guediawaye health center. Recruited patients were (2011) treated with Artesunate + Amodiaquine (ASAQ) for 3 days. No serious adverse events related to the drug were noted. Senegal They were followed until delivery. Infants were assessed at birth and followed up 9 months. Piola et. al.72 RTC 152 2nd and 3rd Open-label, randomized, non-inferiority trial between Birth outcomes: (2010) exposed trimester October 2006 and May 2009, at the antenatal clinics of the spontaneous abortion and neonatal deaths all proportionally lower in the artemether-lumefantrine group. Uganda Mbarara University of Science and Technology Hospital in Uganda. Pregnant women with malaria were randomly No significant difference in birth weight, mean gestational age or premature infants. assigned (1:1) by computer generated sequence to receive either: 3 malformations- N= 152, quinine hydrochloride (7 days) or 1 polydactyly in each group, both had family traits; N= 152, artemether-lumefantrine, 1 with cyanotic heat disease in a woman treated with artemether-lumefantrine at 19 weeks. and were followed up weekly until delivery.

Mutabingwa RTC 83 exposed 2nd and 3rd Pregnant women with non-severe, slide proven, falciparum Failure rates with monotherapy were unacceptably high. The two combinations tested were efficacious and appeared safe. TK, et. al.73 trimester malaria was randomized to one of 4 regimes: 1433 pregnant (2009) women were screened, of whom 272 met entry criteria and 2 maternal deaths. One in CD arm had mild malaria at beginning of trial and the malaria became severe, and the patient Tanzania were randomized; died. One from SP+AQ arm died despite parasite clearance. HIV status was not given. Labs suggested death related to N= 28 sulfadoxine-pyrimethamine [SP] immunosuppression. N= 81 chlorproguanil-dapsone [CD] N= 80 SP + amodiaquine [SP+AQ] No fetal death with 28 days of administration of drug except 1 case of macerated stillbirth in the AQ+AS arm. N = 83 amodiaquine + artesunate [AQ+AS] Randomization was on a 1:2:2:2 ratio. 15 stillbirth or neonatal death occurred within 48 hours of delivery. SP arm- 1 preterm delivery (PTD) at 27 weeks, infant died at 32 hours old.

70 Twomey PS, Smith BL, McDermott C, Novitt-Moreno A, McCarthy W, Kachur SP, et al. Intravenous Artesunate for the Treatment of Severe and Complicated Malaria in the United States: Clinical Use Under an Investigational New Drug Protocol. Ann Intern Med. 2015;163(7):498-506. 71 Ndiaye J.-L., Ndiaye A., Faye B., Ba M., Tine R., Ndiaye D., Gaye A., Gaye O., Brasseur P. Open-label in vivo drug study to evaluate the safety and efficacy of artesunate plus amodiaquine combination in pregnant women with uncomplicated P. falciparum malaria in Senegal. Tropical Medicine and International Health 2011 16 SUPPL. 1 (140-). 72 Piola P, Nabasumba C, Turyakira E, Dhorda M, Lindegardh N,Nyehangane D, et al. Efficacy and safety of artemether-lumefantrine compared with quinine in pregnant women with uncomplicated Plasmodium falciparum malaria: an open-label, randomized, non-inferiority trial. Lancet Infect Dis, 2010; 10: 762–769. doi: 10.1016/S1473-3099(10)70202-4 PMID: 20932805 73 Mutabingwa T.K., Muze K., Ord R., Briceño M., Greenwood B.M., Drakeley C., Whitty C.J.M. Randomized trial of artesunate+Amodiaquine, sulfadoxine- pyrimethamine+amodiaquine, chlorproguanal-dapsone and SP for malaria in pregnancy in Tanzania. PLoS ONE 2009 4:4 Article Number e5138

Reference ID: 4568389

Women were admitted for treatment, and followed at days 7, CD- 1 stillbirth to 40-year old HIV positive women 14, 21, 28 after the start of treatment, at delivery and 6 2 neonatal deaths (1 in a twin delivery at 30 weeks and weeks after delivery to determine adverse events, clinical another due to placental abruption) and parasitological outcomes. Primary outcome was 2 infants died within 24 hours following prolonged labor parasitological failure by day 28. 1 death following obstructed labor SP+AQ- 1 intrauterine death 2 deaths in twins following home delivery 1 death in a child failed to control the neck at 6 weeks postpartum following prolonged second stage of labor AQ-AS arm- 1 breech delivery of a macerated baby at 40 weeks 1 stillbirth at term 1 stillbirth of a twin 1 intrauterine death Tarning J, et PK 103 2 and 3rd AL Plasma concentration and treatment failure rate Day 7, 40% (n = 41/103) plasma concentrations of < 355 ng/ml (which corresponds to approximately < 280 ng/ml in al.74 (2009) venous plasma), a threshold previously associated with an increased risk of therapeutic failure in nonpregnant patients in Thailand this area. The treatment failure rate 16.5% (95% CI 9.9 – 25.1) Kaye DK, et RTC 49 exposed 2 and 3 artemether-lumefantrine (AL) (n = 49) Day 28 CR: AL 100%, CD 100%. Parasite and fever clearance time were comparable. The adverse effects were comparable al.75 (2008) chlorproguanil-dapsone (CD) (n = 49) Clinical and between the two groups. Uganda parasitological response assessed on days 0, 1, 2, 4, 7, 14 and Ten participants lost to follow up, and three developed severe malaria and were given Q therapy 2006 28 McGready RTC 128 2nd and 3rd An open-label randomized controlled trial comparing Birth outcomes and infant (up to age 1 y) outcomes did not differ significantly between the two groups. R, et. al.76 PK In AL exposed trimester directly observed treatment with artemether- lumefantrine 3 (2008) arm only. d (AL) or artesunate monotherapy 7 d (AS7) was conducted Thailand in pregnant women with uncomplicated P. falciparum malaria. N= 125 AL arm N= 128 AS7 arm The primary endpoint was efficacy defined as the P. falciparum PCR-adjusted cure rates assessed at delivery or by day 42 if this occurred later than delivery, as estimated by Kaplan-Meier survival analysis. Infants were assessed at birth and followed until 1 y of life.

74 Tarning J, McGready R, Lindegardh N, et al. Population pharmacokinetics of lumefantrine in pregnant women treated with artemether-lumefantrine for uncomplicated Plasmodium falciparum malaria. Antimicrob Agents Chemother 2009; 53:3837-46. 75 Kaye DK, Nshemerirwe R, Mutyaba TS, et al. A randomized clinical trial comparing safety, clinical and parasitological response to artemether-lumefantrine and chlorproguanil-dapsone in treatment of uncomplicated malaria in pregnancy in Mulago hospital, Uganda. J Infect Dev Ctries 2008; 2:135-9 76 McGready R., et. al. A randomized controlled trial of artemether-lumefantrine versus artesunate for uncomplicated plasmodium falciparum treatment in pregnancy. PLoS Medicine 2008 5:12 (1699-1715)

Reference ID: 4568389

Kalinani L, RTC 47 exposed 2nd Pregnant women in 2nd trimester with uncomplicated Maternal adverse event- artesunate and azithromycin were well tolerated. et al.77 trimester falciparum malaria randomly allocated to one of three Pregnancy outcome- of 118 deliveries with known outcomes, there were 109 live births, 4 SABs and 5 still births. 17 (2007) groups: adverse pregnancy outcomes: Malawi - All 4 SABs, all second trimester, all in AP-azithromycin group, 2 of them are HIV +, 2 are HIV unknown. N= 47, Sulfadoxine-pyrimethamine (SP; 3 tablets, 500 mg - 5 stillbirths: one occurred in SP group due to prolonged labor, 4 in SP-artesunate group (1 was full term with sulfadoxine and 25 mg pyrimethamine per tablet); cord around the neck and HIV + with + malaria parasites detected in maternal or placental blood, 1was due to prolonged labor, one occurred after mother had taken traditional medicine to induce labor, which was also N= 47, SP plus azithromycin (1 g/dayx2 days); or +HIV + and malaria +, one was a preterm delivery at 31 weeks and syphilis+ at delivery). - 8 neonatal deaths, 4 in SP group (2 of which occurred 509 days after delivery, 1 has kernicterus, 1 is HIV+), 1 N= 47, SP plus artesunate (200 mg/dayx3 days). in SP-azithromycin group (malaria + and obstructed labor), 3 in SP-artesunate group (1 was preterm delivery at 28 weeks and HIV+, 1 was obstructed labor, 1 was preterm delivery at 28 weeks). All treatment was repeated in 4 weeks. Dellicour S, Review 14 studies varies Total of 945 women exposed to artemisinin products, 2 maternal death related to malaria et al.78 (includes including IM artemether and artesunate (route not specified) 1 maternal death (unrelated to malaria or treatment) (2007) UK Bounyason (5 RTC), in pregnancy. There was combination of artemisinin 20 had miscarriages g 2001, products with mefloquine or atovaquone-proquanil. 4% lost 19 had still births McGready 945 to follow up. 879 had follow up until delivery and infants 11 were neonatal deaths 2005, 2000, pregnant were followed until 1 year of age. 6 congenital abnormalities (1 aural atresia, 1 polythelia, 1 epidermoid cyst, 3 not specified) 2001, and women 1st trimester (n=123) 1 out of 214 infants followed to 1 year of age had developmental delay Sowunmi 2nd or 3rd trimester (n=822) 1998) No increased risk of serious maternal adverse events (AE), adverse birth outcomes or neurodevelopmental deficits associated with artemisinin use during pregnancy. (studies were not powered to assess safety endpoints). McGready PK 24 exposed 2nd and 3rd Serial plasma concentrations of artesunate and DHA were Artesunate was very rapidly eliminated. For DHA the median [90% range] estimate of oral clearance (CI/F) was 4.0 [0.8– R, et al.79 trimester measured in 24 women after the final dose of a 3-day 20.7] l hour−1 kg−1, total apparent volume of distribution (Vd/f) was 3.4 [0.9–60.7] l/kg, and terminal elimination half-life (2006) treatment with artesunate (4 mg kg−1 day−1) and was 1.0 [0.6–2.4] h. Thailand atovaquone (20 mg kg−1 day−1) plus proguanil (8 mg kg−1 The kinetics of DHA are modified by pregnancy. The plasma levels of the active antimalarial metabolite DHA are lower day−1), daily. than reported previously in non-pregnant adults. Conventional non-compartmental modelling and a population one-compartment pharmacokinetic model were applied to the data. McGready RTC 39 exposed 2nd and 3rd Pregnant women with uncomplicated falciparum malaria There were no significant differences between the groups in birth weight, duration of gestation, or congenital abnormality R, et. al.80 trimester were recruited for a randomized, open-label trial with a rates in newborns or in growth and developmental parameters of infants monitored for 1 year. (2005) restricted sequential trial design of 7 days of supervised

77 Kalilani L, Mofolo I, Chaponda M, Rogerson SJ, Alker AP, Kwiek JJ, et al. A Randomized Controlled Pilot Trial of Azithromycin or Artesunate Added to Sulfadoxine-Pyrimethamine as Treatment for Malaria in Pregnant Women. PLoS One. 2007 Nov 14;2(11):e1166. 78 Dellicour S, et. al. The safety of artemisinins during pregnancy: a pressing question. Malaria Journal 2007; 6:15. 79 McGready R., Stepniewska K., Ward S.A., Cho T., Gilveray G., Looareesuwan S., White N.J., Nosten F. Pharmacokinetics of dihydroartemisinin following oral artesunate treatment of pregnant women with acute uncomplicated falciparum malaria. European Journal of Clinical Pharmacology 2006 62:5 (367-371). 80 McGready R., Ashley E.A., Moo E., Cho T., Barends M., Hutagalung R., Looareesuwan S., White N.J., Nosten F.

Reference ID: 4568389

Thailand quinine (SQ7, n=42) versus 3 days of artesunate-atovaquone- proguanil (AAP, n=39). Deen, JL, et. RTC 287 variable 3317 out of 3615 women of reproductive age who resided in There was no difference in the proportion of SABs, stillbirths, or infant deaths among those exposed or not exposed to the al.81 (2001) exposed villages of Gambia were followed. 517 were pregnant and drugs (placebo plus those women who choose not to participate). Gambia 459 of these pregnant women were followed. Pregnancy outcomes were evaluated. The mean weight of 18 infants born to mothers who had received artesunate and PSD during the third trimester was 3.10 kg N= 287 exposed to single dose artesunate (200 mg) and PSD compared to a mean weight of 2.62 kg of the 10 infants of untreated mothers (adjusted P value = 0.05). (75mg pyridoxine-1500mf sulfadoxine) N= 40 placebo (132 choose not to participate) Exposure to artesunate and PSD is not teratogenic. Bounyaason RTC 60 2nd 60 pregnant women in their 2nd trimester separated into 2 57 out of 60 pregnancy resulted in live birth (95%); 2 cases in artesunate group and 1 case in the quine group were lost to g S,82 (2001) trimester groups follow up before delivery. Thailand N = 28 oral artesunate 2mg/kg first dose, then 1mg/kg every No evidence of maternal or fetal toxicity. 12 hours for at least 5 days with split doses of oral mefloquine 25 mg 1 day after artesunate is stopped.

N = 29 quinine sulfate 10mg/kg/day for at least 7 days

Patient followed until delivery and children followed until 1- 2 years of age. McGready RTC 129 2nd and 3rd 129 pregnant women with uncomplicated P. falciparum 115 singleton delivery and 3 sets of twins, 11 were lost to follow-up. R, et. al.83 trimester infection received either artesunate or quinine/clindamycin - AS group- 1 stillbirth (resulted from prolonged labor of 6 days at home), no malformations. One neonatal (2001a) (QC). death within one week of life unrelated to malaria. 3 infant deaths unrelated to malaria. Thailand N=64 artesunate (AS) 12mg/kg as 2mg/kg/day on day 0, 1, - QC group- 1 stillbirth (resulted from abruption) and 1 congenital abnormality (midline epidermoid cyst just 2, 3 and 4 and 2 mg/kg/day on Day 5 and 6. superior to the bridge of the nose). In addition, in one set of twins one had gastroschisis and died and other is normal. 2 neonatal deaths with in first week of life and unrelated to malaria. 3 infant death unrelated to N=65, quinine/clindamycin (QC) dosed as 10mg/kg quinine malaria. and 5g/kg clindamycin every 8 hours for 7 days. No difference in AE between the groups. Patients are followed until delivery and infants are followed No significant difference between the group on birth weight, placental weight, gestational age, low birth weight, until 1 year of age. developmental milestones.

A randomized comparison of artesunate-atovaquone-proguanil versus quinine in treatment for uncomplicated falciparum malaria during pregnancy. Journal of Infectious Diseases 2005 192:5 (846-853). 81 Deen JL, et. al. The safety of the combination artesunate and pyrimethamine-sulfadoxine given during pregnancy. Transactions of The Royal Society of Tropical Medicine and Hygiene, July-August 2001, 95; 4: 424–428. 82 Bounyasong S. Randomized trial of artesunate and mefloquine in comparison with quinine sulfate to treat P. falciparum malaria pregnant women. Journal of the Medical Association of Thailand = Chotmaihet thangphaet. 2001;84(9):1289-1299. 83 McGready R, Cho T, Samuel, Villegas L, Brockman A, van Vugt M, et al. Randomized comparison of quinine-clindamycin versus artesunate in the treatment of falciparum malaria in pregnancy. Transactions of the Royal Society of Tropical Medicine and Hygiene. 2001a;95(6):651-656.

Reference ID: 4568389

McGready Prospective 461 All 539 patients of acute P. falciparum malaria were treated 2 maternal deaths (one from severe malaria and one from unrelated incident). R, et. al.84 cohort trimesters with: 414 bore singletons, 6 bore twins. All infants are externally and neurologically normal except those listed below. (2001b) 20 experienced a spontaneous abortion (SAB). 7 had still births. 3 congenital abnormalities (anencephaly, midline Thailand (N=44 1st artesunate (IV or oral) (n=528) or epidermoid, normal at birth but preterm), 63 low birth weight infants. trimester) artemether (n=11). First trimester exposure and SAB rate when analyzed separately was (7 out of 37) 19%, which is not significantly different than overall community rate. 461 of 539 were pregnant women. Of the 461 pregnant women, 11 % lost to follow up. Birth outcomes did not differ significantly to community rates for abortion, stillbirth, congenital abnormality and mean gestational age at delivery.

McGready RTC 66 exposed 2nd and 3rd An open randomized trial in 1995–1997 compared the use of MAS3 regimen was more effective than the Q7 regimen: day 63 cure rates were 98.2% (95% CI 94.7-100) (n = 65) for R, et. al.85 trimester quinine and artesunate during pregnancy. MAS3 and 67% (95% CI 43.3-90.8) (n = 41) for Q7, P = 0.001. (2000) Group 1: N=42, quinine (10 mg salt/kg every 8 h) for 7 days Thailand (Q7) The MAS3 regimen was also associated with less gametocyte carriage; the average person-gametocyte-weeks for MAS3 Group 2: N=66, mefloquine 25 mg base/kg (total dose) plus was 2.3 (95% CI 0–11) and for Q7 was 46.9 (95% CI 26–78) per 1000 person-weeks, respectively (P < 0·001). artesunate 4 mg/kg per day for 3 days (MAS3) MAS3 was significantly better tolerated. McGready Prospective 83 exposed Not Artemisinin derivative (oral artesunate or artemether) was 73 pregnancies (88%) resulted in live births, R, et. al.86 cohort specified assessed for the treatment of multidrug-resistant Plasmodium 3 (4%) in SABs and (1998) falciparum malaria in 83 pregnant women in Thailand. 2 (3%) in still births, Thailand The women were followed weekly until delivery. and 5 women were lost to follow-up before delivery.

There were no congenital abnormalities.

46 children followed for more than one year all developed normally. Sowunmi A, RTC 45 exposed 2nd and Day 14 and 28 cure rates, parasite and fever clearance time Both groups had 100% cure rate by day 14 and 28; however, one person in the A group was retreated. There was no et al.87 3rd Artemether (n = 23) correlation between initial parasite density and parasite or fever clearance times in the two groups. Both treatment regimens (1998) trimester Artemether + MQ (n = 22) were well tolerated Nigeria

84 McGready R, Cho T, Keo NK, Thwai KL, Villegas L, Looareesuwan S, et al. Artemisinin antimalarials in pregnancy: a prospective treatment study of 539 episodes of multidrug-resistant Plasmodium falciparum. Clin Infect Dis. 2001b;33(12):2009-2016. 85 McGready R., Brockman A., Cho T., Cho D., Van Vugt M., Luxemburger C., Chongsuphajaisiddhi T., White N.J., Nosten F. Randomized comparison of mefloquine-artesunate versus quinine in the treatment of multidrug-resistant falciparum malaria in pregnancy. Transactions of the Royal Society of Tropical Medicine and Hygiene 2000 94:6 (689-693) 86 McGready R., Cho T., Cho J.J., Simpson J.A., Luxemburger C., Dubowitz L., Looareesuwan S., White N.J., Nosten F. Artemisinin derivatives in the treatment of falciparum malaria in pregnancy. Transactions of the Royal Society of Tropical Medicine and Hygiene 1998 92:4 (430-433). 87 Sowunmi A, Oduola AM, Ogundahunsi OA, et al. Randomized trial of artemether versus artemether and mefloquine for the treatment of chloroquine/sulfadoxine-pyrimethamine-resistant falciparum malaria during pregnancy. J Obstet Gynaecol 1998; 18:322-7.

Reference ID: 4568389

APPENDIX C: Expsoure of ACT in second and third trimesters of pregnancy.88

Study Location and Study Population ACT Comparison 2-3rd Trimester Outcomes time period Exposures Exposures

Bounyaso Thailand Pregnant women with P. falciparum, not AS+MQ = 28 Q = 29 Any Fetal Loss: ng S,89 January 1995- more than 4% parasitized red cells, AS-MQ = 0/28 2001 December 1998 gestational age at least 28 weeks estimated 2-3rd trim = 28 2-3rd trim = 29 Q = 0/29 by ultrasound. Congenital Anomalies (CA) AS-MQ = 0/28 Q = 0/29

Kalilani L, et Malawi Pregnant women (EGA 14–26 weeks) AS+SP = 47 SP = 47 Stillbirth: 90 al. September 2003- between 15 and 49 years old, with AS-SP = 4/38 rd 2007 September 2004 peripheral P. falciparum parasitemia; 2-3 trim = 47/47 2-3rd trim=47 SP = 1/38 method of measuring gestational age not SP+AZM = 0/42 described. SP+AZM =47 Median age 20 (range 17–24). Any fetal loss: 2-3rd trim = 47 AS-SP = 4/38 SP = 0/38 SP+AZM = 4/42

CA: AS-SP = 0/38 SP = 0/38 SP-AZM = 0/42

88 Source: Table 2 RTC identified in the systematic review and included in the meta-analysis. Korvacs 2016 89 Bounyasong S. Randomized Trial of Artesunate and Mefloquine in Comparison with Quinine Sulfate to Treat P. falciparum Malaria Pregnant Women. J Med Assoc Thail. 2001; 84: 1289–1299. 90 Kalilani L, Mofolo I, Chaponda M, Rogerson SJ, Alker AP, Kwiek JJ, et al. A Randomized Controlled Pilot Trial of Azithromycin or Artesunate Added to Sulfadoxine-Pyrimethamine as Treatment for Malaria in Pregnant Women. PLoS One. 2007; doi: 10.1371/journal.pone.0001166 PMID: 18000538

Reference ID: 4568389

McGready R, Thailand October Pregnant women in 2nd or 3rd trimester, AS-MQ = 66 Q = 42 Any Fetal Loss: et al.91 estimated by fundal height, documented by AS-MQ = 2/66 2000 antenatal care (ANC), who had microscopy Q = 0/42 confirmed uncomplicated P. falciparum 1995-July 1997 2-3rd trim = 66 2-3rd trim = 42 CA: AS-MQ = 0/66

Q = 0/42

McGready R, Thailand October Pregnant women in 2nd or 3rd trimester AS = 64 Q+C = 65 Stillbirth: et al. 92 estimated by AS = 1/64 2001 1997-January 2000 fundal height seen at ANCs who had 2-3rd trim = 64 2-3rd trim = 65 Q+C = 1/65 confirmedi P. falciparum infections. Age years Any Fetal Loss: Art = 1/64 Q+C = 1/65 CA: Art = 0/64 Q+C = 1/65

McGready R, Thailand December Pregnant women with first episode of P. AAP = 39 Q = 42 Any Fetal Loss: et al.93 falciparum or 2005 2001-July 2003 mixed infection (P. vivax), 14–31 weeks 2-3rd trim = 39 2-3rd trim = 42 AAP = 0/34 estimated by ultrasound or fundal height, Ht Q = 0/38 > = 20%. Mean age 26 (s.d. 7) years CA: AAP = 2/34 Q = 1/38

91 McGready R, Brockman a, Cho T, Cho D, van Vugt M, Luxemburger C, et al. Randomized comparison of mefloquine-artesunate versus quinine in the treatment of multidrug-resistant falciparum malaria in pregnancy. Trans R Soc Trop Med Hyg. 2000; 94: 689–693. PMID: 11198658 92 McGready R, Cho T, Keo NK, Thwai KL, Villegas L, Looareesuwan S, et al. Artemisinin antimalarials in pregnancy: a prospective treatment study of 539 episodes of multidrug-resistant Plasmodium falciparum. Clin Infect Dis. 2001 33: 2009–2016. doi: 10.1086/324349 PMID: 11712093 93 McGready R, Ashley EA, Moo E, Cho T, Barends M, Hutagalung R, et al. A Randomized Comparison of Artesunate- Atovaquone-Proguanil versus Quinine in Treatment for Uncomplicated Falciparum Malaria during Pregnancy. J Infect Dis. 2005.

Reference ID: 4568389

McGrea Thailand Patients with acute P. falciparum malaria AL = 125 Stillbirth: dy, et April 2005- in 2nd or 3rd trimester estimated by AL = 1/117 94 rd al. August 2006 ultrasound. Originally only allowed 2nd 2-3 trim = 125 AS = 1/120 2008 infection in pregnancy (already failed

quinine), but later widened to allow first AS = 128 Any Fetal Loss: infections in pregnancy. Age range 14–44 AL = 1/117 Years 2-3rd trim = 128 AS7 = 2/120

CA: AL = 3/117 AS7 = 4/120

Mutabing Tanzania Pregnancy with either a positive blood AS-AQ = 83 SP = 28 Any Fetal Loss: wa, et smear for P. falciparum with at least 800 AS-AQ = 4/83 95 al. January 2004- parasites/μL in an asymptomatic woman or 2-3rd trim = 83 2-3rd trim = SP-AQ = 1/80 2009 any of the following symptoms within 2 September 2006 28 SP = 0/28 days prior to consultation: history of fever, CD = 1/81 headache, vomiting, chills/rigors and/or any SP-AQ = 80 of the following signs: temperature 2-3rd trim = CA:* >/=37.5 & <39.5˚C, Hb >/=7 and <9 g/dl) 80 AS+AQ = 3/83 with P. falciparum parasitemia at any SP = 3/28 density. All cases were between 14–34 CD = 81 CD = 7/81 weeks gestation defined by presence of 2-3rd trim = 81 SP+AQ = 8/80 fetal heartbeat. Median age 21 years

94 McGready R, Tan SO, Ashley EA, Pimanpanarak M, Viladpai-nguen J, Phaiphun L, et al. A Randomised Controlled Trial of Artemether-Lumefantrine Versus Artesunate for Uncomplicated Plasmodium falciparum Treatment in Pregnancy. PLoS Med 2008; 5. doi: 10.1371/journal.pmed.0050253 PMID: 19265453 95 Mutabingwa TK, Muze K, Ord R, Briceño M, Greenwood BM, Drakely C, et al. Randomized trial of artesunate+amodiaquine, sulfadoxine- pyrimethamine+amodiaquine, chlorproguanal-dapsone and SP for malaria in pregnancy in Tanzania. PLoS One. 2009; 4: e5138. doi: 10.1371/journal.pone.0005138 PMID: 19352498

Reference ID: 4568389

Piola P, et Uganda Women with viable pregnancy with an AL = 152 Q = 152 Stillbirth: AL = 2/144 al.96 estimated gestation of 13 weeks determined 2-3rdtrim = 152 Q = 3/137 2010 October 2006-May by ultrasound or LMP and malaria infection 2-3rd trim = 152 2009 detected by microscopy (P. falciparum) mixed or mono-infection. SP may have been used for prevention before entry to the study and some Any fetal loss: AL = 5/144 Q = 7/137

CA: AL = 3/144 Q = 2/137

Sowunmi A, Nigeria All patients referred to University College Art+MQ = 23 Stillbirth: et al.97 1998 January Hospital with persistent P. falciparum 2-3rd trim = 23 Art+MQ = 0/23 1994-March parasitemia and acute uncomplicated Art im = 0/22 1997 malaria after failure of supervised therapy Art im = 22 with standard regimen of chloroquine or 2-3rd trim = 22 Any fetal loss: after a single dose of SP or both CQ and Art+MQ = 0/23 SP. Oral fluid intolerance, no history of Art im = 0/22 allergy to known antimalarial drugs, 2nd or 3rd trimester determined by ultrasound CA: Art+MQ = 0/23 Art im = 0/22

96 Piola P, Nabasumba C, Turyakira E, Dhorda M, Lindegardh N,Nyehangane D, et al. Efficacy and safety of artemether-lumefantrine compared with quinine in pregnant women with uncomplicated Plasmodium falciparum malaria: an open-label, randomised, non-inferiority trial. Lancet Infect Dis, 2010; 10: 762–769. doi: 10.1016/S1473-3099(10)70202-4 PMID: 20932805 97 37. Sowunmi A, Oduola AM, Ogundahunsi OA, Fehintola FA, Ilesanmi OA, Akinyinka OO, et al. Randomised trial of artemether versus artemether and mefloquine for the treatment of chloroquine/sulfadoxine-pyrimethamine-resistant falciparum malaria during pregnancy. J Obstet Gynaecol. 1998; 18: 322– 327. doi: 10.1080/01443619867038 PMID: 15512100

Reference ID: 4568389

Source: Table 2. Description of RCT studies identified in the systematic review and included in the meta-analysis (Korvacs, 2016) *Only minor CA. Trim: trimester; ART im: artemether intramuscular; AS: artesunate; AZM: azithromycin; SP: sulfadoxine pyrimethamine; AL: artemether lumefantrine; CA: congenital anomaly; C: Clindamycin; MQ: mefloquine; CD: chlorproguanal-dapsone; iv: intravenous; AP: atovaquone proquanil; Q: quinine; AS7: artesunate 7 days; CQ: chloroquine; AQ: amodiaquine; DP: dihydroartemisinin-piperaquine; IPT: intermittent preventative therapy.

Reference ID: 4568389

APPENDIX D: Effects of artemisinin derivatives or ACTs for treatment of malaria in the ﬁrst trimester of pregnancy in women.98 Study Drug Route Dose Gesta N (1st Exposure Outcome tional trimester age exposure) (week s) McGready AS Oral 840 3-12 15 Treatment of recrudescent SABs occurred in 20% (3/15) of the pregnancies, which 99 R, et. al. mg infections – inadvertently is similar to the background rate of SABs in the general (1998) exposed population. Eight infants were followed and were normal until one year of life.

Deen JL, AS-PSD oral 200 mg 50 Preventive Among the exposed infants (117 pregnant women were exposed et. al.100 AS in any trimester) there was one report of an infant with an (2001) umbilical hernia and one report of an infant with undescended Single testis. No major congenital anomalies, SABs, stillbirths or infant dose deaths related to treatment were reported.

McGready ASb Oral – AS 777 mg 3-12 42 Treatment of conﬁrmed cases Abortion rate was 18.9% within the community range (12.3%). R. et. al.101 ATMb – AS most of all as re-treatment All infants were born externally and (2001) AS-MQ-CLb IV- AS neurologically normal. AS-ATV-PGb 307 mg ATM-LM IM- ATM – ATM

McGready AS-ATV-PG Not 840 mg 3 Treatment of multidrug- There were no congenital abnormalities or increased R, et. al.102 reported – AS resistant P. falciparum maternal adverse effects related to treatment. (2003)

Adam I, et. ATM IM 280mg 10 1 Treatment after failure of There was no SAB, stillbirth or any congenital al. 103 chloroquine or quinine malformation.

98 Gomes A, et. al. Clinical and non-clinical safety of artemisinin derivatives in pregnancy. Reproductive Toxicology. 2016; 65:194-203. 99 R. McGready, T. Cho, J.J. Cho, J.A. Simpson, C. Luxemburger, L. Dubowitz, et al., Artemisinin derivatives in the treatment of falciparum malaria in pregnancy, Trans. R. Soc. Trop. Med. Hyg. 92 (1998) 430–433. 100 J.L. Deen, L. von Seidlein, M. Pinder, G.E. Walraven, B.M. Greenwood, The safety of the combination artesunate and pyrimethamine-sulfadoxine given during pregnancy, Trans. R. Soc. Trop. Med. Hyg. 95 (2001) 424–428. 101 R. McGready, T. Cho, N.K. Keo, K.L. Thwai, L. Villegas, S. Looareesuwan, et al., Artemisinin antimalarials in pregnancy: a prospective treatment study of 539 episodes of multidrug-resistant Plasmodium falciparum, Clin. Infect. Dis. 33 (2001) 2009–2016. 102 R. McGready, N.K. Keo, L. Villegas, N.J. White, S. Looareesuwan, F. Nosten, Artesunate-atovaquone-proguanil rescue treatment of multidrug-resistant Plasmodium falciparum malaria in pregnancy: a preliminary report, Trans. R. Soc. Trop. Med. Hyg. 97 (2003) 592–594. 103 I. Adam, E. Elwasila, D.A. Mohammed Ali, E. Elansari, M.I. Elbashir, Artemether in the treatment of falciparum malaria during pregnancy in eastern Sudan, Trans. R. Soc. Trop. Med. Hyg. 98 (2004) 509–513.

Reference ID: 4568389

(2004) Adam I, et. ATM AS-PSD IM-ATM, Not 6-12 62 Treatment after failure of Most of the women enrolled received ATM injections and had al.104 ATM-LM other oral reported uncomplicated cases normal infants that were followed until one year after birth. (2009) Manyando ATM-LM; Oralc 480mgc LMP- 156 Treatment of episodes of fever The treatment with AL did not enhance perinatal mortality C, et. al.105 ATM-LM- until most of all unconﬁrmed by or impair infant neurodevelopment. The incidence of (2010) and PSD 12 diagnostic tests malformations was 6.9% (mostly umbilical hernia) which was (2015) not higher than the incidence reported for the area. There was 4.5% SAB rate after AL exposure, which is not higher than background SAB rate. There were no effects on perinatal mortality or infant development until one year in a prospective cohort study.

Wilcox Artemisia Not Not 54 Treatment of malaria episodes Two miscarriages were reported, which was considered a ML, et. annua tea reported reported low rate and probably not higher than the incidence in the al.106 population. All infants were normal. (2011) Rulisa JS, ATM-LM Not Not 96 Inadvertent exposure for There was a slightly higher rate of SABs, perinatal et. al.107 reported reported treatment of uncomplicated mortality, stillbirth and premature delivery after (2012) falciparum malaria treatment (in all trimesters) that could not be distinguished from the effects of acute malaria itself. No adverse effects to fetuses or newborns. McGready ASd oral 930mgd <14 64 Treatment of a single episode 24 miscarriages (31%) in the group exposed to AS which R, et. al.108 weeks of malaria was not different from quinine or chloroquine treatment. (2012) No other adverse effect was related to treatment.

104 I. Adam, E.M. Elhassan, E.M. Omer, M.A. Abdulla, H.M. Mahgoub, G.K. Adam, Safety of artemisinins during early pregnancy, assessed in 62 Sudanese women, Ann. Trop. Med. Parasitol. 103 (2009) 205–210. 105 C. Manyando, R. Mkandawire, L. Puma, M. Sinkala, E. Mpabalwani, E. Njunju, et al., Safety of artemether-lumefantrine in pregnant women with malaria: results of a prospective cohort study in Zambia, Malar. J. 9 (2010) 249. C. Manyando, E.M. Njunju, M. Virtanen, K. Hamed, M. Gomes, J.P. Van Geertruyden, Exposure to artemether-lumefantrine (Coartem) in ﬁrst trimester pregnancy in an observational study in Zambia, Malar. J. 14 (2015) 77. 106 M.L. Willcox, S. Burton, R. Oyweka, R. Namyalo, S. Challand, K. Lindsey, Evaluation and pharmacovigilance of projects promoting cultivation and local use of Artemisia annua for malaria, Malar. J. 10 (2011) 84. 107 S. Rulisa, N. Kaligirwa, S. Agaba, C. Karema, P.F. Mens, P.J. de Vries, Pharmacovigilance of artemether-lumefantrine in pregnant women followed until delivery in Rwanda, Malar. J. 11 (2012) 225. 108 R. McGready, S.J. Lee, J. Wiladphaingern, E.A. Ashley, M.J. Rijken, M. Boel, et al., Adverse effects of falciparum and vivax malaria and the safety of antimalarial treatment in early pregnancy: a population-based study, Lancet Infect. Dis. 12 (2012) 388–396.

Reference ID: 4568389

Poespoprod AS 630 mg 18 Treatment of severe malaria There were 5 cases of miscarriage in women that received jo JR, et. DHA-PPQ IV-AS – DHA DHA-PPQ (62.5% of 8 patients) compared with 2.6% (1/38) al.109 AS-DHA-PPQ Oral ACT in ACT which received quinine. (2014) Mosha D, ATM-LM Oral Not 3-12 172 Treatment of malaria, it was There were a 12.3% rate of miscarriage/stillbirth, but the use of et. al.110 ATM-LM- reported not mentioned if there were ACT was not associated with an increased risk of any adverse (2014) QUI conﬁrmed cases or the severity pregnancy outcome. There were 0.6% rate of congenital anomalies which was not higher than global prevalence.

Dellicoure Any ACT Not Not 6-12 299e Inadvertent treatment of There was no increased risk of miscarriage in conﬁrmed S, et. al.111 reported reported malaria conﬁrmed or not exposures (133 women). No fetal outcome was evaluated. (2015)

Moore KA, AS-MQ Oral or Not 3-11 312f Treatment of Falciparum There was no increased risk of miscarriage, even when it et. al,112 ATM-LM parenteral reported malaria as a first choice or after was considered just the exposure on embryo-sensitive window. (2016) AS-CL quinine failure and ACT There was also no increased risk of any major congenital AS malformations in comparison to quinine. DHA-PPQ AS: artesunate; ATM: artemether; PSD: pyrimethamine-sulfadoxine; MQ: mefloquine; CL: chloroquine ATV: atovaquone; PG: proguanil; LM: lumefantrine; GW- gestational weeks; LMP: last menstrual period; DHA: dihydroartemisinin; PPQ: piperaquine; IV: intravenous. IM: intramuscular. a The mean total dose was reported by the authors or corresponds to the amount of all dosage/day received per women, if it was described in mg/kg it was considered as a person of 70 kg. b Artesunate or artemether were administrated alone or in combinations, different dose regimens were used and they were classified together as primary or re- treatment (43 and 57% of patients on first trimester, respectively). c It was considered the dosage recommended for an adult at the label of Coartem® (Novartis), since the authors mentioned that its recommendations was followed. d AS was administered as monotherapy to 21 women and the others were exposed to different ACTs, one with DHA and all other combinations were with AS. The authors mentioned that the women received a range from 12 to 16 mg/kg as total dose of artesunate according to the severity of malaria. e This number includes confirmed and unconfirmed exposed women. f 183 women received any artemisinin derivative alone (AS) or in different combinations to initially treat a falciparum malaria episode in the first trimester and 129 received an artemisinin derivative (mostly AS or AS-CL) in the first trimester after quinine failure. In this number can be included data from other previously published studies in the same area.

109 J.R. Poespoprodjo, W. Fobia, E. Kenangalem, D.A. Lampah, P. Sugiarto, E. Tjitra, et al., Dihydroartemisinin-piperaquine treatment of multidrug resistant falciparum and vivax malaria in pregnancy, PLoS One 9 (2014) e84976. 110 D. Mosha, F. Mazuguni, S. Mrema, E. Sevene, S. Abdulla, B. Genton, Safety of artemether-lumefantrine exposure in first trimester of pregnancy: an observational cohort, Malar. J. 13 (2014) 197. 111 S. Dellicour, M. Desai, G. Aol, M. Oneko, P. Ouma, G. Bigogo, et al., Risks of miscarriage and inadvertent exposure to artemisinin derivatives in the first trimester of pregnancy: a prospective cohort study in western Kenya, Malar. J. 14 (2015) 461. 112 K.A. Moore, J.A. Simpson, M.K. Paw, M. Pimanpanarak, J. Wiladphaingern, M.J. Rijken, et al., Safety of artemisinins in first trimester of prospectively followed pregnancies: an observational study, Lancet Infect. Dis. 16 (2016) 576–583.

Reference ID: 4568389 Signature Page 1 of 1 ------This is a representation of an electronic record that was signed electronically. Following this are manifestations of any and all electronic signatures for this electronic record. ------/s/ ------

WENJIE SUN 02/28/2020 03:48:27 PM

MIRIAM C DINATALE 02/28/2020 04:41:59 PM

LYNNE P YAO 03/02/2020 11:49:30 AM

Reference ID: 4568389 Interdisciplinary Review Team for QT Studies Consultation Review

Submission NDA 213036 Submission Number 001 Submission Date 8/12/201 9 Date Consult Received 10/22/201 9 DrngName Artesunate

Indication The initial treatment of severe i:J I lmalaria in adults and children 2.4 mg/kg intravenously (as slow bolus) at 4 0 12 24 I < f once daily Therapeutic dose (proposed) ' ' ' 4 I (bH l until oral antimalarial medication can be tolerated. Clinical Division DAIP Note: Any text in the review with a light background should be infe1Ted as copied from the sponsor 's document. This review responds to your consult dated 10/22/2019 regarding the sponsor 's QT evaluation. The QT-IRT reviewed the following materials: • Previous QT-IRT review dated 03/06/2019 in DARRTS (link); • Sponsor 's clinical study report # 11 28 (SNOOO 1; link); • Sponsor 's clinical study report # 1142 (SNOOOl ; link) • Sponsor 's proposed product label (SNOOOl , link); and • Highlights of clinical phannacology and cardiac safety (SNOOO 1; Pg-92, link).

1 SUMMARY No significant QTc prolongation effect of a1tesunate was detected in this QT assessment. The effect of a1tesunate was evaluated in Studies# 11 28 and # 1142. Study# 11 28 was a randomized, double-blind, placebo-controlled, single ascending dose study assessing the safety, tolerability, and phannacokinetics of ait esunate following intravenous infusion (dose levels - 0.5, 1, 2, 4, and 8.0 mg/kg; 10 mg/mL) in healthy subjects (n=40). Study# 1142 was a randomized, double-blind, placebo-controlled, multiple ascending dose (3- days) study assessing the safety, tolerability, and phaimacokinetics and phaimacodynamics of aitesunate following intravenous infusion (dose levels - 2, 4, and 8 mg/kg; 10 mg/mL) in healthy subjects (n=26/40). In both studies, the highest dose evaluated was 8 mg/kg (administered as intravenous infusion over 2 min), which is the maximum studied dose and covers the expected therapeutic exposures (C2min: 17650 ng/mL; end-of-infusion). Since the first ECG was collected at 5 min and the infusion duration was 2 min, the peak concentrations of ait esunate were predicted based on the lineai· phannacokinetics.

Reference ID 4562582 The sponsor claims that there are no relevant clinical scenarios with expected higher exposure (worst case scenario exposure) of artesunate or DHA than those observed at therapeutic dose (section 3.1). The data were analyzed using exposure-response analysis as the primary analysis, which did not suggest that artesunate is associated with significant QTc prolonging effect (refer to section 4.5) – see Table 1 for overall results. Table 1: The Point Estimates and the 90% CIs (FDA Analysis) ECG Treatment* Concentration ∆∆QTcF 90% CI parameter (ng/mL) (msec) (msec) QTc Artesunate 0.5 mg/kg 141.4 0.2 (-3.7 to 4.1) QTc Artesunate 1.0 mg/kg 2,908.8 0.3 (-3.5 to 4.2) QTc Artesunate 2.0 mg/kg 5,052.5 0.4 (-3.5 to 4.4) QTc Artesunate 4.0 mg/kg 9,920.0 0.7 (-3.6 to 5.0) QTc Artesunate 8.0 mg/kg 20,603.8 1.2 (-4.8 to 7.3) *Administered as intravenous infusion over 2 min. For further details on the FDA analysis please see section 4. The findings of this analysis are further supported by the available by time analysis (section 4.3) and categorical analysis (section 4.4). Although the submitted clinical studies did not included separate positive control (e.g., moxifloxacin) to demonstrate assay sensitivity, the primary analysis was performed using automated ECG measurements which eliminates the potential measurement bias.

1.1 RESPONSES TO QUESTIONS POSED BY SPONSOR Not applicable.

1.2 COMMENTS TO THE REVIEW DIVISION (b) (4), (b) (5) 

 The proposed label describes that the product should be administered as slow infusion. For this purpose, we used 2 min infusion duration as a conservative estimate. Since the first ECG was collected at 5 min and the infusion duration was only 2 min, the concentrations of artesunate were predicted based on the linear pharmacokinetics. Considering the dose proportionality, the peak concentrations of ~17650 ng/mL are expected at the end of the infusion (concentration at 2 min) at the therapeutic dose (2.4 mg/kg).

Reference ID: 4562582 2 RECOMMENDATIONS

2.1 ADDITIONAL S TUDIES Not applicable.

2.2 PROPOSED LABEL Below are proposed edits to the label (submitted to SDNOOl ) from the QT-IRT. Our changes are highlighted (addition, deletion). Please note, that this is a suggestion only and that we defer final labeling decisions to the Division. 12.2 Pharmacodynamics Cardiac Electrophysiology At the maximum approved recommended dose, artesunate does not prolong the QT 4 interval to any clinically relevant extent. [ Cb> < 1 I- We propose to use labeling language for this product consistent with the "Clinical Pharmacology Section of Labeling for Human Prescription Drug and Biological Products - Content and Format" guidance.

3 SPONSOR'S SUBMISSION

3.1 O VERVIEW

3.1.1 Clinical 4 Amivas LLC is developing aitesunate Cb>< > for the ti·eatment of severe l>~ malai·ia in adults and children. Ait esunate is an endoperoxide antimalai1a dmg and as a succinic acid ester of dihydroait emisinin (DHA), it is rapidly conve1t ed to its primaiy active metabolite, DHA. The mechanism of action involves iron-mediated cleavage of the endoperoxide bridge of DHA generating an unstable organic free radical (activation) which binds to malarial proteins ( alkylation) leading to destm ction of pai·asite membranes. It exhibits schizonticide action by increasing oxidative sti·ess during the intrae1ythrocytic stage of pai·asite replication, and it also exe1t gametocyte toxicity. 4 The product is fo1m ulated as a sterile powder ~ntaining 110 mg of aitesunate < > in a <1>m> vial) for <1>m> and injection. The proposed dose is 4 2.4 mgfls-g- t_o_ b_.- e administered as inti·avenous injection (slow bolus) at 0, 12, 24, (bf<4J until oral antimalarial medication can be tolerated). -=Th-~~~~~~~~e sponsor suggests th-~---~~at the peak-~- concenti·ations of 1020-3260 ng/mL and 2060-3140 ng/mL are expected with aitesunate and DHA . The sponsor has not conducted clinical studies to detennine the highest exposure scenai·io due to inti·insic and exti·insic factors. The sponsor claims that both aitesunate (half-life 2 to 15 min) and DHA (half-life 8 to 64 min) are eliminated rapidly. The sponsor claims that ait esunate has a low diug interaction potential as a victim di11g and the exposures ai·e not expected to change in subjects with renal or hepatic impai1ment. Thus, there are no relevant

Reference ID 4562582 clinical scenarios with expected higher exposure (worst case scenario exposure) of artesunate or DHA than those observed at therapeutic doses. Previously, the QT-IRT reviewed the sponsors proposal of QT evaluation using data from studies # 1128 and # 1142 (Dt: 03/06/2019). The sponsor proposed to use digitized ECGs (i.e., pdf files with waveforms scanned from paper ECGs) and the QT-IRT indicated that the digitized ECGs are not adequate for excluding drug-induced small QT effects (i.e., ΔQTc < 10 ms). Further, it was suggested that the automatic readings prior to digitization (e.g., from the ECG device in the clinical site) may be adequate if ECG sampling schedule is adequate and if sufficiently high multiples of the clinically relevant exposure (e.g., twice the supratherapeutic dose) are reached in the clinical study. In addition, the QT-IRT provided comments on the dose selection, data collection (including ECG quality), analysis and submission. Study # 1128 was a randomized, double-blind, placebo-controlled, inpatient, ascending single dose study to assess the safety, tolerability, and pharmacokinetics of artesunate following intravenous infusion (10 mg/mL solution in phosphate buffer over 2 minutes) in healthy subjects (n=40). Study included 5 dosing cohorts (0.5, 1, 2, 4, and 8.0 mg/kg; n=6 active + 2 placebo per dose level). Subjects in each cohort received a similar infusion of placebo (mannitol in phosphate buffer). ECG were collected at pre-dose, and ~5, 20, 40 min, and 1, 2, 4, 6, and 24 h after completion of infusion (Day -1 &1). Similarly, blood samples were collected at pre-dose, ~5, 20, 40 min, and 1, 2, 4, 6, and 24 h after completion of infusion (Day 1). Study # 1142 was a randomized, double-blind, placebo-controlled, multiple dose (3-days) escalation study to assess the safety, tolerability, and pharmacokinetics and pharmacodynamics of artesunate following intravenous infusion (10 mg/mL solution in phosphate buffer over 2 minutes) in healthy subjects (n=26/40). Study included 3 dosing cohorts (2, 4, and 8.0 mg/kg; n=6 active + 2 placebo per dose level). Subjects in each cohort received a similar infusion of placebo (mannitol in phosphate buffer). On days 1, 2, and 3, ECG (12-lead) samples were collected at pre-dose, and ~5, 20, 40 min, and 1, 2, 4, 8, and 24 h after completion of infusion (Day -1, 1, 2, & 3). Similarly, blood samples were collected at pre-dose, ~5, 20, 40 min, and 1, 2, 4, 8, and 24 h after completion of infusion. Subjects were discharged 24 hours after the third dose of drug or placebo and were followed as outpatients on Days 7, 10, and 15. At the highest dose (8 mg/kg) studied, the peak concentrations of 22400 ±11000 ng/mL (Study # 1142; Day 2) and 5970 ±2250 ng/mL (Study # 1142; Day 1) were observed for artesunate and DHA, respectively. The sponsor’s analysis indicates that the estimated concentrations at the end of the infusion (C0.033) is 14412 ng/mL at a dose of 2 mg/kg (64,336 ng/mL at the highest dose). Since the first ECG was collected at 5 min and the infusion duration was only 2 min, the concentrations of artesunate and DHA were predicted based on the from the log-linear regression of the 2 subsequent data points (5 min and 20 min) to back-extrapolate to 2 min.

Reference ID: 4562582 3.1.2 Nonclinical Safety Pharmacology Assessments Refer to the sponsor’s highlights of clinical pharmacology and clinical safety.

3.2 SPONSOR’S RESULTS

3.2.1 By Time Analysis FDA reviewer performed exploratory analysis using non-parametric method. The primary analysis for artesunate was based on exposure-response analysis, please see section 3.2.3 for additional details.

3.2.1.1 Assay Sensitivity Not applicable.

3.2.1.1.1 QT Bias Assessment No QT bias assessment was conducted by the sponsor.

3.2.2 Categorical Analysis There were no significant outliers per the sponsor’s and FDA’s analyses for QTcF > 500 msec. Per FDA’s analysis, in artesunate 8.0 mg/kg group, one subject experienced ΔQTcF greater than 60 msec. According to sponsor’s analysis, none of the subjects experienced ΔQTcF greater than 60 msec in both studies. Reviewer’s comment: FDA reviewer used dataset derived from single paper ECGs (with automated ECG measurements) to perform all analyses. Sponsor used digitized data for their analyses. FDA reviewer could not locate outlier analysis of HR, PR and QRS in the sponsor’s report.

3.2.3 Exposure-Response Analysis The sponsor used the repeated measure regression to explore the relationship between the serum concentrations of artesunate (/DHA) and QTc changes. For both studies, the sponsor concluded that no relationship is observed between QTc and serum concentrations of artesunate or its metabolite, DHA. Reviewer’s comment: Refer to section 4.5 for our exposure-response analysis.

3.2.4 Cardiac Safety Analysis There were no deaths, serious AEs, or AEs in the SOC “cardiac disorders” during the studies 1128 and 1142. Reviewer’s comment: None of the events identified to be of clinical importance per the ICH E14 guidelines (i.e., seizure, significant ventricular arrhythmias or sudden cardiac death) occurred in this study.

4 REVIEWERS’ ASSESSMENT Review assessment was performed base on automatic data for both studies.

Reference ID: 4562582 4.1 EVALUATION OF THE QT/RR CORRECTION METHOD The sponsor used QTcF for the primary analysis, which is acceptable as no large increases or decreases in heart rate (i.e. |mean| < 10 bpm) were observed (see Section 4.3.2).

4.2 ECG ASSESSMENTS

4.2.1 Overall Digitized ECG waveforms in PDF for both studies were submitted.

4.2.2 QT Bias Assessment Not applicable.

4.3 BY-TIME ANALYSIS The analysis population used for by time analysis included all subjects with a baseline and at least one post-dose ECG. The statistical reviewer evaluated the QTcF effect using nonparametric descriptive statistics. There were only 6 subjects in each dose level for both studies (study 1128 and study 1142).

4.3.1 QTc Figure 1 displays the time profile of ΔΔQTcF for different treatment groups. The maximum ΔΔQTcF values by treatment are shown in Table 2.

Figure 1: Median and 90% CI of ΔΔQTcF Timecourse (unadjusted CIs) for study 1128 and study 1142

Reference ID: 4562582 Table 2: The Point Estimates and the 90% Cls Corresponding to the Largest Upper Bounds for AAQTcF Study Analysis Nominal 90.0% CI Actual Treatment N Time (hours) M QTCF (msec) Identifier Period Day (msec)

Artesunate 0.5 mg/kg 11 28 1 6 0.330 12.0 (3.0 to 21.0)

Artesunate 1.0 mg/kg 11 28 1 6 0.670 3.0 (-12.0 to 18.0)

Artesunate 2.0 mg/kg 11 28 1 6 2.000 18.5 (5.0 to 32.0)

Artesunate 4.0 mg/kg 11 28 1 6 0.330 -2.5 (-220to 17.0)

Artesunate 8.0 mg/kg 11 28 1 6 0.670 6.5 (-9.0 to 22.0)

Artesunate 2.0 mg/kg 1142 3 6 24.000 7.0 (-130 to 27.0)

Artesunate 4.0 mg/kg 1142 3 6 24.000 7.5 (-16.0 to 31.0)

Artesunate 8.0 mg/kg 1142 1 6 0.330 14.0 (-16.0 to 44.0)

4.3.1.1 Assay sensitivity Not Applicable.

4.3.2 HR Figure 2 displays the time profile of Lib.HR for different treatment groups. Figure 2: Median and 90% CI of AAHR Timecourse for study 1128 and study 1142 1128 (Day 1) 1142 (Day 1) 25 20 0 ,...._ 15 ~ · ~ 10 ------

a::~ -;;;iii 05 t~:11c:·~~r------j I _2l .5 i ..._ ~ .._. -10 - -1 5 -20 '------' 1142 (Day 2) 1142 (Day 3) 25 20 0 ,...._ 15 c 0~ 10 0 '§ 5 +I VJ °'a:: ---iii 0 I QJ -5

-- Artesunate 0.5 mg/kg -- Artesunate 2.0 mg/kg -- Artesunate 8.0 mg/kg

-- Artesunate 1.0 mg/kg -- Artesunate 4.0 mg/kg

Reference ID 4562582 4.3.3 PR Figure 3 displays the time profile of ΔΔPR for different treatment groups. Figure 3: Median and 90% CI of ΔΔPR Timecourse for study 1128 and study 1142

4.3.4 QRS Figure 4 displays the time profile of ΔΔQRS for different treatment groups. Figure 4: Median and 90% CI of ΔΔQRS Timecourse for study 1128 and study 1142

Reference ID: 4562582 4.4 CATEGORICAL ANALYSIS Categorical analysis was perfo1med for different ECG measurements either using absolute values, change from baseline or a combination of both. The analysis was conducted using the safety population and includes both scheduled and unscheduled ECGs and data was pooled from both studies. If a catego1y is omitted that means that no subjects had values in that catego1y.

4.4.1 QTc None of the subjects experienced QTcF greater than 480 msec. Table 3 lists the categorical analysis results for D.QTcF (less than 30 msec, between 30 and 60 and greater than 60 msec). One subject in a1tesunate 8.0 mg/kg group experienced D.QTcF greater than 60 msec at 1 hour; however, this outlier appears to be an aitifact because the D.QTc values at times adjacent ai·e below 0 msec. The study did not collect replicate ECGs at each nominal timepoint. Table 3: Categorical Analysis for AQTcF (maximum) 30 msec < Value <= Total (N) Value <= 30 msec Value > 60 msec 60 msec Actual Treatment # Subj. #Obs. # Subj. #Obs. # Subj. #Obs. # Subj. #Obs.

6 42 0 0 0 0 Artesunate 0.5 mg/kg 6 42 (100.0%) (100.0%) (0%) (0%) (0%) (0%) 6 42 0 0 0 0 Artesunate 1.0 mg/kg 6 42 (100.0%) (100.0%) (0%) (0%) (0%) (0%) 9 182 3 4 0 0 Artesunate 2.0 mg/kg 12 186 (75.0%) (97.8%) (25.0%) (2.2%) (0%) (0%) 11 188 2 6 0 0 Artesunate 4.0 mg/kg 13 194 (84.6%) (96.9%) (15.4%) (3.1%) (0%) (0%) 7 175 4 10 1 1 Artesunate 8.0 mg/kg 12 186 (58.3%) (94.1%) (33.3%) (5.4%) (8.3%) (05%) 15 212 1 2 0 0 Placebo 16 214 (93.8%) (99.1%) (6.2%) (0.9%) (0%) (0%)

Reviewer's comment: As commented earlier, FDA reviewer's analysis was based on single paper ECGs (with automated ECG measurements) submitted by the sponsor, thus the data is quite variable in some cases. For the subject with iJQTcF>60 ms, the iJQTcF >60 ms occurred at 1 hour on day 1, iJQTcFs were -56 ms at 0.67 hour, -8 ms at 2 hour on day 1. On days 2 and 3, all iJQTcF values were negative.

4.4.2 HR None of the subjects experienced HR greater than 100 bpm in any of the dose levels of aitesunate in both studies.

4.4.3 PR Table 4 lists the categorical analysis results for PR (less than 200 msec; between 200 and 220 msec and above 220 msec with and without 25% increase over baseline).

Reference ID 4562582 T a ble 4 . C a t e2onca. I A natIys 1.s i or PR Total (N) Value <= 220 msec Value > 220 msec & <25% Actual Treatment # Subj. #Obs. # Subj . #Obs. # Subj. #Obs.

6 42 0 0 Artesunate 0.5 mg/kg 6 42 (100.0%) (100.0%) (0%) (0%) 5 35 1 7 Artesunate 1.0 mg/kg 6 42 (83.3%) (83.3%) (16.7%) (16.7%) 12 186 0 0 Artesunate 2.0 mg/kg 12 186 (100.0%) (100.0%) (0%) (0%) 13 194 0 0 Artesunate 4.0 mg/kg 13 194 (100.0%) (100.0%) (0%) (0%) 10 157 2 29 Artesunate 8.0 mg/kg 12 186 (83.3%) (84.4%) (16.7%) (15.6%) 16 214 0 0 Placebo 16 214 (100.0%) (100.0%) (0%) (0%)

4.4.4 QRS None of the subjects experienced QRS greater than 120 msec in any of the dose levels of aii esunate in both studies.

4.5 EXPOSURE-RESPONSE ANALYSIS The objective of the clinical phaimacology analysis is to assess the relationship between ~QTcF and concentration of artesunic acid. Exposure-response analysis was conducted using all subjects with baseline and at least one post-baseline ECG with time-matched PK. The automated measurements were utilized for this analysis (section 4.2.2). Prior to evaluating the relationship between concentration of artesunic acid and QTc using a linear model, the three key assumptions of the model were evaluated using explorato1y analysis: 1) absence of significant changes in heaii rate (more than a 10 bpm increase or decrease in mean HR); 2) delay between concentration of aii esunic acid and ~~ QTc and 3) presence of non-linear relationship. An explorato1y evaluation of the time-course of aitesunic acid concentration and changes in ~~QTcF is shown in Figure 5, which did not indicate a significant delay. There is an absence of significant changes in heart rate (Figure 2) and the maximum change in heait rate is below 10 bpm (section 4.3.2).

Reference ID 4562582 Figure 5: Time course of dru concentration to and QTc bottom

Analysis Nominal Actual Treatment Period Day Artesunate 0.5 I mg/kg - 1 -- Artesunate 1.0 20000 w 2 mg/kg -- Artesunate 2.0 (f) +I 3 mg/kg -0 ,..-.._ -- Artesunate 4.0 ·u .....J <( E mg/kg -- Artesunate 8.0 <..> O> .... ·c ---.,_c mg/kg en:::l Q) 10000 t: <( Study Identifier 0 1128

0 1142

-50

I·

0 5 10 15 20 25 Time (hours) After confinning the absence of significant heali rate changes or delayed QTc changes, the relationship between aiiesunic acid concentrntion and ~QTcF was evaluated to determine if a linear model would be appropriate. Figure 6 shows the relationship between aiiesunic acid concentration and ~QTc and suppo1is the use of a lineai· model.

Reference ID 4562582 Figure 6: Assessment of linearity of concentration-QTc relationship

• • 40 • • -..<.> • a> • • (/) • ,__,,E ~ • .... LL "'- - • • m- • - - 0 - ~ • c u - 6 f- ...... a • •

Finally, the linear model was applied to the data and the goodness-of-fit plot is shown in Figure 7. Predictions from the concentration-QTc model are provide in Table 1. Fi ure 7: Goodness-of-fit lot for QTc 15

'U' 10 ------Q) (/) .._,,E u 5 - cf. 0 C1l ~ 0 a~ ~ -5

-10

0 10000 20000 30000 40000 Artesunic Acid (ng/ml) The sponsor submitted digitize; however we used the automated measurements for our assessment. We perfo1med sensitivity analysis using QT measurement from the automatic ECG algorithm in the ECG warehouse and the sponsor's digitized ECGs. Considering the

Reference ID 4562582 difference in the slope the relationship between .6..6.QTcF and concentration of artesunic acid, we utilized automated measurement for our assessment (Figure 8). Of note, no difference was obse1ved in the BA-slope overall between digitized and automatic measurements (0.95 [-3 .09 to 4.99] ms per 100 ms). Figure 8: Goodness-of-fit plot for QTc (Digitized Vs. Automated Measurements).

,.-.., Q ii E"' '--' IF (3 0

0~ j en0 +1 l.J... a~ :a -1 0

qtps

- automatic -20 digitized

0 10000 20000 30000 40000 Artesunic Acid (ng/ ml)

Reference ID 4562582 Signature Page 1 of 1 ------This is a representation of an electronic record that was signed electronically. Following this are manifestations of any and all electronic signatures for this electronic record. ------/s/ ------

GIRISH K BENDE 02/18/2020 12:07:00 PM

FERDOUSE BEGUM 02/18/2020 12:09:23 PM

DALONG HUANG 02/18/2020 12:10:43 PM

MICHAEL Y LI 02/18/2020 12:16:57 PM

LARS JOHANNESEN 02/18/2020 12:20:01 PM

CHRISTINE E GARNETT 02/18/2020 12:22:34 PM

Reference ID: 4562582 LABEL AND LABELING REVIEW Division of Medication Error Prevention and Analysis (DMEPA) Office of Medication Error Prevention and Risk Management (OMEPRM) Office of Surveillance and Epidemiology (OSE) Center for Drug Evaluation and Research (CDER)

*** This document contains proprietary information that cannot be released to the public***

Date of This Review: February 7, 2020 Requesting Office or Division: Division of Anti-Infectives (DAI) Application Type and Number: NDA 213036 Product Name and Strength: Artesunate for Injection, 110 mg per vial Product Type: Single Ingredient Product Rx or OTC: Prescription (Rx) Applicant/Sponsor Name: Amivas, LLC FDA Received Date: August 12, 2019 and December 23, 2019 OSE RCM #: 2019-1722 DMEPA Safety Evaluator: Deborah Myers, RPh, MBA DMEPA Team Leader: Otto L. Townsend, PharmD

Reference ID: 4558602 1 REASON FOR REVIEW As part of the approval process for Artesunate for Injection, the Division of Anti-Infectives (DAI) requested that we review the proposed Artesunate prescribing information (PI), container labels, carton labeling, and product packaging samples, for areas of vulnerability that may lead to medication errors.

2 MATERIALS REVIEWED

Table 1. Materials Considered for this Label and Labeling Review Material Reviewed Appendix Section (for Methods and Results) Product Information/Prescribing Information A Previous DMEPA Reviews B – N/A ISMP Newsletters* C – N/A FDA Adverse Event Reporting System (FAERS)* D – N/A Other E – N/A Labels and Labeling F N/A=not applicable for this review *We do not typically search FAERS or ISMP Newsletters for our label and labeling reviews unless we are aware of medication errors through our routine postmarket safety surveillance

3 FINDINGS AND RECOMMENDATIONS Tables 2 and 3 below include the identified medication error issues with the submitted prescribing information (PI), container labels, carton labeling, and product packaging samples, our rationale for concern, and the proposed recommendation to minimize the risk for medication error.

Table 2. Identified Issues and Recommendations for Division of Anti-Infective Products (DAIP) IDENTIFIED ISSUE RATIONALE FOR CONCERN RECOMMENDATION Prescribing Information – General Issues

1. As currently presented The package type term, We defer to the Office of the package type term, “(b) (4) is not Pharmaceutical Quality (OPQ) “(b) (4) ” is included considered an appropriate to determine if it is

Reference ID: 4558602 Table 2. Identified Issues and Recommendations for Division of Anti-Infective Products (DAIP) IDENTIFIED ISSUE RATIONALE FOR CONCERN RECOMMENDATION in the Dosage Forms and package type term.a Also, appropriate to include the Strengths section of the omission of an appropriate package type term, “single- Highlights, but a package package type term can dose” to be used in the PI type term (i.e., “single- result in remaining contents labeling (i.e., Sections 3 and 16 dose”) is not included of the vial being “saved” for prior to the word “vial”). If elsewhere in the PI (e.g., future use resulting in OPQ determines that the Sections 3 and 16). deteriorated drug product package type term “single- medication errors. dose” is the correct package type term and recommends its use in the PI labeling, this recommendation to use the package type term, “single- dose” should also be made for the container label and carton labeling. Highlights of Prescribing Information

1. As currently presented, Medication errors could To provide clarity and the route of occur if the product were to minimize the risk for potential administration is stated be administered more misinterpretation, we as “intravenously (slow rapidly than intended via recommend inclusion of the bolus).” the intravenous bolus. intended rate of “intravenously (slow bolus)” (e.g., over 1 minute to 2 minutes). 2. As currently presented, (b) (4) We defer to OPQ (b) (4) under the header “Dosage Forms and and Strengths” (b) (4) then to provide the accurate This and appropriate(b) (4) inconsistency could lead to throughout the confusion.

a Guidance for Industry: Selection of the Appropriate Package Type Terms and Recommendations for Labeling Injectable Medical Products Packaged in Multiple-Dose, Single-Dose, and Single-Patient-Use Containers for Human Use. 2018. Available from https://www.fda.gov/media/117883/download.

Reference ID: 4558602 Table 2. Identified Issues and Recommendations for Division of Anti-Infective Products (DAIP) IDENTIFIED ISSUE RATIONALE FOR CONCERN RECOMMENDATION labeling (container label, carton labeling and PI). (b) (4) 3. As currently presented, The abbreviation is not Eliminate the abbreviation (b) (4) under the header defined. Abbreviations can by replacing with its “Warnings and be misinterpreted and intended meaning (b) (4) Precautions” (b) (4) result in confusion, as well as medication errors. For example, change the (b) (4) sentence to read “

…”

Full Prescribing Information – Section 2 Dosage and Administration

1. As currently presented, Medication errors could To provide clarity and the route of occur if the product were to minimize the risk for potential administration is stated be administered more misinterpretation, we as “intravenously (slow rapidly than intended via recommend inclusion of the bolus).” intravenous bolus. intended rate of “intravenously (slow bolus)” (e.g., over 1 minute to 2 minutes). Full Prescribing Information – Section 3 Dosage Forms and Strengths

1. As currently presented, If an appropriate package We defer to OPQ to determine the package type term, type term is not included, if it is appropriate to include (i.e., “single-dose”) is not the remaining contents of the package type term, included in the the vial could be “saved” “single-dose” to be used in the description of the drug for future use resulting in PI labeling. If OPQ determines product. use of deteriorated drug that the package type term product medication errors. “single-dose” is correct and recommends its use in the PI labeling, this recommendation to use the package type term, “single-dose” should be

Reference ID: 4558602 Table 2. Identified Issues and Recommendations for Division of Anti-Infective Products (DAIP) IDENTIFIED ISSUE RATIONALE FOR CONCERN RECOMMENDATION included prior to the word “vial.” For example, “in a clear glass single-dose vial (b) (4) …” 2. As currently presented, In Section 16, How To provide consistency of the the identifying Supplied/Storage and identifying characteristic characteristic is stated as Handling, the identifying throughout the PI labeling, we “…white powder…” characteristic is stated as recommend revising “…white “…white or almost white, powder…” to instead “…white fine crystalline powder or almost white, fine (b) (4) crystalline powder (b) (4)

…” This ” inconsistency could lead to confusion. 3. As currently presented, (b) (4) We defer to OPQ to determine (b) (4) (b) (4) and ” then to provide the accurate . This and appropriate consistency inconsistency could lead to throughout the labeling confusion. (container label, carton labeling and PI). Full Prescribing Information – Section 16 How Supplied/Storage and Handling

1. As currently presented, The units of measurement To provide clarity and the storage statement following the first numbers consistency with the storage reads, (b) (4) in the temperature ranges statement, add the Centigrade (b) (4) (e.g., Centigrade symbol (C) symbol (C) following and (b) (4) following the and Fahrenheit symbol (F) (b) (4) Fahrenheit symbol (F) following within the (b) (4) following the are storage statement. missing. The er (b) (4) For example, “ temperatures in the ranges

may be overlooked. .”

Reference ID: 4558602 Table 2. Identified Issues and Recommendations for Division of Anti-Infective Products (DAIP) IDENTIFIED ISSUE RATIONALE FOR CONCERN RECOMMENDATION 2. As currently presented, To facilitate identification of We have provided a the National Drug Code the dosage form, the NDC is recommendation to the (NDC) is not included. required per 21 CFR Applicant to revise their 201.57(c)(17)(iii). current NDC placeholders (i.e., XXXXX-XXX-XX) on their container labels and carton labeling. Additionally, in accordance with 21 CFR 201.57(c)(17)(iii), they will need to be add the NDC to the How Supplied section. 3. We note the inclusion of Statements such as (b) (4) We defer to OPQ for their the statement, “… (b) (4) (b) (4) are not accurate assessment and to determine .” because (b) (4) if the inclusion of the (b) (4) statement, (b) (4) (b) (4) is appropriate.

4. As currently presented, a If an appropriate package We defer to OPQ to determine package type term, (i.e., type term is not included, if it is appropriate to include “single-dose”) is not the remaining contents of the package type term, included. the vial could be “saved” for “single-dose” to be used in the future use resulting in use PI labeling. If OPQ determines of deteriorated drug that the package type term product medication errors. “single-dose” is correct and recommends its use in the PI

b Guidance for Industry and Food and Drug Administration Staff: Recommendations for Labeling Medical Products to Inform Users that the Product or Product Container is not made with Natural Rubber Latex. 2014. Available from: https://www.fda.gov/media/85473/download.

Reference ID: 4558602 Table 2. Identified Issues and Recommendations for Division of Anti-Infective Products (DAIP) IDENTIFIED ISSUE RATIONALE FOR CONCERN RECOMMENDATION labeling, this recommendation to use the package type term, “single-dose” should be included prior to both occurrences of the word “vial.” For example, “…ARTESUNATE single-dose vial contains…” and “…with another glass single-dose vial containing…” 5. We note inclusion of the The abbreviation “AS” is not To provide clarity and statement, “Each box defined. Abbreviations can minimize the potential for contains 4 vials of AS be misinterpreted and misinterpretation, we (b) (4) and 4 vials of result in confusion, as well recommend replacing the (b) (4) as medication errors. abbreviation “AS” with its intended meaning. 6. As currently presented, Per Relocate the directions for the proposed directions 21 CFR 201.57(c)(3)(J)(iv), dilution, preparation, for dilution, preparation, states that, Section 2, administration, and storage administration, and Dosage and Administration conditions of the storage conditions of the of the full prescribing reconstituted product to reconstituted product information “…must also Section 2, Dosage and are included in Section contain specific direction on Administration. Consider use 16, How dilution, preparation…and of subheadings, such as Supplied/Storage and administration of the “Preparation of ARTESUNATE Handling. dosage form, if needed Solution for Administration” (e.g.,…storage conditions and/or “Storage of for stability of the Reconstituted Solutions.” reconstituted drug, when

important…”

7. As currently presented, The lower times, “5” and To provide clarity and two time ranges are “1”, could be missed or minimize the risk for stated as “5 to 6 misinterpreted because misinterpretation, add the unit minutes” and “1-2 they are not followed by the of time, “minute(s)” after the minutes” are included in appropriate unit of time numeral “5” and “1.” We also the directions for (minute(s)). recommend replacing the dilution, preparation, 7

Reference ID: 4558602 Table 2. Identified Issues and Recommendations for Division of Anti-Infective Products (DAIP) IDENTIFIED ISSUE RATIONALE FOR CONCERN RECOMMENDATION administration hyphen (1-2 minutes) with its information. intended meaning “to.” For example, “5 minutes to 6 minutes” and “1 minute to 2 minutes.” Also, see recommendation #6 above. 8. As currently presented, The abbreviation “IV” is not Eliminate the abbreviation the statement, “ (b) (4) defined. Abbreviations can “IV” by replacing with its be misinterpreted and intended meaning result in confusion, as well “intravenous.” as medication errors. For example, change the includes the sentence to read “Inject the abbreviation, “IV” and is (b) (b) (4) (4)constituted not defined. intravenously (through an established intravenous line or needle)…” Also, see recommendation #6 above. Label and Labeling

1. As currently presented, The proposed dosage form We defer to OPQ to determine on the drug product is inconsistent with USP the appropriateness of the container label and General Chapter <7> dosage form (b) (4) carton labeling, the Labelingc and USP General dosage form is (b) (4) Chapter <1121> ” Nomenclature.d .”

c United States Pharmacopoeia (USP) General Chapter <7> Labeling. Available from http://app.uspnf.com/uspnf/pub/index?usp=40&nf=35&s=2&officialOn=December 1, 2017 d United States Pharmacopoeia (USP) General Chapter <1121> Nomenclature. Available from http://app.uspnf.com/uspnf/pub/index?usp=40&nf=35&s=2&officialOn=December 1, 2017

Reference ID: 4558602 Table 2. Identified Issues and Recommendations for Division of Anti-Infective Products (DAIP)

IDENTIFIED ISSUE RATIONALE FOR CONCERN RECOMMENDATION

2. As currently presented The package type term, We defer to OPQ to determine 1(

4 3. We note the incl usion of Statements such asl

Table 3. Identified Issues and Recommendations for Amivas, LLC (entire table to be conveyed to Applicant)

IDENTIFIED ISSUE RATIONALE FOR CONCERN RECOMMENDATION Container Label(s) and Carton Labeling

1. The format for expiration Clearly define the Identify the expiration date date is not defined. expiration date will format you intend to use. FDA minimize confusion and risk recommends that the human- for deteriorated drug readable expiration date on medication errors. the drug package label include

Reference ID 4558602 Table 3. Identified Issues and Recommendations for Amivas, LLC (entire table to be conveyed to Applicant) IDENTIFIED ISSUE RATIONALE FOR CONCERN RECOMMENDATION a year, month, and non-zero day. FDA recommends that the expiration date appear in YYYY-MM-DD format if only numerical characters are used or in YYYY-MMM-DD if alphabetical characters are used to represent the month. If there are space limitations on the drug package, the human-readable text may include only a year and month, to be expressed as: YYYY-MM if only numerical characters are used or YYYY-MMM if alphabetical characters are used to represent the month. FDA recommends that a hyphen or a space be used to separate the portions of the expiration date. 2. As currently presented, We are unable to review Add the intended NDC the National Drug Code the intended NDC for numbers on the container (NDC) is denoted by a appropriateness. labels and carton labeling and placeholder (NDC XXXXX- submit for our review. XXX-XX). 3. As currently presented, Medication errors could Add the route of the route of occur involving the wrong administration “intravenously administration, route of administration (slow bolus over 1 minute to 2 “intravenously (slow (i.e., intramuscularly), as minutes)” to the drug product bolus)” is not included well as the risk of container label and carton on the drug product incorrectly administering labeling. container label and the drug as an intravenous carton labeling. infusion. 4. As currently presented, The storage statement To minimize the risk of the the storage statement, could be overlooked and storage information being “ (b) (4) . improperly storing this overlooked, increase the product (b) (4) prominence of product

Reference ID: 4558602 Table 3. Identified Issues and Recommendations for Amivas, LLC (entire table to be conveyed to Applicant)

IDENTIFIED ISSUE RATIONALE FOR CONCERN RECOMMENDATION t----t-rl"------('bf(4J (D)\4J (bf(4J,------l 1 1requ irements by ""1a_c_k_s_p_ro__m-in_e_n_c_e-.--- bolding t he statement

drug medication errors. I II

Container Label{s)

1. As currently presented, Medication errors involving To provide additional t he container labels (i.e., diluents being incorrectly differentiation between the diluent and drug ad ministered to patients, via ls (i.e., diluent and drug product ) appear similar without t he active drug product) ensure t hat the word and lack differentiation. product , have been "Diluent" is the most reported. prominent word on the diluent label. We f urther recommend capitalization of the letters (i.e., DILUENT), increasi ng the font size, bolding t he font, changing t he color of t he font for the word "DILU ENT", and surrounding t his information with a box, and/ or highlighting t he information to draw attention to this important information (see example below). (6)(4)

2. As currently presented, The net contents statement Relocate t he net contents (b)(4J (b)(4l on t he princi pa l display (i.e., ml /vial) appearing statement (i.e. ml /vial) panel (PDP) of t he directly below your current away from the drug name, "Diluent" container label proposed statement "for such t hat it does not compete t he net contents use only with Artesunate" in size or prominence with • (6)(4f statement (1.e., i cl utters the PDP and takes

Reference ID 4558602 Table 3. Identified Issues and Recommendations for Amivas, LLC (entire table to be conveyed to Applicant) IDENTIFIED ISSUE RATIONALE FOR CONCERN RECOMMENDATION mL/vial) appears directly readers’ attention away important information on the below your current from important information PDP. proposed statement “for such as DILUENT for For example, consider use only with Artesunate. relocating the net contents Artesunate.” statement the bottom left of the PDP, to the left of “AMIVAS.” 3. As currently presented, Because this (i.e., “enclose To provide further clarification the drug product diluent”) statement lacks regarding appropriate container label prominence (i.e., same font (b) (4) diluent, statement, “Must be and bolding pattern as the increase the prominence of (b) (4)constituted with contents statement), the the diluent requirement enclosed diluent prior to requirement to use statement. For example, administration.” lacks enclosed diluent may be consider bolding the font of or prominence. missed. highlighting the words “enclosed diluent.”

4. As currently presented, Omission of instruction or a To provide clarity we the drug product space to indicate the time recommend revising the BUD container label includes that the drug product was statement, such as, “Date and (b) the beyond use date reconstituted could result time of (4) constitution (BUD) statement (b) (4) in the dispensing or __/__/__ __:__. Discard (b) administration of unused portion within(4) hour (b) on the principal display deteriorated product. of (4) constitution.” In a dition, panel (PDP), but does we recommend changing the not include instruction or color of the font, surrounding a space to indicate when this information with a box, the product was and/or highlighting the reconstituted. information to draw attention to this important information (see example below): (b) (4)

6. As currently presented, The established name We recommend you decrease the manufacturer name should be the most the prominence, font size (i.e., AMIVAS) and prominent information on (height) and/or bolding of the graphic design are the the container label. letters within your most prominent Additionally, the product manufacturer name or information on the white strength statement is consider moving the section of the PDP of the considered to be “critical manufacturer name an drug product container information.”f To avoid corresponding graphic to the label. Specifically, the medication errors involving side panel. font size (height) and strength confusion during bolding of the letters product selection, the included in the product strength statement manufacturer name are should be prominently taller and more displayed on the PDP. prominent than the established name “Artesunate.”

(b) (4)

f Guidance for Industry: Safety Considerations for Container Labels and Carton Labeling Design to Minimize Medication Errors (lines 134-151). Food and Drug Administration. 2013. Available from http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM349009.pdf

1. As currently presented, The trailing zero could To avoid misinterpretation and the statement result in a misinterpretation for consistency with the PI, we (b) (4) (e.g., 10 mL) resulting in recommend the removal of with 11.0 mL of…” wrong strength, the trailing zero in the contains a trailing zero. concentration, and/or statement “… (b) (4) wrong dose medication with 11.0 mL of…” errors. (b) (4) For example, with 11 mL of…” 2. As currently presented, Inconsistent labeling may To provide consistency with the statement “(b) (4) contribute to confusion that the drug product container can result in medication label, as well as to provide error. clarity regarding appropriate (b) (4) constitution, revise the statement to read, is “ (b) (4) inconsistent with the the enclosed drug product container diluent only.” label terminology “enclosed diluent.” 3. As currently presented, The product strength We recommend you increase the strength statement statement is considered to the prominence, by increasing (i.e., 110 mg/vial) lacks be “critical information.” the font size (height), bolding, prominence. To avoid medication errors and/or adding color to the involving strength strength statement. confusion, the product strength statement should be prominently displayed on the PDP. 4. As currently presented, The drug package label We recommend you include the intended location of must include the product the intended location of the

Reference ID: 4558602 Table 3. Identified Issues and Recommendations for Amivas, LLC (entire table to be conveyed to Applicant) IDENTIFIED ISSUE RATIONALE FOR CONCERN RECOMMENDATION the human-readable and identifier information (i.e., machine-readable, 2D data machine-readable (2D the NDC, serial number, lot matrix barcode product data matrix barcode) number, and expiration identifier, near the human- product identifier on the date) in both the human- readable portion of the smallest saleable unit readable form and product identifier information (usually the carton) is machine-readable, 2D data (i.e., not provided. matrix barcode format. NDC: [insert product’s NDC] SERIAL: [insert product’s serial number] LOT: [insert product’s lot number] EXP: [insert product’s expiration date]). See draft guidance https://www.fda.gov/ucm/gro ups/fdagov-public/@fdagov- drugs- gen/documents/document/uc m621044.pdf (Lines 255 - 283).

4 CONCLUSION Our evaluation of the proposed Artesunate prescribing information (PI), container labels, carton labeling, and product packaging samples, identified areas of vulnerability that may lead to medication errors. Above, we have provided recommendations in Table 2 for the Division and Table 3 for the Applicant. We ask that the Division convey Table 3 in its entirety to Amivas, LLC so that recommendations are implemented prior to approval of this NDA.

Reference ID: 4558602 APPENDICES: METHODS & RESULTS FOR EACH MATERIAL REVIEWED APPENDIX A. PRODUCT INFORMATION/PRESCRIBING INFORMATION Table 4 presents relevant product information for Artesunate that Amivas, LLC submitted on December 23, 2019.

Table 4. Relevant Product Information for Artesunate Initial Approval Date N/A Active Ingredient artesunate (b) (4) Indication for the initial treatment of severe malaria in adults and children Route of Administration intravenously (slow bolus) Dosage Form sterile powder for injection Strength 110 mg/vial (b) (4) Dose and Frequency Administer 2.4 mg/kg intravenously (slow bolus) at 0, 12, 24, once daily (b) (4) until antimalarial medication can be tolerated. (b) (4)

Artesunate for injection is supplied as a sterile powder for How Supplied (b) (4) constitution and injection. Each artesunate vial contains 110 g of artesunate (in the form of a white or almost white, fine crystalline powder (b) (4) capped with a (b) (4) rubber stopper and aluminum crimp. Artesunate is supplied with another glass vial containing 12 mL of sterile 0.3 M sodium phosphate, pH 8.0±0.1 buffer for (b) (4) Each box contains 4 vials of artesunate for injection powder and 4 vials of phosphate buffer. Storage Store vials of artesunate for injection and phosphate buffer in the carton between (b) (4) before use. Do not freeze. Avoid exposure to heat. Do not use beyond the expiration date. (b) (4) Container Closure clear glass vial capped with a rubber stopper and aluminum crimp seal

Reference ID: 4558602 APPENDIX F. LABELS AND LABELING F.1 List of Labels and Labeling Reviewed Using the principles of human factors and Failure Mode and Effects Analysis,g along with postmarket medication error data, we reviewed the following Artesunate labels and labeling submitted by Amivas, LLC.  Container label(s) received on August 12, 2019  Carton labeling received on August 12, 2019  Prescribing Information received on December 23, 2019 is available at the following link: \\cdsesub1\evsprod\nda213036\0018\m1\us\draft-labeling-text.docx

F.2 Label and Labeling Images Container label(s) (b) (4)

2 Page(s) of Draft Labeling have been Withheld in Full as B4 (CCI/TS) immediately following this page

g Institute for Healthcare Improvement (IHI). Failure Modes and Effects Analysis. Boston. IHI:2004.

Reference ID: 4558602 Signature Page 1 of 1 ------This is a representation of an electronic record that was signed electronically. Following this are manifestations of any and all electronic signatures for this electronic record. ------/s/ ------

DEBORAH E MYERS 02/07/2020 04:05:43 PM

OTTO L TOWNSEND 02/07/2020 04:49:34 PM

Reference ID: 4558602 CLINICAL REVIEW – Request for Priority Review

NDA: 213036

Stamp Date: September 26, 2019

Date of Review: November 13, 2019

Product: IV Artesunate

Indication: Initial treatment of severe (b) (4) malaria in adults and children

Applicant: Amivas, LLC

Reviewed by: Leslie K. Ball, M.D., Clinical Reviewer Yuliya Yasinskaya, M.D. Clinical Team Leader

Overview

Amivas, LLC, has requested Priority Review for NDA 213036 (IV artesunate) with a proposed indication of treatment of severe (b) (4) malaria in adults and children.

In the US, intravenous (IV) artesunate is intended for the treatment of severe malaria in returning travelers, usually from South East Asia or Sub-Saharan Africa. With the discontinuation of IV quinidine from the US market on April 1, 2019, there are currently no US-approved drugs for treatment of severe malaria, and CDC currently recommends IV artesunate as the first-line treatment of severe malaria in adults, children and pregnant women. IV artesunate is currently available from the CDC under IND 76,725 and the drug (known as the WRAIR formulation) is supplied by the US Army.1,2,3 The dose is four weight-based doses of IV artesunate (2.4 mg/kg) at 0, 12, 24, and 48 h before transitioning to oral antimalarials. IV artesunate (WRAIR formulation) is available to US military personnel under IND 64,769. In 2010 World Health Organization recommended Intravenous artesunate as the first-line therapy for

1 Twomey PS, Smith BL, McDermott C, et al. Intravenous Artesunate for the Treatment of Severe and Complicated Malaria in the United States: Clinical Use Under an Investigational New Drug Protocol. Annals of internal medicine. 2015;163(7):498-506. 2 CDC. CDC and Malaria. Updated June 26, 2018: Available at: https://www.cdc.gov/malaria/diagnosis_treatment/artesunate.html 3 Due to a shortage of the WRAIR formulation, the IV artesunate product available under CDC IND 76,725 is also being supplied by Guilin Pharmaceuticals.

Reference ID: 4525306 NDA 213036 IV Artesunate Clinical Review of Priority Review Request

severe malaria in adults and children.4 In 2016 there were 2078 cases of confirmed malaria reported in the U.S., with a total of 1,853 cases associated with an identified species. P. falciparum was found in 1,419 (76.6%) of those with an identified species, and 918 (72.8%) of 1831 patients with hospitalization data.5 The CDC estimates that approximately 300 US cases of severe malaria per year require parenteral therapy. From 1999-2004, 41 deaths from severe malaria were reported in the US.6 Delays in treatment are associated with increased mortality.

Regulatory History

IV Artesunate under IND 64769 received orphan drug designation on March 28, 2006 for “immediate treatment of malaria”, Fast Track designation on October 17, 2006 “for immediate treatment of severe and/or complicated malaria when oral agents can’t be used or speed is required”, and Breakthrough Therapy Designation on September 11, 2018 for “treatment of severe malaria”. This application is eligible for consideration for a Tropical Disease Priority Review Voucher.

Clinical Review

The qualifying criteria for Priority Review designation are outlined in the FDA Guidance document on Expedited Programs for Serious Conditions, Drugs and Biologics.7 The qualifying criteria are as follows:

1. Serious Conditions

Severe malaria is a life-threatening infection and is a medical emergency. CDC estimates a case fatality rate for severe malaria in the US of 1%.8 Most cases are due to P. falciparum. The disease is characterized by hyperparasitemia (≥ 5% parasitized red cells), destruction of parasitized red cells, and sequestration of red cells in small blood vessels causing end-organ dysfunction. Manifestations of severe malaria include high fever, hemolytic anemia, hypoglycemia, metabolic acidosis, renal failure, hepatic injury/jaundice, pulmonary edema, Acute Respiratory Distress Syndrome, cerebral malaria/convulsions, disseminated intravascular coagulation, circulatory shock, and death.

2. Demonstrating the potential to be a significant improvement in safety or effectiveness

In deciding on whether to grant Priority Review, FDA determines at the time of NDA, BLA, or efficacy supplement filing whether the proposed drug would be a significant improvement in the safety or

4 WHO. World Malaria Report 2015. Available from: http://www.who.int/malaria/publications/world-malaria- report-2015/report/en/ 5 Mace, K. E., P. M. Arguin, N. W. Lucchi, and K. R. Tan. 2019. 'Malaria Surveillance - United States, 2016', MMWR Surveill Summ, 68: 1-35. 6 Unpublished data from CDC Artesunate Protocol available at: https://www.cdc.gov/malaria/resources/pdf/DOD 5032 Artesunate IND Protocol 101619.pdf 7 See: https://www.fda.gov/files/drugs/published/Expedited-Programs-for-Serious-Conditions-Drugs-and- Biologics.pdf 8 Newman, R. D., M. E. Parise, A. M. Barber, and R. W. Steketee. 2004. 'Malaria-related deaths among U.S. travelers, 1963-2001', Ann Intern Med, 141: 547-55. 2

Reference ID: 4525306 NDA 213036 IV Artesunate Clinical Review of Priority Review Request

effectiveness of the treatment, prevention, or diagnosis of a serious condition. Significant improvement may be illustrated by the following:

a. Evidence of increased effectiveness in treatment, prevention, or diagnosis of a condition

In the NDA, the Applicant has submitted data supporting improved efficacy (reduction in mortality) of IV artesunate compared with IV quinine. In SEAQUAMAT, a large multicenter trial in 1461 adults and children with severe malaria, mortality in artesunate recipients was 15% (107 of 730) compared with 22% (164 of 731) in quinine recipients; a relative reduction of 34.7% (95% CI 18.5-47.6%; p=0.0002). Patients with hyperparasitemia >10% had significantly greater treatment effect (ratio of OR 0.34, 0.17-0.69, p=0.001). In AQUAMAT, a large multicenter trial in 5425 children age 6 months to 15 years, mortality was 230 of 2712 (8.5%) in artesunate group compared with 297 of 2713 (10.9%) in the quinine group; OR 0.75 (95% CI 0.63-0.90); relative reduction 22.5%, 95% CI 8.1-36.9, p=0.0022.

b. Elimination or substantial reduction of a treatment-limiting adverse reaction

In addition to the mortality benefit, the Applicant has submitted data in the NDA supporting the safety of IV artesunate compared with IV quinine. In SEAQUAMAT, the incidence of hypoglycemia was greater in recipients of quinine compared with artesunate. Hypoglycemia is also a manifestation of severe malaria, and its resolution following treatment results from a reduction in parasitemia and restoration of normal glucose metabolism associated with clinical improvement. Therefore, the lower incidence of hypoglycemia observed in artesunate recipients may be a consequence of faster parasite clearance and superior efficacy compared with quinine. In AQUAMAT, the incidence of neurological sequelae in the two treatment groups did not differ significantly but development of coma, convulsions, and deterioration of coma score all were significantly less frequent in artesunate than quinine recipients.

c. Documented enhancement of patient compliance that is expected to lead to an improvement in serious outcomes

The Applicant has not provided data to support an improvement in patient compliance in patients administered IV artesunate.

d. Evidence of safety and effectiveness in a new subpopulation

The Applicant has submitted substantial evidence of safety and effectiveness for the treatment of severe malaria caused by Plasmodium falciparum in both children (as young as 6 months of age) and adults. The NDA does not contain data to support safety or effectiveness data in other subpopulations of patients.

Reference ID: 4525306 NDA 213036 IV Artesunate Clinical Review of Priority Review Request

Summary and Recommendation

The available evidence from the clinical trials of IV artesunate and other published literature supports efficacy advantage of IV artesunate over quinine for severe malaria due to Plasmodium falciparum. There are currently no US-approved treatments for severe malaria and US patients currently must receive IV artesunate under an expanded access IND.

This clinical reviewer recommends a priority review for NDA 213036 IV Artesunate for treatment of severe malaria based on the data submitted in the NDA supporting a reduction in mortality compared with IV quinine, an acceptable safety profile, and the absence of alternative treatments for severe malaria in the US.

Reference ID: 4525306 Signature Page 1 of 1 ------This is a representation of an electronic record that was signed electronically. Following this are manifestations of any and all electronic signatures for this electronic record. ------/s/ ------

LESLIE K BALL 11/25/2019 04:59:48 PM

YULIYA I YASINSKAYA 12/05/2019 10:27:41 AM

SUMATHI NAMBIAR 12/06/2019 11:55:19 AM

Reference ID: 4525306