Summary Basis of Decision for Amivas-Artesunate

Review decision

The Summary Basis of Decision explains why the product was approved for sale in Canada. The document includes regulatory, safety, effectiveness and quality (in terms of chemistry and manufacturing) considerations.


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Summary Basis of Decision (SBD)

Summary Basis of Decision (SBD) documents provide information related to the original authorization of a product. The SBD for Amivas-Artesunate is located below.

Recent Activity for Amivas-Artesunate

The SBDs written for eligible drugs (as outlined in Frequently Asked Questions: Summary Basis of Decision [SBD] Project: Phase II) approved after September 1, 2012 will be updated to include post-authorization information. This information will be compiled in a Post-Authorization Activity Table (PAAT). The PAAT will include brief summaries of activities such as submissions for new uses of the product, and whether Health Canada's decisions were negative or positive. The PAATs will be updated regularly with post-authorization activity throughout the product life cycle. At this time, no PAAT is available for Amivas-Artesunate. When the PAAT for Amivas-Artesunate becomes available, it will be incorporated into this SBD.

Summary Basis of Decision (SBD) for Amivas-Artesunate

Date SBD issued: 2025-10-10

The following information relates to the New Drug Submission for Amivas-Artesunate.

Artesunate

Drug Identification Number (DIN): 02559056

Amivas Ireland Ltd.

New Drug Submission Control Number: 285622

Submission Type: New Drug Submission (New Active Substance) - Priority Review

Therapeutic Area (Anatomical Therapeutic Chemical [ATC] Classification, second level): P01 Antiprotozoals

Date Filed: 2024-04-03

Authorization Date: 2025-07-04

On July 4, 2025, Health Canada issued a Notice of Compliance to Amivas Ireland Ltd. for the drug product Amivas-Artesunate.

The market authorization of Amivas-Artesunate was based on quality (chemistry and manufacturing), non‑clinical (pharmacology and toxicology), and clinical (pharmacology, safety, and efficacy) information submitted. Based on Health Canada’s review, the benefit-harm-uncertainty profile of Amivas-Artesunate is favourable for the initial treatment of severe malaria in adult and pediatric patients.

1 What was approved?

Amivas-Artesunate, an antimalarial agent, was authorized for the initial treatment of severe malaria in adults and pediatric patients.

Initial treatment of severe malaria with Amivas-Artesunate should always be followed by a complete treatment course with appropriate oral antimalarial therapy. Additionally, Amivas-Artesunate should only be administered after consultation with a physician experienced in managing malaria.

Artesunate does not treat the hypnozoite liver stage forms of Plasmodium and will therefore not prevent relapses of malaria due to Plasmodium vivax or Plasmodium ovale. Concomitant therapy with an antimalarial agent such as an 8-aminoquinoline drug is necessary for the treatment of severe malaria due to Plasmodium vivax or Plasmodium ovale.

Based on the data submitted to Health Canada, the safety and efficacy of Amivas-Artesunate in pediatric patients older than six months of age has been established. As a result, Health Canada has authorized Amivas-Artesunate for use in this age group. However, no clinical data are available for pediatric patients under six months of age. Pharmacokinetic modelling and simulations suggest that, following a 2.4 mg/kg intravenous dose of Amivas-Artesunate, plasma levels of dihydroartemisinin are likely to be higher in infants under six months of age compared to older infants and children.

Available data for the use of Amivas-Artesunate in patients older than 65 years of age is limited.

Amivas-Artesunate (110 mg artesunate) is supplied as a powder for solution, with each vial containing 110 mg of artesunate. In addition to the medicinal ingredient artesunate, the powder also contains the following non-medicinal ingredients: concentrated phosphoric acid, disodium phosphate dihydrate, monosodium phosphate monohydrate, sodium hydroxide, and water for injection. Before administration, Amivas-Artesunate must be reconstituted using the provided sodium phosphate diluent. The resulting solution is then administered as a slow bolus over one to two minutes. Because artesunate is unstable in aqueous solutions, the reconstituted solution must be used within 1.5 hours of preparation.

The use of Amivas-Artesunate is contraindicated in patients who are hypersensitive to this drug, or to any other artemisinin antimalarial agent, or to any ingredient in the formulation or component of the container.

The drug product was approved for use under the conditions stated in its Product Monograph taking into consideration the potential risks associated with its administration. The Product Monograph for Amivas-Artesunate is available through the Drug Product Database.

For more information about the rationale for Health Canada's decision, refer to the Clinical, Non-clinical, and Quality (Chemistry and Manufacturing) Basis for Decision sections.

2 Why was Amivas-Artesunate approved?

Health Canada considers that the benefit-harm-uncertainty profile of Amivas-Artesunate is favourable for the initial treatment of severe malaria in adults and pediatric patients.

Initial treatment of severe malaria with Amivas-Artesunate should always be followed by a complete treatment course of appropriate oral antimalarial therapy. Furthermore, Amivas-Artesunate should only be administered after consultation with a physician experienced in managing malaria.

Amivas-Artesunate does not treat the hypnozoite liver stage forms of Plasmodium and will therefore not prevent relapses of malaria due to Plasmodium vivax or Plasmodium ovale. Concomitant therapy with an antimalarial agent such as an 8-aminoquinoline drug is necessary for the treatment of severe malaria due to Plasmodium vivax or Plasmodium ovale.

Malaria is a life-threatening disease caused by Plasmodium parasites, which are transmitted to humans through the bites of infected female anopheles mosquitoes. There are five species of Plasmodium that can infect humans: Plasmodium falciparum, Plasmodium vivax, Plasmodium ovale, Plasmodium malariae, and Plasmodium knowlesi. Once a person is infected, symptoms typically appear within 10 to 15 days, although this can vary depending on the species and the individual’s immunity response. Symptoms may include: headache, fever, chills, fatigue, nausea and vomiting, and in severe cases, seizures, confusion, difficulty breathing, and organ failure. Plasmodium falciparum malaria may be fatal if treatment is delayed beyond 24 hours after the onset of clinical symptoms. Mortality from untreated severe malaria (particularly cerebral malaria) approaches 100%. Most cases of severe malaria are caused by Plasmodium falciparum. However, it is also possible for Plasmodium vivax and Plasmodium knowlesi to lead to severe malaria in rare cases. In Canada, there are on average about 100 reported cases of severe malaria annually, typically in people who recently travelled from areas with endemic malaria.

Amivas-Artesunate is an antimalarial agent authorized for the initial treatment of severe malaria in adults and pediatric patients. Artesunate, the medicinal ingredient in Amivas-Artesunate, is rapidly metabolized into an active metabolite, dihydroartesunate (DHA). Artesunate and DHA, like other artemisinins, contain an endoperoxide bridge which is activated by heme iron. Interaction with heme iron results in cleavage of the endoperoxide bridge, which generates free radicals. These free radicals cause oxidative stress, disrupting protein and nucleic acid synthesis, and ultimately impairing parasite growth and survival.

Both artesunate and DHA are effective against the asexual forms of the Plasmodium species and typically clear parasites within 48 to 72 hours. In vitro studies show that 50% inhibitory concentrations are broadly similar across Plasmodium falciparum and other human malaria-causing species, including Plasmodium vivax, Plasmodium ovale, Plasmodium malariae, and Plasmodium knowlesi.

Amivas-Artesunate has been shown to be efficacious in the initial treatment of severe malaria in adults and children. The market authorization was based on two pivotal, multicentre, open label Phase III studies, the Southeast Asian Quinine and Artesunate Malaria Trial (SEAQUAMAT) and the African Quinine and Artesunate Malaria Trial (AQUAMAT). Both studies evaluated the efficacy of intravenous artesunate compared to intravenous quinine, which was the standard of care at the time the SEAQUAMAT and AQUAMAT studies were conducted. However, each study focused on a different age group. The SEAQUAMAT study primarily enrolled adults, with a mean age of 28 years, whereas the AQUAMAT study focused on children under 15 years of age, with mean age of 3 years.

In both pivotal studies, the clinical study designs were similar. Patients were randomized in a 1:1 ratio to receive either Amivas-Artesunate or quinine. Amivas-Artesunate was administered intravenously at a dose of 2.4 mg/kg upon hospital admission (0 hours), followed by additional doses at 12 hours, 24 hours, and then once daily until the patient could reliably take oral medication. Quinine was given intravenously at an initial dose of 20 mg/kg over 4 hours, followed by 10 mg/kg three times daily over 2 to 8 hours.

The primary endpoint in both studies was all-cause in-hospital mortality in the intent-to-treat population up to the point of discharge for a maximum of one week.

The SEAQUAMAT study was stopped early due to evidence of benefit, with approximately two-thirds of planned patient enrollment completed at the time of termination. In this study, treatment with intravenous Amivas-Artesunate reduced mortality in patients with severe malaria by over a third when compared to intravenous quinine treatment. The adult mortality rate in the Amivas-Artesunate treatment group was 14.7% (107 of 730 patients), compared to 22.4% (164 of 731 patients) in the quinine group; thereby representing a site-adjusted reduction in the odds of mortality of 40% (p = 0.0002). The benefits of Amivas-Artesunate were most apparent after the first 48 hours of treatment initiation.

In AQUAMAT, intravenous Amivas-Artesunate treatment reduced the overall mortality of children diagnosed with severe malaria. The pediatric mortality rate in the Amivas-Artesunate treatment group was 8.5% (230 of 2,712 patients), compared to 10.9% (297 of 2,713 patients) in the quinine group.

In the SEAQUAMAT study, the most commonly reported treatment-emergent adverse events (TEAEs) in the Amivas-Artesunate treatment group, compared to the quinine group, were dialysis (8.2% vs. 6.6%) and blackwater fever (6.7% vs. 4.5%). In the AQUAMAT study, the most commonly reported TEAEs were acute anemia (5.7% vs. 4.6%), coma (5.1% vs. 3.5%), convulsions (10.1% vs. 8.3%) and hypoglycemia (2.8% vs. 1.8%).

In both studies, the incidence of neurological sequelae did not differ significantly between groups at timepoints later in the respective studies. In SEAQUAMAT, the overall incidence of any persistent neurological sequelae at discharge was 1% (24 of 706 patients) in the Amivas-Artesunate treatment group and 0.3% (23 of 737 patients) in the quinine group at discharge from the study. At Day 28 of the AQUAMAT study, the overall incidence of any persistent neurological sequelae in assessed cerebral malaria survivors was 2.4 % in the Amivas-Artesunate treatment group and 2.3% in the quinine group.

Post‑marketing adverse reactions were also identified based on a retrospective data abstract study, Study R-CDC-060, conducted in the United States among patients treated with Amivas-Artesunate for severe malaria following international travel. Post‑marketing events associated with intravenous Amivas-Artesunate included post-artesunate delayed hemolysis (PADH), pancreatitis, and immune hemolytic anemia. Post-artesunate delayed hemolysis was defined as a decrease of at least 10% in hemoglobin levels from baseline, occurring up to one month after treatment. In some cases, the resulting hemolytic anemia was severe enough to require blood transfusions. The Warnings and Precautions section of the Amivas-Artesunate Product Monograph suggests to monitor for PADH following treatment. Additionally, hypersensitivity reactions, including anaphylaxis, have also been captured in the Warnings and Precautions section of the Amivas-Artesunate Product Monograph.

Artemisinins have been shown to directly inhibit human erythroid precursor cells in vitro and suppress bone marrow activity, particularly red blood cell production, in animal studies. Both non-clinical data and clinical data suggest that intravenous treatment with Amivas-Artesunate is frequently associated with reversible reticulocytopenia. Reticulocyte counts typically return to normal after treatment is discontinued.

A Risk Management Plan (RMP) for Amivas-Artesunate was submitted by Amivas Ireland Ltd. to Health Canada. The RMP is designed to describe known and potential safety issues, to present the monitoring scheme, and when needed, to describe measures that will be put in place to minimize risks associated with the product. Upon review, the RMP was considered to be acceptable.

The submitted inner and outer labels, package insert and Patient Medication Information section of the Product Monograph for Amivas-Artesunate met the necessary regulatory labelling, plain language, and design element requirements.

The sponsor submitted a brand name assessment that included testing for look‑alike sound‑alike attributes. Upon review, the proposed name Amivas-Artesunate was accepted.

Overall, the therapeutic benefits of Amivas-Artesunate therapy seen in the two pivotal studies are considered to outweigh the potential risks. Amivas-Artesunate has been shown to have a favourable benefit-harm-uncertainty profile based on non-clinical and clinical studies. The identified safety issues can be managed through labelling and monitoring. Appropriate warnings and precautions are in place in the Product Monograph for Amivas-Artesunate to address the identified safety concerns.

This New Drug Submission complies with the requirements of sections C.08.002 and C.08.005.1 and therefore Health Canada has issued the Notice of Compliance pursuant to section C.08.004 of the Food and Drug Regulations. For more information, refer to the Clinical, Non-clinical, and Quality (Chemistry and Manufacturing) Basis for Decision sections.

3 What steps led to the approval of Amivas-Artesunate?

The New Drug Submission (NDS) for Amivas-Artesunate was subject to an expedited review process under the Priority Review of Drug Submissions Policy. The sponsor presented substantial evidence of clinical effectiveness to demonstrate that Amivas-Artesunate provides effective treatment of a serious, life-threatening or severely debilitating disease that is not adequately managed by a drug marketed in Canada.

The review of the New Drug Submission (NDS) for Amivas-Artesunate was based on a critical assessment of the data package submitted to Health Canada. In line with the Draft Guidance Document: The Use of Foreign Reviews by Health Canada, review reports completed by the European Medicines Agency (EMA) and the United States Food and Drug Administration (FDA) were used as added references for the review of the quality, non-clinical, and clinical components, as per Method 3. The Canadian regulatory decision on the Amivas-Artesunate NDS was made independently based on the Canadian review.

For additional information about the drug submission process, refer to the Guidance Document: The Management of Drug Submissions and Applications.

Submission Milestones: Amivas-Artesunate

Submission Milestone

Date

Request for priority status filed

2024-01-29

Request for priority status approved

2024-02-26

New Drug Submission filed

2024-04-03

Screening

Screening Deficiency Notice issued

2024-05-06

Response to Screening Deficiency Notice filed

2024-08-09

Screening Acceptance Letter issued

2024-09-06

Review

Two requests were granted to pause review clock (extensions to respond to clarification requests)

121 days in total

Biostatistics evaluation completed

2025-02-11

Non-clinical evaluation completed

2025-04-28

Review of Risk Management Plan completed

2025-06-16

Quality evaluation completed

2025-07-02

Clinical/medical evaluation completed

2025-07-02

Labelling review completed

2025-07-02

Notice of Compliance issued by Director General, Pharmaceutical Drugs Directorate

2025-07-04
4 What follow-up measures will the company take?

Requirements for post-market commitments are outlined in the Food and Drugs Act and Food and Drug Regulations.

5 What post-authorization activity has taken place for Amivas-Artesunate?

Summary Basis of Decision documents (SBDs) for eligible drugs (as outlined in Frequently Asked Questions: Summary Basis of Decision [SBD] Project: Phase II) authorized after September 1, 2012 will include post-authorization information in a table format. The Post-Authorization Activity Table (PAAT) will include brief summaries of activities such as submissions for new uses of the product, and whether Health Canada’s decisions were negative or positive. The PAAT will continue to be updated during the product life cycle.

At this time, no PAAT is available for Amivas-Artesunate. When available, the PAAT will be incorporated into this SBD.

For the latest advisories, warnings and recalls for marketed products, see MedEffect Canada.

6 What other information is available about drugs?

Up-to-date information on drug products can be found at the following links:

7 What was the scientific rationale for Health Canada’s decision?

Refer to the What steps led to the approval of Amivas-Artesunate? section for more information about the review process for this submission.

7.1 Clinical Basis for Decision

Clinical Pharmacology

The precise mechanism by which artesunate, the medicinal ingredient in Amivas‑Artesunate, acts against Plasmodium species is not clearly understood. However, studies suggest that the mechanism of action of artesunate is likely multifactorial. A key component of the antimalarial activity of artesunate is its endoperoxide bridge, a chemical structure essential for its antiplasmodial activity. Within infected red blood cells, the parasite digests hemoglobin, releasing heme, an iron-containing molecule. The heme iron interacts with the endoperoxide bridge, triggering its cleavage, which generates free radicals. These free radicals cause oxidative stress within the infected red blood cells, leading to damage of proteins, lipids, and changes in cellular structure; thereby impairing parasite function and inhibiting growth, resulting in parasite death.

While no formal QT study has been conducted with Amivas-Artesunate, electrograms were included in two Phase I dose-finding studies. In these studies, healthy volunteers received single doses of up to 8 mg/kg, and showed no evidence of QT interval prolongation.

Similarly, while no formal drug-drug interaction studies were conducted, specifically with Amivas-Artesunate, its metabolic pathway is well characterized. Following intravenous administration, artesunate is rapidly converted to dihydroartemisinin (DHA), primarily by esterases and the enzyme cytochrome P450 (CYP) 2A6. Dihydroartemisinin is then further metabolized into inactive glucuronide conjugates by uridine 5'‑diphospho-glucuronosyltransferase (UGT) enzymes 1A9 and 2B7. Since DHA is a substrate of the glucuronosyltransferase enzymes UGT1A9 and UGT2B7, co‑administration of Amivas‑Artesunate with strong UGT enzyme inhibitors (e.g., axitinib, vandetanib, imatinib, diclofenac) may increase plasma exposures to DHA. Therefore, co‑administration of these medications should be avoided. Conversely, co‑administration of Amivas-Artesunate with UGT enzyme inducers (e.g., nevirapine, ritonavir, rifampicin, carbamazepine, phenytoin) may reduce DHA levels, potentially diminishing the drug’s efficacy. Therefore, co-administration of these medications should also be avoided.

Limited data from in vitro studies and from published studies with oral artesunate and/or oral DHA have indicated that DHA may induce CYP3A and inhibit CYP1A2. Caution is advised when co-administering Amivas-Artesunate with substrates of CYP3A4 or CYP1A2 that have narrow therapeutic windows.

For further details, please refer to the Product Monograph for Amivas-Artesunate, approved by Health Canada and available through the Drug Product Database.

Clinical Efficacy

The clinical efficacy of Amivas-Artesunate was assessed in two pivotal, Phase III, multicentre, randomized, open-label, active controlled studies: the Southeast Asian Quinine and Artesunate Malaria Trial (SEAQUAMAT) and the African Quinine and Artesunate Malaria Trial (AQUAMAT). Both studies evaluated the efficacy of intravenous Amivas-Artesunate compared to intravenous quinine, which was the standard of care at the time the SEAQUAMAT and AQUAMAT studies were conducted. However, each study focused on a different age group. The SEAQUAMAT study primarily enrolled adults, with a mean age of 28 years. In contrast, the AQUAMAT study consisted of children under 15 years of age, with mean age of 3 years.

In the SEAQUAMAT study, a total of 1,461 patients were randomized, including 1,259 adults and 202 pediatric patients under 15 years of age. In the AQUAMAT study, 5,425 pediatric patients under the age of 15 were randomized. Inclusion criteria for both studies required a positive blood antigen stick test for Plasmodium falciparum histidine rich protein 2 and a clinical diagnosis of severe malaria made by the admitting physician. A peripheral blood smear was also collected and stored for later quantitative parasite counting.

In both pivotal studies, the clinical study designs were similar. Patients were randomized in a 1:1 ratio to receive either Amivas-Artesunate or quinine. Amivas-Artesunate was administered intravenously at a dose of 2.4 mg/kg upon hospital admission (0 hours), followed by additional doses at 12 hours, 24 hours, and then once daily until the patient could reliably take oral medication. Quinine was given intravenously at an initial dose of 20 mg/kg over 4 hours, followed by 10 mg/kg three times daily over 2 to 8 hours.

The primary endpoint in both studies was all-cause in-hospital mortality in the intent-to-treat population up to the point of discharge for a maximum of one week.

In the SEAQUAMAT study, of the 1,461 patients enrolled, 730 patients were randomized to Amivas-Artesunate treatment group and 731 were randomized to the quinine treatment. Among the participants, 202 were children under the age 15, including 89 children younger than 6 years. The definitive diagnosis of severe malaria was made retrospectively, based on clinical data collected at the time of admission. Not all patients were retrospectively confirmed to have severe disease. In the Amivas-Artesunate treatment group, 509 patients (70%) had severe disease compared to 541 patients (74%) in the quinine group.

In SEAQUAMAT, treatment with intravenous Amivas-Artesunate reduced mortality in patients with severe malaria by over a third compared to intravenous quinine treatment. The adult mortality rate in the Amivas-Artesunate treatment group was 14.7% (107 of 730 patients) compared to 22.4% (164 of 731 patients) in the quinine group, in the intent-to-treat analysis. This corresponds to an odds ratio of mortality with artesunate versus quinine of 0.60 (95% confidence interval [CI]: 0.45 to 0.78; p = 0.0002). In the subpopulation with severe malaria, the mortality rate was 19.8% in the Amivas-Artesunate treatment group versus 28.1% in the quinine group. The corresponding odds ratio estimate was 0.64 (95% CI: 0.48 to 0.87; p = 0.003), further supporting the survival benefit of Amivas‑Artesunate in this high-risk group.

In AQUAMAT, the mortality rate of patients in the Amivas‑Artesunate treatment group was 8.5% (230 of 2,712 patients) compared to 10.9% (297 of 2,713 patients) in the quinine group. This corresponds to a reduction in morality: with an odds ratio for mortality of 0.75 (95% CI: 0.63 to 0.90; p = 0.0022). In the subpopulation with severe malaria, the mortality rate was 9.9% (226 of 2,280 patients) in the Amivas-Artesunate treatment group versus 12.4% (291 of 2,338 patients) in the quinine group. This corresponds to a reduction in mortality: with an odds ratio estimate of 0.77 (95% CI: 0.64 to 0.93; p = 0.0055).

Overall, the primary endpoint of reduced mortality was achieved in both the intent-to-treat population and in patients with confirmed severe malaria in the SEAQUAMAT and AQUAMAT studies. The demonstrated reduction in mortality was both statistically significant and clinically relevant. On the basis of the information reviewed, Amivas‑Artesunate presented an acceptable efficacy profile in consideration of the intended population.

Indication

The New Drug Submission for Amivas-Artesunate was filed by the sponsor with the following proposed indication:

Artesunate is indicated in adults and children for the initial treatment of severe malaria.

Health Canada approved the following indication:

Amivas-Artesunate is indicated for the initial treatment of severe malaria in adults and pediatric patients.

For more information, refer to the Product Monograph for Amivas-Artesunate, approved by Health Canada and available through the Drug Product Database.

Clinical Safety

The clinical safety of Amivas-Artesunate for the initial treatment of severe malaria in adults and pediatric patients was primarily evaluated based on two pivotal, Phase III, multicentre, randomized, open-label, active controlled studies; the Southeast Asian Quinine and Artesunate Malaria Trial (SEAQUAMAT) and the African Quinine and Artesunate Malaria Trial (AQUAMAT). Additional safety data were also submitted from a retrospective data abstract study, Study R-CDC-060, conducted in the United States among patients treated with Amivas-Artesunate for severe malaria following international travel. The SEAQUAMAT study enrolled a total of 1,461 patients, AQUAMAT enrolled 5,435 patients, and Study R-CDC-060 retrospectively evaluated 102 patients.

In SEAQUAMAT, the most commonly reported treatment-emergent adverse events (TEAEs) in the Amivas-Artesunate treatment group compared to the quinine treatment group were dialysis (8.2% vs. 6.6%) and blackwater fever (6.7% vs. 4.5%). The most commonly reported TEAEs in the AQUAMAT study were acute anemia (5.7% vs. 4.6%), coma (5.1% vs. 3.5%), convulsions (10.1% vs. 8.3%) and hypoglycemia (2.8% vs. 1.8%).

In SEAQUAMAT, the overall incidence of any persistent neurological sequelae at discharge was 1% (24 of 706 patients) in the Amivas-Artesunate treatment group and 0.3% (23 of 737 patients) in the quinine group at discharge from the study. At Day 28 of the AQUAMAT study, the overall incidence of any persistent neurological sequelae in assessed cerebral malaria survivors was 2.4% in the Amivas-Artesunate treatment group and 2.3% in the quinine group.

In Study R-CDC-060, the most commonly reported TEAEs were anemia (65%), transaminase elevations (27%), aspartate aminotransferase elevations (22%), and hyperbilirubinemia (14%). Hematologic adverse events labelled in the Amivas-Artesunate Product Monograph included reduced reticulocyte count, post artesunate delayed hemolysis, thrombocytopenia, anemia, neutropenia, lymphopenia and leukocytosis. Post-market adverse reactions included post-artesunate hemolytic anemia (PADH), as well as pancreatitis and immune hemolytic anemia. Post‑artesunate delayed hemolysis was defined as a 10% decrease in hemoglobin occurring within one month after receiving intravenous administration of Amivas-Artesunate. In some cases, post-treatment hemolytic anemia have been severe enough to require blood transfusion. The Warnings & Precautions section of the Amivas-Artesunate Product Monograph contains a recommendation for weekly complete blood count monitoring. If hemoglobin levels decline, additional hematologic investigations are advised to assess for PADH and to determine the potential need for a blood transfusion.

For more information, refer to the Product Monograph for Amivas-Artesunate, approved by Health Canada and available through the Drug Product Database.

7.2 Non-Clinical Basis for Decision

Non-clinical pharmacokinetic studies for Amivas-Artesunate were conducted in rats, dogs and monkeys, following single or repeated intravenous administration.

In the non-clinical species tested, artesunate, the medicinal ingredient in Amivas-Artesunate, was rapidly converted to dihydroartesunate (DHA) following intravenous administration. In a rat mass balance study with radiolabelled artesunate, radioactivity in plasma and blood peaked five minutes after intravenous administration. A second, smaller peak occurred three to four hours after administration, suggesting enterohepatic circulation. Unchanged artesunate and DHA were rapidly cleared from blood and plasma, however metabolites remained detectable. Tissues with the highest exposure to artesunate and/or its metabolites in rats included small intestines (highest exposure at approximately 68%), spleen, large intestine, kidneys, adrenals, liver, bile, bone marrow, and bladder. Exposure was also detected in the brain (approximately 1%), indicating that the blood-brain barrier was crossed. Exposure decreased in all tissues over the course of 192 hours, while concentrations in the spleen remained similar to those observed at one hour post-dose.

Dihydroartesunate is primarily metabolized by uridine 5'‑diphospho-glucuronosyltransferase (UGT) enzymes 1A9 and 2B7 through phase II metabolism to form DHA-glucuronide. The Product Monograph for Amivas-Artesunate includes a statement about potential drug-drug reactions with UGT inducers and inhibitors.

In vitro cytochrome P450 (CYP) interaction studies showed moderate inhibition of CYP1A2 and 2C19. Dihydroartesunate did not substantially inhibit CYP2C9, CYP2D6, or CYP3A4 and did not induce CYP1A, CYP 2B6, or CYP3A in vitro. In a drug interaction study in rhesus monkeys, small but significant changes were observed in the markers for CYP3A4 (slight inhibition), CYP2D6 (induction) and CYP2C9 (slight inhibition) following intravenous artesunate administration. A published study in which healthy adults were given oral artesunate and DHA found that DHA inhibited CYP1A2 and CYP2D6, and induced CYP3A, and artesunate induced CYP3A at one of the timepoints tested. Although the evidence is mixed and clinical relevance based on exposure is unclear, the Product Monograph for Amivas-Artesunate reflects the uncertainty in CYP interactions which is considered acceptable at this time.

Artesunate and DHA displayed weak to moderate inhibition of organic anion transporting peptide 1B1 (OATP1B1), organic anion transporter 3 (OAT3), and organic cation transporter 1 (OCT1) and did not substantially inhibit OATP1B3, OAT1, OCT2, and multidrug and toxin extrusion (MATE) proteins MATE1 and MAKE2K. Artesunate and DHA had no or moderate interactions with multidrug resistance protein 1 (P‑glycoprotein) and breast cancer resistance protein, and inhibited bile salt export pump in a non-specific manner. The physiological relevance is considered to be low due to protein binding.

Single‑ and repeat‑dose toxicity studies of artesunate, administered intravenously, were conducted in rats, dogs, and monkeys. The predominant findings across non-clinical species were hematological toxicities, including anemia, reticulocytopenia, leukopenia, and neutropenia. Similar hematological toxicities were observed in clinical studies and are documented in the Product Monograph for Amivas-Artesunate.

Animal reproduction studies conducted in several species have demonstrated fetal harm from oral and intravenous administration of artesunate. Oral administration of artesunate to pregnant rats, rabbits, and monkeys at 0.4- to 1.6-times the clinical dose based on body surface area resulted in embryotoxicity including embryofetal loss/post-implantation loss, increased resorptions, lower fetal weights, increased incidences of skeletal malformations (curved, shortened, misshapen, and/or unossified/incompletely ossified bones), cardiovascular malformations (including ventricular septal defects, retroesophageal right subclavian vessels), and variations in liver shape. Brain malformations including severely dilated brain ventricles and absent areas (pons) were also observed in rabbits. Non-clinical embryofetal toxicities have been labelled in the Amivas-Artesunate Product Monograph and the proposed warnings for use in pregnancy based on the animal data.

No juvenile toxicity studies have been conducted with artesunate alone. This is a deficiency in the non-clinical package considering the pediatric indication, and the lack of data has been labelled in the Product Monograph for Amivas-Artesunate. However, there is clinical data in the pediatric population. In addition, a juvenile rat toxicity study of a chloroproguanil/dapsone/artesunate combination product (0.235 mg/kg/day of artesunate) was not associated with any adverse effects when administered from postnatal day 4 to 31 (orally).

For more information, refer to the Product Monograph for Amivas-Artesunate, approved by Health Canada and available through the Drug Product Database.

7.3 Quality Basis for Decision

The quality (chemistry and manufacturing) information submitted for Amivas-Artesunate has demonstrated that the drug substance and drug product can be consistently manufactured to meet the approved specifications. Proper pharmaceutical development and supporting studies were conducted and an adequate control strategy is in place for the commercial processes. Changes to the manufacturing process and formulation (if any) made throughout the pharmaceutical development are considered acceptable upon review. Based on the stability data submitted, the proposed shelf life of 24 months is acceptable when the drug product is stored at room temperature (15 ºC to 30 ºC) and protected from light. The reconstituted solution must be used within 1.5 hours of preparation.

The proposed drug-related impurity limits are considered adequately qualified (e.g., within International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use limits and/or qualified from toxicological studies, as needed).

A risk assessment for the potential presence of nitrosamine impurities was conducted according to requirements outlined in Health Canada’s Guidance on Nitrosamine Impurities in Medications. The risks relating to the potential presence of nitrosamine impurities in the drug substance and/or drug product are considered negligible or have been adequately addressed (e.g., with qualified limits and a suitable control strategy).

All sites involved in production are compliant with good manufacturing practices.

None of the non-medicinal ingredients (excipients) in the drug product are prohibited for use in drug products by the Food and Drug Regulations.

None of the excipients used in the formulation of Amivas-Artesunate is of human or animal origin.

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