Since 2007, Investigational Intravenous (IV) Artesunate has been available in the US only through an expanded access investigational new drug (IND) program managed by the Centers for Disease Control and Prevention (CDC). FDA approval allows Amivas (US), LLC to manufacture, distribute and commercialize Artesunate for Injection.
Amivas was formed in 2016 expressly for the purpose of making this life-saving drug readily available in the US.
Approximately 2,000 US cases of malaria are diagnosed annually. Without appropriate treatment, about 15 percent become severe. Mortality from untreated severe malaria (particularly cerebral malaria) approaches 100 percent.
Amivas (US), LLC, specialists in treatments for rare and neglected tropical diseases, including severe malaria, announced today that Artesunate for Injection 110 mg, powder and solvent for solution has received marketing approval by the US Food and Drug Administration (FDA). Artesunate for Injection is indicated for the initial treatment of severe malaria in adult and pediatric patients. It is the first FDA-approved product that Amivas, headquartered in Frederick, Maryland, has introduced to their commercial portfolio.
Amivas will now manufacture, distribute, and commercialize Artesunate for Injection and is completing set-up of a nationwide product distribution network. Prior to FDA approval, access to investigational IV Artesunate had been managed by the Centers for Disease Control and Prevention (CDC) since 2007 via an expanded access investigational new drug (IND) program. Additional information regarding commercial availability of Artesunate for Injection as produced by Amivas will be posted to https://ivartesunate.com. The CDC will continue to make investigational IV artesunate available under the CDC-sponsored expanded access IND 76,725, in effect per FDA's authorization since 2007 until nationwide availability of Amivas-produced Artesunate for Injection is in place in the next few months.
"We are extremely pleased to have secured this important regulatory milestone for Artesunate for Injection," said Bryan Smith, MD, Chief Medical Officer at Amivas. "As most medical professionals know, when a patient with severe malaria arrives in the clinic, emergency room or elsewhere, immediate treatment with a safe, efficacious, fast-acting, injectable therapy is absolutely critical to saving that life. Given today's FDA approval of Artesunate for Injection and the deep expertise that Amivas can bring to the challenges of treating rare tropical diseases, we look forward to making significant ongoing contributions to saving the lives of patients with severe malaria."
Until Amivas' Artesunate for Injection is available in hospitals, healthcare professionals seeking IV artesunate for treatment of patients with severe malaria should contact the CDC for obtaining investigational IV artesunate (www.cdc.gov/malaria/diagnosis_treatment/artesunate.html (770-488-7788) Monday–Friday, 9 am–5 pm EST. Outside these hours, providers should call 770-488-7100). This transition will progress rapidly in coming months. Updates will appear on CDC and Amivas webpages.
Development of Artesunate for Injection in the US has been under US Army Medical Research and Development Command (USAMRDC). Within USAMRDC, the Walter Reed Army Institute of Research and the US Army Medical Materiel Development Activity (USAMMDA) joint collaborative work has provided the CDC a constant supply of IV artesunate since 2007. USAMMDA established a cooperative research and development agreement with Amivas to modernize Artesunate manufacture and register the product with the FDA.
"FDA approval of Artesunate for Injection is another notable achievement for the US Army in its long history of developing therapies for combating malaria. With a lack of alternate FDA approved therapies to treat life-threatening severe malaria, Artesunate for Injection fills a critical gap for the military and US population. This difficult undertaking was accomplished through a competitively bid, public/private partnership and is testament to the professionalism and dedication of the team involved," said Major Victor Zottig, PhD, Artesunate Product Manager for USAMMDA.
Bryan Smith, MD, himself a US Army Veteran, further commented, "Proceeds from the sale of any Priority Review Voucher (PRV) that may be awarded to Amivas have been earmarked to support a US Army nominated Veteran charity, to augment global supply of IV Artesunate and to continue post-marketing studies agreed with FDA."
For more information about Artesunate for Injection, including the US prescribing information, visit https://ivartesunate.com.
Clinical Studies The safety and efficacy of IV Artesunate was studied in three trials including the South East Asian Quinine Artesunate Malaria Trial (SEAQUAMAT)[i] and the African Quinine Artesunate Malaria Trial (AQUAMAT). These two studies examined a total of 6,886 patients and included adults, children and pregnant women. IV Artesunate reduced mortality by 34.7 percent and 22.5 percent compared with the injectable standard of care drug in the SEAQUMAT and AQUAMAT studies respectively. Data were also collected between January 2007 and December 2010 on 102 US patients with severe or complicated malaria who were supplied IV Artesunate under the CDC expanded access protocol. Ninety two patients received at least one administration of drug at 0, 12, 24 and 48 hours. These US patients included adults, children, pregnant women and older adults. Most were Black or African American, 25 percent were White, 9 percent were Asian. Seven patients died from complications of severe malaria (mortality rate, 6.9 percent). Primary funding source for the data analysis from patients enrolled in the CDC study was the Office of the Surgeon General, Department of the US Army. While no service personnel were actively recruited into any of the clinical trials of IV Artesunate, several service members were offered emergency treatment under the CDC protocol.
Important Safety Information Contraindications Known serious hypersensitivity to artesunate, such as anaphylaxis.
Warnings and Precautions Post Artesunate Delayed Hemolysis: Post-artesunate delayed hemolysis is characterized by decreased hemoglobin with laboratory evidence of hemolysis (such as decreased haptoglobin and increased lactate dehydrogenase) occurring at least 7 days after initiating artesunate treatment. Cases of post-treatment hemolytic anemia severe enough to require transfusion have been reported. Monitor patients for 4 weeks after artesunate treatment for evidence of hemolytic anemia. Since a subset of patients with delayed hemolysis after artesunate therapy have evidence of immune-mediated hemolysis, consider performing a direct antiglobulin test to determine if therapy, e.g. corticosteroids, is necessary.
Hypersensitivity reactions: Hypersensitivity to artesunate including cases of anaphylaxis have been reported during the use of parenteral artesunate (including Artesunate for Injection). If hypotension, dyspnea, urticaria, or generalized rash occur during administration of Artesunate for Injection, consider discontinuing Artesunate for Injection administration and continuing therapy with another antimalarial drug.
Adverse Reactions The most common adverse reactions (2 percent or greater) occurring more frequently in patients receiving intravenous artesunate in the SEAQUAMAT trial were acute renal failure requiring dialysis, hemoglobinuria, and jaundice. The most common adverse reactions in the CDC expanded access protocol were anemia (65 percent), transaminase increase (27 percent), thrombocytopenia (18 percent), hyperbilirubinemia (14 percent), acute renal failure (10 percent), leukocytosis (10 percent), acute respiratory distress syndrome (8 percent), lymphopenia (7 percent), neutropenia (5 percent), disseminated intravascular coagulation (3 percent), elevated creatinine (3 percent), pneumonia (3 percent), pulmonary edema (3 percent), and diarrhea (3 percent).
Drug Interactions Published clinical reports or in vitro reports indicate that concomitant use of Artesunate for Injection with oral ritonavir, nevirapine, or UGT inducers may decrease dihydroartemisinin (DHA) AUC and Cmax, which may reduce the efficacy of Artesunate for Injection. If Artesunate for Injection is co-administered with ritonavir, nevirapine or strong UGT inducers (e.g., rifampin, carbamazepine, phenytoin), monitor for possible reduced antimalarial efficacy of Artesunate for Injection.
Published reports of in vitro data indicate that concomitant use of Artesunate for Injection with UGT inhibitors may increase DHA AUC and Cmax, which may increase DHA associated adverse reactions. Monitor for adverse reactions when co-administering Artesunate for Injection with strong UGT inhibitors (e.g., axitinib, vandetanib, imatinib, diclofenac).
Use in Specific Populations Pregnancy: There are serious risks to the mother and fetus associated with untreated severe malaria during pregnancy; delaying treatment of severe malaria in pregnancy may result in serious morbidity and mortality to the mother and fetus. Pregnancy outcomes reported from a prospective surveillance study with intravenous artesunate are insufficient to identify a drug-associated risk of major birth defects, miscarriage, and or fetal death.
Pediatric Use: The safety and effectiveness of Artesunate for Injection for the treatment of severe malaria have been established in pediatric patients.
Geriatric Use: Clinical studies of Artesunate for Injection did not include sufficient numbers of patients aged 65 years and older to determine whether they respond differently than younger subjects.
To report SUSPECTED ADVERSE REACTIONS, contact Amivas LLC at [1-855-526-4827 (1-855-5AMIVAS)] or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.
About Malaria and Severe Malaria Malaria is one of the world's leading killers of people, especially children. Severe malaria, a medical emergency, typically includes neurologic symptoms, severe anemia, acute renal injury, acute respiratory distress syndrome, or jaundice, as a large number of the patient's red blood cells become infected by a malaria parasite. Uncomplicated falciparum malaria can progress rapidly to severe forms of the disease, especially in people with no or low immunity, and severe falciparum malaria is almost always fatal without treatment. Prompt, effective treatment within 24-48 hours of the onset of malaria symptoms is necessary.
Malaria is a rare disease in the US. Therefore, it is not always recognized, diagnosed and treated in timely fashion. Nearly all cases in the US occur in persons who acquire the infection while in a malaria endemic area and who are diagnosed after returning to the US. Most are US residents with no acquired immunity to malaria and who are, therefore, at risk of developing severe malaria. A major contributing factor to continued malaria-associated mortality in the US is delay in initiation of appropriate treatment. Malaria chemoprophylaxis and the use of bed nets and insect repellants help reduce the risk of contracting malaria.
About Amivas Amivas is a US joint venture focused on the development, manufacture and commercialization of therapeutic products for the treatment of infectious diseases. Headquartered in Frederick, Maryland, Amivas was formed in 2016 expressly for the purpose of bringing treatments to market for rare and neglected tropical diseases.
Disclaimer: The views expressed in this release are those of the author and do not necessarily represent the views of the US Army or the Department of Defense (DoD). Discussion of specific pharmaceutical products does not reflect an endorsement of those products.