2.1 Recommended Dosage and Administration in Adult and Pediatric Patients

The recommended dosage of Artesunate for Injection is 2.4 mg/kg administered intravenously at 0 hours, 12 hours, and 24 hours, and thereafter, administered once daily until the patient is able to tolerate oral antimalarial therapy.

Administer constituted Artesunate for Injection intravenously as a slow bolus over 1 minute to 2 minutes [see Dosage and Administration (2.2)]. Do NOT administer Artesunate for Injection via continuous intravenous infusion.

Administer Artesunate for Injection with an antimalarial agent that is active against the hypnozoite liver stage forms of Plasmodium, such as an 8-aminoquinoline drug, to patients with severe malaria due to P. vivax or P. ovale.

2.2 Preparation of Artesunate for Injection for Intravenous Administration

Constitution

Artesunate for Injection must be constituted with the supplied diluent prior to administration. A diluent consisting of 12 mL of sterile 0.3 M pH 8.0 sodium phosphate buffer is provided with Artesunate for Injection. To constitute Artesunate for Injection, withdraw 11 mL of this diluent with a needle and syringe and inject into the artesunate vial (when constituted the final concentration of artesunate is 10 mg/mL). Swirl gently (do not shake) for up to 5 to 6 minutes until the powder is fully dissolved and no visible particles remain.

Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit. Do not administer Artesunate for Injection if particulate matter and/or discoloration is observed.

After constitution, inject the constituted solution intravenously (through an established intravenous line or needle) as a slow bolus over 1 to 2 minutes. Discard the vial and any unused portion of the drug product after use.

Storage of the Constituted Solution

Administer the constituted solution within 1.5 hours of constitution with the supplied diluent.

4.1 Hypersensitivity

Known serious hypersensitivity to artesunate, such as anaphylaxis [See Warnings and Precautions (5.2) and Adverse Reactions (6.2)].

5.1 Post-Treatment 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 [see Adverse Reactions (6.2)]. Monitor patients for 4 weeks after artesunate treatment with Artesunate for Injection 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, are necessary.

5.2 Hypersensitivity

Hypersensitivity to artesunate including cases of anaphylaxis have been reported during the use of parenteral artesunate (including Artesunate for Injection) [see Adverse Reactions (6.1, 6.2)]. If hypotension, dyspnea, urticaria, or generalized rash occurs during administration of Artesunate for Injection, consider discontinuing Artesunate for Injection administration and continuing therapy with another antimalarial drug.

5.3 Embryo-Fetal Toxicity in Animals

Extensive experience with oral artesunate and other artemisinin class drugs in pregnant women has not identified a drug-associated risk of major birth defects, miscarriage, or adverse maternal or fetal outcomes.

Animal reproduction studies show that a single intravenous administration of artesunate to rats early in gestation results in embryolethality and oral administration (not an approved route of administration) of artesunate in rats, rabbits, and monkeys induces a dose-dependent increase in embryolethality and fetal malformations. However, the clinical relevance of these data is uncertain [see Use in Specific Populations (8.1)].

Delaying treatment of severe malaria in pregnancy may result in serious morbidity and mortality to the mother and fetus [see Use in Specific Populations (8.1) and Patient Counseling Information (17)].

6.1 Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared with rates in the clinical trials of another drug and may not reflect the rates observed in practice.

The data described below reflect exposure to intravenous artesunate in a randomized controlled trial in patients with severe malaria in South East Asia, including 730 patients treated with intravenous artesunate (Trial 1), a supportive published randomized, controlled trial of parenteral artesunate in pediatric patients with severe malaria in Africa (Trial 2) and an uncontrolled open label study in the US in 102 patients with severe malaria treated with Artesunate for Injection (Trial 3).

In Trial 1, 730 patients received artesunate 2.4 mg/kg intravenously at 0 hours, 12 hours, 24 hours and then once daily and 730 patients received the comparator quinine as a 20 mg/kg intravenous loading dose then 10 mg/kg intravenously three times daily for treatment of severe malaria in South East Asia. The median age of patients was 28 years (range 2-87 years) and 74% were male, 14% were pediatric patients < 15 years, and 3% were pregnant females. Patients received a median of 3 doses (range 1-9 doses) of intravenous artesunate. Once able to tolerate oral therapy, patients in the artesunate arm received oral artesunate 2 mg/kg daily (not an approved route or dosing regimen) and patients in the quinine arm received oral quinine 10 mg/kg every 8 hours to complete 7 days of total therapy. A subset of patients also received oral doxycycline (100 mg twice daily for 7 days) in addition to oral artesunate or oral quinine.

In Trial 2, pediatric patients younger than 15 years of age with severe malaria in 9 African countries were treated with parenteral artesunate or parenteral quinine.

In Trial 3, 92 of 102 (90%) patients received four 2.4 mg/kg doses of artesunate intravenously at 0 hours, 12 hours, 24 hours, and 48 hours followed by oral antimalarial therapy. The median (range) age of the patients was 39 (1 to 72) years and 61% were male; 63% were African American, 25% were White, and 9% were Asian.

For Trial 1, Trial 2, and Trial 3 adverse reactions were reported during hospitalization and no post-treatment laboratory monitoring was performed.

Most Common Adverse Reactions in Trial 1

The most common adverse reactions (2% or greater) occurring more frequently in patients receiving intravenous artesunate in Trial 1 were dialysis, hemoglobinuria, and jaundice ().

Neurologic Sequelae

Patients in Trial 1 were assessed for neurologic sequelae at the time of hospital discharge. The reported neurologic sequelae included loss of balance, hemiplegia/paresis, ataxia, neuropsychiatric symptoms, tremor, generalized weakness, and confusion and restlessness. At hospital discharge, 7 patients (1%) in the artesunate arm had significant neurologic impairments compared with 3 patients (0.4%) in the quinine arm.

Adverse Reactions Reported in Trial 2

In a published randomized controlled open label trial (Trial 2) comparing parenteral artesunate 2.4 mg/kg to parenteral quinine in pediatric patients (<15 years of age) with severe malaria in Africa, the safety profile of intravenous artesunate was generally similar to that described for Trial 1 including greater incidence of neurological impairments at hospital discharge in the artesunate arm compared to the quinine arm.

Most Common Adverse Reactions in Trial 3

The most common adverse reactions in Trial 3 were anemia (65%), transaminase increase (27%), thrombocytopenia (18%), hyperbilirubinemia (14%), acute renal failure (10%), leukocytosis (10%), acute respiratory distress syndrome (8%), lymphopenia (7%), neutropenia (5%), disseminated intravascular coagulation (3%), elevated creatinine (3%), pneumonia (3%), pulmonary edema (3%), and diarrhea (3%).

Clinically Significant Adverse Reactions Reported with Artesunate for Injection in Clinical Trials for Uncomplicated Malaria (not an approved indication) and in Healthy Volunteers

The following clinically significant adverse reactions occurred in ≥ 2% of healthy volunteers or patients:

Blood and lymphatic system disorders: leukopenia, reduced reticulocyte count

Gastrointestinal disorders: abdominal pain, vomiting

General disorders and administration site conditions: pyrexia

Nervous system disorders: dysgeusia, tinnitus, dizziness, and headache

Respiratory, thoracic and mediastinal disorders: cough

Skin and subcutaneous tissue disorders: rash

The following clinically significant reactions occurred in <2% of healthy volunteers or patients:

Immune system disorders: Stevens-Johnson syndrome

Skin and subcutaneous tissue disorders: urticaria

6.2 Postmarketing Experience

The following adverse reactions have been identified during use of parenteral artesunate outside the United States. Because the reactions are reported voluntarily from a population of uncertain size, it is not possible to estimate their frequency reliably or to establish a causal relationship to drug exposure.

Blood and lymphatic system disorders: delayed hemolysis, immune hemolytic anemia

Gastrointestinal disorders: pancreatitis

Immune system disorders: hypersensitivity, anaphylaxis

7.1 Effect of Other Drugs on Artesunate and Dihydroartemisinin (DHA)

Ritonavir, Nevirapine or Strong UDP-Glucuronosyltransferase (UGT) Inducers:

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 [see Clinical Pharmacology (12.3)], 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.

Strong UGT Inhibitors

Published reports of in vitro data indicate that concomitant use of Artesunate for Injection with UGT inhibitors may increase DHA AUC and Cmax [see Clinical Pharmacology (12.3)], 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).

8.1 Pregnancy

8.2 Lactation

8.4 Pediatric Use

The safety and effectiveness of Artesunate for Injection for the treatment of severe malaria have been established in pediatric patients. Use of Artesunate for Injection for this indication is supported by evidence from adequate and well-controlled studies in adults and pediatric patients with additional pharmacokinetic and safety data in pediatric patients aged 6 months and older [see Adverse Reactions (6.1) and Clinical Studies (14)].

For pediatric patients younger than 6 months of age, a pharmacokinetic (PK) extrapolation approach using modeling and simulation indicated comparable or higher predicted PK steady-state AUC of DHA between this age group and older children or adults at the recommended 2.4 mg/kg dose regimen of Artesunate for Injection. No notable safety issues were identified in limited published safety and outcome data for Artesunate for Injection in pediatric patients younger than 6 months of age with severe malaria. No dose adjustment is necessary for pediatric patients regardless of age or bodyweight [see Dosage and Administration (2.1), Clinical Pharmacology (12.3)].

8.5 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 patients.

8.6 Renal Impairment

No specific PK studies have been carried out in patients with renal impairment. Most patients with severe malaria present with some degree of related renal impairment. No specific dosage adjustments are needed for patients with renal impairment.

8.7 Hepatic Impairment

No specific PK studies have been carried out in patients with hepatic impairment. Most patients with severe malaria present with some degree of related hepatic impairment. No specific dose adjustments are needed for patients with hepatic impairment.

12.1 Mechanism of Action

Artesunate is an antimalarial drug [see Microbiology (12.4)].

12.2 Pharmacodynamics

Artesunate and DHA exposure-response relationships and their time course of pharmacodynamic responses are unknown.

Cardiac Electrophysiology

At the approved intravenous dose of 2.4 mg/kg Artesunate for Injection, artesunate and DHA do not cause large mean increases (i.e., 20 msec) in the QTc interval.

12.3 Pharmacokinetics

Following administration of 2.4 mg/kg Artesunate for Injection, artesunate is rapidly converted to DHA by blood esterases. The PK parameters of artesunate (AS) and DHA in patients with severe malaria following administration of multiple doses of 2.4 mg/kg Artesunate for Injection are shown in Table 2.

Specific Populations

Pediatric:

PK simulations, using a published population-based meta-analysis of DHA PK indicate a dosing regimen of 2.4 mg/kg results in comparable or greater predicted steady-state DHA AUC0-12 in infants less than 6 month of age compared to that observed in older children or adults (Figure 1). The difference in predicted exposures in infants less than 6 month of age is presumed to be due to immature development of the UGT elimination pathway for DHA.

Figure 1. Predicted Steady-State DHA AUC0-12 in Pediatric Patients 0 to 3 Years of Age with Severe Malaria after 2.4 mg/kg Artesunate for Injection

Each box represents the 25th and 75th percentile of the DHA exposure measure. The bar and cross inside the box represent the median and mean respectively, whiskers represent 1.5 times the interquartile range. The gray band represents the interquartile range for patients weighing 20 to 25 kg (8 to 10 years of age) and adults. Clearance was estimated using a combination of allometric weight scaling with a sigmoid function to account for organ maturation.

Pregnant Women:

In a published PK study involving 20 pregnant women with acute uncomplicated malaria administered 4 mg/kg IV artesunate, systemic exposures (Cmax and AUC) of artesunate and DHA were comparable between the pregnant acute malaria patients and the 3-months post-partum healthy patients. Therefore, no dose adjustment is necessary.

Published Clinical Drug-Drug Interaction Studies

Nevirapine:

Co-administration of oral artesunate with nevirapine resulted in a decrease in Cmax and AUC of DHA by 59% and 68%, respectively. This reduction in systemic PK exposure of DHA is also likely to occur with Artesunate for Injection and may result in the potential loss of antimalarial efficacy.

Ritonavir:

Co-administration of oral artesunate with ritonavir resulted in a 27% and 38% decrease in Cmax and AUC, respectively of DHA. This reduction in systemic PK exposure of DHA is also likely to occur with Artesunate for Injection and may result in the potential loss of antimalarial efficacy.

Other Anti-Malarial Drugs:

No clinically significant drug interactions were reported with co-administration of oral artesunate with atovaquone/proguanil, mefloquine, amodiaquine and sulfadoxine/pyrimethamine. Therefore, drug interactions between Artesunate for Injection and these drugs are not expected.

In Vitro Studies:

In vitro studies demonstrated that artesunate and DHA are not metabolized to any significant extent by CYP1A2, 2D6, 2C19, 2A6, 2E1 or 3A; therefore, no dosage adjustments are needed for inhibitors/inducers of these enzymes when co-administered with Artesunate for Injection. DHA is a substrate of UDP-UGT 1A9 or UGT 2B7.

Transporter Systems:

DHA is not a substrate or inhibitor of P-gp or BCRP. Artesunate is a substrate of BCRP and P-gp. Artesunate is a weak inhibitor of OATP1B1 (IC50 = 19 mcg/mL) and OAT3.

12.4 Microbiology

Mechanism of Action

Artesunate is rapidly metabolized into an active metabolite DHA. Artesunate and DHA, like other artemisinins contain an endoperoxide bridge that is activated by heme iron leading to oxidative stress, inhibition of protein and nucleic acid synthesis, ultrastructural changes as well as a decrease in parasite growth and survival.

Both artesunate and DHA are active against the different asexual forms of the Plasmodium parasites and clear parasitemia within 48 to 72 hours.

Antimicrobial Activity

Artesunate and DHA are active against the blood-stage asexual parasites and gametocytes of Plasmodium species including the chloroquine resistant strains [see Clinical Studies (14)]. However, artesunate and DHA are not active against the hypnozoite liver stage forms of P. vivax and P. ovale.

Resistance

There is a potential for development of resistance to artesunate and DHA. Strains of P. falciparum with a decrease in sensitivity to artesunate can be selected in vitro or in vivo. Alterations in some genetic regions of P. falciparum genes such as multidrug resistant 1 (pfmdr1), chloroquine resistance transporter (pfcrt), and kelch13 (K13) have been reported based on in vitro testing and/or identification of isolates in endemic areas where artemisinin therapy has been used.

Recrudescence occurs in patients treated with artesunate monotherapy. Decreased sensitivity to artesunate and other artemisinins, manifesting clinically as slower rates of parasite clearance has been documented in some parts of Southeast Asia and is associated with mutation in the K13 gene.

Cross-resistance

Nonclinical studies in vitro and in malaria animal models suggest a potential for development of cross-resistance with quinine, halofantrine, and amodiaquine. However, the clinical significance of these findings is not known.

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, the published literature indicates that artesunate induced DNA damage in human lymphocytes and Hep2G liver cells in a Comet assay and increased micronuclei formation in human lymphocytes. The published literature also indicates that in vivo, artesunate is positive for micronucleus formation but negative for DNA damage in peripheral blood cells in mice following oral administration. 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.

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.

16.1 How Supplied

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 73607-002-01

Sterile Diluent for Constitution single-dose vial: NDC 73607-003-02

Packages of 4 total vials (2 vials of Artesunate for Injection, 110 mg and 2 vials sterile diluent for Artesunate for Injection): NDC 73607-011-11

16.2 Storage and Handling

Store vials of Artesunate for Injection and sterile diluent in the carton at 20°C to 25°C (68°F to 77°F); excursions permitted to 15°C to 30°C (59°F to 86°F) [See USP Controlled Room Temperature]. Do not freeze. Avoid exposure to heat. Keep protected from light. Do not use beyond the expiration date.