ARTESUNATE Powder for solution for injection Ref.[27495] Active ingredients: Artesunate

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)].

The following clinically significant adverse reactions observed with Artesunate for Injection are discussed in detail in the Warnings and Precautions section:

• Post-treatment Hemolysis [See Warning and Precautions (5.1)]
• Hypersensitivity [See Warning and Precautions (5.2)]

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.

Table 1. Selected Adverse Reactions Occurring in ≥2% of Patients treated for Severe Malaria in Trial 1:

¹ In Trial 1, 1 patient randomized to the quinine arm did not receive any doses of the study drug.
² Includes the terms: dialysis, hemodialysis, and peritoneal dialysis.

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

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 C_max [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 C_max [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).

Risk Summary

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 (see Clinical Considerations). Pregnancy outcomes reported from a prospective surveillance study with intravenous artesunate are insufficient to identify a drug-associated risk of major birth defects, miscarriage, or fetal death. Experience with oral artesunate (not an approved route of administration) and other artemisinin class drugs (via various routes of administration) 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 that 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.

The estimated background risk of miscarriage and maternal and fetal death for the indicated population is higher than the general population. The estimated background risk of major birth defects for the indicated population is unknown. All pregnancies have a background risk of birth defects, 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.

There is a pregnancy safety study for Artesunate for Injection. If Artesunate for Injection is administered during pregnancy, healthcare providers should report Artesunate for Injection exposure by contacting Amivas LLC at 1-855-526-4827 (1-855-5AMIVAS) or www.amivas.com/our-products.

Disease-Associated Maternal and/or Embryo/Fetal Risk

Malaria during pregnancy increases the risk for adverse pregnancy outcomes, including maternal anemia, severe malaria, spontaneous abortion, stillbirth, preterm delivery, low birth weight, intrauterine growth restriction, congenital malaria, and maternal and neonatal mortality.

Data

Human Data

Reports of first trimester use of intravenous artesunate, published randomized control trials, observational studies and cohort studies in over 1300 women exposed to oral artesunate and other artemisinin class drugs (via various routes of administration) in the first trimester of pregnancy and over 6500 women exposed to oral artesunate or other artemisinin class drugs (via various routes of administration) in the second and third trimester of pregnancy have not demonstrated an 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, 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 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% of detected radioactivity) to feto-placental tissues.

Pregnant rats dosed orally during organogenesis (GD 6 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, abnormal origin of subclavian artery) and skeletal (e.g., bent and/or shortened scapulae, humeri, femurs, and fibulae) 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 (ventricular septal defects, abnormal origin of subclavian artery), skeletal (e.g., cleft sternebrae, shortened and/or displaced ribs) and brain (dilated ventricles, pons absent) malformations in the absence of maternal toxicity. Additionally, administration of artesunate at 12 mg/kg/day to pregnant rabbits during organogenesis resulted in abortions and postimplantation loss. 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.

Risk Summary

DHA, a metabolite of artesunate, is present in human milk. There are no data on the effects of artesunate or DHA 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 for Injection and any potential adverse effects on the breastfed child from Artesunate for Injection or from the underlying maternal condition.

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)].

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.

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.

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.