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adverse reactions
6 ADVERSE REACTIONS 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 )] The most common adverse reactions (incidence of 2% or greater) reported with Artesunate for Injection in clinical trials of severe malaria include acute renal failure requiring dialysis, hemoglobinuria, and jaundice. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Amivas, Inc at [1-855-526-4827 (1-855-5AMIVAS)] or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 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 (). 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. Adverse Reaction Artesunate (n=730) Quinine (n=730) 1 Acute renal failure requiring dialysis 2 65 (8.9%) 53 (7.3%) Hemoglobinuria 49 (6.7%) 33 (4.5%) Jaundice 17 (2.3%) 14 (1.9%) 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