PRODUCT INFORMATION

Hypersensitivity to artesunate including cases of anaphylaxis have been reported during the use of parenteral artesunate (including Artesunate.)

Post Artesunate Delayed Hemolysis
Post-artesunate delayed haemolysis (PADH) is characterised by decreased haemoglobin with laboratory evidence of haemolysis (such as decreased haptoglobin and increased lactate dehydrogenase) with onset at least 7 days and sometimes several weeks after initiating artesunate treatment. PADH has been reported to occur very commonly after successful treatment of severe malaria that commenced with IV artesunate in returning travellers. The risk of PADH may be highest in patients with hyperparasitaemia and in younger children. Patients should be monitored for evidence of haemolytic anaemia for 4 weeks after starting artesunate treatment. Spontaneous recovery from PADH usually occurs within a few weeks. Some patients require transfusion.

Reticulocytopenia
The artemisinins have shown direct inhibitory effects on human erythroid precursors in vitro and inhibit bone marrow responses (especially red blood cell precursors) in animal models. Both animal preclinical data and human data from clinical trials have suggested that reversible reticulocytopenia occurs at least commonly in association with treatment with intravenous artesunate (see section 4.8). The reticulocyte count recovers after cessation of treatment.

Malaria due to Plasmodium vivax, Plasmodium malariae or Plasmodium ovale
Artesunate has not been evaluated in the treatment of severe malaria due to Plasmodium vivax, Plasmodium malariae or Plasmodium ovale. Available data indicates that it is effective against all Plasmodium species (see section 5.1). It 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. Patients treated initially with artesunate for severe malaria due to P. vivax or P. ovale should receive an antimalarial agent that is active against the hypnozoite liver stage forms of Plasmodium.

Infants aged less than 6 months
Pharmacokinetics modelling and simulations indicate that the DHA plasma exposure after 2.4 mg/kg of IV artesunate in infants less than 6 months are likely to be higher than those in older infants and children. Pharma modeling and simulations indicate that after 2.4 mg/kg IV artesunate, the DHA plasma exposure is limited.

Elderly
There are insufficient clinical data to establish the safety and efficacy of intravenous artesunate in patients aged 65 years and older with severe malaria.

Information about excipients
This medicinal product contains 193 mg sodium per the recommended single dose for a 60 kg adult, equivalent to 9.6 % of the recommended maximum daily intake of 2 g sodium for an adult. As the first and second doses are recommended 12 hours apart, on days when two doses are given in a 24-hour period, then the dose would be 386 mg sodium per day, equivalent to 19.2 % of the recommended maximum daily intake of 2 g sodium for an adult.

Pregnancy
There is limited clinical experience with the use of Artesunate in the first trimester of pregnancy. A risk to the fetus cannot be excluded. Animal studies have shown reproductive toxicity. The use of Artesunate in the first trimester is therefore not recommended unless the benefit to the mother outweighs the risk to the fetus. A moderate amount of clinical data on pregnant women (between 300-1000 pregnancy outcomes) indicate no malformative or feto/neonatal toxicity of artesunate when given IV in their second or third trimester. As a precautionary measure, it is preferable to avoid the use of Artesunate  during the second or third trimester of pregnancy. A pregnancy registry has been set up to monitor all pregnancies and their outcomes following treatment with Artesunate.

Breast-feeding
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 benefits of breastfeeding to mother and infant should be weighed against potential risk from infant exposure to DHA through breast milk.

Fertility
No fertility data are available in humans. Animal studies have reported effects on the male reproductive organs.

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%), 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).

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.

No clinical drug-drug interactions studies have been conducted with Artesunate. After intravenous administration, artesunate is converted to DHA by esterases and by CYP2A6. DHA is converted to inactive glucuronide UGT1A9. Co-administration of intravenous artesunate with strong inhibitors of UGT enzymes (e.g. axitinib, vandetanib, imatinib, diclofenac) may increase plasma exposures to DHA. Co-administration should be avoided if possible. Co-administration of Artesunate with UGT inducers (e.g. nevirapine, ritonavir, rifampicin, carbamazepine, phenytoin) may decrease DHA exposures, leading to a reduction in, or loss of, efficacy. Co-administration should be avoided. Limited data from in-vitro studies and from clinical drug-drug interaction studies with oral artesunate and/or oral DHA have indicated that DHA induces CYP3A and inhibits CYP1A2. Caution is advised when co-administering intravenous artesunate with substrates of CYP3A4 or CYP1A2 that have narrow therapeutic windows.

To report SUSPECTED ADVERSE REACTIONS, contact your local AMIVAS or / and local authorities.