Artesunate Amivas

HOS-099817 · has-adverse-reaction-information · PDF-Seite 6

Summary of the safety profile The most common adverse drug reaction reported in clinical trials has been anaemia. While anaemia occurs very commonly in patients with severe malaria as a result of the disease and effective treatment, anaemia that was not dose-related was also reported in healthy subjects in clinical pharmacology studies with intravenous artesunate. Post-Artesunate Delayed Haemolysis (PADH) has been reported very commonly following effective treatment of severe malaria with intravenous artesunate in travellers and in children (see section 4.4). Reticulocytopenia that resolves after completion of treatment with intravenous artesunate occurs commonly or very commonly (see section 4.4). Tabulated list of adverse reactions Adverse events considered at least possibly related to artesunate are listed below by body system, organ class and absolute frequency. Frequencies are defined as very common (≥ 1/10), common (1/100-1/10), uncommon (1/1 000-1/100) and unknown (frequency cannot be determined) (Table 1). Table 1. Summary of adverse drug reactions by organ system and frequency Organ Systems Very common Common Uncommon Not known Infections and Rhinitis infestations Blood and Anaemia Immune lymphatic system Reduced haemolytic disorders reticulocyte count anaemia Post-artesunate delayed haemolysis Immune system Anaphylaxis disorders Metabolism and Anorexia nutrition disorders Nervous system Dizziness, disorders Dysgeusia, Headache Cardiac disorders Bradycardia Electrocardiogram QT prolonged Vascular disorders Hypotension, Flushing Phlebitis Respiratory, Cough thoracic and mediastinal disorders Gastrointestinal Abdominal Pain, Nausea, disorders Diarrhoea, Vomit

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HOS-099813 · has-contraindication-information · PDF-Seite 3

Hypersensitivity to the active substance, to any other artemisinin antimalarial agent or to any of the excipients listed in section 6.1.

HOS-099812 · has-indication-information · PDF-Seite 2

Artesunate Amivas is indicated for the initial treatment of severe malaria in adults and children (see sections 4.2 and 5.1). Consideration should be given to official guidance on the appropriate use of antimalarial agents.

HOS-099815 · has-interaction-information · PDF-Seite 5

No clinical drug-drug interactions studies have been conducted with Artesunate Amivas. Effect of other medicinal products on artesunate and/or dihydroartemisinin (DHA) After intravenous administration, artesunate is converted to DHA by esterases and by CYP2A6. DHA is converted to inactive glucuronide conjugates primarily by 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 (see section 4.4). Co-administration of Artesunate Amivas 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 (see section 4.4). Effect of artesunate and/or DHA on other medicinal products 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.

HOS-099816 · has-pregnancy-information · PDF-Seite 5

Pregnancy There is limited clinical experience with the use of Artesunate Amivas in the first trimester of pregnancy. A risk to the fetus cannot be excluded. Animal studies have shown reproductive toxicity (see section 5.3). The use of Artesunate Amivas 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 intravenous in their second or third trimester. As a precautionary measure, it is preferable to avoid the use of Artesunate Amivas during the second or third trimester of pregnancy. Pregnancy registry A pregnancy registry has been set up to monitor all pregnancies and their outcomes following treatment with Artesunate Amivas. 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, however studies on female rats show no effect on fertility (see section 5.3). 5

HOS-099814 · has-warning-information · PDF-Seite 3

Hypersensitivity Allergic reactions to intravenous artesunate, including anaphylaxis have been reported. Other reported allergic reactions include urticaria, rash and pruritus (see section 4.8). Post-artesunate delayed haemolysis 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 intravenous 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. However, cases of post-artesunate haemolytic anaemia severe enough to require transfusion have been reported. Since a subset of patients with 3 delayed haemolysis after artesunate therapy have evidence of immune haemolytic anaemia, performing a direct antiglobulin test should be considered to determine if therapy, e.g. with corticosteroids, is necessary. See section 4.8. Reticulocytopenia The artemisinins have shown direct inhibitory effects on human erythroid precursors invitro 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 Amivas 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 live

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