ARTESUNATE AMIVAS Powder and solvent for solution for injection Ref.[28241] Active ingredients: Artesunate

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 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. See section 4.8.

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 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 liver stage forms of Plasmodium.

Infants aged less than 6 months

There are insufficient clinical data to establish the safety and efficacy of Artesunate Amivas in infants below 6 months of age. Pharmacokinetic modelling and simulations indicate that after 2.4 mg/kg IV artesunate the dihydroartemisinin (DHA) plasma exposures in infants agedless than 6 months are likely to be higher than those in older infants and children (see section 5.2).

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 (see section 5.2).

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 WHO 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 WHO recommended maximum daily intake of 2 g sodium for an adult.

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.

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.

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.

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 IV 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 (see section 5.3).

No studies on the effects on the ability to drive and use machines have been performed. Patients should be warned not to drive or use machines if they feel tired or dizzy.

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 IV artesunate.

Post-Artesunate Delayed Haemolysis (PADH) has been reported very commonly following effective treatment of severe malaria with IV artesunate in travellers and in children (see section 4.4).

Reticulocytopenia that resolves after completion of treatment with IV 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 (1/1000-1/100) and unknown (frequency cannot be determined) (Table 1).

Table 1. Summary of adverse drug reactions by organ system and frequency:

In the absence of compatibility studies, this medicinal product must not be mixed with other medicinal products.