Artesunate

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 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.

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.

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.

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

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.

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.

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.

Reticulocytopenia that resolves after completion of treatment with IV artesunate occurs commonly or very commonly.

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).

Summary of adverse drug reactions by organ system and frequency: