Artesunate

Chemical formula: C₁₉H₂₈O₈  Molecular mass: 384.425 g/mol  PubChem compound: 6917864

Interactions

Artesunate interacts in the following cases:

UGT inducers

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.

Strong inhibitors of UGT enzymes

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.

CYP3A4 substrates, CYP1A2 substrates

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.

Fertility

Population group: men, irrespective of age

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

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.

Nursing mothers

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.

Carcinogenesis, mutagenesis and fertility

Fertility

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

Effects on ability to drive and use machines

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.

Adverse reactions


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:

Organ Systems Very CommonCommon UncommonUnknown
Infections and
Infestations
 Rhinitis  
Blood and Lymphatic
System Disorders
Anaemia
Reduced reticulocyte
count
Post-artesunate
delayed haemolysis
   
Metabolism And
Nutrition Disorders
  Anorexia 
Nervous System
Disorders
 Dizziness, Dysgeusia
Headache
  
Cardiac Disorders  Bradycardia  
Vascular Disorders  Hypotension, PhlebitisFlushing 
Respiratory, Thoracic
and Mediastinal
Disorders
 Cough  
Gastrointestinal
Disorders
 Abdominal Pain,
Diarrhoea, Vomiting
Nausea, Constipation 
Hepatobiliary
Disorders
 Hyperbilirubinaemia
Jaundice
  
Skin and
Subcutaneous Tissue
Disorders
  Stevens-Johnson
Syndrome, Pruritus,
Rash, Urticaria
 
Renal and Urinary
Disorders
 Haemoglobinuria
Acute renal failure
  
General Disorders and
Administration Site
Conditions
 PyrexiaFatigue, Pain at
injection site
 
Immune System
Disorders
   Anaphylaxis
Investigations  ALT increased,
AST increased
  

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