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IMPORTANT SAFETY IMFORMATION
 
Special warnings and precautions for use
Non-falciparum malaria
Artesunate has not been evaluated in the treatment of severe malaria due
to Plasmodium vivax, Plasmodium malariae or Plasmodium ovale.
Switching to oral treatment regimen
Acute treatment of severe falciparum malaria with Artesun® should always
be followed by a complete treatment course of an appropriate oral
combination antimalarial regimen (see Section 4.2)
Resistance to antimalarials
Local information on the prevalence of resistance to antimalarials should be
considered in choosing the appropriate combination antimalarial regimen
for use with Artesun® Relevant treatment guidelines should be consulted.
Post-treatment anaemia
   Despite transient decreases in reticulocyte counts, clinically signicant anaemia associated with IV artesunate has not been common in clinical
trials. However, occasional cases of post-treatment haemolytic anaemia severe enough to require transfusion have been reported (see Section
4.8).
Hepatic / renal impairment
Data regarding artesunate pharmacokinetics in patients with hepatic and/or renal impairment are limited. Based on data from studies in patients
with severe malaria,
as well as the known metabolism of artesunate (see Section 5.2), dosage adjustment is not considered necessary in patients with hepatic or
renal impairment.
Paediatric population
In clinical trials, the ecacy and safety of intravenous and intramuscular artesunate have been similar in adult and paediatric populations.
Interaction with other medicinal products and other forms of interaction
Artesunate is rapidly and extensively converted to dihydroartemisinin (DHA), the active metabolite, primarily by plasma and erythrocyte
esterases. DHA elimination is
also rapid (half-life approximately 45 min) and the potential for drug-drug interactions appears limited. In vitro drug-interaction studies have
demonstrated minimal
eects of artesunate on cytochrome P450 isoenzymes. Few clinical drug-drug interaction studies have been performed, however no clinically
signicant interactions
have been identied.

Pregnancy and lactation
Pregnancy
Severe malaria is especially hazardous during pregnancy, therefore full dose parenteral antimalarial treatment should be administered without
delay.
There has been limited clinical experience with the use of artesunate in pregnancy. In animal studies, artesunate has been associated with foetal
toxicity during the rst
trimester of pregnancy. To date, clinical data regarding safety in the rst trimester have not indicated an increased risk of foetal harm. Treatment
with artesunate should
not be withheld during the rst trimester if it is potentially life-saving for the mother. As in other populations, the evidence that artesunate
reduces the risk of death
from severe malaria compared to other treatments should be borne in mind.
In a study of 461 pregnant Thai women (44 in their rst trimester) who were treated with artemisinins (predominantly artesunate), there was no
obvious evidence of
adverse eects amongst the 414 women for whom pregnancy outcomes were known. The observed rates of abortion, stillbirth, congenital
anomalies and low birth
weight were comparable to community rates.
In clinical trials from 1999 to 2006, 2,045 pregnant women in Thailand, the Gambia, and Sudan were treated with artesunate, either alone or in
combination with other
antimalarials, including quinine, meoquine, atovaquone-proguanil and sulfadoxine-pyrimethamine. In these patients, most of whom were in
their second or third
trimesters of pregnancy, there were no signicant dierences compared to the general community in birth weights, duration of gestations,
placental weights, or rates
of congenital abnormalities, or in growth and developmental parameters of infants monitored for one year.
Breastfeeding / lactation
Limited information indicates that dihydroartemisinin, the active metabolite of artesunate, is present at low levels in breast milk. The drug levels
are not expected to
cause any adverse eects in breastfed infants. The amount of drug present in breast milk does not protect the infant from malaria.

Effects on ability to drive and use of machines
There is no information on the eect of artesunate on the ability to drive or use machines. The patientĄ¯s clinical status should be considered
when assessing ability to
drive or operate machinery.

Undesirable effects
The most important reported side eect of artesunate is a rare severe allergic reaction (estimated risk approximately 1 in 3000 patients), which
has involved urticarial rash as well as other symptoms, including hypotension, prutitus, oedema, and/or dyspnoea.
More common minor side eects associated with IV administration have included dizziness, light-headedness, rash, and taste alteration
(metallic/ bitter taste). Nausea, vomiting, anorexia and diarrhea have also been reported, however it is uncertain whether such events have been
symptoms of severe malaria.
Adverse events considered at least possibly related to artesunate are listed below by body system, organ class and absolute frequency.
Frequencies are dened as very common (1/10), common (1/100¨C1/10), uncommon (1/1000¨C1/100), rare (1/10 000¨C1/1000), and very rare (<
1/10 000).
Blood and lymphatic systems disorders
Uncommon: Neutropenia and anaemia (both occasionally severe), thrombocytopenia
Very rare: Pure red cell aplasia
Frequency unknown: Post-treatment anaemia (see below), mild and transient decrease in reticulocyte count
Nervous system disorders
Common: Dizziness, light-headedness, headache, insomnia, tinnitus (with or without decrease in auditory function)
Very rare: Peripheral neuropathy (or paraesthesia)
Respiratory disorders
Common: Cough, nasal symptoms
Gastrointestinal disorders
Common: Altered taste, nausea, vomiting, abdominal pain or cramps, diarrhoea
Rare: Raised serum amylase, pancreatitis
Hepatobiliary disorders
Uncommon: Transient rises in liver transaminases (AST, ALT)
Rare: Hepatitis
Skin and subcutaneous tissue disorders
Common: Rash, alopecia
Musculoskeletal and connective tissue disorders
Common: Arthralgia, muscle disorders
General disorders and administration site conditions
Common: Fatigue, malaise, fever, pain at injection site
Immune system disorders
Uncommon: hypersensitivity
Post-treatment anaemia
In general, despite transient decreases in reticulocyte counts, clinically signicant anaemia attributed to IV artesunate has not been common in
clinical trials in severe malaria. However, in a case-series of 25 patients in Europe who were treated with IV artesunate for severe malaria acquired
in an endemic area, 6 patients developed signicant post-treatment haemolytic anaemia, presenting as late as 3 weeks after treatment, and 5 of
them required transfusion. The aetiology of the haemolysis remains unknown.
4.9 Overdose
Experience of acute overdose with artesunate is limited. A case of overdose has been documented in a 5-year-old child who was inadvertently
administered rectal artesunate at a dose of 88 mg/kg/day over 4 days, representing a dose more than 7-fold higher than the highest
recommended artesunate dose. The overdose was associated with pancytopenia, melena, seizures, multiorgan failure and death.
Treatment of overdose should consist of general supportive measures.




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