INJECTABLE *

ARTESUNATE FOR
SEVERE MALARIA WHO
RECO
MMEN
TRE DED
ATME
USER GUIDE NT
* 60 mg vials of artesunic acid

Severe malaria is a medical emergency.

Malaria caused over 627,000 deaths in 2012,
mainly in children 1.

World Health Organization (WHO) recommends injectable artesunate

for the treatment of severe malaria 2
 SEVERE MALARIA IS LIFE THREATENING

Signs and symptoms of severe malaria 3 Early diagnosis and prompt

treatment will save lives
Administer antimalarial medicines to patient
Adults Children with suspected severe malaria without delay.
Duration of illness 5–7 days Shorter (1–2 days)
Respiratory distress/ Common Common
Initiate urgent treatment steps
deep breathing
(acidosis)
Convulsions Common (12%) Very common (30%) 1 Start resuscitative measures immediately
Posturing (decorticate/ Uncommon Common 2 Establish intravenous access
decerebrate and
opisthotonic rigidity) 3 Correct hypoglycaemia
Prostration/obtundation Common Common 4 Control convulsions
Resolution of coma 2–4 days Faster (1–2 days)
Neurological sequelae Uncommon (1%) Common (5-30%)
after cerebral malaria
Do not forget to do:
Jaundice Common Uncommon a detailed history
Hypoglycaemia Less common Common a thorough clinical examination
Metabolic acidosis Common Common AND laboratory investigations to confirm
diagnosis and complications
Pulmonary oedema Uncommon Rare
Renal failure Common Rare Start treatment even as the diagnosis is being
CSF opening pressure Usually normal Usually raised confirmed via laboratory testing.
Bleeding/clotting Up to 10% Rare
disturbances
Invasive bacterial Uncommon (<5%) Common (10%)
infection (co-infection)

PRODUCT Dose for children < 20 kg:

3.0 mg/kg
DESCRIPTION 4 Dose for children > 20 kg
60 and adults: 2.4 mg/kg
Ar
te

ion
mg
su

lut Can be given by intravenous route (IV)

na

l
5m

so
te

e
at
um n
di rbo line
l

or intramuscular route (IM).

1m

So ica
B Sa
IV is the preferred route of
Artesunate Bicarbonate Saline administration.
powder 60 mg ampoule solution * * Water for injection is not
an appropriate dilutant

What does the drug do?

Injectable artesunate is the 6first
Ar

0m line treatment recommended by WHO for severe malaria caused by Plasmodium

te

ion
su

g
lut
na

l
5m

falciparum, in both children and adults. It is a short-acting agent that kills so parasites more rapidly than conventional
te

te
m ona e
lin
u
l

di rb
1m

antimalarials, in particular because it is active against

So ica
B both the sexualSaand asexual stages of the parasite cycle -
killing all stages including young rings resulting in more rapid recovery.

Why has WHO changed its recommended drug for severe malaria?
Clinical evidence from two large-scale, multi-centre trials in South East Asia (SEAQUAMAT) 5 and Africa (AQUAMAT) 6
showed a reduction in the risk of death using injectable artesunate compared to quinine.
If used throughout Africa, injectable artesunate could save up to an additional 195,000 lives each year 7.

The advantages of injectable artesunate versus quinine

An overwhelming body of scientific evidence supports the superiority of artesunate over quinine
for the treatment of severe malaria in both adults and children across the world.
• Injectable artesunate saves more lives than quinine 7.
• Injectable artesunate is better tolerated than quinine and has fewer side effects 8.
• Injectable artesunate is easier to use than quinine and is less painful 8.

MMV - January 2015

 7 STEPS FROM PREPARATION TO ADMINISTRATION ate
Artesunate

Saline solution
5 ml
Arte
su
Artesunate Artesunate
60mg 60mg
30mg 60mg nate

Bicarbonate
1ml
Artesun
60mg ate

Sodium
Ar
12 tesu
0m nat
g e

1 WEIGH THE PATIENT 3

Artesunate
ate
RECONSTITUTE
Activate the drug: Artesunate powder
60mg

+ bicarbonate ampoule
Artesunate

1ml
60mg
Bicarbonate
1ml

A B Inject full contents of

Sodium

bicarbonate ampoule
(1 ml) into artesunate vial.
Arte Art
esu
su

n
60mg nate 60mg nate

5 ml
lutio
e so
e
1ml
at

Salin
rbon
Bicadium
So
Arte Arte Arte
su su su
30mg naattee 60mg naattee 120mg naattee

Saline solution
Saline solution
5 ml

Artesunate
Artesunate 60mg

Artesunate bicarbonate

Bicarbonate
1ml
60mg

Sodium
powder ampoule
Artesunate
ate

Saline solution
5 ml
Artesunate

The person prescribing artesunate must calculate 60mg

C Shake until dissolved. D The reconstituted solution
60mg
Artesunate Artesunate
60mg 60mg

Solution will be cloudy. will clear in about 2 mins.

Bicarbonate
1ml
Sodium
the dose using the patient’s weight. The adminis- Discard if not clear.
Arte
tering nurse or doctor must check the calculation suna Arte
suna ate
te te nate
Artesu
Saline solution
5 ml

to confirm that it is correct. Arte

suna
Artesunate Artesunate
60mg 60mg
30mg 60mg te
Bicarbonate
1ml

Artesun
60mg ate
Sodium

1ml
Artesunate

Artesunate
ate
Saline solution
5 ml

60mg

Bicarbonate
1ml
Ar

Sodium
12 tesu
Artesunate
60mg 60mg
0m nat
g e
Artesunate

2
60mg

Bicarbonate
1ml
CHECK VIALS NEEDED Artesunate
ate
Sodium

Based on the weight of the patient you will 60mg IMPORTANT Arte
su
need to determine how many vials to prepare. 60mg nate

Saline solution
5 ml
You may not use the entire vial. You can expect • Follow sterile procedures for all steps. Artesunate
60mg

• Use full content of bicarbonate vial.

Artesunate

some wastage, since any unused solution must

60mg
Bicarbonate
1ml
Sodium

be discarded, unless used for another patient • Do not shake too vigorously.
Saline solution
5 ml
Artesunate

• Discard if solution does not clear.

60mg

within an hour.
Artesunate
ate
Arte Arte
su su60mg

n
60mg nate 60mg nate

5 ml
lutio
60 mg
Why must artesunate be reconstitued

e so
ate
1ml

Saline solution
5 ml
Ar
with sodium bicarbonate?

Salin
rbon
Bicadium

less than 25 kg 1 Artesunate

60mg
So

Artesunate is the sodium salt of the hemisuccinate

2

1ml
26-50 kg
Saline solution
5 ml

Saline solution
5 ml

Artesunate
60mg
ester of artemisinin. It is soluble in water but has poor
Artesunate
60mg

51-75 kg 3 stability in aqueous solutions at neutral or acid pH.

Artesunate
ate
76-100 kg 4 60mg In the injectable form, artesunic acid is reconstituted
in sodium bicarbonate to form sodium artesunate,
Calculation the active formArteof the drug. Art
su e nate suna
te
Less than 20 kg
Due to the poor stability of the drug it must be
1ml

Target dose: Vials of artesunate needed:

Saline solution
5 ml

Artesunate reconstituted or activated immediately before

3.0 mg per kg 60mg
3.0 mg x body weight (kg)
of body weight
dilution and then administered within 1 hour.
Product strength (60 mg)

More than 20 kg
Target dose: Vials of artesunate needed:
2.4 mg per kg 2.4 mg x body weight (kg)
of body weight Product strength (60 mg)

IMPORTANT
• Each vial requires separate reconstitution,
dilution and administration.
• Reconstitute immediately before use.

MMV - January 2015

 Arte Arte Arte
su su su
30mg naattee 60mg naattee 120mg naattee

IV intravenous route IM intramuscular route

Bicarbonate
1ml
Sodium
Artesunate
60mg

4 DILUTE ate
Artesunate
Arte
su
30mg naattee

30mg
Arte
Reconstituted su artesunate
Arte
su
60mg naattee
Arte
su
120mg naattee
5 CALCULATE THE DOSE
Calculate and withdraw the required dose
60mg nate

Bicarbonate
1ml
Sodium

Bicarbonate
1ml
Artesun
60mg ate

Sodium
Artesunate + saline solutionAr (or dextrose 5%) in ml according to route of administration:
12 tesu
60mg

ate 0 n
Volume for dilution
mg
IV IM For intravenous route (IV) For intramuscular route (IM)
Artesu ate
nate
Bicarbonate
30mg
Arte solution
sun 1 ml 1 ml Concentration: 10 mg/ml Concentration: 20 mg/ml
60m ate

Bicarbonate
1ml
Artesun
60mg ate

Sodium
g
Saline solution
Ar 5 ml 2 ml 3.0 mg30 texsunaatteebody60weight
Ar tesu
naattee (kg)
Ar tesu
120 naattee
Ar
3.0 mg x body weight (kg)
tes
mg mg mg

20 1 un
Total volume mg ate 6 ml 3 ml IV artesunate solution IM artesunate solution

Bicarbonate
1ml
Sodium
Artesunate
concentration 10 mg/ml concentration 20 mg/ml
Artesunate 60mg 10 mg/ml 20 mg/ml
60mg
Round up to the next whole number Round up to the next whole number

1ml
Artesunate
60mg

solution concentration Example: Example:

ate for 8 kg child:
Artesun(ml)
Saline solution

Dose needed Dose needed (ml) for 8 kg child:

5 ml

Less than 20 kg
Arte
su
Artesunate Artesunate
60mg 60mg
30mg 60mg nate
3.0 x 8 3.0 x 8

Bicarbonate
Bicarbonate

1ml
1ml

Artesuna
te

Arte
60mg
Artesunate

Sodium
Sodium

su B Withdraw all the air

60mg

A = 2.4Ar ml = 1.2 ml
n

1ml

60mg nate
5 ml
lutio

e
from the vial. 10 12 tesu
0m nat
20
e so

g e
ate

2.4 ml rounded up to 3 ml 1.2 ml rounded up to 2 ml

1ml

Salin
bon
Bicarium
Sod

esu Art
Artesunate
ate Weight Dose Weight Dose
n

ate 60mg nate

5 ml
lutio

60mg
kg mg ml kg mg ml
e so
e
1ml
at

Salin
rbon
Bicadium

6-7 20 2 6-7 Artesunate

20 1
So

Artesunate 60mg

1ml
60mg
Bicarbonate
1ml

7 - 10 30 3 7 - 10 30 2
Sodium

Artesunate saline
Artesunate Artesunate
60mg 60mg

reconstituted solution 11 - 13 40 4 11 - 13 40 2
Arte Art
su 14 - 16 esu
50 5 14 - 16 50 3

n
60mg nate 60mg nate

5 ml
lutio
Arte C Inject
Ar required volume D Artesunate solution
of tsaline

e so
suna esun into the is now ready for use. 17 - 20 60 6 17 - 20 60 3
e

Arte Arte Arte

1ml
at

te ate su su su

Salin
30mg naattee 60mg naattee 120mg naattee
rbon
Bicadium

reconstituted solution.
So

Arte

Bicarbonate
1ml
Arte

Sodium
Saline solution
5 ml

suna suna
te te
Artesunate
60mg
Artesunate
Concentration: 10 mg/ml Concentration: 20 mg/ml
60mg

Artesunate
ate 2.4 mg x body weight (kg) 2.4 mg x body weight (kg)
60mg
IV artesunate solution IM artesunate solution
Artesunate
Arteconcentration 10 mg/ml
Saline solution
5 ml

concentration 20 mg/ml
suna
Artesunate
60mg
30mg 60mg Roundte Aup to the next whole number

Bicarbonate
1ml
Artesuna

Arte
te

Round up to the next whole number

60mg

rt

Sodium
suna nate esu
te Ar
12 tesu Example: Example:
0m nat
g e
1ml
Saline solution
5 ml

Artesunate
60mg
Dose needed (ml) for 26 kg child: Dose needed (ml) for 26 kg child:
Can regular water forate injection be used
Artesunate
2.4 x 26 = 6.24 ml
2.4 x 26 = 3.12 ml
as a dilutant? 60 mg 10 20
6.24 ml rounded up to 7 ml 3.12 ml rounded up to 4 ml
Artesunate
There is no data to show that water for injection is Artesunate
60mg

an appropriate dilutant. Artesunate should only be

1ml

60mg

Weight Dose Weight Dose

diluted with either 5% dextrose or normal saline. kg mg ml kg mg ml
20 - 25 60 6 20 - 25 60 3
Arte Art
esu
suna
n

How to proceed with preparation60 60mg nate 26 - 29

5 ml

te
70 7 26 - 29 70 4
lutio

mg
e so
More than 20 kg

of more than 1 artesunate vial?

e
1ml
at

30 - 33 80 8 30 - 33 80 4
Salin
rbon
Bicadium
So

1. Line up your reconstituted vials for one patient. 34 - 37 90 9 34 - 37 90 5

Saline solution
5 ml

Artesunate
60mg 2. Use one syringe to reconstitute each vial with 38 - 41 100 10 38 - 41 100 5
the bicarbonate and carefully
Artesunate
ate
set each recons- 42 - 45 110 11 42 - 45 110 6
tituted vial to one 60side.
mg
46 - 50 120 12 46 - 50 120 6
3. Use a new syringe to dilute each vial with
51 - 54 130 13 51 - 54 130 7
the correct volume of saline and set aside Artesunate Arte
suna
te
4. Administer the contents of vials to the patient 55 - 58 140 14 55 - 58 140 7
59 - 62 150 15 59 - 62 150 8
1ml

Artesunate
by using a new syringe that is large enough
63 - 66 160 16 63 - 66 160 8
60mg

to draw up the full dose from each of your

reconstituted and diluted vials. 67 - 70 170 17 67 - 70 170 9
71 - 75 180 18 71 - 75 180 9
76 - 79 190 19 76 - 79 190 10
IMPORTANT
80 - 83 200 20 80 - 83 200 10
Water for injection is not an appropriate dilutant
84 - 87 210 21 84 - 87 210 11
88 - 91 220 22 88 - 91 220 11
92 - 95 230 23 92 - 95 230 12
96 - 100 240 24 96 - 100 240 12
Remark: the upper limit for each weight band is 0.9 kg e.g. 14 - 16 kg covers
14 - 16.9 kg.
6 ADMINISTER
Withdraw the required dose (ml)
from the prepared vial(s) and inject.
Intravenous route (IV) Intramuscular route (IM)
Slow bolus 3-4 ml per Inject slowly. Spread doses of
minute. more than 2 ml over different
sites for young babies and
5 ml for adults.
IMPORTANT
• Prepare the correct size syringe.
• Double check dose required (mls) for patient’s
weight (kg) before injecting.
• Inject immediately after preparation.
• Discard any solution not used within 1 hour.
• Prepare a fresh solution for each administration.
Why IV better than IM?
The purpose of giving artesunate via the IV route
is to initiate a rapid systemic response. The drug
is immediately available to the body to fight the
malaria infection. IM artesunate is injected into
muscle tissues and absorbed less rapidly and takes
effect more slowly. Hence the need for a higher
concentration of the drug for IM route (20mg/ml).
Is pain management needed with IV/IM
administration?
There should be no pain with administration of
artesunate IV unless the line is not sitting in the vein.
IM injections can be painful. Nurses should use skills
to relax or distract patients.
Why must you push the IV drug slowly?
Artesunate must be administered at 3-4 mls per
minute. If the drug is administered faster the patient
will likely experience speed shock which is a sudden
adverse serious physiologic reaction to the drug
that was administered too quickly. In addition,
administering at the prescribed rate will allow you
to monitor the patient and to stop if you see signs
of a serious adverse reaction.
Why must the IV line be flushed?
The line must be flushed with 3ml of normal saline
before administration or checked for patency by
pulling back on the syringe to check for a flashback
of blood. Flushing after administration ensures
complete delivery of the prescribed dose into the
bloodstream. It also avoids interactions between
artesunate and possible incompatible medications
subsequently administered through
the same line.
7 DOSING
SCHEDULE
1. Give 3 parenteral doses over 24 hours
as indicated in the opposite table
2. Give parenteral doses for a minimum
of 24 hours once started irrespective of the
patients ability to tolerate oral treatment earlier.
• Day 1 Dose 1: on admission (0 Hours)
Dose 2: 12 hours later
• Day 2 Dose 3: 24 hours after first dose
-- When the patient can take oral medication,
prescribe a full 3-day course of recommended
first line oral Artemisinin Combination Therapy
(ACT)*. The first dose of ACT should be
taken between 8 and 12 hours after the last
injection of artesunate.
-- Until the patient is able to take oral
medication, continue parenteral treatment
(one dose a day) for a maximum of 7 days.
-- A course of injectable artesunate should
always be followed by a 3-day course of ACT.
• Evaluate the patient’s progress regularly.
IMPORTANT
• Prepare a fresh solution for each administration.
• Discard any unused solution after use.
* Oral ACT – what are they and what are
they used for?
Artemisinin-based Combination Therapy or ACT
are combination drugs (artemesinin derivatives
combined with partner compounds that are elimi-
nated more slowly) used to treat uncomplicated
P. falciparum malaria or to complete the treatment
of severe malaria after administration of injectable
artesunate. ACT are administered over 3 days and
the current options recommended by WHO are:
• artemether plus lumefantrine
• artesunate plus amodiaquine
• artesunate plus mefloquine
• artesunate plus sulfadoxine-pyrimethamine
• dihydroartemisinin plus piperaquine
This document is intended to demonstrate to health workers how to
prepare and administer injectable artesunate, a treatment for severe
malaria. It is not intended to provide personal medical advice. The
responsibility for the interpretation and use of this material lies with the
reader. In no event shall MMV be liable for damages arising from its use.
© 2014 Medicines for Malaria Venture (MMV). All rights reserved. A copy
of this document can only be made upon MMV’s written authorization.
INJECTABLE ARTESUNATE

Is injectable artesunate safe in pregnancy?

Given the life-threatening nature of severe malaria, parenteral antimalarials should be given to pregnant women
with severe malaria in full doses without delay. Injectable artesunate is preferred over quinine in the second and
third trimesters, because quinine is associated with recurrent hypoglycaemia. Artesunate has not been evaluated
in the first trimester of pregnancy, however both artesunate and quinine may be considered as options until more
evidence becomes available. Treatment must not be delayed; so if only one of the drugs artesunate, artemether
or quinine is available, then it should be started immediately.

Use only if the benefit out weights the risk during the first 3 months of pregnancy.

Is artesunate safe to use with premature infants?

Injectable artesunate is considered safe in children of 6 kgs and higher. No data is available for children with lower
body weight.

How to trouble shoot in the case of overdose & toxicity?

Experience of acute overdose with artesunate is limited. A case of overdose has been documented in which
a 5-year-old child was inadvertently given rectal artesunate at a dose of 88 mg/kg daily for 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.

Elimination of artesunate is very rapid, and antimalarial activity is determined by dihydroartemisinin elimination
(half-life approximately 45 min).

Treatment of overdose should consist of general supportive measures; ECG monitoring might be considered due
to the possibility of QT interval prolongation and associated risk of ventricular arrhythmias.

What are the side effects of artesunate?

Artemisinin and its derivatives are safe and remarkably well tolerated. Injectable artesunate like any other
medication, may cause side effects, but not everybody gets them. It may not be possible to distinguish
the effects of severe malaria from the side effects of the medicine. Please see product insert leaflet for more details.

Interactions
No significant adverse interactions have been documented.

Where to report

1 WHO, World Malaria Report 2013 - http://www.who.int/malaria/publications/world_malaria_report_2013/wmr13_avant_propos.pdf?ua=1

2 World Health Organization (WHO)/Organisation mondiale de la santé (OMS), Directives pour le traitement du paludisme, 2° Édition, Genève, 2011 ;
http://www.who.int/malaria/publications/atoz/9789241547925/fr/index.html
3 WHO, Management of Severe Malaria - A practical handbook - Third edition - April 2013 - http://www.who.int/malaria/publications/atoz/9789241548526/en/
4 World Health Organization (WHO) List of Prequalified Medicinal Products (http://apps.who.int/prequal/query/ProductRegistry. aspx?list=ma): artesunate
injectable, reference N° MA051, prequalified on 05-Nov-2010.
5 Dondorp A. et al. South East Asian Quinine Artesunate Malaria Trial (SEAQUAMAT) group ; Artesunate versus quinine for Treatment of severe falciparum
malaria: a randomised trial ; The Lancet, Volume 366, Issue 9487, Pages 717-725, 27 August 2005.
6 Dondorp A. et al. Artesunate versus quinine for Treatment of severe falciparum malaria in African Children (AQUAMAT): an open-label, randomised trial ;
The Lancet, Volume 376, Issue 9753, Pages 1647-1657, 13 November 2010.
7 Médecins Sans Frontières. Malaria: Making the Switch (2011):
http://www.msf.org/shadomx/apps/fms/fmsdownload.cfm?file_uuid=27E406A3-2B31-4C64-8D47-6EB733128EDF&siteName=msf
8 White NJ et al. Severe hypoglycemia and hyperinsulinemia in falciparum malaria. N Engl J Med 309:61–66 (1983).

Acknowledgements
The materials was developed by Medicines for Malaria Venture (MMV).
MMV gratefully acknowledges the following partners who contributed to the technical content:
Clinton Health Access Initiative (CHAI)
Malaria Consortium
Médecins Sans Frontières (MSF)
Global Malaria Programme/World Health Organization (WHO)