INJECTABLE ARTESUNATE

INJECTABLE ARTESUNATE FOR SEVERE MALARIA

USER GUIDE

*

60 mg vials of artesunic acid*

Severe malaria is a medical emergency. Malaria caused over 627,000 deaths in 2012, mainly in children1.

World Health Organization (WHO) recommends injectable artesunate for the treatment of severe malaria2

WHO RECOMMENDEDTREATMENT

SEVERE MALARIA IS LIFE THREATENING

MMV - January 2015

What does the drug do? Injectable artesunate is the first line treatment recommended by WHO for severe malaria caused by Plasmodium falciparum, in both children and adults. It is a short-acting agent that kills parasites more rapidly than conventional antimalarials, in particular because it is active against both the sexual and 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 quinineAn 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.

Bicarbonateampoule

Artesunatepowder 60 mg

Saline solution *

PRODUCT DESCRIPTION 4

Artesunatenate

60mg

1 ml

Sodium

Bicarbonate

Saline solutio

n

5 ml

Artesunatenate

60mg

1 ml

Sodium

Bicarbonate

Saline solutio

n

5 ml

Dose for children < 20 kg: 3.0 mg/kg Dose for children > 20 kg and adults: 2.4 mg/kg

Can be given by intravenous route (IV) or intramuscular route (IM).IV is the preferred route of administration.* Water for injection is not an appropriate dilutant

Signs and symptoms of severe malaria3

Adults Children

Duration of illness 5–7 days Shorter (1–2 days)

Respiratory distress/ deep breathing (acidosis)

Common Common

Convulsions Common (12%) Very common (30%)

Posturing (decorticate/decerebrate and opisthotonic rigidity)

Uncommon Common

Prostration/obtundation Common Common

Resolution of coma 2–4 days Faster (1–2 days)

Neurological sequelae after cerebral malaria

Uncommon (1%) Common (5-30%)

Jaundice Common Uncommon

Hypoglycaemia Less common Common

Metabolic acidosis Common Common

Pulmonary oedema Uncommon Rare

Renal failure Common Rare

CSF opening pressure Usually normal Usually raised

Bleeding/clotting disturbances

Up to 10% Rare

Invasive bacterial infection (co-infection)

Uncommon (<5%) Common (10%)

4

Early diagnosis and prompttreatment will save lives Administer antimalarial medicines to patient with suspected severe malaria without delay.

Initiate urgent treatment steps

Start resuscitative measures immediately

Establish intravenous access

Correct hypoglycaemia

Control convulsions

3

21

Start treatment even as the diagnosis is being confirmed via laboratory testing.

a detailed historya thorough clinical examination AND laboratory investigations to confirm diagnosis and complications

Do not forget to do:

IMPORTANT

•Follow sterile procedures for all steps.•Use full content of bicarbonate vial.•Do not shake too vigorously.•Discard if solution does not clear.

3

7 STEPS FROM PREPARATION TO ADMINISTRATION

WEIGH THE PATIENT 1

ArtesunateateArtesunateate

Artesunateate

Artesunateate

Artesunateate60mg

Artesunateate30mg

Artesunateate60mg

Artesunateate120mg

Artesunateate120mg

Artesunateate30mg

ArtesunateateArtesunateate60mg 60mg

1ml

1ml

60mg

60mg

Artesunate60mg

Artesunate60mg

Artesunate60mg

Artesunate60mg

1ml

Sodi

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carb

onat

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Artesunate60mg

Artesunate60mg

1ml

Sodi

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carb

onat

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1ml

Sodi

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carb

onat

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1ml

Sodi

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Artesunate60mg

1ml

Sodi

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Salin

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n5

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Salin

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lutio

n5

ml

Salin

e so

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n5

ml

Salin

e so

lutio

n5

ml

Artesunate60mg

Inject full contents of bicarbonate ampoule (1 ml) into artesunate vial.

ArtesunateateArtesunateate

Artesunateate

Artesunateate

Artesunateate60mg

Artesunateate30mg

Artesunateate60mg

Artesunateate120mg

Artesunateate120mg

Artesunateate30mg

ArtesunateateArtesunateate60mg 60mg

1ml

1ml

60mg

60mg

Artesunate60mg

Artesunate60mg

Artesunate60mg

Artesunate60mg

1ml

Sodi

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carb

onat

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Artesunate60mg

Artesunate60mg

1ml

Sodi

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carb

onat

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1ml

Sodi

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carb

onat

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1ml

Sodi

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carb

onat

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Artesunate60mg

1ml

Sodi

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Salin

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n5

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Salin

e so

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n5

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Salin

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n5

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Salin

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n5

ml

Artesunate60mg

Artesunatepowder

bicarbonateampoule

BA

ArtesunateateArtesunateate

Artesunateate

Artesunateate

Artesunateate60mg

Artesunateate30mg

Artesunateate60mg

Artesunateate120mg

Artesunateate120mg

Artesunateate30mg

ArtesunateateArtesunateate60mg 60mg

1ml

1ml

60mg

60mg

Artesunate60mg

Artesunate60mg

Artesunate60mg

Artesunate60mg

1ml

Sodi

umBi

carb

onat

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Artesunate60mg

Artesunate60mg

1ml

Sodi

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carb

onat

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1ml

Sodi

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carb

onat

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1ml

Sodi

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carb

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Artesunate60mg

1ml

Sodi

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carb

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Salin

e sol

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n5

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Salin

e so

lutio

n5

ml

Salin

e so

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n5

ml

Salin

e so

lutio

n5

ml

Artesunate60mg The reconstituted solution

will clear in about 2 mins. Discard if not clear.

Shake until dissolved. Solution will be cloudy.

ArtesunateateArtesunateate

Artesunateate

Artesunateate

Artesunateate60mg

Artesunateate30mg

Artesunateate60mg

Artesunateate120mg

Artesunateate120mg

Artesunateate30mg

ArtesunateateArtesunateate60mg 60mg

1ml

1ml

60mg

60mg

Artesunate60mg

Artesunate60mg

Artesunate60mg

Artesunate60mg

1ml

Sodi

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Artesunate60mg

Artesunate60mg

1ml

Sodi

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carb

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1ml

Sodi

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1ml

Sodi

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Artesunate60mg

1ml

Sodi

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Salin

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Salin

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n5

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Salin

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Salin

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Artesunate60mg

DC

MMV - January 2015

2

Why must artesunate be reconstitued with sodium bicarbonate? Artesunate is the sodium salt of the hemisuccinate ester of artemisinin. It is soluble in water but has poor stability in aqueous solutions at neutral or acid pH. In the injectable form, artesunic acid is reconstituted in sodium bicarbonate to form sodium artesunate, the active form of the drug. Due to the poor stability of the drug it must be reconstituted or activated immediately before dilution and then administered within 1 hour.

RECONSTITUTE Activate the drug: Artesunate powder + bicarbonate ampoule

The person prescribing artesunate must calculate the dose using the patient’s weight. The adminis-tering nurse or doctor must check the calculation to confirm that it is correct.

CHECK VIALS NEEDED Based on the weight of the patient you will need to determine how many vials to prepare. You may not use the entire vial. You can expect some wastage, since any unused solution must be discarded, unless used for another patient within an hour.

Target dose:

Target dose:

Calculation

3.0 mg per kg of body weight

2.4 mg per kg of body weight

Vials of artesunate needed:

Vials of artesunate needed:

3.0 mg x body weight (kg)

Product strength (60 mg)

2.4 mg x body weight (kg)

Product strength (60 mg)

60 mg

less than 25 kg 1

26-50 kg 2

51-75 kg 3

76-100 kg 4

IMPORTANT

•Each vial requires separate reconstitution, dilution and administration.

•Reconstitute immediately before use.

Less than 20 kg

More than 20 kg

Withdraw all the air from the vial.

ArtesunateateArtesunateate

Artesunateate

Artesunateate

Artesunateate60mg

Artesunateate30mg

Artesunateate60mg

Artesunateate120mg

Artesunateate120mg

Artesunateate30mg

ArtesunateateArtesunateate60mg 60mg

1ml

1ml

60mg

60mg

Artesunate60mg

Artesunate60mg

Artesunate60mg

Artesunate60mg

1ml

Sodi

umBi

carb

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Artesunate60mg

Artesunate60mg

1ml

Sodi

umBi

carb

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1ml

Sodi

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carb

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1ml

Sodi

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Artesunate60mg

1ml

Sodi

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Salin

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Salin

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Salin

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Artesunate60mg

Artesunate60mg

Artesunate60mg

4 5DILUTEReconstituted artesunate + saline solution (or dextrose 5%)

7 STEPS FROM PREPARATION TO ADMINISTRATION

Can regular water for injection be used as a dilutant? There is no data to show that water for injection is an appropriate dilutant. Artesunate should only be diluted with either 5% dextrose or normal saline.

How to proceed with preparation of more than 1 artesunate vial?1. Line up your reconstituted vials for one patient.2. Use one syringe to reconstitute each vial with

the bicarbonate and carefully set each recons-tituted vial to one side.

3. Use a new syringe to dilute each vial with the correct volume of saline and set aside

4. Administer the contents of vials to the patient by using a new syringe that is large enough to draw up the full dose from each of your reconstituted and diluted vials.

CALCULATE THE DOSECalculate and withdraw the required dose in ml according to route of administration:

IV IM

Bicarbonate solution 1 ml 1 ml

Saline solution 5 ml 2 ml

Total volume 6 ml 3 ml

Artesunate 60mg solution concentration

10 mg/ml 20 mg/ml

Volume for dilution

ArtesunateateArtesunateate

Artesunateate

Artesunateate

Artesunateate60mg

Artesunateate30mg

Artesunateate60mg

Artesunateate120mg

Artesunateate120mg

Artesunateate30mg

ArtesunateateArtesunateate60mg 60mg

1ml

1ml

60mg

60mg

Artesunate60mg

Artesunate60mg

Artesunate60mg

Artesunate60mg

1ml

Sodi

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carb

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Artesunate60mg

Artesunate60mg

1ml

Sodi

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carb

onat

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1ml

Sodi

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carb

onat

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1ml

Sodi

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carb

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Artesunate60mg

1ml

Sodi

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carb

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Salin

e sol

utio

n5

ml

Salin

e so

lutio

n5

ml

Salin

e so

lutio

n5

ml

Salin

e so

lutio

n5

ml

Artesunate60mg

Inject required volume of saline into the reconstituted solution.

ArtesunateateArtesunateate

Artesunateate

Artesunateate

Artesunateate60mg

Artesunateate30mg

Artesunateate60mg

Artesunateate120mg

Artesunateate120mg

Artesunateate30mg

ArtesunateateArtesunateate60mg 60mg

1ml

1ml

60mg

60mg

Artesunate60mg

Artesunate60mg

Artesunate60mg

Artesunate60mg

1ml

Sodi

umBi

carb

onat

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Artesunate60mg

Artesunate60mg

1ml

Sodi

umBi

carb

onat

e

1ml

Sodi

umBi

carb

onat

e

1ml

Sodi

umBi

carb

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Artesunate60mg

1ml

Sodi

umBi

carb

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Salin

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utio

n5

ml

Salin

e so

lutio

n5

ml

Salin

e so

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n5

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Salin

e so

lutio

n5

ml

Artesunate60mg

BA

Artesunate solution is now ready for use.

ArtesunateateArtesunateate

Artesunateate

Artesunateate

Artesunateate60mg

Artesunateate30mg

Artesunateate60mg

Artesunateate120mg

Artesunateate120mg

Artesunateate30mg

ArtesunateateArtesunateate60mg 60mg

1ml

1ml

60mg

60mg

Artesunate60mg

Artesunate60mg

Artesunate60mg

Artesunate60mg

1ml

Sodi

umBi

carb

onat

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Artesunate60mg

Artesunate60mg

1ml

Sodi

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carb

onat

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1ml

Sodi

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carb

onat

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1ml

Sodi

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carb

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Artesunate60mg

1ml

Sodi

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Salin

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Salin

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Salin

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Salin

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Artesunate60mg

DC

Artesunatereconstituted

saline solution

IMPORTANT

Water for injection is not an appropriate dilutant

intravenous route intramuscular route IV IM

Remark: the upper limit for each weight band is 0.9 kg e.g. 14 - 16 kg covers 14 - 16.9 kg.

Weight kg

Dosemg ml

20 - 25 60 3

26 - 29 70 4

30 - 33 80 4

34 - 37 90 5

38 - 41 100 5

42 - 45 110 6

46 - 50 120 6

51 - 54 130 7

55 - 58 140 7

59 - 62 150 8

63 - 66 160 8

67 - 70 170 9

71 - 75 180 9

76 - 79 190 10

80 - 83 200 10

84 - 87 210 11

88 - 91 220 11

92 - 95 230 12

96 - 100 240 12

Weight kg

Dosemg ml

20 - 25 60 6

26 - 29 70 7

30 - 33 80 8

34 - 37 90 9

38 - 41 100 10

42 - 45 110 11

46 - 50 120 12

51 - 54 130 13

55 - 58 140 14

59 - 62 150 15

63 - 66 160 16

67 - 70 170 17

71 - 75 180 18

76 - 79 190 19

80 - 83 200 20

84 - 87 210 21

88 - 91 220 22

92 - 95 230 23

96 - 100 240 24

Example: Example:

6.24 ml rounded up to 7 ml 3.12 ml rounded up to 4 ml

Dose needed (ml) for 26 kg child: Dose needed (ml) for 26 kg child:

102.4 x 26 = 6.24 ml

202.4 x 26 = 3.12 ml

2.4 mg x body weight (kg)

IV artesunate solutionconcentration 10 mg/ml

2.4 mg x body weight (kg)

IM artesunate solutionconcentration 20 mg/mlRound up to the next whole numberRound up to the next whole number

Example: Example:

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

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

103.0 x 8 = 2.4 ml

203.0 x 8 = 1.2 ml

3.0 mg x body weight (kg)

IV artesunate solutionconcentration 10 mg/ml

3.0 mg x body weight (kg)

IM artesunate solutionconcentration 20 mg/ml

Round up to the next whole number Round up to the next whole number

Weight kg

Dosemg ml

6 - 7 20 1

7 - 10 30 2

11 - 13 40 2

14 - 16 50 3

17 - 20 60 3

Weight kg

Dosemg ml

6 - 7 20 2

7 - 10 30 3

11 - 13 40 4

14 - 16 50 5

17 - 20 60 6

Mo

re t

han

20 k

gLe

ss t

han

20 k

g

Concentration: 10 mg/ml

For intravenous route (IV)

Concentration: 20 mg/ml

For intramuscular route (IM)

Concentration: 10 mg/ml Concentration: 20 mg/ml

7 DOSING SCHEDULE

6 ADMINISTERWithdraw the required dose (ml) from the prepared vial(s) and inject.

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.

IMPORTANT

•Prepare a fresh solution for each administration.•Discard any unused solution after use.

Intramuscular route (IM)Inject slowly. Spread doses of more than 2 ml over different sites for young babies and 5 ml for adults.

Intravenous route (IV) Slow bolus 3-4 ml per minute.

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.

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.

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.

* 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

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.

InteractionsNo significant adverse interactions have been documented.

Where to report

AcknowledgementsThe 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)

Early diagnosis and prompttreatment will save lives Administer antimalarial medicines to patient with suspected severe malaria without delay.

Initiate urgent treatment steps

Start resuscitative measures immediately

Establish intravenous access

Correct hypoglycaemia

Control convulsions

a detailed historya thorough clinical examination AND laboratory investigations to confirm diagnosis and complications

Do not forget to do:

1 WHO, World Malaria Report 2013 - http://www.who.int/malaria/publications/world_malaria_report_2013/wmr13_avant_propos.pdf?ua=12 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=msf8 White NJ et al. Severe hypoglycemia and hyperinsulinemia in falciparum malaria. N Engl J Med 309:61–66 (1983).