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User guide - Medicines for Malaria Venture
INJECTABLE * ARTESUNATE FOR SEVERE MALARIA USER GUIDE WHO RECO MMEN DED TRE ATME 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 with suspected severe malaria without delay. 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 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%) PRODUCT DESCRIPTION 4 at Artesunate powder 60 mg Correct hypoglycaemia 4 Control convulsions Establish intravenous access Start treatment even as the diagnosis is being confirmed via laboratory testing. ne li Sa Bicarbonate ampoule 3 a detailed history a thorough clinical examination AND laboratory investigations to confirm diagnosis and complications e 1m um n di rbo So ica B l ion lut so 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 5m te na su mg Start resuscitative measures immediately Do not forget to do: te Ar 60 1 2 l Prostration/obtundation Common Initiate urgent treatment steps Saline solution * What does the drug do? Ar 0m Injectable artesunate is the 6first line treatment recommended by WHO for severe malaria caused by Plasmodium g ion lut te falciparum, in both children and adults. It is a short-acting agent that kills so parasites more rapidly than conventional m ona e u di rb lin So ica antimalarials, in particular because it is active against both the sexualSaand asexual stages of the parasite cycle B killing all stages including young rings resulting in more rapid recovery. 1m l 5m l te na su te 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 ate Artesunate 5 ml Saline solution 7 STEPS FROM PREPARATION TO ADMINISTRATION Artesunate 1ml Sodium Bicarbonate 60mg 1 Artesunate 60mg 30mg Artesun ate 60mg 3 WEIGH THE PATIENT RECONSTITUTE Artesunate ate Arte su 60mg nate Ar 12 tesu 0m nat g e Activate the drug: Artesunate powder + bicarbonate ampoule 60mg 1ml Artesunate B Inject full contents of A bicarbonate ampoule (1 ml) into artesunate vial. Arte su 60mg nate Art lutio 5 ml n esu 60mg nate Salin C Shake until dissolved. 60mg 1ml Sodium Bicarbonate Artesunate 60mg Solution will be cloudy. Arte suna te 60mg Artesun Saline solution 1ml 60mg will clear in about 2 mins. Discard if not clear. suna ate te nate Artesu 30mg ate Arte suna te 60mg Artesunate ate 1ml 5 ml 1ml 60mg Artesunate Arte Artesunate 60mg Artesunate 60mg Artesunate 60mg Ar 12 tesu 0m nat g e Artesunate 60mg 1ml Sodium Bicarbonate Artesunate ate Arte 76-100 kg 60mg 5 ml Saline solution Artesunate 60mg Vials of artesunate needed: 3.0 mg x body weight (kg) Product strength (60 mg) More than 20 kg Target dose: Vials of artesunate needed: 2.4 mg per kg of body weight 2.4 mg x body weight (kg) Product strength (60 mg) IMPORTANT •Each vial requires separate reconstitution, dilution and administration. •Reconstitute immediately before use. MMV - January 2015 1ml 5 ml 60mg In the injectable form, artesunic acid is reconstituted in sodium bicarbonate to form sodium artesunate, Arteof the drug. Art the active form su e nate Less than 20 kg 3.0 mg per kg of body weight Artesunate Artesunate ate Calculation Target dose: 60mg ester of artemisinin. It is soluble in water but has poor stability in aqueous solutions at neutral or acid pH. 3 4 Ar Artesunate Artesunate is the sodium salt of the hemisuccinate suna te Due to the poor stability of the drug it must be reconstituted or activated immediately before dilution and then administered within 1 hour. 1ml 51-75 kg Saline solution 1ml 5 ml 60mg e so Why must artesunate be reconstitued with sodium bicarbonate? So Bicadium rbon ate 2 Artesunate Artesunate ate su60mg 60mg nate 5 ml 26-50 kg Saline solution 5 ml 60mg Saline solution 1 Saline solution less than 25 kg 60mg n Artesunate Arte su 60mg nate 60 mg Artesunate 5 ml 60mg Arte su 60mg nate •Follow sterile procedures for all steps. •Use full content of bicarbonate vial. •Do not shake too vigorously. •Discard if solution does not clear. Salin 1ml Sodium Bicarbonate Artesunate IMPORTANT lutio Based on the weight of the patient you will 60mg 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. 5 ml CHECK VIALS NEEDED Saline solution 2 60mg Saline solution 1ml Sodium Bicarbonate Artesunate D The reconstituted solution Sodium Bicarbonate Artesunate 60mg 5 ml Saline solution The person prescribing artesunate must calculate the dose using the patient’s weight. The administering nurse or doctor must check the calculation to confirm that it is correct. 60mg Sodium Bicarbonate Artesunate bicarbonate powder ampoule Artesunate ate 5 ml 60mg Arte su 120mg naattee Artesunate Saline solution Artesunate Arte su 60mg naattee Arte su 30mg naattee 5 ml Saline solution So Bicadium rbon at 1ml e e so 1ml Sodium Bicarbonate 60mg Arte su 60mg naattee Arte su 30mg naattee Arte su 120mg naattee intravenous route IM intramuscular route 1ml Sodium Bicarbonate IV Artesunate 60mg 5 Arte su 120mg naattee CALCULATE THE DOSE Calculate and withdraw the required dose in ml according to route of administration: 12 tesu 0 n ate mg Volume for dilution For intravenous route (IV) For intramuscular route (IM) 1 ml Concentration: 10 mg/ml Concentration: 20 mg/ml 5 ml 2 ml 6 ml 3 ml 10 mg/ml 20 mg/ml mg Artesunate Artesunate 60mg lutio 5 ml n Artesunate B Withdraw all the air 60mg from the vial. n 5 ml lutio 60mg e so e 1ml Salin So Bicadium rbon at Artesunate ate te 3.0 x 8 10 Arte su 60mg nate 7 - 10 30 3 11 - 13 40 50 Art 17 - 20 Arte su 120mg naattee ml 20 1 7 - 10 30 2 4 11 - 13 40 2 5 14 - 16 50 60 3 6 17 - 20 60 3 Artesunate 60mg 1ml Concentration: 10 mg/ml Concentration: 20 mg/ml 2.4 mg x body weight (kg) 2.4 mg x body weight (kg) 30mg Artesuna Arte te 60mg 2.4 x 26 10 Art 20 = 3.12 ml 3.12 ml rounded up to 4 ml More than 20 kg e 1ml So Bicadium rbon at 5 ml Saline solution Arte suna te Dose 60mg Dose Weight kg mg ml Weight kg mg ml 20 - 25 60 6 20 - 25 60 3 26 - 29 70 7 26 - 29 70 4 30 - 33 80 8 30 - 33 80 4 34 - 37 90 9 34 - 37 90 5 38 - 41 100 10 38 - 41 100 5 42 - 45 110 11 42 - 45 110 6 46 - 50 120 12 46 - 50 120 6 51 - 54 130 13 51 - 54 130 7 55 - 58 140 14 55 - 58 140 7 59 - 62 150 15 59 - 62 150 8 63 - 66 160 16 63 - 66 160 8 67 - 70 170 17 67 - 70 170 9 71 - 75 180 18 71 - 75 180 9 76 - 79 190 19 76 - 79 190 10 80 - 83 200 20 80 - 83 200 10 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 Salin esu 60mg nate 1. Line up your reconstituted vials for one patient. 2. Use one syringe to reconstitute each vial with the bicarbonate and carefully set each reconsArtesunate ate mg tituted vial to one 60side. 3. Use a new syringe to dilute each vial with the correct volume of saline and set aside Artesunate 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. 1ml 2.4 x 26 = 6.24 ml Artesunate suna te Water for injection is not an appropriate dilutant Example: Dose needed (ml) for 26 kg child: 6.24 ml rounded up to 7 ml 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. IMPORTANT Round up to the next whole number esu nate Ar 12 tesu Example: 0m nat g e Dose needed (ml) for 26 kg child: Artesunate mg IM artesunate solution concentration 20 mg/ml suna te Aup to the next whole number 60mg Round rt suna te 1ml 60mg 1ml 60mg 1ml Artesunate IV artesunate solution Arteconcentration 10 mg/ml Sodium Bicarbonate 5 ml Saline solution Artesunate 5 ml Saline solution 6-7 60mg Arte 60mg 2 Sodium Bicarbonate Artesunate How to proceed with preparation60 of more than 1 artesunate vial? Artesunate 20 Dose mg n 60mg mg 60mg 6-7 5 ml Artesunate Can regular water for Artesunate ate injection be used 60 as a dilutant? Artesunate Weight kg esu 60mg nate = 1.2 ml lutio suna te 60mg 60mg Dose ml Arte su 60mg naattee Artesunate ate Artesunate 20 1.2 ml rounded up to 2 ml mg 14 - 16 Arte su 30mg naattee 3.0 x 8 Weight kg 5 ml Arte suna te Saline solution Arte 60mg is now ready for use. su 60mg nate = 2.4 Ar ml 12 tesu 0m nat g e 2.4 ml rounded up to 3 ml Artesunate D Artesunate solution esun into the of tsaline ate reconstituted solution. 1ml Example: Dose needed (ml) for 4 kg child: e 1ml Sodium Bicarbonate required volume C Inject Ar Round up to the next whole number 30mg 1ml saline solution 60mg IM artesunate solution concentration 20 mg/ml Round up to the next whole number ate for 4 kg child: Artesun(ml) Dose needed Arte 60mg Artesunate IV artesunate solution concentration 10 mg/ml 1ml Artesuna 60mg mg Example: Artesunate Artesunate reconstituted suna te 60mg Salin 1ml Sod ium Bicar bon ate Art esu 60mg nate ate Arte Less than 20 kg Arte su 60mg nate A e Artesunate e so 1ml Sodium Bicarbonate 60mg 1ml Artesunate 3.0 mg x body weight (kg) Ar mg Sodium Bicarbonate 60mg 5 ml Saline solution Artesunate 60mg solution concentration Ar Ar Sodium Bicarbonate un ate 20 mg Total volume tesu tesu naattee 120 naattee 3.0 mg30 texsunaatteebody60weight (kg) 1ml 1 tes 5 ml g Saline solution Ar So Bicadium rbon at 60mg lutio n IV ate 60m ate 1ml IM 1 ml ate nate Artesu Arte solution Bicarbonate sun 30mg Artesun 1ml 60mg Sodium Bicarbonate Artesunate 1ml ate Sodium Bicarbonate 1ml Sodium Bicarbonate Arte su Reconstituted artesunate 30mg 60mg nate + saline solution (or dextrose 5%) Ar Artesun 60mg e so Arte su 60mg naattee Arte su 30mg naattee Salin DILUTE ate Artesunate e so 4 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) Slow bolus 3-4 ml per minute. Intramuscular route (IM) Inject slowly. Spread doses of more than 2 ml over different sites for young babies and 5 ml for adults. 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 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. -- 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 eliminated 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)
