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Role of ACT,s (Artemether + Lumefantrine) In The Treatment of Malaria

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WHO Guidelines for The Treatment of Malaria World Malaria Report 2008

Malaria Today

Global Malaria Action Plan

4/28/12

WORLD MALARIA REPORT 2008
Persistent burden of malaria have become a familiar part of discussions in the global public health forum:
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3 billion people at risk of infection in 109 malarious countries and territories and around 250 million cases annually, leading to approximately
1.Global burden of disease: 2004 update. Geneva, World Health Organization, 2008 (www.who.int/healthinfo/bodestimates/en/index.html).

1 million deaths. In 2004

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Plasmodium falciparum was among the 4/28/12 leading causes of death worldwide from a

Population at risk
The 109 countries and territories classified as endemic The four groups describe the transition from control to elimination Malaria-free countries and malaria-endemic countries in phases of control, pre-elimination, elimination and prevention of reintroduction, end 2007

Source: World Malaria Report 2008. Geneva, World Health Organization,

4/28/12

Burden of Malaria in Pakistan
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Malaria has been a persistent problem

in Pakistan. There were an estimated 1.5 million malaria episodes in 2006
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Most cases occur between July and November About 30% are due to P falciparum .

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WORLD MALARIA REPORT 2008 4/28/12

EPIDEMIOLOGICAL PROFILE PAKISTAN Population (000) % v v v 2006 160 943 19 012 141 931 12 All age groups < 5 years > 5 years 88 Population by malaria endemicity (000) v % v v 2006 7 149 521 High transmission 1/1000 Low transmission (0–1/1000) 93 11 422 v WORLD MALARIA REPORT Malaria-free (0 cases) 4/28/12 2008 00 .

Diagnosis and treatment of malaria.Policies. including malaria-related anemia Prevent the progression of uncomplicated malaria into severe and 4/28/12 Ø Ø . including preventive treatment The objectives of an anti-malarial treatment policy are to: Ø Ensure rapid cure of the infection Reduce morbidity and mortality. Strategies for Malaria Control The government of every country affected by malaria has a national malaria control policy covering prevention and case-management.

The use of insecticide-treated nets (ITNs) 4/28/12 . There are two main approaches to malaria prevention by mosquito control:1.Malaria Prevention Through Mosquito Control The main objective of malaria vector control is to reduce significantly the incidence and prevalence of both parasite infection and clinical malaria.

falciparum malaria is widely prevalent in 1. 2(4) April.Antimalarial Drug Resistance A key factor contributing to the increasing malaria mortality rate is the widespread resistance of P falciparum to conventional antimalarial drugs. Parassitologia 42 (1-2) June 101-110 . (2000). such as : Ø Ø Ø Chloroquine Sulphadoxine + Pyrimethamine (SP) Amodiaquine Multi-drug resistant P . . Kidson. et al (2002). Epidemiology of drug-resistant malaria. 209-18. 24/28/12 Infectious Diseases.C. The Lancet Southeast Asia and some Amazonian regions of South America.C. The malaria cauldron of Southeast Asia: conflicting strategies of contiguous nation states.Wongsrichanalai. et al.

WHO Recommenda tions for Clinical Diagnosis 4/28/12 .

WHO Guidelines for the treatment of malaria – 2nd edition 2010 page 23 children. 2000 inmost reliable sign in young appears to be the WHO Technical Report Series. World Health Organization. clinical diagnosis of uncomplicated malaria should be based on:- The degree of exposure to malaria Ø History of fever in the previous 3 days with no features of other severe diseases. for which pallor of the palms WHO Expert Committee on Malaria. In settings where the risk of malaria is high. Geneva.WHO Recommendations for the Clinical diagnosis In settings where the risk of malaria is low. No. clinical diagnosis should be based on:Ø History of fever in the previous 24 hours Ø the presence of anemia. 892. Twentieth report. Ø 4/28/12 .

WHO Recommendations for the Treatment of Malaria 4/28/12 .

Artemether – Lumefantrine Artesunate . 4/28/12 2.s are currently recommended for use: 1. . treated with an ACT. 4. 3.WHO Recommendations for the treatment of malaria Recommendations unchanged from the first edition of the Guidelines (2006) Ø All uncomplicated P falciparum infections should be .s (Artemisinin .pyrimethamine.WHO Guidelines for the treatment of malaria – Mefloquine Artesunate –2nd edition 2010 Executive summary IX Sulfadoxine .based combination therapy) Five ACT.Amodiaquine Artesunate .

Ø Artesunate plus tetracycline or doxycycline or clindamycin. any of these combinations to be given for7 days.Second-line antimalarial treatment Ø Alternative ACT known to be effective in the region. any of Executive summary IX these Ø Combinations should be given for 7days 4/28/12 . Ø WHO Guidelines for the treatment of malaria – 2nd edition 2010 Ø Quinine plus tetracycline or doxycycline or clindamycin.

full doses of Parenteral antimalarial treatment should be started without delay with whichever effective antimalarial is first available. artesunate IV or IM: Ø Quinine is an acceptable alternative if parenteral artesunate is not available WHO Artesunate IV or IM Guidelines for the treatment of malaria – 2nd edition 2010 Executive summary X Ø 4/28/12 .TREATMENT OF SEVERE MALARIA Ø Severe malaria is a medical emergency. After rapid clinical assessment and confirmation of the diagnosis. Ø Ø For adults.

to ensure early diagnosis and treatment of complications that can lead to death within hours. Ø The choice of an antimalarial depends on a variety of factors including: Ø Ø Ø Parasite type 4/28/12 Level of drug resistance Patient’s general health and medical history .Treating Malaria & The Role of Drugs The aim of treatment is to fight an established parasite infection and includes: Ø Ø Elimination of the parasites supportive measures to overcome morbidity associated with infection monitoring .

reduce gametocyte carriage. Studies in Southeast Asia have shown that combinations of 4/28/12 artemisinin . are well tolerated by patients and . artemether and dihydroartemisinin – have been deployed on an increasingly large scale. no parasite resistance to these compounds has been detected.Artemisinin Derivatives (ACT’s) Over the past decade. are active against multi-drug resistant P falciparum malaria. a new group of antimalarial – the Artemisinin Compounds. To date. especially Artesunate. These produce a rapid therapeutic response.

hydrophilic derivative.Artemisinin Derivatives (ACT’s) Cont…… Artemisinin is a sesquiterpene lactone containing a bridged endoperoxide. dihydroartemisinin. artemether and arteether A lesser. dihydroartemisinin. Ø Ø The artemisinin derivatives (artesunate. artesunate A major active metabolite in vivo. artemether or arteether) are fast acting and potent antimalarial that offer an 4/28/12 important . It has:Ø Two main lipophilic derivatives.

Ø Lumefantrine has a much longer elimination half-life (several days) than artemether With a low recrudescence rate the complementary properties of artemether with its fast onset of action and Lumefantrine with its long duration of action and high cure rate result in a highly effective combination. and lumefantrine (120 mg) a highly lipophilic aryl amino alcohol.Artemether + Lumefantrine A highly effective fixed combination Ø Artemether (20 mg). a derivative of artemisinin. Ø Ø 4/28/12 .

Artemether + Lumefantrine Product Characteristics Ø overview of Highly effective against acute. parallel-group. comparative safety. particularly when compared to most established antimalarials3 1. Int J Antimicrob Agents 1999. A randomized. The comparative efficacy and tolerability of CGP 56697 (artemether +lumefantrine) versus halofantrine in the treatment of uncomplicated Ø An easy-to-use fixed-dose combination treatment: falciparum malaria in travellers returning from the tropics to The Netherlands and France. and efficacy trial of oral co-artemether versus oral chloroquine in the treatment of acute uncomplicated Plasmodium falciparum malaria in adults in India. Gogtay NJ. et al. uncomplicated malaria caused by P falciparum in areas of multi-drug resistance . et al. Am J Trop Med Hyg 2000. double-blind. Looareesuwan S. van Vugt M. Kshirsagar NA.2 Is rapidly gametocytocidal. Eliminates parasites and symptoms significantly faster than most current antimalarials1. helping to reduce transmission Achieves high cure rates Ø Ø Ø Ø Ø Well tolerated. Artemether-lumefantrine for the treatment . Malvy D. Moorthy NS. 12: 159-169 Ø simplifies compliance 2. et al. Wilairatana P. van Agtmael M.62: 402-408 Ref: 4/28/12 3. Bouchaud O.

or for treating severe malaria. pulmonary edema. children including cerebral malaria.Indications Artemether + lumefentrine is indicated for the Treatment of uncomplicated infections due to P. Falciparum in adults and for prophylaxis. or renal failure. because treatment of severe malaria requires Injectable medication 4/28/12 . falciparum or mixed Artemether + lumefentrine is Not Indicated infections including P.

van Vugt M. Wilairatana P.Efficacy of Ø Artemether + Lumefantrine 28-day cure rates in a multi-drug resistant area with 6-dose Artemether + Lumefentrine Co-Artemether 4 doses Co-Artemether 6 doses/ 60 hours Co-Artemether 6 doses/ these (van Vugt One of 95 hours et al. . Am J Trop Med Hyg1999. 1999) was a Mefloquine + doseoptimisation study Artesunate for coartemether in multidrug resistant areas.1 The 4-dose regimen was compared with two 6-dose regimens 1. et al. Gemperli B. Efficacy of six doses of artemether-lumefantrine 4/28/12 (given (benflumetol) in multidrugresistant Plasmodium falciparum malaria.

Comparator * Patient number to small in the Evaluation population 4/28/12 . evaluable population.Overview of Cure Rates in adults and Adolescents Ø 28-day parasitological cure rates by treatment. PCR-corrected The following graphic provides an overview of 28-day cure rates for coartemether and other antimalarials. based on pooled results from evaluable patients >12 years of age. pooled studies.

001) for patients receiving co-artemether than for tested comparators.Fast Parasite Elimination in P falciparum . Malaria Comparator Median percentage parasite reduction at 24 hours was significantly better (p<0. 4/28/12 Ø .

7%) of patients achieved clearance within 24 hours. and 302/307 (98. Nigeria and Tanzania) with the 6-dose regimen of co-artemether demonstrated that.Parasite Clearance in Infants and Children study on infants and small children in sub-Saharan Africa (Kenya. overall.170/305 (55.4%) within 48 hours 4/28/12 .

et al. fever clearance (and hence. A randomized controlled trial of artemether / benflumetol. Am J Trop Med Hyg 1998. a new antimalarial and pyrimethamine/sulfadoxine in the treatment of 4/28/12 uncomplicated falciparum malaria in African children. 58(5): 638-644 . Jones P.5°C (n=144) Sulphadoxine + pyrimethamine (n=143) von Seidlein L. symptomatic improvement) occurred significantly faster with co-artemether than with sulphadoxine+ pyrimethamine (SP) African children with fever Co-Artemether >37.Prompt Reduction in Fever clearance in infants & children In African children. Bojang K.

Fever Clearance in Adults and Adolescents Fever clearance times. pooled studies Comparato r 4/28/12 .

6-dose regimen 4/28/12 0-3 days Day 7 Day 14 .Gametocyte Clearance in Infants and Children Rapid gametocyte clearance.

pooled studies Comparato r Gametocyte Clearance in Adults and Adolescents 4/28/12 .Proportion of patients with gametocytes by Day 28.

Safety & Tolerability 4/28/12 .

DISCUSSION DOSAGE Click to edit Master ArtemethersubtitleLumefantrine + style Suspension 4/28/12 .

WHO dosage guidelines for ArtemetherLumefantrine 4/28/12 .

36. Calculated as mg artemether per kg body weight (bw).2 mg/kg of Ø .WHO guidelines for the treatment of malaria The recommended dose for Artemether/ Lumefantrine tablets (Coartem®) when used for children between 5 and 14 kg is 1 tablet at time 0h and 1 tablet at time 8h followed by two tablets a day for two days (24. Ø Moreover. Ø Evidence that this high dose of more than 4 mg/kg bw of artemether is needed for small babies (± 5kg) is scanty or non existent. 48 and 60h). this “overdosing” situation is in contrast with the adult dose of 8 pills a day divided over two intakes. Ø 4/28/12 This means that an adult of 50 kg takes a dose of 3. this means that for a child of 5 kg a dose of 8 mg artemether/kg per day spread over two doses is given.

Ø 4/28/12 The dose of Artemether necessary to obtain antimalarial .. The pharmacokinetics of Artesunate and Artemether are quite similar (Newton et al... almost immediately for Artesunate and somewhat later for artemether. pages 24. 2006. 25) it is clearly stated for Artesunate that the total recommended dose given per day for three days is 4 mg/kg bw.Ø WHO guidelines (WHO.. Ø Ø Artesunate and Artemether can be considered as prodrugs for dihydroartemisinin. 2003).Biotransformation into the active metabolite dihydroartemisinin occurs rapidly. 2000 and Silamut et al. Ø The reported elimination halflife of Artesunate is less than 1 hour (Newton et al. 2000) and for between ± 2hours Artemether Ø (Silamut et al. 2003).

Calculate for every kg bw how many mg artemether is given at the recommended dose of Coartem® and compare those values with those obtained with Co .Artesiane® we see the following picture: 4/28/12 .

3 mg/kg artemether per day (correctdose) ↔ Coartem®: 14 kg child receives a dose of 2.2 mg/kg artemether per day (correct dose) ↔ Coartem®: 5 kg child receives a dose of 8 mg/kg per day (overdosing) Co-Artesiane®: 14 kg child receives a dose of 4. considered by WHO as the necessary dose. For example: Ø Ø Co-Artesiane®: 5 kg child receives a dose of 4. Excessive overdosing for very small children and potential under dosing in some weight groups are avoidable. The suspension enables an adequate daily dosing of artemether over the whole body weight range (5 to 30 kg). The syrup therefore allows dosing around the baseline of 4mg/kg artemether.86 mg/kg per day (underdosing) 4/28/12 .Ø Dafra Pharma developed a paediatric Artemether-Lumefantrine suspension that allows correct dosing for that target group.

Artesian® syrup then obtained with the twice daily dosing of the Coartem® tablets. Ø This could be due to two facts: Either there were strain 4/28/12 differences of the parasite between .Ø Our results did clearly demonstrate that we achieved One Dose Versus Two Doses a Day the same efficacy with single dosing per day of the Co.

Ø The following graphs were calculated based on a bioequivalence study. • • Coartem® dosing leads to a low and constant baseline plasma concentration which could facilitate the induction of tolerance. 4/28/12 .Artesiane® suspension than with the 6 intakes of Coartem®. It is clearly shown that the peak plasma concentrations of artemether and dihydroartemisinin are higher with 3 intakes of Co.

Peak plasma concentrations of Artemether 4/28/12 .

Peak plasma concentrations of Dihydroartemisinin 4/28/12 .

Nosten F (2007) Pharmacokinetic study of artemether-lumefantrine given once daily for the treatment of uncomplicated multidrug-resistant falciparum malaria. Hutagalung R. Annerberg A. Suputtamongkol Y. Rasameesoraj M.Antimicrob Agents Chemother. Teja-Isavadharm P. Pukrittayakamee S. Sipilanyambe N (2006) Assessment of the therapeutic efficacy of a paediatric formulation of artemether-lumefantrine (Coartesiane) for the treatment of uncomplicated Plasmodium falciparum in children in Zambia. Singtoroj T. Newton PN. Antimicrob Agents Chemother. Brockman A. White NJ (2003) Artemether bioavailability after oral or intramuscular administration in uncomplicated falciparum malaria. qChanda P. Wilahphaingern J. Kango M. 44(4):972-7 qSilamut K. Bates I. Singhasivanon P. Navaratnam V. Hawela M. McGready R. Malar J. Lindegardh N. Pukrittayakamee S. Hla G.Trop Med Int Health. Siriyanonda D. 12(2):201-8. White N (2000) Antimalarial bioavailability and disposition of artesunate in acute falciparum malaria. Teja-Isavadharm P. 47(12):3795-8) 4/28/12 qWorld Health Organisation (2006) Guidelines for the treatment of malaria. White NJ.References Ashley EA. Stepniewska K. 5:75 qNewton P. Proux S. q . Suputtamongkol Y.

Misomal is a new. safe 4/28/12 and effective fixed dose combination Antimalarial therapy that provides an important addition to the armory against .Complying with need of time and recommendations of WHO proudly presents Tabros Pharma Co .

DOSAGE CONVENIENCE & COMPLIANCE IN CHILDREN 4/28/12 .

Complying with need of time and recommendations of WHO proudly presents Tabros Pharma 4/28/12 .

23kg 24kg .5 ml 9 ml 11 ml 12.3 ( 4.29kg .2 4.1 .5 ml 18.8 ) ( 4.26kg 27kg .1 .5 ml 4.1 .3.3 .8kg 9kg -10kg 7 ml 8 ml 10 ml 13 ml 15 ml 18 ml 22 ml 25 ml 29 ml 33 ml 37 ml 3.5ml 4 ml 5 ml 6.8 ) ( 4.9 ) ( 4.9) ( 4.3.8 ) ( 4.17kg 18kg .8 ) ( 4. r / mg/kg Artemether 15mg+Lumefantrine 90mg Artemether 30mg+Lumefantrine 180mg bw Daily Dose (ml) Daily Dose (ml) 5kg 6kg 7kg .3.4 .5 ml 16.9) ( 4.3.5 ml 14.3.8 ) ( 4.1 .3.3 .3.3.3.1 .5 ml 7.1 .8 ) COMISOMAL DS 30 ml 11kg -12kg 13kg -14kg 15kg .CO-MISOMAL DS SUSPENSION SCHEDULE Product strength COMISOMAL DS 15 ml DOSAGE Body Weight   CO-MISOMAL CO-MISOMAL DS Artemethe SUSP SUSP.20kg COMISOMAL DS 60 ml 4/28/12 21kg .

Complying with need of time and recommendations of WHO proudly presents Tabros Pharma 4/28/12 .

THANKS 4/28/12 .