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WHO Guidelines for World Malaria Malaria Global Malaria

The Treatment of Malaria Report 2008 Today Action Plan


Persistent burden of malaria have become a familiar

part of discussions in the global public health forum:
 3 billion people at risk of infection in 109
malarious countries and territories and around 250
million cases annually, leading to approximately
1 million deaths. In 2004
 Plasmodium falciparum was among the leading
causes of death worldwide from a single infectious
agent (1).
1.Global burden of disease: 2004 update. Geneva,
World Health Organization, 2008 (
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, 2008; 2006 data.
Burden of Malaria in Pakistan
 Malaria has been a persistent problem in Pakistan. There
were an estimated 1.5 million malaria episodes in 2006
 Most cases occur between July and November
 About 30% are due to P. falciparum


Population (000) 2006 %
• All age groups 160 943
• < 5 years 19 012 12
• > 5 years 141 931 88

Population by malaria endemicity (000) 2006 %

• High transmission � 1/1000 11 422 7
• Low transmission (0–1/1000) 149 521 93
• Malaria-free (0 cases) 0 0
• Rural population 104 222 65
Vector and parasite profile

• Major Anopheles species:

• culicifacies, stephensi


Policies, Strategies for Malaria Control
The government of every country affected by malaria has a national malaria
control policy covering prevention and case-management.
Diagnosis and treatment of malaria, including
preventive treatment
The objectives of an anti-malarial treatment policy are to:
 Ensure rapid cure of the infection
 Reduce morbidity and mortality, including malaria-related anemia
 Prevent the progression of uncomplicated malaria into severe and
potentially fatal disease
 Reduce the impact of malaria infection on the fetus during pregnancy
 Reduce the reservoir of infection
 Prevent the emergence and spread of drug resistance
 Prevent malaria in travelers.
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.

There are two main approaches to malaria

prevention by mosquito control:-

1.The use of insecticide-treated nets (ITNs)

2.Indoor residual spraying (IRS)

Antimalarial Drug Resistance
A key factor contributing to the increasing malaria mortality rate is the
widespread resistance of P. falciparum to conventional antimalarial drugs,
such as :

 Chloroquine
 Sulphadoxine + Pyrimethamine (SP)
 Amodiaquine

Multi-drug resistant P.falciparum malaria is widely prevalent in Southeast

Asia and some Amazonian regions of South America.

South-East Asia has the most drug resistant malaria parasites in the world1,2

1- Wongsrichanalai,C. et al (2002). Epidemiology of drug-resistant malaria. The Lancet Infectious

Diseases. 2(4) April, 209-18.

2- Kidson,C. et al. (2000). The malaria cauldron of Southeast Asia: conflicting strategies of contiguous
nation states. Parassitologia 42 (1-2) June 101-110
WHO Recommendations for the Clinical diagnosis
In general, settings where the risk of malaria is low, clinical
diagnosis of uncomplicated malaria should be based on:-

 The degree of exposure to malaria

 History of fever in the previous 3 days with no features of

other severe diseases.

In settings where the risk of malaria is high, clinical

diagnosis should be based on:-

 History of fever in the previous 24 h

 the presence of anaemia, for which pallor of the palms
appears to be the most reliable sign in young children.
WHO Guidelines for the treatment of malaria 2006 page 8
WHO Recommendations for the treatment of malaria

 All uncomplicated P. falciparum infections should be treated with

an ACT,s (Artemisinin - based combination therapy)1
Four ACT,s are currently recommended for use:
1- Artemether - Lumefantrine
2- Artesunate - Amodiaquine
3- Artesunate - Mefloquine
4- Artesunate – Sulfadoxine - pyrimethamine.

 Severe malaria should be treated parenterally with either an

artemisinin derivative or quinine until the patient can swallow, when a
complete course of ACT must be administered.

(The choice of the ACT should be based on the efficacy of the partner
medicine in the country or area of intended deployment)

WHO Guidelines for the treatment of malaria 2006 page 23

Treating Malaria & The Role of Drugs
The aim of treatment is to fight an established parasite infection and
 Elimination of the parasites
 supportive measures to overcome morbidity associated with infection
 monitoring - to ensure early diagnosis and treatment of complications
that can lead to death within hours.

The choice of an antimalarial depends on a variety of

factors including:
 Parasite type
 Level of drug resistance
 Patient’s general health and medical history
 Availability of medications in the country of
 Country policy and guidelines
 Intended use (prophylactic or therapeutic).
Artemisinin Derivatives (ACT’s)
Over the past decade, a new group of antimalarial –
the Artemisinin Compounds, especially
Artesunate, artemether and dihydroartemisinin –
have been deployed on an increasingly large scale.

These produce a rapid therapeutic response, are active against multi-drug

resistant P. falciparum malaria, are well tolerated by patients and reduce
gametocyte carriage.

To date, no parasite resistance to these compounds has been detected.

Studies in Southeast Asia have shown that combinations of artemisinin
compounds with certain other antimalarial produce high cure rates in
just 3 days of treatment1,2

1.Lefèvre G, Looareesuwan S, Treeprasertsuk S, et al. A clinical and pharmacokinetic trial of six doses of artemether
lumefantrine for multidrug-resistant Plasmodium falciparum malaria in Thailand. Am J Trop Med Hyg 2001; 64: 247-256

2.van Vugt M, Wilairatana P, Gemperli B, et al. Efficacy of six doses of artemether lumefantrine (benflumetol) in
multidrugresistant Plasmodium falciparum malaria. Am J Trop Med Hyg1999; 60(6): 936-942
Artemisinin Derivatives (ACT’s) Cont……
Artemisinin is a sesquiterpene lactone containing a bridged endoperoxide.
It has:-
 Two main lipophilic derivatives, artemether and arteether
 A lesser, hydrophilic derivative, artesunate
 A major active metabolite in vivo, dihydroartemisinin.

The artemisinin derivatives (artesunate, dihydroartemisinin, artemether or

arteether) are fast acting and potent antimalarial that offer an important
alternative to current treatments.
Complying with need of time and recommendations of
WHO, Tabros Pharma proudly presents

Co - Misomal is a new, safe and effective fixed dose

combination antimalrial therapy of artemether-lumefantrine
that provides an important addition to the armory against
Artemether + Lumefentrine - A highly effective
fixed combination
 Artemether (20 mg), a derivative of artemisinin, and lumefantrine (120
mg) a highly lipophilic aryl amino alcohol.
 Lumefantrine has a much longer elimination half-life (several days) than
 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.
Artemether + Lumefentrine overview of Product
 Highly effective against acute, uncomplicated malaria caused by
P. falciparum in areas of multi-drug resistance
 Eliminates parasites and symptoms significantly faster than most
current antimalarials1,2
 Is rapidly gametocytocidal, helping to reduce transmission
 Achieves high cure rates
 Well tolerated, particularly when compared to most established
 An easy-to-use fixed-dose combination treatment:
~ simplifies compliance

1. van Agtmael M, Bouchaud O, Malvy D, et al. The comparative efficacy and tolerability of CGP 56697
(artemether +lumefantrine) versus halofantrine in the treatment of uncomplicated falciparum malaria in
travellers returning from the tropics to The Netherlands and France. Int J Antimicrob Agents 1999; 12: 159-169
2. Kshirsagar NA, Gogtay NJ, Moorthy NS, et al. A randomized, double-blind, parallel-group, comparative
safety, and efficacy trial of oral co-artemether versus oral chloroquine in the treatment of acute uncomplicated
Plasmodium falciparum malaria in adults in India. Am J Trop Med Hyg 2000;62: 402-408
3. van Vugt M, Looareesuwan S, Wilairatana P, et al. Artemether-lumefantrine for the treatment of multidrug-
resistant falciparum malaria. Trans R Soc Trop Med Hyg 2000; 94: 545-548
Artemether + lumefentrine is indicated for the Treatment
of uncomplicated infections due to P. falciparum or mixed
infections including P. Falciparum in adults and children

Artemether + lumefentrine is Not Indicated for

prophylaxis, or for treating severe malaria, including
cerebral malaria, pulmonary edema, or renal failure,
because treatment of severe malaria requires
Injectable medication
Efficacy of Artemether + Lumefentrine
 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/
95 hours
Mefloquine + Artesunate

One of these (van Vugt et

al. 1999) was a
doseoptimisation study for
coartemether in multidrug
resistant areas.1
The 4-dose regimen was
compared with two 6-dose
regimens (given
over either 60or 96 hours).
1.van Vugt M, Wilairatana P, Gemperli B, et al. Efficacy of six doses of artemether-lumefantrine (benflumetol)
in multidrugresistant Plasmodium falciparum malaria. Am J Trop Med Hyg1999; 60(6): 936-942
Overview of Cure Rates in adults and Adolescents
 28-day parasitological cure rates by treatment, pooled studies,
evaluable population, PCR-corrected
The following graphic provides an overview of 28-day cure rates for co-artemether
and other antimalarials, based on pooled results from evaluable patients >12 years
of age.


Patient number to small

in the Evaluation population
Fast Parasite Elimination in P. falciparum Malaria

 Median percentage parasite reduction at 24 hours was significantly better
(p<0.001) for patients receiving co-artemether than for tested comparators.
Parasite Clearance in Infants and Children
study on infants and small children in sub-Saharan Africa (Kenya, Nigeria
and Tanzania) with the 6-dose regimen of co-artemether demonstrated
that, overall,170/305 (55.7%) of patients achieved clearance within 24
hours, and 302/307 (98.4%) within 48 hours
Prompt Reduction in Fever
 Fever clearance in infants and children
In African children, fever clearance (and hence, symptomatic improvement)
occurred significantly faster with co-artemether than with
sulphadoxine+ pyrimethamine (SP) African children with fever >37.5°C

Co-Artemether (n=144)

Sulphadoxine +
pyrimethamine (n=143)

von Seidlein L, Bojang K, Jones P, et al. A randomized controlled trial of artemether / benflumetol, a new
antimalarial and pyrimethamine/sulfadoxine in the treatment of uncomplicated falciparum malaria in African
children. Am J Trop Med Hyg 1998; 58(5): 638-644
Fever Clearance in Adults and Adolescents
Fever clearance times, pooled studies

Gametocyte Clearance in Infants and Children
Rapid gametocyte clearance, 6-dose regimen

0-3 days
Day 7
Day 14
Gametocyte Clearance in Adults and Adolescents
Proportion of patients with gametocytes by Day 28, pooled studies

Safety & Tolerability
Dosage & Administration

Body weight in No. of tablets at approximate timing of

kg dosing
(age in years) 0 : Hrs 8 : Hrs 24 : Hrs 36 : Hrs 48 : Hrs 60 : Hrs

5-14 (< 3) 1 1 1 1 1 1
15-24 (≥ 3–8) 2 2 2 2 2 2
25-34 (≥9 –14) 3 3 3 3 3 3
> 34 ( >1 4) 4 4 4 4 4 4
Dosage & Administration

Body weight in No. of tablets at Approximate timing of dosing

0 : Hrs 8 : Hrs 24 : Hrs 36 :Hrs 48 :Hrs 60 : Hrs
(age in years)

15-24 (≥ 3–8) 1 1 1 1 1 1

11/2 11/2 11/2 11/2 11/2 11/2

25-34 (≥9 –14)
2 2 2 2 2 2
> 34 ( >1 4)
Dosage & Administration

5Kg 7 ml 7 ml 7ml
7.5 Kg 10ml 10ml 10ml
10 Kg 14 ml 14 ml 14 ml
15 Kg 20 ml 20 ml 20 ml