co misomal presentation

Malaria Today

Global Malaria Action Plan

WHO Guidelines forThe Treatment of Malaria

World Malaria Report 2008

WORLD MALARIA REPORT 2008

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 (www.who.int/healthinfo/bodestimates/en/index.html).

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


EPIDEMIOLOGICAL PROFILE PAKISTAN

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 treatmentThe 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

WHO Expert Committee on Malaria. Twentieth report. Geneva, World Health Organization, 2000 in WHO Technical Report Series, No. 892. WHO Guidelines for the treatment of malaria – 2nd edition 2010 page 23

In 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 hours the presence of anemia, for which pallor of the palms appears to be the most reliable sign in young children.

Recommendations unchanged from the first edition of the Guidelines (2006)

All uncomplicated P. falciparum infections should be treated with an ACT,s (Artemisinin - based combination therapy)

Five ACT,s are currently recommended for use:

1. Artemether – Lumefantrine2. Artesunate - Amodiaquine3. Artesunate - Mefloquine4. Artesunate – Sulfadoxine - pyrimethamine.5. Artesunate – piperaquine

Artemisinin and its derivatives should not be used as monotherapy

WHO RECOMMENDATIONS FOR THE TREATMENT OF MALARIA

WHO Guidelines for the treatment of malaria – 2nd edition 2010 Executive summary IX

Alternative ACT known to be effective in the region;

Artesunate plus tetracycline or doxycycline or clindamycin; any of these combinations to be given for7 days;

Quinine plus tetracycline or doxycycline or clindamycin; any of these Combinations should be given for 7days

WHO Guidelines for the treatment of malaria – 2nd edition 2010 Executive summary IX

SECOND-LINE ANTIMALARIAL TREATMENT

TREATMENT OF SEVERE MALARIA

Severe malaria is a medical emergency. After rapid clinical assessment and confirmation of the diagnosis, full

doses of Parenteral antimalarial treatment should be started without delay with whichever effective antimalarial is first available.

For adults, artesunate IV or IM:

Quinine is an acceptable alternative if parenteral artesunate is not available

Artesunate IV or IM

Quinine (IV infusion or divided IM injection)

Artemether IM

WHO Guidelines for the treatment of malaria – 2nd edition 2010 Executive summary X

TREATING MALARIA & THE ROLE OF DRUGS

The aim of treatment is to fight an established parasite infection andincludes: 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 prescription 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 injust 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.

ARTEMETHER + LUMEFANTRINE 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 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.

ARTEMETHER + LUMEFANTRINE

OVERVIEW OF PRODUCT CHARACTERISTICS

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

antimalarials3

An easy-to-use fixed-dose combination treatment: simplifies compliance

Ref: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: 159-1692. 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: 402-4083. 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

INDICATIONS

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 + LUMEFANTRINE

28-day cure rates in a multi-drug resistant area with 6-dose Artemether + Lumefentrine

One of these (van Vugt et al. 1999) was a doseoptimisation study forcoartemether in multidrugresistant areas.1The 4-dose regimen was compared with two 6-dose regimens (givenover 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

Co-Artemether 4 doses Co-Artemether 6 doses/ 60 hours Co-Artemether 6 doses/ 95 hours Mefloquine + Artesunate

OVERVIEW OF CURE RATES IN ADULTS AND ADOLESCENTS

28-day parasitological cure rates by treatment, pooled studies, evaluable population, PCR-correctedThe 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.

Comparator

* 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.

Comparator

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 CLEARANCE IN INFANTS & 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

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

Co-Artemether (n=144) Sulphadoxine + pyrimethamine (n=143)

FEVER CLEARANCE IN ADULTS AND ADOLESCENTS

Fever clearance times, pooled studies

Comparator

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

Comparator

Proportion of patients with gametocytes by Day 28, pooled studies

SAFETY & TOLERABILITY

DISCUSSION DOSAGEArtemether + Lumefantrine

Suspension

WHO DOSAGE GUIDELINES FOR ARTEMETHER-LUMEFANTRINE

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, 36, 48 and 60h).Calculated as mg artemether per kg body weight (bw), this means that for a child of 5 kg a dose of 8 mg artemether/kg per day spread over two doses is given. 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. Moreover, this “overdosing” situation is in contrast with the adult dose of 8 pills a day divided over two intakes. This means that an adult of 50 kg takes a dose of 3.2 mg/kg of artemether and an adult of 75 kg takes one of 2.1 mg/kg per day.

There is no dose finding study published that we could find to justify this variation in dosing.

WHO guidelines (WHO, 2006, pages 24, 25) it is clearly stated for Artesunate that the total recommended dose given per day for three days is 4 mg/kg bw.

The pharmacokinetics of Artesunate and Artemether are quite similar (Newton et al., 2000 and Silamut et al., 2003).

Artesunate and Artemether can be considered as prodrugs for dihydroartemisinin.Biotransformation into the active metabolite dihydroartemisinin occurs rapidly, almost immediately for Artesunate and somewhat later for artemether.

The reported elimination halflife of Artesunate is less than 1 hour

(Newton et al., 2000) and for Artemether between ± 2hours (Silamut et al., 2003).

The dose of Artemether necessary to obtain antimalarial activity is considered to be the same for Artesunate, which is 4 mg/kg bw per day for 3 days as stated in the WHO guidelines for Artesunate

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:

Dafra Pharma developed a paediatric Artemether-Lumefantrine suspension that allows correct dosing for that target group. 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, considered by WHO as the necessary dose.

Excessive overdosing for very small children and potential under dosing in some weight groups are avoidable. For example:

Co-Artesiane®: 5 kg child receives a dose of 4.2 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 4.3 mg/kg artemether per day (correctdose) ↔ Coartem®: 14 kg child receives a dose of 2.86 mg/kg per day (underdosing)

ONE DOSE VERSUS TWO DOSES A DAY Our results did clearly demonstrate that we achieved the same efficacy with single dosing per day of the Co- Artesian® syrup then obtained with the twice daily

dosing of the Coartem® tablets. This could be due to two facts: Either there were strain differences of the parasite between the two studies

(Asian study versus African study) or the absorption of Lumefantrine out of the syrup is much better then the absorption out of the tablet.

We therefore recommend the syrup with a single dose daily.

The following graphs were calculated based on a bioequivalence study. It is clearly shown that the peak plasma concentrations of artemether and dihydroartemisinin are higher with 3 intakes of

• Co- Artesiane® suspension than with the 6 intakes of Coartem®.

• Coartem® dosing leads to a low and constant baseline plasma concentration which could facilitate the induction of tolerance.

Peak plasma concentrations of Artemether

Peak plasma concentrations of Dihydroartemisinin

ReferencesAshley EA, Stepniewska K, Lindegardh N, McGready R, Annerberg A, Hutagalung R,Singtoroj T, Hla G, Brockman A, Proux S, Wilahphaingern J, Singhasivanon P, White NJ,Nosten F (2007) Pharmacokinetic study of artemether-lumefantrine given once daily for thetreatment of uncomplicated multidrug-resistant falciparum malaria.Trop Med Int Health,12(2):201-8.Chanda P, Hawela M, Kango M, Sipilanyambe N (2006) Assessment of the therapeuticefficacy of a paediatric formulation of artemether-lumefantrine (Coartesiane) for the treatmentof uncomplicated Plasmodium falciparum in children in Zambia. Malar J, 5:75Newton P, Suputtamongkol Y, Teja-Isavadharm P, Pukrittayakamee S, Navaratnam V, BatesI, White N (2000) Antimalarial bioavailability and disposition of artesunate in acutefalciparum malaria. Antimicrob Agents Chemother, 44(4):972-7Silamut K, Newton PN, Teja-Isavadharm P, Suputtamongkol Y, Siriyanonda D, RasameesorajM, Pukrittayakamee S, White NJ (2003) Artemether bioavailability after oral or intramuscularadministration in uncomplicated falciparum malaria.Antimicrob Agents Chemother,47(12):3795-8)World Health Organisation (2006) Guidelines for the treatment of malaria.

Complying with need of time and recommendations of WHO Tabros Pharma proudly presents

Co - Misomal is a new, safe and effective fixed dose combination Antimalarial therapy that provides an important addition to the armory against malaria

DOSAGE CONVENIENCE & COMPLIANCE IN CHILDREN

CO-MISOMAL DS SUSPENSION DOSAGE SCHEDULE

Product strength

Body Weight

CO-MISOMAL SUSP Artemether 15mg+Lumefantrine

90mg

CO-MISOMAL DS SUSP. Artemether

30mg+Lumefantrine 180mg

Artemether / mg/kg bw

CO-MISOMAL DS 15 ml

Daily Dose (ml) Daily Dose (ml)

5kg 7 ml 3.5ml 4.2

6kg 8 ml 4 ml 4,3

7kg - 8kg 10 ml 5 ml ( 4,3 - 3,8 )

CO-MISOMAL DS 30 ml

9kg -10kg 13 ml 6.5 ml ( 4,3 - 3,9)

11kg -12kg 15 ml 7.5 ml ( 4,1 - 3,8 )

13kg -14kg 18 ml 9 ml ( 4,1 - 3,9)

CO-MISOMAL DS 60 ml

15kg - 17kg 22 ml 11 ml ( 4,4 - 3,9 )

18kg - 20kg 25 ml 12.5 ml ( 4,1 - 3,8 )

21kg - 23kg 29 ml 14.5 ml ( 4,1 - 3,8 )

24kg - 26kg 33 ml 16.5 ml ( 4,1 - 3,8 )

27kg - 29kg 37 ml 18.5 ml ( 4,1 - 3,8 )

30kg 40 ml 20 ml 4,3

THANKS

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