APPLICATION FOR REVISION AND INCLUSION OF MALARIA MEDICINES IN WHO MODEL LIST OF ESSENTIAL MEDICINES

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1 APPLICATION FOR REVISION AND INCLUSION OF MALARIA MEDICINES IN WHO MODEL LIST OF ESSENTIAL MEDICINES The objective of this application is to assure compatibility between the WHO Model list of essential drugs with the revised WHO Guidelines for the Treatment of Malaria (WHO/HTM/MAL/ ). There are 2 main sections to this application. The first part deals with uncomplicated malaria, while the second part deals with severe malaria. A). ARTEMISININ COMBINATION THERAPY FOR UNCOMPLICATED MALARIA 1. Summary statement of the proposed inclusion The worsening problems of drug resistance in many parts of the world and the limited number of antimalarial drugs available have led to increasing difficulties in developing antimalarial drug policies and the provision of prompt and effective treatment to all in need. There is a considerable amount of evidence demonstrating the relationship between increased resistance to first line antimalarial therapy and increased morbidity and mortality. Drug resistance has also been implicated in the increasing frequency and severity of epidemics. The burden of malaria can only be reduced if effective medicines are available at all levels of the health services, particularly at the periphery where the majority of malaria illness and mortality occurs. As a response to this situation, WHO now recommends that treatment policies for falciparum malaria, should be artemisinin based combination therapy (ACTs). This is based on the potential of two or more simultaneously administered schizontocidal drugs (of which one is an artemisinin derivative) with independent modes of action to improve therapeutic efficacy and also to delay the development of resistance to the individual components of the combination. The advantages of artemisinin derivatives that make them ideal combination partners are: Rapid reduction of parasite biomass (> 10 times that of montherapies); Rapid resolution of clinical symptoms; Effective action against multi drug resistant P.falciparum; No documented resistance as yet with the use of artemisinin and its derivatives; Few clinical adverse reactions; and Reduction of gametocyte carrier rate which may reduce transmission. 1

2 The following ACTs are currently recommended: Artemether lumefantrine; Artesunate (3days) plus amodiaquine (in areas where amodiaquine efficacy remains high day 28 failure rates>80%); Artesunate (3days) plus sulfadoxine pyrimethamine (SP) (in areas where SP efficacy remains high day 28 failure rates>80%); Artesunate (3 days) plus mefloquine (reserved for areas of low transmission) These conclusions are the rational culmination of the recommendations of a series of WHO informal consultations and is based on formal systematic reviews, such as Cochrane reviews, comparative clinical trials, observation studies and expert opinion. The superiority of ACTs over monotherapies has been clearly demonstrated. Formal systematic reviews of randomized clinical trials of oral artemether lumefantrine, artesunateamodiaquine, artesunate mefloquine and artesunate sulfadoxine pyrimethamine, indicate that, although there are some minor differences in oral absorption and bioavailability between the different artemisinin derivatives, there is no evidence that these differences are clinically significant in current formulations. It is the properties of the partner drug that determine the effectiveness and choice of combination. Artemether, artesunate and lumefantrine are safe and remarkably well tolerated. The adverse reactions to amodiaquine are similar to chloroquine. Concerns over severe liver or skin reactions to sulfadoxine pyrimethamine treatment has receded with increasing numbers of negative reports. ACTs have been adopted in National Treatment Policies for the management of uncomplicated falciparum malaria in 67 malaria endemic countries. Deployment is being rapidly scaled up in most of these countries, with ACTs procurement through the WHO mechanism for public sector use increasing from 11 million for 2005 to over 60 million between Jan to September WHO Focal Point for this application. Dr P. Olumese Global Malaria Programme 3. Organization supporting the application Global Malaria Programme World Health Organization Geneva Switzerland 2

3 4. International Nonproprietary Names (INNs) of medicines included in application. Artesunate plus amodiaquine Artesunate plus mefloquine; and Artesunate plus sulfadoxine pyrimethamine 5. Formulations proposed for inclusion * 5.1. Artesunate plus amodiaquine Available as separate scored tablets as co packaged blister packs containing 50mg of artesunate and 153mg of amodiaquine base. Co formulated tablets are under development Artesunate plus mefloquine Available as separate scored tablets as co packaged blister packs containing 50mg of artesunate and 250mg of mefloquine base. Co formulated tablets are under development Artesunate plus sulfadoxine-pyrimethamine Available as separate scored tablets as co packaged blisters containing 50mg of artesunate and tablets containing 500mg sulfadoxine and 25mg of pyrimethamine. 6. International availability The production capacity for ACTs manufactured to GMP standards have increased significantly over the last 2 years, with increased investments by already producing manufactures and new manufacturers entering into ACT production. ACT orders have increased from 2 million to over 60million treatment doses between 2003 and the first 9 months of 2006 respectively. A demand forecast of 110 million treatment doses for 2006 was matched by a projected production capacity of at least 130 million doses by the industry. 7. Whether application is requested for an individual medicine or therapeutic group. All are individual medicines 8. Public Health Relevance 8.1. Malaria as a disease burden Malaria is an important cause of death and illness in children and adults living in tropical countries. It is estimated that million people suffer from malaria related illness * Oral formulations of artemether-lumefantrine as a fixed combination and the components of the ad hoc combinations of artesunate with amodiaquine, mefloquine and sulfadoxinepyrimethamine were all currently included in the 14 th Edition of WHO Model List of Essential Medicines (revised March 2005). 3

4 and over one million people die as a result of malaria disease. Malaria mortality has risen in recent years, probably due to increasing resistance to antimalarial drugs. If ineffective drugs are given or treatment delayed in falciparum malaria, the parasite burden increases and severe malaria ensues. A patient may progress from having minor symptoms to having severe disease within a few hours. In areas of high and stable transmission, such as in most of Africa south of the Sahara and Oceania, young children and pregnant women are at greatest risk. In contrast, in areas of unstable malaria with low or moderate transmission such as Asia and Latin America, people of all ages are at risk. Malaria in humans is caused by four species of Plasmodium, P.falciparum, P. vivax, P. ovale and P. malariae. P. falciparum is responsible for the majority of deaths and illness. P. vivax accounts globally for around 40% of malaria cases and is the dominant species outside tropical Africa. In most areas where P. vivax is prevalent, transmission rates are low and consequently people of all ages are at risk. P.ovale and P.malariae are less prevalent but are distributed worldwide 8.2. Uncomplicated malaria Uncomplicated malaria is defined as symptomatic malaria without signs of severity or evidence of vital organ dysfunction. In acute falciparum malaria there is a continuum from mild to severe malaria. Young children and non immune adults with malaria may deteriorate rapidly Current objectives of treatment of uncomplicated malaria The objectives of treating uncomplicated malaria are to: Cure the infection and prevent progression to severe disease; Reduce transmission of the infection to others, i.e. to reduce the infectious reservoir; and Prevent the emergence and spread of resistance of the parasite to antimalarial drugs Current constraints for the treatment of uncomplicated malaria These objectives can no longer be achieved by previously used monotherapies. The affordable and widely available antimalarial, chloroquine is not longer effective in areas where Plasmodium falciparum is endemic and resistance to combinations of sulfadoxine pyrimethamine (SP) is increasing rapidly. Recent research has shown that combinations of SP with either chloroquine or the alternative 4 aminoquinoline, amodiaquine, are also compromised by the high levels of resistance to these drugs. At present, these constraints do not apply to the treatment of uncomplicated malaria caused by the other 3 species of human malaria parasites. Although chloroquine resistant vivax malaria exists, it is confined largely to Indonesia, East Timor, Papua New Guinea and other Except for Central America and the island of Hispaniola 4

5 parts of Oceania. Drug resistance appears not to be problem for the treatment of ovale and malariae malaria to which these parasites appear to be susceptible to chloroquine Recent changes in WHO treatment policy for uncomplicated falciparum malaria WHO now recommends that the treatment of uncomplicated P. falciparum malaria should be with artemisinin based combination therapy (ACT). Artemisinin and its derivatives produce rapid clearance of malaria parasitaemia, rapid resolution of symptoms and reduce gametocyte carriage and thus parasite transmission (see Section 8.6 below). These drugs are generally well tolerated and adverse reactions are rare (see Section 11 below). The consequence of these changes in antimalarial drug policy are that: chloroquine, amodiaquine and sulfadoxine pyrimethamine are no longer recommended as monotherapy for use for the treatment of uncomplicated falciparum malaria; Chloroquine is however still recommended for the treatment of uncomplicated malaria due to P.vivax, P.ovale and P.malariae. These recommendations were based on formal systematic reviews, such as Cochrane reviews, comparative clinical trials, observation studies and expert opinion. Full details can be found in WHO (2006) Guidelines for the treatment of malaria. pp251. WHO/HTM/MAL/ Rationale for antimalarial combination therapy Antimalarial combination therapy is the simultaneous use of two or more blood schizontocidal drugs with independent modes of action and thus unrelated biochemical targets in the parasite. The rationale for combining two or more antimalarials with different modes of action is twofold: (a) the combination is often more effective; and (b) in the rare event that a mutant parasite that is resistant to one of the drugs arises de novo during the course of the infection, the parasite will be killed by the other drug. This mutual protection is thought to prevent or delay the emergence of resistance. To realize the two advantages, the partner drugs in a combination must be independently effective. The possible disadvantages of combination treatments are the potential for increased risk of adverse effects and the increased cost. The concept is based on the potential of two or more simultaneously administered schizontocidal drugs with independent modes of action to improve therapeutic efficacy and also to delay the development of resistance to the individual components of the combination. ACT is a combination of artemisinin or one of its derivatives with an antimalarial or antimalarials of a different class. Drug combinations such as sulfadoxine-pyrimethamine, sulfalene-pyrimethamine, proguanil-dapsone, chlorproguanil-dapsone and atovaquone-proguanil rely on synergy between the two components whose drug targets in the malaria parasite are linked. These combinations are operationally considered as single products and treatment with them is not considered to be antimalarial combination therapy. Other multiple-drug therapies that include a non-antimalarial medicine to enhance the antimalarial effect of a blood schizontocidal medicine (e.g. chloroquine plus chlorpheniramine) are also not considered as antimalarial combination therapy. 5

6 8.7. Artemisinin-based combination treatments Artemisinin and its derivatives (artesunate, artemether, artemotil, dihydroartemisinin) produce rapid clearance of parasitaemia and rapid resolution of symptoms. They reduce parasite numbers by a factor of approximately in each asexual cycle, which is more than other current antimalarials (which reduce parasite numbers 100 to 1000 fold per cycle). Artemisinin and its derivatives are eliminated rapidly. When given alone or in combination with other rapidly eliminated compounds, a 7 day course of treatment is required, but when given in combination with slowly eliminated antimalarials, shorter courses of treatment (3 days) are effective. The evidence of their superiority in comparison to monotherapies has been clearly documented (See also Section 10.1 and Annex 1). The artemisinin compounds are active against all four species of malaria parasites that infect humans and are generally well tolerated. Significant adverse effect to emerge from extensive clinical trials with artemisinins has been rare (circa 1:3000)(see Section 11). The artemisinins also have the advantage from a public health perspective of reducing gametocyte carriage and thus the transmissibility of malaria. This contributes to malaria control in areas of low endemicity. In 3 day ACT regimens, the artemisinin component is present in the body during only two asexual parasite life cycles (each lasting 2 days, except for P. malariae infections). This exposure to 3 days of artemisinin treatment reduces the number of parasites in the body by a factor of approximately one hundred million ( = 10 8 ). However, complete clearance of parasites is dependent on the partner drug being effective and persisting at parasiticidal concentrations until all the infecting parasites have been killed. Thus the partner compounds need to be relatively slowly eliminated. As a result, the artemisinin component is protected from resistance by the partner drug provided it is efficacious, and the partner drug is partly protected by the artemisinin derivative. Shorter courses of ACTs (1 2 days) are not recommended. They are less efficacious, and provide less protection of the slowly eliminated partner antimalarial. 6

7 9. Deployment and Treatment Details of ACTs 9.1 Recommended ACTs and their dosage regimens Artemether-lumefantrine The total recommended treatment is a 6 dose regimen of artemether lumefantrine twice a day for 3 days as follows (bases on comparative randomized trials and expert opinion): Body weight in kg. No. of tablets at approx. timing of dosing a 0h 8h 24h 36h 48h 60h > a The regimen can be expressed more simply for ease of use at the programme level as follows: the second dose on the first day should be given at any time between 8-12h after the first dose. Dosage on second and third days is twice a day (morning and evening) Artesunate plus amodiaquine The total recommended treatment is 4mg/kg body weight of artesunate and 10mg amodiaquine base/kg body weight given once a day for 3 days Artesunate plus mefloquine The total recommended treatment is 4mg/kg body weight of artesunate given once a day for 3 days and 25mg mefloquine base/kg body weight usually split over 2 or 3 days Artesunate plus sulfadoxine-pyrimethamine The total recommended treatment is 4mg/kg body weight of artesunate given once a day for 3 days and a single administration of sulfadoxine pyrimethamine (25 /1.25 mg base/kg body weight ) on day Diagnostic requirements Prompt and accurate diagnosis of malaria is part of effective disease management and will, if implemented effectively, help to reduce the unnecessary use of antimalarials. The current recommendations of WHO on the diagnosis of malaria are highlighted below (WHO Guidelines for the treatment of malaria WHO/HTM/MAL ): 7

8 In areas of low to moderate transmission, prompt parasitological confirmation of malaria diagnosis is recommended before treatment is started. This should be achieved by light microscopy or Rapid Diagnostic Tests (RDTs) where microscopy is unavailable; In areas of high stable malaria transmission, the probability that a fever in a child is caused by malaria is high. Children under 5 years of age should, therefore, be treated on the basis of a clinical diagnosis of malaria. A parasitological diagnosis is recommended before treatment is started in older children and adults, including pregnant women; In settings where malaria incidence is low, parasitological diagnosis of all fever cases may lead to considerable expenditure to detect only a few cases of malaria. In such settings, health workers should be trained to identify, through the history, patients that have been exposed to malaria risk before they conduct a parasitological test. 10. Comparative effectiveness of ACTs Comparison of ACT with monotherapies (i) Summary of Randomized Clinical Trials The systematic review and meta analysis of individual patient data from 16 randomized clinical trials (total of 5948 people) demonstrated that ACTs were more effective than monotherapies with amodiaquine (in Gabon, Kenya and Senegal), with sulfadoxine pyrimethamine (in The Gambia, Kenya, Malawi, Peru and Uganda) and mefloquine (in Thailand) (Adjuik et al., 2004). The analysis compared odds ratio (OR) of parasitological failure at days 14 and 28 (artesunate combinations compared to monotherapy) and calculated combined summary ORs across trials using standard methods. The results were comprised of parasite failure including re infections by day 28 in 14 trials (see Annex 1, section 1.1) and parasite failure excluding re infections in 11 trials (Annex 1, section 1.2). There was a clear benefit of adding 3 days of artesunate to amodiaquine, chloroquine, mefloquine or sulfadoxine pyrimethamine for uncomplicated malaria. The combination treatment resulted in fewer parasitological failures at day 28 and reduced gametocyte carriage compared with the baseline value. Adding artesunate treatment for 1 day (6 RCTs) was also associated with fewer treatment failures by day 28 but was significantly less effective than the 3 day regimen (OR %CI ; p<0.0001) Clinical trials comparing ACTs ** Although there are some minor differences in oral absorption and bioavailability between the different artemisinin derivatives, there is no evidence that these differences are clinically significant in current formulations. It is the properties of the partner drug that determine the effectiveness and choice of combination. For further details see Annex 1 ** For further details see Annex 4 8

9 (i) Summary of Randomized Clinical Trials This is based on formal systematic reviews of randomized clinical trials of oral artemether lumefantrine, artesunate + amodiaquine, artesunate + mefloquine and artesunate + sulfadoxine pyrimethamine (Omari et al., 2004; Lefevre et al., 2001; Ndayiragije et al., 2004). Artesunate + mefloquine has been compared with the 6 dose regimen of artemether lumefantrine in a systematic review including 2 small RCTs from Thailand. There was a higher proportion of patients with parasitaemia on day 28 following administration of artemetherlumefantrine but this difference not statistically significant. An additional randomized clinical trial in the Lao Peopleʹs Democratic Republic also reported higher proportions of patients with parasitaemia at day 42 following artemether lumefantrine administration but this was also not statistically significant (Omari et al., 2004). The choice of an ACT in a country or region is based on the level of resistance to the partner medicine in the combination. 11. Comparative safety of ACTs Estimation of total patient exposure to ACTs A surrogate marker of doses of ACTs procured is being used as an estimate to patientʹs exposure to ACTs world wide. Over the last 3 years more countries have progressively changed their treatment policies to include an ACT, with currently 67 malaria endemic countries having adopted an ACT as treatment policy. In 2005, approximately 11.6 million treatment doses of ACTs were procured through WHO for public sector use. This amount have increased significantly in 2006, with over 60 million treatment doses of ACT procured through the WHO / RBM procurement mechanism between January and September This amounts excludes the private sector procurement and use Adverse effects/reactions to ACTs Adverse effects to components of recommended ACTs (i) Artemisinin derivatives Artemether and artesunate are safe and remarkably well tolerated (Ribeiro and Olliaro, 1998; Price et al, 1999). There have been reports of mild gastrointestinal disturbances, dizziness, tinnitus, reticulocytopaenia, elevated liver enzymes values, and ECG abnormalities, including bradycardia and prolongation of QT values. Most of the studies have not found any ECG abnormalities. The only potentially serious adverse effect reported is Type 1 hypersensitivity reactions in approximately 1 in 3000 (Leonardi et al., 2001) The neurotoxicity observed in animals treated with artemisinin derivatives has prompted large prospective assessments in humans but no evidence of neurotoxicity has been found (Kissinger et al., 2000; van Vugt et al., 2000; Hien et al., 2003). 9

10 Evidence of deaths of embryo and morphological abnormalities in early pregnancy has been demonstrated also in animals but not in humans treated during the second and third trimesters. Artemisinin derivatives have not been evaluated in the first trimester of pregnancy in humans and therefore their use in patients with uncomplicated malaria during this period should be avoided until more information is available (ii) Amodiaquine Neurotoxicity observed in animals treated with amodiaquine has prompted large prospective assessments in humans but no evidence of neurotoxicity has been found. The adverse effects of amodiaquine are similar to those of chloroquine. Amodiaquine is associated with less pruritus and is more palatable than chloroquine but is associated with a much higher risk of agranulocytosis and, to a lesser extent, of hepatitis when use for prophylaxis (Hatton et al., 1986), an indication for which it is no longer recommended. (iii) Lumefantrine Lumefantrine seems to be remarkably well tolerated. Reported side effects are generally mild nausea, abdominal discomfort, headache, and dizziness and can not be distinguished from symptoms of acute malaria. Despite similarities with the structure and pharmacokinetic properties of halofantrine, lumefantrine does not significantly prolong ECG QT interval and has no other significant toxicity (van Vugt et al., 1999). (iv) Mefloquine Minor adverse reactions following mefloquine treatment, are most frequently nausea, vomiting, abdominal pain, anorexia, diarrhoea, headache, dizziness, loss of balance, dyphoria, somnolence and sleep disorders. Neuropsychiatric disturbances (seizures, encephalopathy, psychosis) occur in approximately 1 in travellers receiving mefloquine prophylaxis, 1 in 1000 patients treated in Asia, 1 in 200 patients treated in Africa and in 1 in 20 patients following severe malaria (Bem, et al., 1992; ter Kuile et al., 1995; Phillips Howard and ter Kuile, 1995; Mai et al., 1996). Rare side effects include skin rashes, pruritus and urticaria, hair loss, muscle weakness, liver function disturbances and, very rarely, thrombocytopenia and leukopenia. Cardiovascular effects have included postural hypotension, bradycardia and, rarely, hypertension, tachycardia or palpitations, and minor ECG changes. Overdose may cause cardiac, hepatic and neurological symptoms and fatalities have been recorded. (v) Sulfadoxine pyrimethamine Sulfadoxine shares the adverse effect profile of other sulphonamides although allergic reactions may be severe because of its slow elimination. Nausea, vomiting, anorexia, and diarrhea may occur. Crystalluria, causing haematuria and oliguria is rare compared with more rapidily eliminated sulphonamdes. Cutaneous manifestations can be severe and include pruritus, exfoliative dermatitis, toxic epidermal necrolysis and Steven Johnson syndrome (Miller et al., 1986). Reported blood disorders include agranulcytosis, aplastic anaemia, thrombocytopenia, leucopenia and hypoprothrombinaemia. Other adverse reactions that have been reported include hypoglycaemia, jaundice in neonates, faique, headache, ataxia, drowsiness, convulsions, neuropathies, psychosis and pseudomembranous colitis. 10

11 Pyrimethamine is generally well tolerated. Administration for prolonged periods may cause depression of haematopoiesis due to interference with folic acid metabolism. Skin rashes and hyposensitivity reactions also occur. Large doses may cause gastrointestinal symptoms, haematological effects including megaloblastic anaemia, leucopenia, thrombopenia, and central nervous system effects such as headache and dizziness Safety in specific population groups Use of ACTs in pregnant women Pregnant women with systematic acute malaria are a high risk group and must receive effective treatment. There is insufficient information on the safety and efficacy of most antimalarials in pregnancy, particularly for exposure during the first trimester. There is increasing experience with artemisinin derivatives in the second and third trimesters of pregnancy (at present over 1000 documented cases) There have been no adverse effects on mother or fetus. The current comparative assessment of benefits with risks suggest that artemisinin derivatives should be used to treat uncomplicated falciparum malaria in the second and third trimesters but should not be used in the first trimester until more information is available. The choice of the partner to be used in ACT during pregnancy is difficult. Mefloquine has been associated with the increased risk of still births in Thailand but not in Malawi. Amodiaquine, and lumefantrine have not been evaluated sufficiently enough. However though sulfadoxine pyrimethamine is considered safe but it may be ineffective in may areas because of increasing resistance. Despite these uncertainties, the benefits of administering an effective treatment in pregnancy outweighs the potential risks, thus effective treatment must not be delayed in pregnant women. Given the disadvantages of quinine, i.e. the long course of treatment and the increased risk of hypoglycaemia in the second and third trimesters, ACTs are considered suitable alternatives for these trimesters. Analysis of data from four randomized and two quasi randomized clinical trials involving 512 pregnant women indicated that there were fewer treatment failures with artesunate mefloquine than with quinine in one trial (day 63:RR:0.09; 95%Cl: ; 106 participants). there were no differences reported between treatments in terms of the effect on the mother or the fetus. Data from other comparisons are limited Use of ACTs in infants. Malaria is common in infants and children under 2 years of age. Artemisinin derivatives appear to be safe in and well tolerated by young children and the choice of ACT will be determined largely by the safety and tolerability of the partner drug. The limited information available does not indicate particular problems with currently recommended ACTs in infancy. 11

12 Co-infections with HIV Increasing numbers of people in malaria endemic areas are living with HIV infections. There is insufficient information at present on how HIV infections modifies the therapeutic response to antimalarials and randomized clinical trials of the efficacy and safety of ACTs in people infected with HIV have not been carried out. Observational studies suggest that malaria is more severe in patients co infected with HIV. There is concern that severe adverse reactions to sulfonamides may be more frequent in HIV patients receiving cotrimoxazole (trimethoprim sulfamethoxazole) for prophylaxis against opportunistic infections and who are also treated with sulfadoxine pyrimethamine for malaria. There is insufficient evidence to recommend modifications to antimalarial treatment regimens in patients infected with HIV; and. SP should be avoided for malaria treatment in HIV infected patients receiving cotrimoxazole prophylaxis Comparative safety of ACTs Comparison of 6 doses with 4 doses of artemether-lumefantrine The randomized clinical trial reported all adverse events to be mild or moderate in severity and possibly associated with malaria. There were no significant differences between the treatment groups and no obvious cardiovascular effects. There were no changes in QRS duration and PR interval during treatment in 66 people who had regular ECG monitoring, Similarly, there were no differences in mean and median QTC values in the treatment groups. Four serious effects were reported but these were considered to be unrelated to treatment Comparison of artemether-lumefantrine (6 doses) and artesunate (3 days) plus amodiaquine The randomized clinical trial found no significant difference in adverse events between the treatment groups other than vomiting which was significantly less frequent on days 1 and 2 in the artemether lumefantrine treatment group. (Day1 5% in artemether lumefantrine group and 13% in the artesunate amodiaquine group: Day2 1% in artemether lumefantrine group and 5% in the artesunate amodiaquine group; p value was not reported). 12. Comparative costs ACTs Costs Products Min cost* Max cost* Median Artesunate+ Adult amodiaquine Paediatric Artesunate + Adult mefloquine Paediatric Artesunate+sulfadoxinepyrimethamine Adult Paediatric Artemetherlumefantrine** Adult Paediatric * US dollars ** Newly revised prices 12

13 13. Regulatory Status of ACTs ACTs have currently being adopted in National treatment policies as first and /or second line treatment for uncomplicated malaria in over 60 malaria endemic countries, with a break down as follows: AS+AQ = 15; AL = 28; AS+SP=12; AS+MQ=6 In addition to the countries where ACTs have been adopted in National treatment policies, registration have also being undertaken by other malaria endemic countries who have yet to adopt and implement them in their National Treatment Policies. 14. Pharmacopoeial Standards Standards for the individual components of artemisinin based combinations i.e. artemether, artesunate, amodiaquine, mefloquine, and sulfadoxine pyrimethamine are included in the 5 th Edition of the International Pharmacopoeia. They have not been published yet for lumefantrine. 15. Proposed text for WHO Model Formulary. See below at the end of document Angola, Argentina, Aruba, Australia, Bangladesh, Benin, Botswana, Brazil, Bulgaria, Burkina Faso, Burundi, Cameroon, Central African Republic, Chile, China, Colombia, Congo (Brazzaville), Curacao, Democratic Republic of Congo, Dominican Republic, Ecuador, El Salvador, Ethiopia, French Guyana, Gabon, Ghana, Guatemala, Guinea (Conakry), Guyana, Haiti, Honduras, Hong Kong, Ivory Coast, India, Jamaica, Kenya, Libya, Madagascar, Malawi, Malaysia, Mali, Mayotte Island, Mauritania, Mexico, Myanmar, Nicaragua, Niger, Nigeria, Pakistan, Panama, Peru, Philippines, Romania, Rwanda, Sao Tome & Principe, Senegal, Sierra Leone, Singapore, South Africa, Sudan, Switzerland, Tanzania, Thailand, Togo, Trinidad and Tobago, Uganda, Venezuela, Vietnam, Yemen, Zambia, Zanzibar, Zimbabwe 13

14 Annex 1: Comparison of ACTs with non-artemisinin monotherapies 1.1. Artemisinin derivatives administered in combination compared with monotherapy alone: total failures by day 28 (re-infections included) Data from the International Artemisinin Study Group individual patient data meta analysis (Adjuik et al., 2004) 14

15 1.2. Artemisinin derivatives administered in combination compared with monotherapy alone: total failures by day 28 (re-infections excluded) Data from the International Artemisinin Study Group individual patient data meta analysis (Adjuik et al., 2004) 15

16 Annex 2 Comparison of efficacy of ACTs 2.1. Artemether-lumefantrine (6 doses) compared with artesunate (3 days) plus mefloquine). The conclusions below are based on one systematic review (search date 2004), two randomized clinical trials conducted in 419 people in Thailand in and (Omari et al., 2004). The review found a higher proportion of people with parasitaemia on day 28 with artemether lumefantrine treatment than with artesunate mefloquine although the pooled difference did not reach statistical significance (PCR unadjusted parasitaemia rate 11/289) (4%) with artemether lumefantrine, 0/100 (0%) with artesunate mefloquine, RR: 4.20; 95%Cl: , p= 0.2; PCR adjusted parasitaemia rate 9/289 (3%) with artemether lumefantrine, 0/100 (0%), RR:3.50; 95%Cl: , p=0.2; see comment below). The first randomized clinical trial (219 adults and children aged over 12 years in Thailand ) identified by the review found no significant difference in median parasite clearance time between the two treatment groups (29h; 95%Cl:29 32h in 164 people receiving artemether lumefantrine, 31h:95%Cl: 26 31h in 55 people receiving artesunate mefloquine, p value not reported) (Lefevre et al., 2001). Similarly it found no significant difference in median fever clearance time (29h; 95%Cl: 23 37h in 76 people receiving artemether lumefantrine, 23h;95%Cl:15 30h in 29 people receiving artesunate mefloquine, p value not reported) or in median gametocyte clearance time between treatments (72h; 95%Cl: h in 26 people receiving artemether lumefantrine, 85h;95%Cl: h in 10 people receiving artesunatemefloquine, p value not reported) Artemether-lumefantrine (6 doses) compared with artesunate (3 days) plus amodiaquine One clinical trail with a 14 day follow up period has been carried out in Burundi ( ) in 295 children under 5 years of age. This trial found not significant difference between treatments in the proportion of people with adequate clinical and parasitological response (140/141 (99.3%); 95%Cl: % with artemether lumefantrine, 142/149 (95.3%); 95%Cl: % with artesunate amodiaquine, p value not reported (Ndayiragije et al.,2004). Clinical trials with a 28 day follow up period have not been reported. 16

17 REFERENCES Adjuik M et al., (2004). Artesunate combinations for treatment of malaria: meta analysis. Lancet, 2004, 363:9 17 (search date 2003; primary sources, studies sponsored by the WHO/UNICEF/UNDP/World Bank Special Programme for Research and Training in Tropical Diseases, Medline, Cochrane Controlled Trials Register, and contact with investigators of published trials). Bem JL ETAL., (1992). Mefloquine prophylaxis: an overview of spontaneous reports of severe psychiatric reactions and convulsions. Journal of Tropical Medicine and Hygiene, 95: Hatton CS et al., (1986). Frequency of severe neutropenia associated with amodiaquine prophylaxis against malaria. Lancet, 1: Hien TT et al., (2003). Neuropathological assessment of artemether treated severe malaria. Lancet,, 362: Kissinger E et al., (2000). Clinical and neurophysiological study of the effects of multiple doses of artemisinin on brain stem function in Vietnamese patients. American Journal of Tropical Medicine and Hygiene, 63: Lefevre G et al., (2001). A clinical and pharmacokinetic trial of six doses of artemetherlumefantrine for multidrug resistant Plasmodium falciparum malaria in Thailand. American Journal of Tropical Medicine and Hygiene, 64: Leonardi E et al., (2001). Severe allergic reactions to oral artesunate: a report of two cases. Transactions of the Royal Society of Tropical Medicine and Hygiene, 95: McIntosh HM.(2004). Chloroquine or amodiaquine combined with sulfadoxine pyrimethamine for treating uncomplicated malaria. In: The Cochrane Library, Issue 4. Chichester, John Wiley & Sons, (Search date Primary sources: The Cochrane Infectious Diseases Group trials register, the Cochrane Controlled Trials Register, Medline, Embase, Science Citation Index, African Index Medicus and Lilacs, plus contact with experts in the field and pharmaceutical manufacturers). Miller KD et al., (1986). Severe cutaneous reactions among American travelers using pyrimethamine sulfadoxine (Fansidar) for malaria prophylaxis. American Journal of Tropical Medicine and Hygiene, 35: Ndayiragije A et al., (2004). Efficacité de combinaisons thérapeutiques avec les dérivés de l artémisinine dans le traitement de l accès palustre non compliqué au Burundi. [Efficacy of therapeutic combinations with artemisinin derivatives in the treatment of non complicated malaria in Burundi.] Tropical Medicine and International Health, 9:

18 Omari AA, et al., (2004).. Artemether lumefantrine for treating uncomplicated falciparum malaria. In: The Cochrane Library, Issue 4, Chichester, John Wiley & Sons (search date 2004, primary sources Cochrane Infectious Diseases Group trials register, the Cochrane Controlled Trials Register, Medline, Embase, Science Citation Index, African Index Medicus and Lilacs, plus contact with experts in the field and pharmaceutical manufacturers). Ribeiro IR and Olliaro P. (1998). Safety of artemisinin and its derivatives. A review of published and unpublished clinical trials. Médicine Tropical (Mars), 58(3 Suppl.): Phillips Howard PA and ter Kuile FO. (1995). CNS adverse events associated with antimalarial agents. Fact or fiction? Drug Safety, 12: Price R et al.. (1999). Adverse effects in patients with acute falciparum malaria treated with artemisinin derivatives. American Journal of Tropical Medicine and Hygiene, 60: ter Kuile FO et al., (1995) Mefloquine treatment of acute falciparum malaria: a prospective study of non serious adverse effects in 3673 patients. Bulletin of the World Health Organization, 73: Van Vugt MV et al., (1999). Efficacy of six doses of artemether lumefantrine (benflumetol) in multidrug resistant Plasmodium falciparum malaria. American Journal of Tropical Medicine and Hygiene, 60: Van Vugt M et al. (2000) A case control auditory evaluation of patients treated with artemisinin derivatives for multidrug resistant Plasmodium falciparum malaria. American Journal of Tropical Medicine and Hygiene, 62:

19 Proposed text for WHO Model Formulary. Antimalarial medicines 1. For curative treatment of uncomplicated malaria infections Plasmodium falciparum Artemisinin combination therapy (ACT) is the recommended treatment for uncomplicated P. falciparum malaria. The use of artemisinin derivatives or the component antimalarial medicines of ACTs are not recommended as monotherapy. Artemether lumefantrine Tablet: 20mg artemether + 120mg lumefantrine Artesunate Tablet: 50mg To be used only in combination with one of the following: Amodiaquine Tablet: 153mg or 200mg base Mefloquine Tablet: 250mg as hydrochloride Sulfadoxine pyrimethamine Tablet: 500mg sulfadoxine plus 25mg pyrimethamine Quinine Tablet: 300mg as sulphate or bisulphate 1.2. P.vivax, P.ovale and P.malariae Chloroquine Amodiaquine Primaquine For P. vivax and P.ovale malaria only Tablet: 100mg or 150mg as phosphate or sulphate Syrup: 50mg as phosphate or sulphate/ 5ml. Tablet: 153mg or 200mg base Tablet: 7.5mg or 15mg as diphosphate For first trimester of pregnancy 28

20 2. For curative treatment of severe P.falciparum and P.vivax infections. Artesunate Injection: ampoules containing 60mg anhydrous artesunic acid with a separate ampoule containing 5%sodium bicarbonate solution Rectal capsules containing 100mg and 400mg sodium artesunate Artemether Injection: 80mg/ml in 1ml ampoules Quinine Tablet; 300mg as sulphate or bisulphate Injection: 300mg as dihydrochloride/ml in 2ml ampoules Doxycycline *** Capsule or tablet:100mg as hydrochloride 3. For preventive chemotherapy chloroquine Tablet: 100mg or 150mg as phosphate or sulphate Syrup: 50mg as phosphate or sulphate/ 5ml. doxycycline Capsule or tablet, 100 mg (hydrochloride) mefloquine Tablet: 250mg as hydrochloride proguanil Tablet:100mg as hydrochloride Sulfadoxine pyrimethamine Tablet: 500mg sulfadoxine plus 25mg pyrimethamine For use only as pre referral treatment of severe malaria *** In combination with oral quinine. Indicated for P. vivax Only for use with chloroquine For use only as Intermittent Preventive Treatment in Pregnancy (IPTp) 29