Background
Chemoprophylaxis
Treatment
Synthesis of evidence
Discussion of reviewed data
Pharmacokinetic basis for the dosage regimen of weekly mefloquine chemoprophylaxis
Reference | Children Total (n) | Age (in years) | Children (n) using Mefloquine | Main findings |
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CHEMOPROPHYLAXIS DATA
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Research Report Salako, Nigeria, 1989 Data on file of F. Hoffmann-La Roche | 280 | 6-10 y | 140 (with body weight range 14-40 kg including 62 children weighing ≤ 20 kg) | Weekly 62.5 mg mefloquine or 125 mg mefloquine every two weeks (in the form of Fansimef®) was effective and well tolerated even in the children weighing < 20 kg. The 62.5 mg weekly dose used here is equivalent to the currently recommended quarter tablet for malaria chemoprophylaxis in this weight category |
Weiss W. R. et al. [5] Daily Primaquine Is Effective for Prophylaxis against Falciparum Malaria in Kenya: Comparison with Mefloquine, Doxycycline, and Chloroquine plus Proguanil. The Journal of Infectious Diseases, 171, 1569-1575, 1995 | 165 | 9-14 y | 30 (weighing 20-54 kg) | Kenyan school children aged 9-14 had lower than expected trough levels of mefloquine after standard doses (5 mg/kg/week) (mean 406 ng/mL after 6 weeks of chemoprophylaxis). This lower trough level is explained by increased mefloquine clearence in older children. |
TREATMENT DATA
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Luxemburger C. et al. [18] Mefloquine in infants and young children. Annals of Tropical Paediatrics 16, 281-5, 1996 | >500 and | <5 y | 417 (with 102 children weighing 8-12 kg with mean body weight 8 kg) | No serious toxicity or adverse events. High dose of mefloquine (25 mg/kg) was associated with vomiting. Mefloquine was administered to very young children aged 3-30 months. Young age was associated with a higher risk of vomiting. Split treatment dose is recommended: 15 mg/kg initially, followed by 10 mg/kg > 12 hours later. Apart from vomiting, mefloquine was very well tolerated by young children. |
Fryauff DJ, et al. [23] Mefloquine treatment for uncomplicated Falciparum malaria in young children 6-24 months of age in northern Ghana Am J Trop Med Hyg, 76(2); 224-231, 2007 | 186 | 0.5-2 y | 186 (with mean body weight 8 kg) | Mefloquine single dose 20 mg/kg was evaluated in Ghanaian infants. Drug levels among infants that tolerated MQ well were not associated with age, weight or pre-existing symptoms of vomiting or diarrhea. |
Bourahla A. et al. [10] Stereoselective pharmacokinetics of mefloquine in young children. European Journal of Clinical Pharmacology 50, 241-244, 1996. | 12 | 0.5-2 y | 12 (with mean body weight of 9.5 kg) | Stereoselective pharmacokinetics in children aged 6 to 24 months are similar to those observed in adults |
Hellgren U. et al. [24] Standard and reduced doses of mefloquine for treatment of Plasmodium falciparum in Tanzania: whole blood concentrations in relation to adverse reactions, in vivo response, and in vitro tolerability. Am J Trop Med Hyg 45, 254-262, 1991 | 53 | 7-10 y | 53 | The dose of 6 mg/kg and higher doses eliminated P. falciparum parasites in children whereas a 2.5 mg/kg dose was not as effective. This supports the currently recommended 5 mg/kg dosage. |
Nosten F. et al. [25] Mefloquine pharmacokinetics and resistance in children with acute falciparum malaria. Brit J Clin Pharmacol 31, 556-559, 1991 | 12 | 5-10 y | 12 | A single dose of 15 mg/kg led to whole blood Cmax of 2031 ug/L, tmax mean of 8 hours (6-24) and a mean oral clearance of 0.031 L/h/kg. Comparable to adults. |
Singhasivanon V. et al. [8] Pharmacokinetics of mefloquine in children aged 6 to 24 months. European Journal of Drug Metabolism and Pharmacokinetics 17, 275-279, 1992 | 12 | 0.5-2 y | 12 | A single dose of mefloquine 25 mg/kg led to a Cmax of 3320 ug/L, tmax 12.8 hours, elimination half-life (10.3 days), volume of distribution (12 L/kg) and AUC (35.6 mg/L/day) in children aged 6 months to 2 years. Comparable to adults. |
Singhasivanon V. et al. [9] Pharmacokinetics of mefloquine in Thai children aged 5-12 years suffering from uncomplicated falciparum malaria treated with MSP or MSP plus primaquine. Eur J Drug Metab Pharmacokin 19, No 1, 27-32, 1994 | 18 | 5-12 y | 18 | Pharmacokinetic values in older children similar to children aged 6 months to 2 years except that clearance per body weight (0.049 L/h/kg) was higher in older children. |
Total No. of children | Age years/weight kg | No. of children treated with mefloquine | Important findings | |
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Faye B et al. [11] A randomized trial of artesunate mefloquine versus artemether lumefantrine for the treatment of uncomplicated Plasmodium falciparum malaria in Senegalese children. Am J Trop Med Hyg 82(1), 140-144, 2010 | 320 | 4-5 y (10-20 kg) | 160 | The mefloquine (25 mg/kg) combination was effective > 96% and well tolerated. Even in very low weight children, vomiting in mefloquine arm was less than in comparator: 30% versus 36% |
Sowunmi A et al. [12] Therapeutic efficacy and effects of artesunate-mefloquine and mefloquine alone on malaria-associated anemia in children with uncomplicated Plasmodium falciparum malaria in southwest Nigeria. Am J Trop Med Hyg 81(6), 979-986, 2009 | 342 | <10 y (7-46 kg) | 342 | Fever and parasite clearance were faster with artesunate-mefloquine (25 mg/kg) than with mefloquine (25 mg/kg) alone. Resolution of anemia was similar in both groups. Both regimens were effective and well tolerated. |
Tietche F et al. [13] Tolerability and efficacy of a pediatric granule formulation of artesunate-mefloquine in young children from Cameroon with uncomplicated falciparum malaria. Am J Trop Med Hyg 82(6), 1034-1040, 2010 | 213 | Mean age 3 y (10-20 kg) | 213 | The combination was well tolerated and highly efficacious |
Mayxay M et al, [14] A phase III, randomized, non-inferiority trial to assess the efficacy and safety of dihydroartemisin-piperaquine versus artesunate-mefloquine in patients with uncomplicated Plasmodium falciparum malaria in Southern Laos. Am J Trop Med Hyg, 83(6)1221-1229, 2010 | 205 | < 15 y | 69 | Both regimens were effective, more adverse events were recorded for the AM group |
Frey SG et al. [15] Artesunate-mefloquine combination therapy in acute Plasmodium falciparum malaria in young children: a field study regarding neurological and neuropsychiatric safety. Malaria J,9:291, 2010 | 220 | 10-20 kg | 220 | Mefloquine (125 mg/day) for 3 days (in combination with artesunate (50 mg/day) was well tolerated by small children with a low incidence of neurological and neuropsychiatric adverse events, mainly sleeping disorder. All events resolved spontaneously. |
Ramharter M et al. [16] Pharmacokinetics of two paediatric artesunate-mefloquine drug formulations in the treatment of uncomplicated falciparum malaria in Gabon. J Antimicrob Chemother 60, 1091-1096, 2007 | 24 | 2-12 y and 11-37 kg | 24 | Exploratory analysis of mefloquine plasma levels showed a trend towards higher concentrations in younger age groups. All children, regardless of formulation used, achieved therapeutic and post treatment prophylactic protective levels of mefloquine |
Malaria treatment studies Author/Reference | Age (in years) | No. of children treated with mefloquine | Location of the study |
---|---|---|---|
Tin F et al. [26] Single dose treatment of falciparum malaria with mefloquine: field studies with different doses in semi-immune adults and children in Burma. Bull WHO 60, 913-917, 1982 | 5-12 | 89 | Myanmar |
Chongsuphajaisiddhi T. et al. [27] A phase-III clinical trial of mefloquine in children with chloroquine-resistant falciparum malaria in Thailand. Bull WHO 65, 223-226, 1987 | 5-12 | 82 | Thailand |
Guo X.B. [28] Double-blind dose finding study of mefloquine-sulfadoxine-pyrimethamine in children with acute falciparum malaria. Trans Roy Soc Trop Med & Hyg 82: 538-540, 1988 | 5-15 | 60 | China |
Sowunmi A. et al. [29] Clinical efficacy of mefloquine in children suffering from chloroquine-resistant Plasmodium falciparum malaria in Nigeria. Transactions of the Royal Society of Tropical Medicine & Hygiene, 84, 761-764, 1990 | 0.5-11 | 62 | Nigeria |
Trinh T.K. [30] Double-blind studies with mefloquine alone and in combination with sulfadoxine-pyrimethamine in 120 adults and 120 children with falciparum malaria in Vietnam. Trans Roy Soc Trop Med & Hyg 84, No 1, 50-53, 1990 | 6-12 | 80 | Vietnam |
Slutsker L.M. et al. [31] Mefloquine therapy for Plasmodium falciparum malaria in children under 5 years of age in Malawi: in vivo/in vitro efficacy and correlation of drug concentration with parasitological outcome. Bulletin of the World Health Organization 68, 53-59, 1990. | < 5 | 121 | Malawi |
Nosten F. et al. [32] Mefloquine-resistant falciparum malaria on the Thai-Burmese border. Lancet 337, 1140-1143, 1991. | < 15 | 245 | Thai-Myanmar border |
Sowunmi A. et al. [33] Evaluation of the relative efficacy of various antimalarial drugs in Nigerian children under five years of age suffering from acute uncomplicated falciparum malaria. Annals of Tropical Medicine and Parasitology 86, 1-8, 1992. | < 5 | 100 | Nigeria |
Sowunmi A. et al. [34] The relationship between the response of Plasmodium falciparum malaria to mefloquine in African children and its sensitivity in vitro. Trans Roy So Trop Med & Hyg 86, 368-371, 1992 | 4-12 | 85 | Nigeria |
Ter Kuile F. et al. [21] High-dose mefloquine in the treatment of multidrug-resistant falciparum malaria. Journal of Infectious Diseases 166, 1393-1400, 1992. | < 15 | 117 | Thai- Myanmar border |
Ter Kuile F. et al [35] Halofantrine versus mefloquine in treatment of multi-drug resistant falciparum malaria. Lancet; 341:1044-1049, 1993 | < 15 | 95 | Thai - Myanmar border |
Smithuis F.M. [36] Comparison of two mefloquine regimens for treatment of Plasmodium falciparum malaria on the north eastern Thai-Cambodian border. Antimicrobial agents and chemotherapy, 37, No 9, 1977-1981, 1993 | < 15 | 27 | Thai-Cambodian border |
Piarroux R. [37] Choice of therapy for imported cases of falciparum malaria in children: a retrospective study of 100 cases seen in Marseilles, France. Trans Roy Soc Trop Med & Hyg 87 No 1, 72-74, 1993 | < 15 | 12 | Imported paediatric malaria in France |
Luxemburger C. et al. [38] Single day mefloquine-artesunate combination in the treatment of multi-drug resistant falciparum malaria. Trans Roy Soc Trop Med & Hyg, 88, 213-217, 1994. | < 15 | 237 | Thai-Myanmar border |
Sowunmi A. et al. [39] Open comparison of mefloquine, MSP and chloroquine in acute uncomplicated falciparum malaria in children. Trans Roy Soc Trop Med & Hyg, 89, 303-305, 1995. | 0.5-10 | 43 | Nigeria |
Ter Kuile F. et al. [40] Predictors of mefloquine treatment failure: a prospective study of 1590 patients with uncomplicated falciparum malaria. Transactions of the Royal Society of Tropical Medicine and Hygiene 89, 660-664, 1995. | < 15 | 752 | Thai- Myanmar border |
Ter Kuile F. et al. [19] Mefloquine treatment of acute falciparum malaria: a prospective study of non-serious adverse effects in 3673 patients. Bulletin World Health Organization 73, 631-642, 1995. | < 14 | 1319 | Thai- Myanmar border |
Radloff PD. et al. [41] Arteflene compared with mefloquine for treating Plasmodium falciparum malaria in children. American Journal of Tropical Medicine and Hygiene, 55, 259-262, 1996 | 7-12 | 21 | Gabon |
Sowunmi A. et al. [42] Open comparison of artemether and mefloquine in uncomplicated Plasmodium falciparum hyperparasitaemia in children. Annals of Tropical Paediatrics 16, 5-9, 1996 | 1-10 | 43 | Nigeria |
Price RN. [43] Artesunate/mefloquine treatment of multi-drug resistant falciparum malaria. Trans Roy Soc Trop Med & Hyg 91 573-577, 1997 | < 14 | 1453 | Thai-Myanmar Border |
Ranford-Cartwright LC. et al. [44] Molecular analysis of recrudescent parasites in a Plasmodium falciparum drug efficacy trial in Gabon. Trans Roy Soc Trop Med & Hyg 91, 719-724, 1997 | < 15 | 64 | Gabon |
Okoyeh J.N. [45] Responses of multidrug-resistant Plasmodium falciparum parasites to mefloquine in Nigerian children. Trop Med Int Health, 2, No 4, 319-324, 1997 | 0.5-7 | 33 | Nigeria |
Lell B.et al. [46] Malaria chemotherapy trial at a minimal effective dose of mefloquine-sulfadoxine-pyrimethamine compared with equivalent doses of Sulfadoxine/Pyrimethamine or Mefloquine alone. Am J Trop Med Hyg 58, No 5, 619-624, 1998 | < 15 | 76 | Gabon |
Luxemburger C. et al. [47] Early vomiting of mefloquine in children with malaria is not modified by the timing of antipyretic treatment. Trans Roy Soc Trop Med & Hyg, 92, 562-563, 1998 | 2-15 | unclear | Thai- Myanmar border |
Position of international expert groups with regard to mefloquine chemoprophylaxis
Authority/Expert Group | MQ Chemoprophylaxis in children | MQ Therapy of uncomplicated malaria including Stand-by emergency self treatment (SBET) in children |
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WHO International Travel and Health [1] | Mefloquine recommended for chemoprophylaxis for children weighting > 5 kg. Dosage 5 mg/kg/week | Treatment of uncomplicated malaria in children weighing > 5 kg. Dosage 25 mg/kg as split dose (15 mg/kg followed by 10 mg/kg 6-24 hours apart) |
DTG [48] Deutsche Tropenmed. Gesellschaft | Mefloquine recommended for chemoprophylaxis for children weighing > 5 kg. Dosage 5 mg/kg/week | No longer routinely recommended for SBET |
Canadian Guidelines CATMAT[49] | Mefloquine recommended for chemoprophylaxis in travellers > 5 kg body weight (5 mg/kg once weekly)-start 3 weeks before travel | Not routinely recommended for SBET |
5-10 kg 1/8 Tablet | ||
10-20 kg ¼ Tablet | ||
20-30 kg 1/2 Tablet | ||
30-35 kg ¾ Tablet | ||
> 45 kg 1 tablet | ||
CDC [50] | Begin 1-2 weeks before travel | Not routinely recommended for SBET |
≤ 9 kg (5 mg/kg salt once weekly) | ||
> 9 kg-19 kg ¼ Tablet once weekly | ||
> 19-30 kg 1/2 Tablet once weekly | ||
> 31-45 kg ¾ Tablet once weekly | ||
> 45 kg 1 Tablet once weekly | ||
UK Guidelines [51] | Weekly mefloquine | Not routinely recommended for SBET |
< 6 kg not recommended | ||
6-9.9 kg ¼ Tablet weekly | ||
10-15.9 kg ¼ Tablet weekly | ||
16-24.9 kg 1/2 Tablet weekly | ||
25-44.9 kg ¾ Tablet weekly | ||
45 kg and over 1 Tablet weekly | ||
French Guidelines [53] | Mefloquine 5 mg/kg per week. | Not routinely recommended for SBET |
Start 10 days before travel, take throughout the exposure period and for 3 weeks thereafter | ||
< 15 kg not recommended | ||
15-19 kg: ¼ Tablet weekly | ||
19-30 kg: 1/2 Tablet weekly | ||
30-45 kg: ¾ Tablet weekly |