title: Adverse effects of mefloquine for the treatment of uncomplicated malaria in Thailand: A pooled analysis of 19, 850 individual patients.
abstract: Mefloquine (MQ) has been used for the treatment of malaria since the mid-1980s, first as monotherapy or as fixed combination with sulfadoxine-pyrimethamine (MSP) and since the mid-1990s in combination with artesunate. There is a renewed interested in MQ as part of a triple therapy for the treatment of multi-drug resistance P. falciparum malaria. The widespread use of MQ beyond south-East Asia has been constrained by reports of poor tolerability. Here we present the side effect profile of MQ for the treatment of uncomplicated malaria on the Thai-Myanmar/Cambodia borders. In total 19,850 patients received seven different regimens containing either 15 or 24-25 mg/kg of MQ, the latter given either as a single dose, or split over two or three days. The analysis focused on (predominantly) gastrointestinal and neuropsychiatric events as compared to the new fixed dose combination of MQ plus artesunate given as equal doses of 8 mg/kg MQ per day over three days. Gastrointestinal side effects were dose-dependent and associated with the severity of malaria symptoms. Serious neuropsychiatric side effects associated with MQ use were rare: for a single 25 mg/kg dose it was 11.9 per 10,000 treatments (95% confidence interval, CI, 4-285) vs. 7.8 (3-15) for the 15 mg/kg dose. The risk with 25 mg/kg was much higher when it was given as repeat dosing in patients who had failed treatment with 15 mg/kg MQ in the preceding month; (RR 6.57 (95% CI 1.33 to 32.4), p = 0.0077). MQ was best tolerated as 15 mg/kg or as 24 mg/kg when given over three days in combination with artesunate. We conclude that the tolerance of a single dose of MQ in the treatment of uncomplicated malaria is moderate, but can be improved by administering it as a split dose over three days.
authors.affiliation: Mahidol Oxford Research Unit, Mahidol University, Bangkok, Thailand.|Centre for Tropical Medicine and Global Health, Nuffield Department of Medicine, University of Oxford, Oxford, United Kingdom.
authors.forename: Sue J
authors.initials: SJ
authors.lastname: Lee
authors.affiliation: Department of Clinical Sciences, Liverpool School of Tropical Medicine, Liverpool, United Kingdom.
authors.forename: Feiko O
authors.initials: FO
authors.lastname: Ter Kuile
authors.affiliation: Centre for Tropical Medicine and Global Health, Nuffield Department of Medicine, University of Oxford, Oxford, United Kingdom.|Global and Tropical Health Division, Menzies School of Health Research and Charles Darwin University, Darwin, Northern Territory, Australia.
authors.forename: Ric N
authors.identifier: http://orcid.org/0000-0003-2000-2874
authors.initials: RN
authors.lastname: Price
authors.affiliation: Shoklo Malaria Research Unit, Mahidol-Oxford Tropical Medicine Research Unit, Faculty of Tropical Medicine, Mahidol University, Mae Sot, Thailand.
authors.forename: Christine
authors.initials: C
authors.lastname: Luxemburger
authors.affiliation: Centre for Tropical Medicine and Global Health, Nuffield Department of Medicine, University of Oxford, Oxford, United Kingdom.|Shoklo Malaria Research Unit, Mahidol-Oxford Tropical Medicine Research Unit, Faculty of Tropical Medicine, Mahidol University, Mae Sot, Thailand.
authors.forename: François
authors.identifier: http://orcid.org/0000-0002-7951-0745
authors.initials: F
authors.lastname: Nosten
mesh_terms: D000293:Adolescent; D000328:Adult; D000855:Anorexia / Q000139:chemically induced; D000962:Antimalarials / Q000009:adverse effects / Q000627:therapeutic use; D037621:Artemisinins / Q000009:adverse effects / Q000627:therapeutic use; D000077332:Artesunate; D002648:Child; D002675:Child, Preschool; D004244:Dizziness / Q000139:chemically induced; D004305:Dose-Response Relationship, Drug; D004338:Drug Combinations; D004359:Drug Therapy, Combination; D005260:Female; D006790:Host-Parasite Interactions / Q000187:drug effects; D006801:Humans; D008288:Malaria / Q000188:drug therapy* / Q000469:parasitology; D008297:Male; D015767:Mefloquine / Q000009:adverse effects / Q000627:therapeutic use*; D009325:Nausea / Q000139:chemically induced; D017063:Outcome Assessment, Health Care / Q000379:methods / Q000706:statistics & numerical data; D010963:Plasmodium falciparum / Q000187:drug effects* / Q000502:physiology; D010966:Plasmodium vivax / Q000187:drug effects* / Q000502:physiology; D011618:Psychotic Disorders / Q000209:etiology; D011739:Pyrimethamine / Q000009:adverse effects / Q000627:therapeutic use; D013413:Sulfadoxine / Q000009:adverse effects / Q000627:therapeutic use; D013785:Thailand; D014839:Vomiting / Q000139:chemically induced; D055815:Young Adult
chemical_list: D000962:Antimalarials; D037621:Artemisinins; D004338:Drug Combinations; C001205:fanasil, pyrimethamine drug combination; D000077332:Artesunate; D013413:Sulfadoxine; D015767:Mefloquine; D011739:Pyrimethamine