OVERVIEW

CASE REPORT

PRODUCT INFORMATION

CHEMICAL FORMULA AND STRUCTURE

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DRUG	CAS REGISTRY NUMBER	MOLECULAR FORMULA	STRUCTURE
Mefloquine	51773-92-3	C17-H16-F6-N2-O.Cl-H

ANNOTATED BIBLIOGRAPHY

References updated: 07 February 2017

• Zimmerman HJ. Antiprotozoal agents. In, Zimmerman HJ. Hepatotoxicity: the adverse effects of drugs and other chemicals on the liver. 2nd ed. Philadelphia: Lippincott, 1999, pp. 623-5.

  (Expert review of hepatotoxicity published in 1999; mentions that mefloquine can lead to elevated ALT levels).
• Vinetz JM, Clain J, Bounkeua V, Eastman RT, Fidock D. Chemotherapy of malaria.l In, Brunton LL, Chabner BA, Knollman BC, eds. Goodman & Gilman.s the pharmacological basis of therapeutics. 12th ed. New York: McGraw-Hill, 2011, pp. 1383-418.

  (Textbook of pharmacology and therapeutics).
• Reisinger EC, Horstmann RD, Dietrich M. Tolerance of mefloquine alone and in combination with sulfadoxine-pyrimethamine in the prophylaxis of malaria. Trans R Soc Trop Med Hyg 1989; 83: 474-7. [PubMed: 2694482]

  (Controlled trial of mefloquine alone vs mefloquine and sulfadoxine/pyrimethamine in 175 travelers; ALT or AST became abnormal in 18%, peak ALT 122 U/L with similar frequency in both groups; all resolving spontaneously).
• Lobel HO, Miani M, Eng T, Bernard KW, Hightower AW, Campbell CC. Long-term malaria prophylaxis with weekly mefloquine. Lancet 1993; 341: 848-51. [PubMed: 8096560]

  (Study on 421 Peace Corps volunteers in West Africa on different antimalarial regimens including mefloquine, chloroquine and proguanil; no serious adverse events were reported, but ALT levels were not monitored; mefloquine decreased P. falciparum infection rate).
• Steffen R, Fuchs E, Schildknecht J, Naef U, Funk M, Schlagenhauf P, Phillips-Howard P, et al. Mefloquine compared with other malaria chemoprophylactic regimens in tourists visiting east Africa. Lancet 1993; 341: 1299-303. [PubMed: 8098447]

  (Inflight questionnaires of returning travelers from East Africa between 1985 and 1991; side effects of mefloquine reported in 17-35% of subjects, higher with combinations; 4 deaths, evidently from malaria).
• Boudreau E, Schuster B, Sanchez J, Novakowski W, Johnson R, Redmond D, Hanson R, et al. Tolerability of prophylactic malaria regimens. Trop Med Parasitol 1993; 44: 257-65. [PubMed: 8256107]

  (Controlled trial of mefloquine vs chloroquine in 359 US Marines for 12 weeks; no differences in ALT levels between groups; mefloquine caused mild psychological side effects and insomnia).
• Palmer KJ, Holliday SM, Brogden RN. Mefloquine. A review of its antimalarial activity, pharmacokinetic properties and therapeutic efficacy. Drugs 1993; 45: 430-75. [PubMed: 7682911]

  (Review on mefloquine which is used as prophylaxis and treatment of chloroquine resistant P. falciparum malaria; transient increases of ALT have been observed with prophylactic and therapeutic regimens; 4 cases of hepatitis have been reported to the manufacturer).
• Jaspers CAJJ, Hoperus Buma APCC, Van Thiel PPAM, Van Hulst RA, Kager PA. Tolerance of mefloquine chemoprophylaxis in Dutch military personnel. Am J Trop Med Hyg 1996; 55: 230-4. [PubMed: 8780466]

  (Study of 73 volunteers on mefloquine for 25 weeks; slight increase in mean ALT levels but no value rose above normal).
• Barrett PJ, Emmins PD, Clarke PD, Bradley DJ. Comparison of adverse events associated with the use of mefloquine and combination of chloroquine and proguanil as antimalarial prophylaxis: a postal and telephone survey of travelers. BMJ 1996; 313: 525-8. [PMC free article: PMC2351944] [PubMed: 8789977]

  (Mail questionnaire of 3851 British travelers taking mefloquine or chloroquine/proguanil for malaria prophylaxis; rates of side effects were similar [~41%], no mention of hepatic adverse events).
• Grieco A, Vecchio FM, Natale L, Gasbarrini G. Acute fatty liver after malaria prophylaxis with mefloquine. Lancet 1999; 353: 295-6. [PubMed: 9929030]

  (46 year old developed nausea, weight loss and edema, found to have hepatomegaly and fatty liver [ALT 41 U/L, Alk P 161 U/L, no bilirubin values given], resolving over next month, but relationship to therapy unclear).
• Gotsman I, Azaz-Livshits T, Fridlender Z, Muszkat M, Ben-Chetrit E. Mefloquine-induced acute hepatitis. Pharmacotherapy 2000; 20: 1517-9. [PubMed: 11130224]

  (68 year old man developed fatigue and nausea after 6 weeks of mefloquine prophylaxis [bilirubin 1.9 mg/dL, ALT 1277 U/L, LDH 7770 U/L, Alk P normal, INR 7.4], with rapid recovery on stopping; patient also had atrial flutter and heart failure and clinical presentation was more typical of ischemic hepatitis than drug induced liver injury).
• Overbosch D, Schilthuis H, Bienzle U, Behrens RH, Kain KC, Clarke PD, Toovey S, et al. Malarone International Study Team. Atovaquone-proguanil versus mefloquine for malaria prophylaxis in nonimmune travelers: results from a randomized, double-blind study. Clin Infect Dis 2001; 33: 1015-21. [PubMed: 11528574]

  (Controlled trial of atovaquone-proguanil vs mefloquine for malaria prophylaxis in 483 travelers; similar efficacy [100%], but neuropsychiatric side effects were more common with mefloquine [29% vs 14%] including insomnia, anxiety, vivid dreams, dizziness and trouble concentrating; no mention of liver injury and ALT levels were not monitored).
• Croft AM, Herxheimer A. Adverse effects of the antimalaria drug, mefloquine: due to primary liver damage with secondary thyroid involvement? BMC Public Health 2002; 2: 6. [PMC free article: PMC101408] [PubMed: 11914150]

  (Systematic review of 516 published case reports of adverse effects of mefloquine suggests that many such as malaise, fever, anorexia, headache, abdominal pain and nausea are due to “transient, anicteric chemical hepatitis,” although abnormal liver tests are found in only a proportion).
• Croft AM, Whitehouse DP, Cook GC, Beer MD. Safety evaluation of the drugs available to prevent malaria. Expert Opin Drug Saf 2002; 1: 19-27. [PubMed: 12904156]

  (Review of adverse side effects of antimalarial agents, pointing out the need for careful prospective randomized controlled trials of prophylactic regimens).
• Taylor WR, White NJ. Antimalarial drug toxicity: a review. Drug Saf 2004; 27: 25-61. [PubMed: 14720085]

  (Review of the toxicities and side effects of antimalarials; mentions that mefloquine can cause transient ALT elevations and rarely hepatitis).
• Bruguera M, Herrera S. [Acute hepatitis associated with mefloquine therapy]. Gastroenterol Hepatol 2007; 30: 102-3. Spanish. [PubMed: 17335720]

  (35 year old woman physician developed nausea and pruritus followed by jaundice 2 months after starting mefloquine prophylaxis [bilirubin 7.1 mg/dL, ALT 2411 U/L, Alk P 614 U/L], resolving 5 weeks after stopping: Case 1).
• Chalasani N, Fontana RJ, Bonkovsky HL, Watkins PB, Davern T, Serrano J, Yang H, Rochon J; Drug Induced Liver Injury Network (DILIN). Causes, clinical features, and outcomes from a prospective study of drug-induced liver injury in the United States. Gastroenterology 2008; 135: 1924-34. [PMC free article: PMC3654244] [PubMed: 18955056]

  (Among 300 cases of drug induced liver disease in the US collected between 2004 and 2008, one case was attributed to artesunate, but no other antimalarial agent was mentioned).
• Devarbhavi H, Dierkhising R, Kremers WK, Sandeep MS, Karanth D, Adarsh CK. Single-center experience with drug-induced liver injury from India: causes, outcome, prognosis, and predictors of mortality. Am J Gastroenterol 2010; 105: 2396-404. [PubMed: 20648003]

  (313 cases of drug induced liver injury were seen over a 12 year period at a large hospital in Bangalore, India; none were attributed to antimalarials).
• Tine RC, Faye B, Sylla K, Ndiaye JL, Ndiaye M, Sow D, Lo AC, et al. Efficacy and tolerability of a new formulation of artesunate-mefloquine for the treatment of uncomplicated malaria in adult in Senegal: open randomized trial. Malar J. 2012 Dec 12; 11: 416. [PMC free article: PMC3554515] [PubMed: 23234606]

  (310 Senegalese patients with malaria were treated with artesunate and mefloquine vs artesunate and lumefantrine for 3 days; both regimens were highly effective and well tolerated, mean serum ALT levels did not change and no serious adverse events were reported).
• Rueangweerayut R, Phyo AP, Uthaisin C, Poravuth Y, Binh TQ, Tinto H, Pénali LK, et al; Pyronaridine–Artesunate Study Team. Pyronaridine-artesunate versus mefloquine plus artesunate for malaria. N Engl J Med 2012; 366: 1298-309. [PubMed: 22475593]

  (Among 1271 patients in Asia and Africa treated for malaria with an artesunate combination regimen for 3 days, ALT elevations occurred in none of 423 mefloquine treated, but in 2.5% [21 of 848] of pyronaridine-artesunate treated subjects including 15 with ALT above 5 times ULN and 2 patients with jaundice, but with symptomatic hepatitis).
• Hernández N, Bessone F, Sánchez A, di Pace M, Brahm J, Zapata R, A Chirino R, et al. Profile of idiosyncratic drug induced liver injury in Latin America: an analysis of published reports. Ann Hepatol 2014; 13: 231-9. [PubMed: 24552865]

  (Among 176 reports of drug induced liver injury from Latin America published between 1996 and 2012, none were attributed to an antimalarial agent).
• Björnsson ES, Bergmann OM, Björnsson HK, Kvaran RB, Olafsson S. Incidence, presentation and outcomes in patients with drug-induced liver injury in the general population of Iceland. Gastroenterology 2013; 144: 1419-25. (In a. [PubMed: 23419359]

  population based study from Iceland, 96 cases of drug induced liver injury were identified over a 2 year period [2010 and 2011], but none were attributed to an antimalarial agent).
• Chalasani N, Bonkovsky HL, Fontana R, Lee W, Stolz A, Talwalkar J, Reddy KR, et al.; United States Drug Induced Liver Injury Network. Features and outcomes of 899 patients with drug-induced liver injury: The DILIN Prospective Study. Gastroenterology 2015; 148: 1340-52. [PMC free article: PMC4446235] [PubMed: 25754159]

  (Among 899 cases of drug induced liver injury enrolled in a US prospective study between 2004 and 2013, none were attributed to an antimalarial agentl).
• Advice for travelers. Treat Guidel Med Lett 2015: 57 (1466): 52-8.

  (Concise guidelines on prevention of malaria in travelers indicates that mefloquine can be used as prophylaxis in chloroquine-reistant malaria areas of the world and is an appropriate prophylactic agent for patients who cannot tolerate chloroquine).