OVERVIEW

PRODUCT INFORMATION

CHEMICAL FORMULA AND STRUCTURE

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DRUG	CAS REGISTRY NUMBER	MOLECULAR FORMULA	STRUCTURE
Amodiaquine	86-42-0	C20-H22-Cl-N3-O

ANNOTATED BIBLIOGRAPHY

References updated: 02 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; amodiaquine has been associated with many cases of severe hepatitis, some fatal, with onset ranging from a few days to as long as one year after starting).
• Vinetz JM, Clain J, Bounkeua V, Eastman RT, Fidock D. Chemotherapy of malaria. 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; amodiaquine is a congener of chloroquine that is no longer recommended because of its toxicity).
• Glick L. Fatal agranulocytosis during treatment with amodiaquine. Br Med J 1957; 1: 932. [PMC free article: PMC1973250] [PubMed: 13413258]

  (53 year old woman with photosensitive rash was given amodiaquine for 8 weeks and developed fatal agranulocytosis and jaundice; on autopsy, the liver was enlarged and had a nutmeg appearance).
• Pomeroy H, Warren C, Mills D, Clark GM. The effect of amodiaquin (Camoquin) on the course of rheumatoid arthritis. Arthritis Rheum 1959; 2: 396-402. [PubMed: 14433954]

  (Placebo controlled crossover study of amodiaquine in 7 elderly patients with rheumatoid arthritis; mentions in discussion that 2 of 32 patients receiving amodiaquine at their institution developed jaundice 4 and 16 weeks after starting, one dying of liver failure).
• Bepler CR, Baier HN, McCracken S, Rentschler CL, Rogers FB, Lansbury J. A 15-month controlled study of the effects of amodiaquin (Camoquin) in rheumatoid arthritis. Arthritis Rheum 1959; 2: 403-13. [PubMed: 13799077]

  (Placebo controlled crossover study of amodiaquine in 14 patients with rheumatoid arthritis; 400 mg dose was not tolerated; long term 50 mg daily doses led to jaundice in 2, Alk P elevations in 2, and AST in 4 patients [peak levels 100 U/L]).
• Perry HO, Bartholomew LG, Hanlon DG. Nearly fatal reaction to amodiaquine. JAMA 1962; 179: 598-601. [PubMed: 14485571]

  (33 year old man with systemic lupus developed fever and fatigue after 6 days of intermittent amodiaquine therapy with rash and neutropenia [bilirubin 2.3 mg/dL, AST 101 U/L], resolving rapidly with corticosteroid therapy; neutropenia lasted 2 weeks).
• Gillespie P, Wagner F. Amodiaquine agranulocytosis. Med J Aust 1977; 1: 298-9. [PubMed: 859490]

  (26 year old woman on amodiaquine prophylaxis developed skin abscess and septicemia with white count of 300/µL and no neutrophils; liver tests were “consistent with hepatocellular damage”, but no specifics given).
• Hatton CS, Peto TE, Bunch C, Pasvol G, Russell SJ, Singer CR, Edwards G, et al. Frequency of severe neutropenia associated with amodiaquine prophylaxis against malaria. Lancet 1986; 1: 411-4. [PubMed: 2868340]

  (7 cases of severe neutropenia [0-400/µL] after 3 to 13 weeks of amodiaquine therapy, lasting 3-20 days, all with recovery; some patients were jaundiced, but no specifics given).
• Hirschel B. Amodiaquine and hepatitis. Ann Intern Med 1986; 105: 467. [PubMed: 3740693]

  (Mentions that there have been 20 cases of agranulocytosis [12 with hepatitis] in Switzerland among travelers taking amodiaquine, and describes two patients who acquired malaria despite the prophylaxis).
• Woodtli W, Vonmoos P, Siegrist P, Zollikofer H. [Amodiaquine-induced hepatitis with leukopenia]. Schweiz Med Wochenschr 1986; 116: 966-8. German. [PubMed: 3764379]

  (Two cases; 40 and 55 year old travelers with fever and dark urine arising 4 and 8 weeks after starting amodiaquine [bilirubin 0.8 and 6.0 mg/dL, ALT 320 and 50 U/L, Alk P 171 and 186 U/L], resolving within 1-2 months of stopping and recurring in both with rechallenge).
• Larrey D, Castot A, Pëssayre D, Merigot P, Machayekhy JP, Feldmann G, Lenoir A, et al. Amodiaquine-induced hepatitis. A report of seven cases. Ann Intern Med 1986; 104: 801-3. [PubMed: 2871789]

  (Report of 7 cases of liver injury due to amodiaquine prophylaxis; 6 men and 1 woman, ages 34-64 years, taking 200-800 mg/week for 4 to 15 weeks, no eosinophilia or rash; 4 anicteric cases had fatigue and abdominal pain [ALT 3-6.5 times ULN, Alk P 0.6-2.7 times ULN], rapid resolution after stopping in all; 3 other cases had jaundice [bilirubin 17.5-39.7 mg/dL, ALT 11-77 times ULN, Alk P 1.5-4.5 times ULN, bilirubin 17.5-39.7 mg/dL], and slow resolution with minor ALT or GGT elevations persisting for more than a year after stopping).
• Desaint B, Conrad M, Florent C, Legendre C, Levy VG. [Is amodiaquine (Flavoquine) hepatotoxic?]. Gastroenterol Clin Biol 1986; 10: 440. [PubMed: 3732752]

  (Two cases of amodiaquine hepatotoxicity; 41 year old woman developed fatigue and jaundice 3 weeks after starting therapy [bilirubin 24.6 mg/dL, ALT 1700 U/L, Alk P 300 U/L], resolving within two months of stopping; 35 year old woman developed fatigue and abdominal pain [ALT 600 U/L] 3 months after starting amodiaquine, and was jaundiced and had ascites at 5 months [bilirubin 14.3 mg/dL, ALT 150 U/L, Alk P 213 U/L], requiring 4 months to resolve).
• Amouretti M, Raymond JM, Baldit C, Dumas F, Couzigou P, Béraud C. [Amodiaquine (Flavoquine) is hepatotoxic]. Gastroenterol Clin Biol 1986; 10: 855. French. [PubMed: 3803831]

  (38 year old woman developed fatigue followed by jaundice 5 weeks after switching from chloroquine to amodiaquine [ALT 1136 U/L, bilirubin 8.8 mg/dL], with progression to hepatic failure and death; autopsy showed massive hepatic necrosis).
• Neftel KA, Woodtly W, Schmid M, Frick PG, Fehr J. Amodiaquine-induced agranulocytosis and liver damage. Br Med J 1986; 292: 721-3. [PMC free article: PMC1339778] [PubMed: 3082410]

  (Seven cases of agranulocytosis [five with liver involvement] and 2 of liver damage due to amodiaquine seen between 1981-83; agranulocytosis arose 38-69 days after starting amodiaquine for malaria prophylaxis, persisting for 8-45 days, all had infectious complications leading to death in 2 patients; 2 with liver damage included a 55 year old man and a 36 year old woman who developed liver injury 42 and 120 days after starting amodiaquine [bilirubin 2.9 and 48.5 mg/dL, ALT 142 and 651 U/L, Alk P 126 and 166 U/L], one case fatal).
• Charmot G, Goujon C. [Minor hepatitis probably caused by amodiaquine]. Bull Soc Pathol Exot Filiales 1987; 80: 266-70. [PubMed: 3608009]

  (8 patients, including 4 men and 4 women, ages 21-56 years, were found to have asymptomatic ALT elevations [86-577 U/L] without jaundice 25-300 days after starting amodiaquine, resolving within 1 week).
• Stürchler D, Schär M, Gyr N. Leucopenia and abnormal liver function in travelers on malaria chemoprophylaxis. J Trop Med Hyg 1987; 90: 239-43. [PubMed: 3669125]

  (Analysis of 451 travelers from Switzerland on malarial prophylaxis found higher ALT levels in those on amodiaquine than on chloroquine or no prophylaxis).
• Bernuau J, Larrey D, Campillo B, Degott C, Verdier F, Rueff B, Pessayre D, et al. Amodiaquine-induced fulminant hepatitis. J Hepatol 1988; 6:109-12. [PubMed: 3346531]

  (3 patients, ages 12, 41 and 51 years, developed jaundice 4-10 months after starting amodiaquine prophylaxis [bilirubin 30.9, 31.6 and 10.5 mg/dL, ALT 13-47 times ULN, Alk P 1.8-2.2 times ULN], all dying of hepatic failure or requiring liver transplant; liver histology showed massive necrosis).
• Raymond JM, Dumas F, Baldit C, Couzigou P, Beraud C, Amouretti M. Fatal acute hepatitis due to amodiaquine. J Clin Gastroenterol 1989; 11: 602-3. [PubMed: 2794450]

  (38 year old woman developed fatigue, dark urine and then jaundice 5 weeks after switching from chloroquine to amodiaquine [bilirubin 8.8 mg/dL, ALT 1,136 U/L], with rapid improvement on stopping but relapse 1 week after restarting [bilirubin 21.8 mg/dL, ALT 1010 U/L, Alk P 313 U/L] and progressive hepatic failure and death; autopsy showed massive hepatic necrosis).
• Phillips-Howard PA, West LJ. Serious adverse drug reactions to pyrimethamine-sulphadoxine, pyrimethamine-dapsone and to amodiaquine in Britain. J R Soc Med 1990; 83: 82-5. [PMC free article: PMC1292502] [PubMed: 2138674]

  (Analysis of postmarketing adverse event reports on antimalarial drugs from UK sources; major problems were Stevens Johnson syndrome and agranulocytosis; serious hepatotoxicity occurred in 1:111,000 pyrimethamine-sulphadoxine, 1:75,200 pyrimethamine-dapsone, and 1:15,500 amodiaquine users; far fewer with chloroquine-proguanil).
• Clarke JB, Neftel K, Kitteringham NR, Park BK. Detection of antidrug IgG antibodies in patients with adverse drug reactions to amodiaquine. Int Arch Allergy Appl Immunol 1991; 95: 369-75. [PubMed: 1959977]

  (Amodiaquine antibodies found in 6 of 7 patients with adverse reaction and 7 of 22 without while on amodiaquine prophylaxis; reactivity not blocked by other aminoquinones).
• Orrell C, Taylor WR, Olliaro P. Acute asymptomatic hepatitis in a healthy normal volunteer exposed to 2 oral doses of amodiaquine and artesunate. Trans R Soc Trop Med Hyg 2001; 95: 517-8. [PubMed: 11706664]

  (In a single dose crossover study in 15 volunteers, one developed rise in ALT from normal to peak of 483 U/L 6 weeks after dosing with amodiaquine and artesunate without symptoms or bilirubin rise, resolving in 4-8 weeks).
• Hirschel B. Questions about the antimalarial amodiaquine. Lancet 2003; 361: 1229; author reply 1229-30. [PubMed: 12686075]

  (Letter questioning the advisability of using amodiaquine because of the risk of severe granulocytopenia; authors reply that the crisis of malaria and chloroquine resistance in Africa warrants use of amodiaquine for treatment, estimated fatality rate being 1:31,000 and severe hepatotoxicity as 1:15,650).
• 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; amodiaquine is linked to agranulocytosis and hepatitis in 1:2000 recipients).
• Sowunmi A, Fehintola FA, Adedeji AA, Gbotosho GO, Tambo E, Fateye BA, Happi TC, Oduola AM. Open randomized study of artesunate-amodiaquine vs. chloroquine-pyrimethamine-sulfadoxine for the treatment of uncomplicated Plasmodium falciparum malaria in Nigerian children. Trop Med Int Health 2005; 10: 1161-70. [PubMed: 16262741]

  (Controlled trial of 3 day regimens of artesunate-amodiaquine vs chloroquine-pyrimethamine-sulfadoxine in 153 children with malaria; “biochemical … parameters remained normal before and after treatment in all subjects”).
• Fanello CI, Karema C, van Doren W, Rwagacondo CE, D'Alessandro U. Tolerability of amodiaquine and sulphadoxine-pyrimethamine, alone or in combination for the treatment of uncomplicated Plasmodium falciparum malaria in Rwandan adults. Trop Med Int Health 2006; 11: 589-96. [PubMed: 16640610]

  (Controlled trial of amodiaquine vs sulfadoxine/pyrimethamine vs both in 351 patients with malaria in Rwanda; ALT levels decreased during therapy and no mention of hepatotoxicity or hepatitis).
• Zongo I, Dorsey G, Rouamba N, Tinto H, Dokomajilar C, Guiguemde RT, Rosenthal PJ, Ouedraogo JB. Artemether-lumefantrine versus amodiaquine plus sulfadoxine-pyrimethamine for uncomplicated falciparum malaria in Burkina Faso: a randomised non-inferiority trial. Lancet 2007; 369 (9560): 491-8. [PubMed: 17292769]

  (Controlled trial of artemether-lumefantrine vs sulfadoxine-pyrimethamine and amodiaquine in 521 patients with malaria; adverse event rates were similar and no mention of ALT levels or hepatotoxicity).
• Markham LN, Giostra E, Hadengue A, Rossier M, Rebsamen M, Desmeules J. Emergency liver transplantation in amodiaquine-induced fulminant hepatitis. Am J Trop Med Hyg 2007; 77: 14-5. [PubMed: 17620624]

  (39 year old woman developed fatigue and then jaundice ~10 weeks after starting amodiaquine prophylaxis for malaria [bilirubin 14 mg/dL, ALT 1475 U/L, Alk P 108 U/L, protime 17%] and underwent successful liver transplant 6 days later; liver showed massive necrosis).
• Gasasira AF, Kamya MR, Achan J, Mebrahtu T, Kalyango JN, Ruel T, Charlebois E, et al. High risk of neutropenia in HIV-infected children following treatment with artesunate plus amodiaquine for uncomplicated malaria in Uganda. Clin Infect Dis 2008; 46: 985-91. [PubMed: 18444813]

  (Analysis of safety of artesunate and amodiaquine in children with malaria; ALT elevations occurred in less than 1%).
• Maiteki-Sebuguzi C, Jagannathan P, Yau VM, Clark TD, Njama-Meya D, Nzarubara B, Talisuna AO, et al. Safety and tolerability of combination antimalarial therapies for uncomplicated falciparum malaria in Ugandan children. Malar 2008; 7: 106. [PMC free article: PMC2441629] [PubMed: 18547415]

  (Controlled trial of 3 combination regimens in 382 children with malaria in Uganda; ALT elevations occurred in 0.5% with amodiaquine/artesunate, 0.3% with amodiaquine/sulfadoxine/pyrimethamine and 0.6% with artemether-lumefantrine).
• Adjei GO, Kurtzhals JA, Rodrigues OP, Alifrangis M, Hoegberg LC, Kitcher ED, Badoe EV, et al. Amodiaquine-artesunate vs artemether-lumefantrine for uncomplicated malaria in Ghanaian children: a randomized efficacy and safety trial with one year follow-up. Malar 2008; 7: 127. [PMC free article: PMC2478668] [PubMed: 18620577]

  (Controlled trial of artesunate-amodiaquine vs artemether-lumefantrice in 227 children with malaria in Ghana; similar efficacy; ALT levels improved during therapy and no reports of hepatitis or ALT increases).
• Sirima SB, Tiono AB, Gansané A, Diarra A, Ouédraogo A, Konaté AT, Kiechel JR, et al. The efficacy and safety of a new fixed-dose combination of amodiaquine and artesunate in young African children with acute uncomplicated Plasmodium falciparum. Malar J 2009; 8: 48. [PMC free article: PMC2662869] [PubMed: 19291301]

  (Controlled trial of fixed vs “loose” dose combinations of amodiaquine and artesunate in 750 children with P. falciparum malaria reported similar efficacy [92%] and safety, 7 [~1%] had ALT elevations, one child had levels >1000 U/L, but bilirubin levels were normal and there were no symptoms).
• Guévart E, Aguémon A. [Two cases of fulminant hepatitis during a curative treatment with an artesunate-amodiaquine combination]. Med Mal Infect 2009; 39: 57-60. French. [PubMed: 19013042]

  (Two cases of acute liver failure; 32 year old African given artesunate and amodiaquine for fever developed fatigue and anemia 3 days later with ALT 483 U/L and progressive hepatic failure; 44 year old African physician treated for fever with artesunate and amodiaquine developed fatigue after 3 and jaundice after 5 days with ALT 15,000 U/L and progressive hepatic failure).
• Ndiaye JL, Randrianarivelojosia M, Sagara I, Brasseur P, Ndiaye I, Faye B, Randrianasolo L, et al. Randomized, multicentre assessment of the efficacy and safety of ASAQ--a fixed-dose artesunate-amodiaquine combination therapy in the treatment of uncomplicated Plasmodium falciparum malaria. Malar J 2009; 8: 125. [PMC free article: PMC2698916] [PubMed: 19505304]

  (Controlled trial of artesunate-amodiaquine vs artemether-lumefantine for 3 days in 940 patients with malaria; response rates and side effects were similar in the two groups; rates of ALT elevations decreased during therapy and follow up, from 9% to 6%).
• 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).
• Bojang K, Akor F, Bittaye O, Conway D, Bottomley C, Milligan P, Greenwood B. A randomised trial to compare the safety, tolerability and efficacy of three drug combinations for intermittent preventive treatment in children. PLoS One 2010; 5(6): e11225. [PMC free article: PMC2888611] [PubMed: 20574538]

  (Controlled trial comparing 3 regimens for prevention of endemic malaria in 1008 Gambian children, 331 of whom received amodiaquine once monthly for 2-3 months; no severe adverse reactions were detected and no mention of liver injury, hepatitis or jaundice).
• Zwang J, Dorsey G, Djimdé A, Karema C, Mårtensson A, Ndiaye JL, Sirima SB, et al. Clinical tolerability of artesunate-amodiaquine versus comparator treatments for uncomplicated falciparum malaria: an individual-patient analysis of eight randomized controlled trials in sub-Saharan Africa. Malar J 2012; 11: 260. [PMC free article: PMC3468407] [PubMed: 22856598]

  (Among 3113 patients treated with artesunate and amodiaquine for falciparum malaria in 8 controlled trials, common treatment emergent side effects were cough [33%], anorexia [17%], vomiting [15%], diarrhea [17%], pruritus [18%] and weakness [16%]; 4 patients [1%] developed jaundice, but no details provided).
• Thanh NX, Trung TN, Phong NC, Quang HH, Dai B, Shanks GD, Chavchich M, et al. The efficacy and tolerability of artemisinin-piperaquine (Artequick®) versus artesunate-amodiaquine (Coarsucam™) for the treatment of uncomplicated plasmodium falciparum malaria in south-central Vietnam. Malar J 2012; 11: 217. [PMC free article: PMC3411481] [PubMed: 22741618]

  (Controlled trial comparing aremisinin with either piperaquine [n=63] for 2 days or with amodiaquine [65] for 3 days for falciparum malaria in Vietnam reported similar efficacy and tolerance; no severe adverse events reported and no mention of liver injury, jaundice or ALT elevations).
• 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).
• Yeka A, Lameyre V, Afizi K, Fredrick M, Lukwago R, Kamya MR, Talisuna AO. Efficacy and safety of fixed-dose artesunate-amodiaquine vs. artemether-lumefantrine for repeated treatment of uncomplicated malaria in Ugandan children. PLoS One 2014; 9: e113311. [PMC free article: PMC4249977] [PubMed: 25436614]

  (Among 413 children with malaria treated with repeated courses of either artesunate-amodiaquine or artemether-lumefantrine over a 2 year period, both response and adverse event rates were similar with the 2 regimens, abnormal liver tests arising in 5.6% of children but were asymptomatic except in two children; nevertheless, all abnormalities resolved without specific treatment and did not recur despite readministration).
• 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).
• Advice for travelers. Treat Guidel Med Lett 2015: 57 (1466): 52-8.

  (Concise guidelines on prevention of malaria in travelers; amodiaquine is not recommended for prophylaxis against malaria for travelers).
• Yeka A, Kigozi R, Conrad MD, Lugemwa M, Okui P, Katureebe C, Belay K, et al. Artesunate/amodiaquine versus artemether/lumefantrine for the treatment of uncomplicated malaria in Uganda: a randomized trial. J Infect Dis 2016; 213: 1134-42. [PMC free article: PMC4836737] [PubMed: 26597254]

  (Among 602 Ugandan children with malaria treated with artesunate-amodiaquine or artemether-lumefantrine, adverse event rates were similar with the 2 regimens and there were no serious hepatic adverse events; no mention of ALT elevations).
• Coulibaly B, Pritsch M, Bountogo M, Meissner PE, Nebié E, Klose C, Kieser M, et al. Efficacy and safety of triple combination therapy with artesunate-amodiaquine-methylene blue for falciparum malaria in children: a randomized controlled trial in Burkina Faso. J Infect Dis 2015; 211: 689-97. [PubMed: 25267980]

  (Among 221 children with falciparum malaria treated with artesunate-amodiaquine with or without methylene blue for 3 days, serious adverse events were uncommon and none were liver related; no mention of ALT elevations or hepatotoxicity).
• 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.e7. [PMC free article: PMC4446235] [PubMed: 25754159]

  (Among 899 cases of drug induced liver injury enrolled in a US prospective study between 2004 and 2013, no cases were attributed to an antimalarial drug).