OVERVIEW

CASE REPORT

PRODUCT INFORMATION

CHEMICAL FORMULA AND STRUCTURE

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DRUG	CAS REGISTRY NO	MOLECULAR FORMULA	STRUCTURE
Amlodipine	88150-42-9	C20-H25-C1-N2-O5

ANNOTATED BIBLIOGRAPHY

References updated: 01 March 2016

• Zimmerman HJ. Calcium channel blockers. Drugs used in cardiovascular disease. In, Zimmerman HJ. Hepatotoxicity: the adverse effects of drugs and other chemicals on the liver. 2nd ed. Philadelphia: Lippincott, 1999, pp. 646-7.

  (Expert review of hepatotoxicity published in 1999; among calcium channel blockers, diltiazem, nifedipine, bepridil and verapamil have been incriminated in instances of hepatic injury; amlodipine is not mentioned).
• De Marzio DH, Navarro VJ. Calcium channel blockers. Hepatotoxicity of cardiovascular and antidiabetic drugs. In, Kaplowitz N, DeLeve LD, eds. Drug-induced liver disease. 3rd ed. Amsterdam: Elsevier, 2013, pp. 524.

  (Review of hepatotoxicity of calcium channel blockers; diliazem and verapamil have been implicated in causing cholestatic liver injury in a small number of patients; amlodipine is not specifically mentioned).
• Michel T, Hoffman BB. Calcium channel antagonists. Treatment of myocardial ischemia. In, Brunton LL, Chabner BA, Knollman BC, eds. Goodman & Gilman’s the pharmacological basis of therapeutics. 12th ed. New York: McGraw-Hill, 2011, pp. 755-60.

  (Textbook of pharmacology and therapeutics).
• Osterloh I. The safety of amlodipine. Am Heart J 1989; 118:1114-9. [PubMed: 2573265]

  (Analysis of adverse events in a pooled database of 2495 patients treated with amlodipine and ~1800 controls reported similar rate of ALT elevations with amlodipine [4.3%] as with hydrochlorthiazine [6.3%], and no serious liver toxicity).
• de Luis DA, Aller R, Moreira V. Hepatic toxicity and amlodipine. Med Clin (Barcelona). 1998; 110: 638-9 [Spanish]. [PubMed: 9656204]

  (66 year old man developed serum enzyme elevations 3 months after starting amlodipine [bilirubin normal, ALT 211 U/L, Alk P 369 U/L], resolving within 2 months of stopping).
• Basile C, Mascia E. Dihydropyridine calcium channel blockers: a rare and reversible cause of hepatotoxicity with cholestasis in a CAPD patient. Nephrol Dial Transplant 1999; 14: 2776-7. [PubMed: 10534534]

  (76 year old man developed jaundice 3 years after starting nifedipine [bilirubin 6.2 mg/dL, ALT 79 U/L, Alk P 955 U/L], resolving within 1 month of stopping and recurring within 6 weeks of starting amlodipine [bilirubin 6.3 mg/dL, ALT 74 U/L, Alk P 398 U/L], resolving in 3 weeks: Case 1).
• Lafuente NG. Calcium channel blockers and hepatotoxicity. Am J Gastroenterol 2000; 95: 2145. [PubMed: 10950093]

  (69 year old developed jaundice 10 months after starting amlodipine [bilirubin 4.0 mg/dL, ALT 256 U/L, Alk P 344 U/L]; subsequent switching to diltiazem caused a similar pattern of injury after 5 months [bilirubin 3.3 mg/dL, ALT 355 U/L, Alk P 415 U/L], resolving in several weeks of stopping).
• Khemissa-Akouz F, Ouguergouz F, Sulem P, Tkoub el M, Vaucher E. Amlodipine-induced acute hepatitis. Gastroenterol Clin Biol 2002; 26: 637-8. French. [PubMed: 12193867]

  (77 year old man developed jaundice one month after starting amlopidine [bilirubin 7.4 mg/dL, ALT 30 times ULN, Alk P 2 times ULN, ANA positive], resolving within 8 weeks of stopping).
• Lopez Vivancos J, Bara Olivan B, Muniz Garcia R. [Toxic hepatitis caused by amlodipine] Gastroenterol Hepatol 2002; 25: 112. Spanish. [PubMed: 11841767]

  (66 year old man developed asymptomatic enzyme elevations 2 months after starting amlodipine [bilirubin normal, ALT 267 rising to 694 U/L, Alk P 367 U/L], resolving within 3 months of stopping).
• Zinsser P, Meyer-Wyss B, Rich P. Hepatotoxicity induced by celecoxib and amlodipine. Swiss Med Wkly 2004; 134:201. [PubMed: 15106034]

  (87 year old woman developed jaundice and pruritus after several years of amlodipine therapy [bilirubin 20.8 mg/dL, ALT 300 U/L, Alk P 1019 U/L]; after withdrawal she began to recover, but then developed urosepsis and died 3 weeks after presentation).
• ALLHAT. Major outcomes in high-risk hypertensive patients randomized to angiotensin-converting enzyme inhibitor or calcium channel blocker vs diuretic: the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT). JAMA 2002; 288:2981-97. [PubMed: 12479763]

  (Large controlled trial of antihypertensive agents including amlodipine which included 33,357 participants; no mention of ALT elevations or liver related adverse events).
• Russo MW, Galanko JA, Shrestha R, Fried MW, Watkins P. Liver transplantation for acute liver failure from drug-induced liver injury in the United States. Liver Transpl 2004; 10: 1018-23. [PubMed: 15390328]

  (Among ~50,000 liver transplants reported to UNOS between 1990 and 2002, 270 [0.5%] were done for drug induced acute liver failure, but none were attributed to a calcium channel blocker).
• Björnsson E, Jerlstad P, Bergqvist A, Olsson R. Fulminant drug-induced hepatic failure leading to death or liver transplantation in Sweden. Scand J Gastroenterol 2005; 40: 1095-101. [PubMed: 16165719]

  (Summary of 25 years of adverse drug reaction reporting in Sweden identified 103 cases of drug induced acute liver failure; only one case was possibly linked to a calcium channel blocker--felodipine).
• 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 from 2004 to 2008, calcium channel blockers were implicated as a sole agent in 2 cases [1 amlodipine, 1 verapamil] and as one of several agents in 2 cases [both amlodipine]).
• Reuben A, Koch DG, Lee WM; Acute Liver Failure Study Group. Drug-induced acute liver failure: results of a U.S. multicenter, prospective study. Hepatology 2010; 52: 2065-76. [PMC free article: PMC3992250] [PubMed: 20949552]

  (Among 1198 patients with acute liver failure enrolled in a US prospective study between 1998 and 2007, 133 were attributed to drug induced liver injury, none of which were attributed to a calcium channel blocker).
• 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. [PubMed: 23419359]

  (In a population based study of drug induced liver injury from Iceland, 96 cases were identified over a 2 year period, but amlodipine was not implicated in any case, despite being among the top 10 most commonly prescribed drugs in Iceland).
• 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]

  (Systematic review of literature of drug induced liver injury in Latin American countries published from 1996 to 2012 identified 176 cases; one case was attributed to verapamil, but none were linked to amlodipine or other calcium channel blockers).
• Demirci H, Polat Z, Kantarcioglu M, Kekilli M, Uygun A, Bagci S. Short-term amlodipine induced liver injury : an extremely rare acute complication. Acta Gastroenterol Belg 2013; 76 (4): 441. [PubMed: 24592551]

  (46 year old man was found to have abnormal liver tests one week after switching from ramipril to amlodipine [bilirubin 1.4 mg/dL, ALT 923 U/L, Alk P 102 U/L, INR 1.02], resolving within 3 weeks of stopping).
• Hammerstrom AE. Possible amlodipine-induced hepatotoxicity after stem cell transplant. Ann Pharmacother 2015; 49: 135-9. [PubMed: 25239629]

  (34 year old man with leukemia and graft-vs-host disease after hematopoietic cell transplant developed ALT and AST elevations without jaundice a few days after starting high doses of methylprednisolone and amlodipine [for hypertension], values improving wihtin two weeks of stopping amlodipine and decreasing the dose of corticosteroids).
• 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, amlodipine was implicated as probable in one case and as definite or highly likely in none).