OVERVIEW

PRODUCT INFORMATION

CHEMICAL FORMULA AND STRUCTURE

View in own window

DRUG	CAS REGISTRY NO	MOLECULAR FORMULA	STRUCTURE
Felodipine	72509-76-3	C18-H19-C12-N-O4

ANNOTATED BIBLIOGRAPHY

References updated: 11 January 2017

• 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, only diltiazem, nifedipine, bepridil and verapamil have been incriminated in instances of hepatic injury; felopidine 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; felodipine 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).
• Edgar B, Lundborg P, Regardh CG. Clinical pharmacokinetics of felodipine. A summary. Drugs 1987; 34: (Suppl 3): 16-27. [PubMed: 3327676]

  (Review of pharmacokinetics of felodipine; felodipine is highly protein bound and is extensively metabolized by the liver).
• Lown KS, Bailey DG, Fontana RJ, Janardan SK, Adair CH, Fortlage LA, Brown MB, et al. Grapefruit juice increases felodipine oral availability in humans by decreasing intestinal CYP3A protein expression. J Clin Invest 1997; 99: 2545-53. [PMC free article: PMC508096] [PubMed: 9153299]

  (Pharmacokinetic study in 10 volunteers demonstrated downregulation of enterocyte CYP 3A4 by grapefruit juice and a three fold increase in bioavailability of felodipine).
• Gradman AH, Cutler NR, Davis PJ, Robbins JA, Weiss RJ, Wood BC, Michelsen EL. Enalapril-Felodipine ER Factorial Study Group. Long-term efficacy, tolerability, and safety of the combination of enalapril and felodipine ER in the treatment of hypertension. Clin Ther 1998; 20: 527-38. [PubMed: 9663368]

  (Among 507 patients treated with felodipine and enalapril for an average of 8 months, one patient stopped therapy because of a rise in ALT [from 72 to 93 U/L]).
• McClennen W, Wilson T. National Trial Group. Felodipine extended release versus conventional diuretic therapy for the treatment of systolic hypertension in elderly patients. Clin Invest Med 1998; 21: 142-50. [PubMed: 9627768]

  (Among 216 patients with hypertension treated with either felodipine or diuretics for 8 weeks, ALT or AST levels became elevated in 5-6% of felodipine- vs 1-2% of diuretic treated patients, but none required early discontinuation).
• Black HR, Elliott WJ, Weber MA, Frishman WH, Strom JA, Liebson PR, Hwang CT, Ruff DA, Montoro R, DeQuattro V, Zhang D, Schleman MM, Klibaner MI. One-year study of felodipine or placebo for stage 1 isolated systolic hypertension. Hypertension 2001; 38: 1118-23. [PubMed: 11711508]

  (In a controlled trial of felodipine vs placebo in 171 patients with hypertension, "there were no clinically meaninful changes from baseline" of ALT or AST).
• 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).
• Liu L, Zhang Y, Liu G, Li W, Zhang X, Zanchetti A. FEVER Study Group. The Felodipine Event Reduction (FEVER) Study: a randomized long-term placebo-controlled trial in Chinese hypertensive patients. J Hypertens 2005; 23: 2157-72. [PubMed: 16269957]

  (A trial in 9800 patients treated with diuretics with or without felodipine for an average of 3 years reported no liver related adverse events).
• 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]

  PubMed Citation (Summary of 25 years of adverse drug reaction reporting in Sweden identified 103 cases of drug induced acute liver failure; felodipine was possibly linked one case, but another hepatotoxic agent was being used [details not provided]).
• Frishman WH, Hainer JW, Sugg J; M-FACT Study Group. A factorial study of combination hypertension treatment with metoprolol succinate extended release and felodipine extended release results of the Metoprolol Succinate-Felodipine Antihypertension Combination Trial (M-FACT). Am J Hypertens 2006; 19: 388-95. [PubMed: 16580575]

  (In a controlled trial of multiple combinations of metoprolol and felodipine or placebo in 1092 patients with hypertension, no liver related side effects were reported).
• 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. PubMed Citation. [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, none of which was attributed to a calcium channel blocker or other antihypertensive medication).
• 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 felodipine or other calcium channel blockers).
• 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, 39 [4%] were due to antihypertensive agents including 4 due to calcium channel blockers [amlodipine in 1 and verapamil in 3 instances]).