OVERVIEW

PRODUCT INFORMATION

CHEMICAL FORMULA AND STRUCTURE

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DRUG	CAS REGISTRY NO	MOLECULAR FORMULA	STRUCTURE
Diltiazem	42399-41-7	C22-H26-N2-O4-S

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 mentions that among calcium channel blockers, diltiazem, nifedipine, bepridil and verapamil have been incriminated in instances of hepatic injury).
• 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 mentions that diltiazem and verapamil have been implicated in causing cholestatic liver injury in a small number of patients).
• 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).
• McGraw BF. Diltiazem hydrochloride. Drug Intell Clin Pharm 1982; 16: 366-70. [PubMed: 7044735]

  (Review of structure, chemistry, pharmacology, mechanism of action, clinical efficacy and safety of diltiazem; neither hepatotoxicity or ALT elevations are discussed in the section on adverse reactions).
• Sawai K. Effects of long-term administration of diltiazem hydrochloride in hypertensive patients. Clin Ther 1983; 5: 422-35. [PubMed: 6871924]

  (Analysis of side effects in 8 patients with hypertension treated with diltiazem for up to 5 years; there were no significant changes in ALT or AST levels during treatment).
• Poulain D, Guimbail P, Florent F. [Median- and long-term tolerability of diltiazem]. Therapie 1984; 39: 177-84. French. [PubMed: 6729767]

  (Among 162 patients with hypertension treated with diltiazem for 6-18 months, 3 [1.8%] had transient elevations in aminotransferase levels).
• Scolnick B, Brinberg D. Diltiazem and generalized lymphadenopathy. Ann Intern Med 1985; 102: 558. [PubMed: 3156549]

  (50 year old man developed lymphadenopathy 4 days after starting diltiazem followed by rash and fever with normal liver tests initially which later rose [bilirubin 0.4 mg/dL, ALT 250 U/L, 6% eosinophils], symptoms resolving within a month of stopping).
• Sarachek NS, London RL, Matulewicz TJ. Diltiazem and granulomatous hepatitis. Gastroenterology 1985; 88: 1260-2. [PubMed: 3979751]

  (54 year old man developed headache, fever and liver test elevations 2 weeks after starting diltiazem [bilirubin normal, ALT 254 U/L, Alk P 384 U/L, 3% eosinophils, liver biopsy showing granulomas], resolving within 3 weeks of stopping).
• Shallcross H, Padley SP, Glynn MJ, Gibbs DD. Fatal renal and hepatic toxicity after treatment with diltiazem. Br Med J 1987; 295:1236-7. [PMC free article: PMC1248306] [PubMed: 3120959]

  (72 year old man developed rash followed by renal failure 2 days after switching from nifedipine to diltiazem, followed by jaundice and multiorgan failure [bilirubin not given, ALT 2500 U/L, Alk P not given] and death 1 week later).
• Buckley MM, Grant SM, Goa KL, McTavish D, Sorkin EM. Diltiazem. A reappraisal of its pharmacological properties and therapeutic use. Drugs 1990; 39: 757-806. [PubMed: 2191851]

  (Review of pharmacology, clinical efficacy and safety of diltiazem; no mention of liver related side effects or effect on ALT levels).
• Toft E, Vyberg G, Therkelsen K. Diltiazem-induced granulomatous hepatitis. Histopathology 1991; 18: 474-5. [PubMed: 1885169]

  (68 year old woman developed fever and fatigue 2 weeks after starting diltiazem [bilirubin not given, AST 94 U/L, Alk P 1331 U/L, liver biopsy showing granulomas], resolving within 5 weeks of stopping).
• Traverse JH, Swenson LJ, McBride JW. Acute hepatic injury after treatment with diltiazem. Am Heart J 1994; 127: 1636-9. [PubMed: 8197999]

  (74 year old woman with angina developed sudden increase in liver tests [bilirubin 1.0 mg/dL, ALT 605 U/L, Alk P 60 U/L, LDH 990 U/L] 2 days after switching from nifedipine to diltiazem, with subsequent acidosis, hypoxia and hypotension, ultimately recovering and enzymes falling to normal within 10 days of stopping).
• Weir MR. Diltiazem: ten years of clinical experience in the treatment of hypertension. J Clin Pharmacol 1995; 35: 220-32. [PubMed: 7608309]

  (Review of efficacy and safety of diltiazem in hypertension; adverse events leading to drug discontinuation occurred in 45 to 5% of patients taking diltiazem in randomized controlled trials; no details of liver related adverse events provided).
• Claas SA, Glasser SP. Long-acting diltiazem HCl for the chronotherapeutic treatment of hypertension and chronic stable angina pectoris. Expert Opin Pharmacother 2005; 6: 765-76. [PubMed: 15934903]

  (Review of safety and efficacy of diltiazem; adverse events are reported to be no more frequent with diltiazem than with placebo; no hepatic adverse events were mentioned).
• Schroeder JS, Beier-Scott L, Ginsburg R, Bristow MR, McAuley BJ. Efficacy of diltiazem for medically refractory stable angina: long-term follow up. Clin Cardiol 1985; 8: 480-5. [PubMed: 2864152]

  (Among 31 patients treated with diltiazem for 8 to 47 months, 5 had transient enzyme elevations and 3 had chronic asymptomatic elevations).
• Kanathur N, Mathai MG, Byrd RP Jr, Fields CL, Roy TM. Simvastatin-diltiazem drug interaction resulting in rhabdomyolysis and hepatitis. Tenn Med 2001; 94 (9): 339-41. [PubMed: 11550401]

  (53 year old man developed nausea and fatigue 2 months after adding diltiazem to a chronic regimen of simvastatin [bilirubin 2.4 mg/dL, ALT 1707 U/L, Alk P 330 U/L, CPK 1390 U/L, myoglobin in the urine, protime 23 seconds], with resolution within 10 days of stopping both drugs).
• Lewin JJ 3rd, Nappi JM, Taylor MH. Rhabdomyolysis with concurrent atorvastatin and diltiazem. Ann Pharmacother 2002; 36: 1546-9. (60 year old man developed fatigue and abdominal pain 3 weeks after adding diltiazem to a drug regimen that included atorvastatin with rhabdomyosis and liver test abnormalities [bilirubin 0.7 mg/dL, ALT 1610 U/L, Alk P 287 U/L, CPK 1898 U/L] [PubMed: 12243603]

  that resolved within 3 months of stopping both drugs).
• 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, none of which were attributed to a calcium channel blocker or other antihypertensive medication).
• Deng W, Farricielli L. Hypoxic hepatitis and acute liver failure in a patient with newly onset atrial fibrillation and diltiazem infusion. BMJ Case Rep 2013; 2013. pii: bcr2013200573. [PMC free article: PMC3794224] [PubMed: 24042208]

  (70 year old man with symptomatic atrial fibrillation developed hypotension 15 hours after starting intravenous diltiazem followed by transient severe liver injury [bilirubin 2.3 mg/dL, ALT 3472 U/L, Alk P not given, creatinine 4.4 mg/dL, and platelets 51,000/uL], resolving rapidly upon stopping suggestive of ischemic 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]

  (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 diltiazem 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], but none to diltiazem).