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The mission of the Manchester University Drug Information Center is to distribute drug information, promote evidence-based medicine, improve medication safety, and enhance patient-centered pharmaceutical care in Northeast Indiana through practice, scholarship, and teaching. This newsfeed supports this mission by:

  •  Informing the community regarding important developments in the clinical use of medications.
  •  Advocating for evidence-based use of medications that maximizes safety, efficacy, and cost-effectiveness.

The questions posted in this newsfeed are real questions received in the DI Center, concisely formatted in order to increase the reach of our findings to a wider community of interested health care professionals, students, and partners.


Should pancreatitis be considered a contraindication for use of fibric acid derivatives and could fibric acid derivatives cause pancreatitis?

by Robert D. Beckett, PharmD, BCPS | Nov 28, 2016

Introduction

Hypertriglyceridemia, especially with serum triglycerides greater than 1,000 mg/dL, is a frequently cited risk factor for acute pancreatitis.1,2 Epidemiological evidence suggests that for every increase of approximately 100 mg/dL, absolute risk for hospitalization due to pancreatitis increases by 4%.1 Clinical practice guidelines suggest evaluating and treating triglyceride serum concentrations elevated at 500 mg/dL or greater.3,4 In addition to therapeutic lifestyle changes (i.e., 5 to 10% body weight reduction, decreasing added sugars and increasing unsaturated fats while eliminating trans fats, increasing exercise, abstinence from alcohol), pharmacological therapy with fibrates, niacin, omega-3 fatty acids, statins, and ezetimibe have been listed as potential triglyceride lowering therapies.3 Fenofibrate, associated with a 30 to 50% reduction in triglycerides, has been recommended for consideration for triglyceride lowering when concentrations are greater than 500 mg/dL, in combination with low- or moderate- intensity.1,4

Rare risk for development of acute pancreatitis (based on post-marketing case reports) has been listed as a warning and potential adverse drug reaction for fenofibrate and fenofibric acid, but not gemfibrozil.5,6 Fibric acid derivatives were not listed as having a definite or probably association with acute or chronic pancreatitis in Drug-Induced Diseases.7 It has been postulated that occurrence of pancreatitis associated with fibric acid derivatives could be related to treatment failure (i.e., insufficient triglyceride reduction), an unknown direct effect of the drug, or due to drug-induced formation of biliary tract stones or sludge leading to bile duct obstruction.6 It should be noted that acute and chronic pancreatitis are listed as contraindications in the Canadian formulations (i.e., Lipidil EZ, Lipidil Micro, Lipidil Supra); however, these contraindications were not identified in US formulations.5,6 Additionally, use of fibric acid derivatives has been described as an appropriate intervention following hypertiglyceride-induced pancreatitis, although this recommendation was predominantly based on case reports.1

Primary Literature

In order to gather further information regarding association of fibric acid derivatives with drug-induced pancreatitis, a PubMed search was conducted using various combinations of the following terms: fibric acid, fenofibrate, gemfibrozil, pancreatitis. Searches were conducted with and without use of medical subject headings (MeSH terms).

Several case reports involving patients who developed pancreatitis while on treatment with a fibric acid derivative were identified; however, the overwhelming majority involved patients who had other, more strongly associated risk factors for acute pancreatitis including serum triglyceride concentrations greater than 1,000 mg/dL, concomitant statin therapy, or both.8 One definite case report involving a patient with three cases of acute pancreatitis and no other risk factors besides treatment with bezafibrate was identified.9

A retrospective cohort study evaluated 584,784 new users of statins (n = 507,932), fibric acid derivatives (n = 73,337), or combination therapy (n = 3,515) in order to examine risk for rhabdomyolysis and pancreatitis.10 Patients were followed up until health plan disenrollment or up to 3 years of treatment. Incidence of pancreatitis was defined clinically, with patients required to have symptomatic (e.g., nausea, vomiting, abdominal pain) or radiologic evidence of pancreatitis accompanied by lipase or amylase elevated at least twice the laboratory upper limit of normal (ULN), as well as by International Classification of Diseases (ICD)-9 codes. At the end of the observation period, there were 45 cases of pancreatitis in patients who received fenofibrate (0.13 per 100 patient years), 9 cases in patients who received gemfibrozil (0.09 per 100 patient years), 42 cases in patients who received fenofibrate with a statin (0.16 per 100 patient years), and 4 cases in patients who received gemfibrozil with a statin (0.08 per 100 patient years). When compared to patients using only a statin (and adjusted for age, biliary disease, diabetes, gender, hypertension, and number of comorbidities as covariates), the adjusted incidence rate ratios were 2.67 (95% CI 1.93 to 3.69) for fenofibrate, 1.82 (95% CI 0.93 to 3.55) for gemfibrozil, 2.87 (95% CI 2.05 to 4.02) for fenofibrate with a statin, and 1.45 (95% CI 0.54 to 3.92) for gemfibrozil with a statin. Investigators concluded that the risk for pancreatitis is higher with fenofibrate, regardless of combination with a statin, compared to statins alone.

A meta-analysis of clinical trials of statins or fibrates was conducted in order to determine whether fibrates are associated with development of pancreatitis.11 Each trial had to contain at least 1,000 patients exposed to treatment for at least 1 year (mean follow up 5.3 +/- 0.5 years), and could not involve combination therapy (compared to placebo) or contain patients with history of hemodialysis or organ transplantation. The meta-analysis for fibrates ultimately included 7 clinical trials. There were 84 cases of incident pancreatitis among 20,371 patients who received a fibrate (0.41%) compared to 60 cases among 20,894 patients who received control (0.29%). The relative risk for incident pancreatitis for patients who received a fibrate was 1.39 (95% CI 1.00 to 1.95, p = 0.61) with low heterogeneity (I2 = 0.0%). Results were not broken down by individual agents; studies assessed clofibrate (n = 2), gemfibrozil (n = 2), bezafibrate (n = 1), and fenofibrate (n = 2). Investigators concluded that there was not an association between fibrates and pancreatitis.

Summary

 

  • History of pancreatitis is not considered a contraindication for treatment with fibric acid derivatives according to FDA-approved labeling.5,6 Rare risk for development of acute pancreatitis (based on post-marketing case reports) has been listed as a warning and potential adverse drug reaction for fenofibrate and fenofibric acid, but not gemfibrozil.5,6
  • It has been postulated that occurrence of pancreatitis associated with fibric acid derivatives could be related to treatment failure (i.e., insufficient triglyceride reduction), an unknown direct effect of the drug, or due to drug-induced formation of biliary tract stones or sludge leading to bile duct obstruction and subsequent pancreatitis.6
  • When compared to patients using only a statin, the adjusted incidence rate ratio for pancreatitis were 2.67 (95% CI 1.93 to 3.69) for patients on fenofibrate and 2.87 (95% CI 2.05 to 4.02) for patients on fenofibrate with a statin in a retrospective cohort study.10
  • The relative risk for incident pancreatitis for patients who received a fibrate compared to control was 1.39 (95% CI 1.00 to 1.95, p = 0.61) with low heterogeneity (I2 = 0.0%) in a meta-analysis of 7 clinical trial.11 It should be noted that results were pooled for all agents, including both fenofibrate and other agents.
  • Overall rates of pancreatitis with fenofibrate, although statistically significant in one observational study, appear very low (0.13 per 100 patient years on monotherapy and 0.16 per 100 patient years in combination with a statin).10

 

References

 

  1. Preiss D. Triglyceride levels, pancreatitis and choice of lipid-modifying therapy. Expert Rev Gastroenterol Hepatol. 2013; 7(3): 193-195.
  2. Yuan G, Al-Shali KZ, Hegel RA. Hypertriglyceridemia: its etiology, effects and treatment. CMAJ. 2007; 176(8): 1113-1119.
  3. Miller M, Stone NJ, Ballantyne C, et al. Triglycerides and cardiovascular disease. Circulation. 2011; 123: 2292-2333.
  4. Stone NJ, Robinson J, Lichtenstein AH, et al. 2013 ACC/AHA guidelines on the treatment of blood cholesterol to reduce atherosclerotic cardiovascular risk in adults. Circulation. 2013; DOI: 10.1161/01.cir.0000437738.63853.7a.
  5. Multiple entries. Micromedex DrugDex. Thomson Micromedex 2.0. Greenwood Village, CO. Available at: http://thomsonhc.com. Accessed May 27, 2016.
  6. Multiple entries. Lexi-Drugs.  Lexicomp.  Wolters Kluwer Health, Inc.  Hudson, OH.  Available at:  http://online.lexi.com.  Accessed May 27, 2016.
  7. Kale-Pradhan PB, Wilhelm SM. Pancreatitis. In: Tisdale JE, Miller DA, eds. Drug-Induced Diseases: Prevention, Detection, and Management. 2nd ed. Bethesda, MD: American Society of Health-Systems Pharmacists; 2010.
  8. McDonald KB, Garber BG, Perreault MM. Pancreatitis associated with simvastatin plus fenofibrate. Ann Pharmacother. 2002; 36: 275-279.
  9. Gang N, Langevitz P, Livneh A. Relapsing acute pancreatitis induced by re-exposure to the cholesterol lowering agent bezafibrate. Am J Gastroenterol. 1999; 94(12): 3626-3628. [Abstract]
  10. Enger C, Gately R, Ming EE, et al. Pharmacoepidemiology safety study of fibrate and statin concomitant therapy. Am J Cardiol. 2010; 106: 1594-1601.
  11. Preiss D, Tikkanen MJ, Welsh P, et al. Lipid-modifying therapies and risk of pancreatitis. JAMA. 2012; 308(8): 804-811.