CASE REPORT  Fenofibrate

C A S E  R E P O R T

Probable fenofibrate-induced acute generalized exanthematous pustulosis

F

Anna E. Power, Linda V. Graudins, Catriona A. McLean, and Ingrid Hopper

enofibrate is a lipid-lowering drug indicated for use in treating hypertriglyceridemia, hypercholesterolemia, and dyslipidemia in type 2 diabetes mellitus and in reducing the progression of diabetic retinopathy. The evidence for the use of fenofibrate in diabetic retinopathy in type 1 diabetes mellitus is limited.1 The drug’s mechanism of action is to activate peroxisome proliferator– activated nuclear receptors and modulate lipoprotein synthesis and catabolism. The approved fenofibrate dosage for adults is 145 mg once daily. Common adverse reactions include gastrointestinal disturbances and increased aminotransferase levels; although uncommon, severe idiosyncratic cutaneous reactions have been recorded.1 Acute generalized exanthematous pustulosis (AGEP) is a predominantly drug-induced severe cutaneous adverse reaction characterized by edematous erythema with eruptions of numerous nonfollicular pustules.2 Here we report a case in which a patient developed AGEP after taking a single dose of fenofibrate.

Purpose. The case of a patient who experienced a severe adverse reaction requiring emergency treatment after a single dose of fenofibrate is described. Summary. A 58-year-old woman with type 1 diabetes was hospitalized for treatment of an extensive blistering rash on the buttocks and trunk accompanied by fever, hypotension, tachycardia, neutrophilia, impaired renal function, and liver enzyme abnormalities. She reported that two days previously she had developed fever and vomiting four hours after taking her first dose of fenofibrate (145 mg). The patient required vasopressor support and was initially treated with broad-spectrum antibiotics for 3 days and a course of immune globulin. On hospital day 4, histopathology returned results consistent with acute generalized exanthematous pustulosis (AGEP), and the patient was subsequently treated with topical steroids. Gradual

Case report A 58-year-old woman with a 34-year history of type 1 diabetes mellitus, hypothyroidism, and hypercholesterolemia arrived at the

Anna E. Power is a medical student, Monash University, Melbourne, Australia, and Summer Vacation Scholar, Centre of Cardiovascular Research & Education (CCRE) in Therapeutics, School of Public Health and Preventive Medicine, Alfred Centre, Melbourne. Linda V. Graudins, B.Pharm., D ip.HospPharm., PGrad.ClinEpid., FSHP, is Senior Pharmacist, Pharmacy Department, Alfred Health, Melbourne. C atriona A. Mc L ean , B.Sc., M.B.B.S., FRACPA, M.D., FFSc, is Pathologist, Department of Anatomical Pathology, Alfred Hospital, Melbourne. Ingrid Hopper, M.B.B.S., B.Med.Sc., FRACP, is Clinical Pharma-

resolution of AGEP was noted at the time of her discharge from the hospital on day 7 and at one-week follow-up. Analysis of the case using the adverse drug reaction probability scale of Naranjo et al. yielded a score of 5, indicating a probable association between fenofibrate use and AGEP development. AGEP is a predominantly drug-induced condition but is not typically associated with fenofibrate use. Cutaneous eruptions in AGEP are often accompanied by systemic symptoms (e.g., fever, leukocytosis), and the disorder can also be associated with impaired creatinine clearance and elevated aminotransaminase levels. Conclusion. A woman with type 1 diabetes developed AGEP after taking a single dose of fenofibrate. Her cutaneous symptoms began to resolve within days of discontinuation of fenofibrate use. Am J Health-Syst Pharm. 2015; 72:2061-3

emergency department with a painless pustular exanthematous rash on her trunk, buttocks, and proximal flexural surfaces; there was no mucosal involvement. A recent ophthal-

cologist, Alfred Health, and National Health and Medical Research Council Postgraduate Scholar, CCRE in Therapeutics, School of Public Health and Preventive Medicine, Alfred Centre. Address correspondence to Dr. Hopper (ingrid.hopper@monash. edu). The authors have declared no potential conflicts of interest. Copyright © 2015, American Society of Health-System Pharmacists, Inc. All rights reserved. 1079-2082/15/1201-2061. DOI 10.2146/ajhp150171

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CASE REPORT  Fenofibrate

mologic evaluation had resulted in the initiation of fenofibrate 145 mg for the treatment of retinal cholesterol deposits. The patient reported that 4 hours after taking the first dose of fenofibrate she had become unwell, with fever and vomiting, and had spent the next 24 hours in bed with no food or insulin. The patient arrived at the emergency department approximately 48 hours after taking her first fenofibrate dose with a blistering rash, which was initially thought to be a burn caused by an electric blanket. At the time of presentation, the patient was febrile (temperature, 39 °C), hypotensive (requiring norepinephrine infusion to maintain blood pressure), and tachycardic (heart rate, 124 beats/ min), with an elevated blood glucose concentration (13.5 mmol/L; normal range, 5–10 mmol/L) and a normal lactate concentration (1.3 mmol/L; normal range, 0.6–2.2 mmol/L). The patient’s medications at the time of admission were insulin aspart (10 units in the morning, 7 units at midday, and 5 units in the evening with meals each day), insulin detemir (15 units each morning and 17 units each evening), levothyroxine sodium (100 mg each morning for many years), calcium (600 mg daily for many years), vitamin D (7000 units weekly for many years), and fenofibrate 145 mg daily (started two days previously). Her only previous adverse drug reaction was codeineinduced hallucination. Due to confusion over soundalike brand names, the atorvastatin product Lipitor (Pfizer Inc.) was initially thought to be implicated, as the patient had taken that medication in the past; however, on medication reconciliation, the fenofibrate product Lipidil (BGP Products Pty Ltd) was identified as the correct medication and likely cause of the patient’s symptoms. Fenofibrate therapy was ceased prior to admission. The patient was admitted to the intensive care unit 2062

for hemodynamic support, requiring norepinephrine (45 mg/min, adjusted to attain a mean arterial pressure of >70 mm Hg), and i.v. immune globulin (2 g/kg until weaning from vasopressor support), for suspected toxic shock syndrome. Infusions of insulin aspart and 25% glucose solution (0–10 units per infusion) were administered as needed to attain target blood glucose levels. Intravenous infusions of sodium lactate in 0.9% sodium chloride injection were administered to maintain hydration over two days. The infectious diseases and dermatology teams were consulted. Broad-spectrum antibiotics were commenced, including piperacillin–tazobactam 4.5 g four times daily, lincomycin 900 mg thrice daily, and meropenem 1 g thrice daily to treat toxic shock syndrome; in addition, three doses of vancomycin 1 g were administered, and flucloxacillin 2 g i.v. was given for suspected bacterial superinfection. Laboratory results on admission had revealed neutrophilia (8.51 × 109 cells/L; normal range, 1.9–8.0 × 109 cells/L), an elevated C-reactive protein concentration (180 mg/L; normal, 90 mL/min/1.73 m2), and normal liver enzyme levels. The patient’s serum alanine aminotransferase concentration peaked on day 3 at 164 units/L (normal range, 7–55 units/L); peak concentrations of gglutamyltranspeptidase (187 units/L; normal,