AAC Accepted Manuscript Posted Online 21 March 2016 Antimicrob. Agents Chemother. doi:10.1128/AAC.00054-16 Copyright © 2016, American Society for Microbiology. All Rights Reserved. 1 Drug-Drug Interaction Associated with Mold-Active Triazoles among Hospitalized 2 Patients 3 4 DDI with Mold-Active Triazoles 5 Authors: David Andes1, Nkechi Azie2, Hongbo Yang3, Rachel Harrington2, Caroline Kelley3, 6 Ruo-Ding Tan3, Eric Q Wu3, Billy Franks2, Rita Kristy2, Edward Lee2, Nikhil Khandelwal2, James 7 Spalding2 8 1 Departments of Medicine and Medical Microbiology and Immunology, University of Wisconsin, 9 Madison, WI 10 2 Astellas Pharma Global Development, Inc., Northbrook, IL 11 3 Analysis Group, Inc., Boston, MA 12 Keywords: mold-active triazoles, drug-drug interactions, itraconazole, voriconazole, 13 posaconazole 14 Key points: Majority of hospitalized patients receiving mold active triazoles are at risk of drug- 15 drug interactions (DDI). Efforts are needed to increase awareness of DDIs that pose a serious 16 risk of adverse events. 17 Corresponding Author: David Andes 18 19 1 20 Abstract 21 Background: Triazoles remain the most commonly utilized antifungals. Recent developments 22 have included the mold-active triazoles (MAT) itraconazole, voriconazole, and posaconazole, 23 which are first-line agents for the treatment of filamentous fungal infections but have the 24 potential for drug-drug interactions (DDI). This objective of this study was to evaluate the 25 prevalence of triazole DDI. 26 Methods: Hospitalized US adults with MAT use were identified in the Cerner HealthFacts 27 database which contained data from over 150 hospitals (2005-2013). DDIs of MAT were 28 categorized using drug labels and DRUGDEX® (Thompson Micromedex) into 4 groups 29 (contraindicated; major; moderate; minor). Minor DDIs were not counted. A DDI event was 30 considered to have occurred if two conditions were met: 1) used at least one drug with at least a 31 moderate interaction classification with the MAT during the hospitalization and 2) there was at 32 least a 1-day administration overlap between the MAT and the interacting drug. 33 Results: 6962 hospitalizations were identified with MAT use. Among them, 88% of voriconazole, 34 86% of itraconazole, and 93% of posaconazole hospitalizations included a concomitant 35 interacting drug. 68% of posaconazole, 34% of itraconazole, and 20% of voriconazole 36 hospitalizations had at least one contraindicated DDI. 83% of posaconazole, 61% of 37 itraconazole, and 82% of voriconazole hospitalizations had at least one severe DDI. 38 Conclusion: The findings of this study demonstrate that a majority of hospitalized patients 39 receiving MAT were at risk for severe drug-drug interactions and highlight the need for 40 antifungal stewardship. 41 INTRODUCTION 2 42 Triazoles are widely used for prophylaxis and treatment of invasive fungal infections (IFI). 43 Fluconazole, the first triazole agent, was introduced in 1990 and quickly became one of the 44 most commonly prescribed antifungal agents. Itraconazole was the first agent with activity 45 against mold pathogens. More recent triazole developments have included drugs with 46 predominant activity against opportunistic mold infections (e.g., Aspergillus spp). These mold- 47 active triazoles, voriconazole, posaconazole, and most recently isavuconazole, have become 48 first line options for both treatment and prophylaxis of filamentous fungal infections [1, 2]. 49 Although these newer triazoles have a broader spectrum of activity compared to 50 fluconazole, they exhibit complex pharmacokinetics, including a propensity for drug-drug 51 interactions (DDI) with co-administered drugs [3]. All mold-active triazoles are inhibitors of one 52 or more phase 1 (cytochrome P-450) biotransformation enzymes and may also be inhibitors or 53 substrates of phase 2 biotransformation enzymes or transporter proteins such as P-glycoprotein 54 [4]. Mold-active triazoles may alter the drug absorption, distribution, excretion and metabolism of 55 co-administered agents such as benzodiazepines, anxiolytics, dihydropyridine calcium channel 56 blockers, sulfonylureas, calcineurin inhibitors, prednisone, or anticoagulants [3]. Mold-active 57 triazoles are also associated with QTc prolongation, so use should be cautioned with other 58 agents having similar effects [5]. 59 The definition of DDI varies across literature. Some studies define DDI as the 60 concomitant use of interacting drugs, while others define DDI based on clinical evidence of 61 interactions that are confirmed by either laboratory tests or by symptoms. In this paper, we use 62 the DDI term to describe the concomitant use of interacting drugs. DDI account for 3-5% of 63 preventable in-hospital adverse drug reactions and are an important cause of emergency room 64 and hospital visits [6]. DDI are associated with significant clinical consequences and higher 65 resource use and costs [7, 8]. DDI are common among patients taking multiple medications with 66 an estimated prevalence ranging from 60.0% to 70.3% among hospitalized patients and are 3 67 associated with increased length of stay, morbidity, mortality and higher health care costs [7-14]. 68 The risk of DDI among mold-active triazoles has been an important factor contributing to the 69 recommendation of consistent therapeutic drug monitoring of mold-active triazoles in the 70 guidelines from the Infectious Diseases Society of America. 71 Although mold-active triazoles are often used in patients with multiple co-morbid 72 conditions experiencing polypharmacy, to date, there is limited information available regarding 73 the rates of DDI among patients receiving mold-active triazoles in real-world settings [15]. To fill 74 this gap, this retrospective study aimed to evaluate the prevalence of DDI among hospitalized 75 patients with evidence of mold-active triazole utilization. Understanding the real-world 76 occurrence of DDI associated with mold-active triazoles may inform antimicrobial stewardship 77 efforts to enhance patient safety. 78 METHODS 79 Data source 80 The Cerner HealthFacts® electronic medical records (EMR) dataset (April 2005-Dec 81 2013), an electronic capture system containing information from clinical and laboratory systems 82 at over 150 hospitals, was used for this study. The database represents 110 million encounters 83 across the majority of states in the United States and includes patient demographic variables 84 (age, gender and race), diagnoses and procedures (both coded using International 85 Classification of Diseases, Ninth Revision, Clinical Modification [ICD-9-CM] codes). Pharmacy 86 data are available including the national drug codes (NDC), date and time dispensed, and route 87 of administration. Only medications administered through the hospital pharmacies are captured. 88 Data are de-identified and comply with the patient confidentiality requirements of the Health 89 Insurance Portability and Accountability Act (HIPAA). 90 Interacting drugs 4 91 A list of drugs that have been reported to interact with each mold-active triazole agent 92 (itraconazole, posaconazole, and voriconazole) were collected from the DRUGDEX® 93 (Thompson Micromedex) system, and supplemented with relevant prescribing information (PI). 94 The DRUGDEX® system contains evidence-based, expert-reviewed documents covering Food 95 and Drug Administration (FDA) and European Medicines Agency (EMA) approved, 96 investigational, and nonprescription drugs. These databases include information on cautions, 97 DDI, clinical applications, and related DDI adverse effects. 98 The DRUGDEX® system classifies the severity of DDI into four levels: contraindicated 99 (life-threatening and the concomitant use is contraindicated), major (potentially life-threatening 100 or capable of causing permanent damage), moderate (might cause deterioration in a patient’s 101 clinical status; additional treatment, hospitalization, or extension of hospital stay might be 102 necessary), and minor (mild effects due to DDI that do not significantly affect the therapeutic 103 outcomes) [16, 17]. Interacting drugs with contraindicated, major and moderate severity of DDI 104 were considered in this study; interacting drugs with minor severity were excluded. 105 Sample selection 106 Hospitalized patients who received a systemic mold-active triazole (itraconazole, 107 voriconazole or posaconazole) during the hospitalization were selected from the database. 108 Patients were included in the study if they met the following inclusion/exclusion criteria: received 109 at least one administration/dose of IV/oral itraconazole, voriconazole and/or posaconazole 110 during the hospitalization; were at least 18 years of age at the time of hospital admission; did 111 not receive multiple mold-active triazoles (IV or oral formulation of the same drug is counted as 112 one); and had non-missing drug initiation and discontinuation dates for the mold-active triazole 113 and its interacting drug(s), where present. The mold-active triazole used during the hospital stay 114 was defined as the index triazole, and the corresponding hospital stay was defined as the 5 115 index hospitalization. Among patients with multiple eligible hospitalizations, a random 116 encounter was selected. 117 Analyses 118 A DDI event was considered to have occurred if patients used at least one drug reported 119 to interact with the index triazole during the index hospitalization, and there was at least a one- 120 day overlap between the index triazole and