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Abstract

Introduction: Use of medications for non-Food and Drug Administration (FDA) approved indications is considered "off-label". A multicenter, 24-hour snapshot study in the intensive care unit (ICU), indicates off-label use occurs with 36% of prescribed medications. Medications used for off-label indications raises concern for potential patient safety and resultant adverse drug reactions (ADRs), as the drug has not been subjected to the same scientific inquiry as medications being utilized for FDA approved indications. Medications are used commonly for off-label indications in the ICU; however, the frequency and severity of ADRs due to off-label use is unknown. Methods: This was a prospective, observational, multi-site study of adult patients admitted to medical ICUs (MICU) at two academic medical centers for a 3 month period. Upon admission of the patient to the MICU, all inpatient medications were reviewed by a pharmacist extender to determine if medications were being used for FDA approved or unapproved indications. Subsequently, newly prescribed medications for each patient were evaluated for indication every 24 hours. Patients were evaluated daily for the development of an ADR by the clinical pharmacist during patient care rounds and through electronic medical record review. When the clinical pharmacist identified a possible ADR, the ADR was assessed using 3 objective, published ADR causality instruments (Kramer, Naranjo, and Jones). Agreement between 2 of the 3 instruments for events ranking "possible" or greater, were considered an ADR. Upon completion of data collection, the culprit medications associated with ADRs evaluated by the pharmacist were matched to the medication indication list generated by independent reviewers. The severity of the ADR was classified based upon two commonly used severity scales. The National Cancer Institute's (NCI) Common Terminology Criteria for Adverse Events was used with a grade of 3-5 considered severe/life threatening. A MEDMARX classification was applied and A-D was considered "no harm", while E-I was considered "harm" to the patient. Descriptive statistics are provided and chi-square tests were utilized as appropriate Results: Overall, 13,580 medications, during 950 patient days, were evaluated with, 41.5% (5636/ 13580) being used for an off-label indication. Off-label use was categorized into 4 types: 1) non-indicated patient population (132/5636); 2) non-indicated condition (4662/5636); 3) non-indicated dose (662/5636) and 4) non-indicated route of administration (180/5636). A total of 100 ADRs per 1000 patient days were identified, with opioids and sedatives accounting for over 25% of the ADRs. A total of 44 ADRs per 1000 patient days occurred for medications used for off-label indications and 56 ADRs per 1000 patient days occurred for medications used for approved indications. There was no statistical difference in the frequency of ADRs between medications being used for FDA approved or off-label indications with 0.67 % vs 0.73%, respectively (p=0.38). Upon evaluation of ADR severity, there was no difference in the frequency of ADRs that received a NCI grade of severe/life threatening, between medications used for a FDA approved or off-label indication (17 vs 19; p=0.10). There was also no difference in the number of ADRs that resulted in a MEDMARX classification of "harm" between medications being used for FDA approved or off-label indications (31 vs 28; p=0.26). Conclusions: Off-label use occurs frequently in the ICU; however, this does not result in additional patient safety concerns based on frequency or severity of ADRs.