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ABSTRACT• Background:Ondansetronisfrequentlyprescribedin

hospitalizedpatients fornauseaandvomiting.How-ever, the Food and Drug Administration (FDA) hasapproved this agent only for prophylaxis of nauseaandemesisrelatedtochemo-andradiationtherapyorpostoperativestates.

• Objective: To determine prevalence and predictorsofoff-labelondansetronuseinhospitalizedadultpa-tients.

• Methods: Retrospective cohort study of 158 hos-pitalized medical patients who received non-FDA-approvedondansetron; treatmentwithpromethazineor prochlorperazine in151patientswas consideredstandard treatment. Patterns of non-FDA-approveduse were analyzed using descriptive statistics. Mul-tivariable logistic regressionmodelswere then fit toidentifypredictorsofsuchuse.

• Results: In hospitalized medical patients, ondanse-tronasfirst-linetreatmentfornauseaoutsideofFDA-approvedindicationswas5timesmoreprevalentthanstandardtherapy(4169dosesversus750doses).Inarandomsample,patientstreatedwithondansetronwereolder(54.6versus48.8years,P<0.01),morelikelytobehypertensive(50.6%vs.39.7%,P=0.05),andlessfrequentlyprescribedmultipleantiemeticsatthe timeofadmission (32.3%vs.43.7%,P=0.04).Receipt of prochlorperazine or promethazine in theemergency department (ED) was associated withdecreasedlikelihoodofreceivingnon-FDA-approvedondansetron therapy as the first antiemetic afteradmission(oddsratio0.27,95%confidenceinterval0.11–0.66).

• Conclusions:Althoughondansetrontherapyfornon-FDAapprovedindicationsishighlyprevalent inhos-pitalizedmedicaladults,useofstandardanti-nausea

treatment in theEDmaycurtail thispractice. Imple-menting policies for targeting use of medications intheEDmaysignificantlyinfluenceinpatientpractice.

Nausea and vomiting are symptoms that frequent-ly necessitate hospital admission [1]. Despite varied etiologies, treatment of nausea and vom-

iting are primarily directed towards symptom control through antiemetic therapy. Antiemetic agents, such as promethazine, prochlorperazine, and 5-HT3-receptor antagonists, represent the mainstay of this therapy [2,3]. Because available evidence regarding potency, cost, and adverse reactions related to the 5-HT3-receptor antag- onist ondansetron suggested a narrow therapeutic window, the Food and Drug Administration (FDA) approved the use of this agent only for prophylaxis of postoperative nausea and vomiting or cancer-related emesis associated with chemo- or radiation therapy [4].

Anecdotally, 5-HT3-receptor antagonists are often used to treat nausea and vomiting for conditions that do not meet FDA-approved criteria. Limited data exists comparing their efficacy to standard therapies for these conditions [2,5–7]. However, such use may be associated with important cost, therapeutic, and safety implica-tions. While studies have reported benefits of off-label ondansetron use in pediatric populations in the emer-gency department (ED) [8,9], no such evidence exists for adult hospitalized patients. Additionally, when the FDA approves new therapeutic agents, their growing avail-ability may highlight additional cost and safety concerns, such as concerns regarding the risk of prolonged QT

Off-Label Use of Ondansetron In Hospitalized Medical Patients: Prevalence, Patterns, and PredictorsSarah Hartley, MD, Latoya Kuhn, MPH, Staci Valley, MD, Nabil Fallouh, MD, MS, Kathleen B. Dussán, MD, Stephanie Judd, MD, Susan L. Murphy, ScD, OTR, Sanjay Saint, MD, MPH, and Vineet Chopra, MD, MSc

From the Division of General Internal Medicine and the De-partment of Physical Medicine and Rehabilitation, University of Michigan, Ann Arbor, MI.

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and arrhythmia associated with ondansetron. These pat-terns are not unique to 5-HT3-receptor antagonists. For example, the use of angiotensin receptor blockers (ARBs) was similarly evaluated in the cardiology literature prior to their availability in a generic formulation. ARBs were not more efficacious when compared with a generic ACE inhibitor in patients with heart failure or left ventricular dysfunction after a myocardial infarction, although their use was associated with an increased cost of care [10]. As efforts continue to make health care more cost-effective, these trends have broad implications. Understanding off-label use of ondansetron may thus provide insights on how therapies diffuse—and may be controlled—across inpatient medicine [11]. Given these considerations, we designed a retrospective cohort study to examine the use of ondansetron in hospitalized adults at a single tertiary academic medical center.

METHODSDesign and SubjectsWe conducted a retrospective cohort study of antiemetic use in patients admitted to a single academic medical cen-ter between 1 May 2008 and 30 September 2009. Using electronically available data, we identified a cohort of pa-tients ≥ 18 years of age who were admitted to a non-ICU medical or surgical service from the ED and received either ondansetron, promethazine, or prochlorperazine as their first antiemetic medication. From this pool, we randomly selected individuals to constitute 2 groups: those that received ondansetron (n = 475) versus those that received either promethazine or prochlorperazine (n = 248) as their first antiemetic agent after admission to the hospital (Figure). Patients receiving any anti-emetic treatment at home, already receiving ondansetron for FDA-approved indications (eg, active cancer treat-ment), with documented allergies to prochlorperazine, promethazine or ondansetron or pregnant at the time of enrollment were excluded. Post hoc, a decision was made to exclude surgical patients as 89% of ondansetron use in these patients occurred in the perioperative period, thus meeting FDA-approved indications.

Data CollectionAn electronic template was created to abstract data. Ondansetron therapy was considered non-FDA-approved when administered independent of a procedure requiring general anesthesia or administration of chemo- or radia-tion therapy within the previous 30 days. All included

medical records were evaluated for patient and provider variables related to antiemetic therapy. Patient-related variables included age, gender, comorbidities (eg, diabe-tes mellitus, hypertension, cirrhosis, chronic kidney dis-ease), and number of prior hospital admissions. Provider-related variables included admitting service, admitting and discharge diagnoses, whether multiple antiemetic agents were prescribed at the time of admission and use of antiemetic in the ED.

Two independent reviewers abstracted data from medical records of included patients using an electronic template. To assess inter-rater reliability of the data abstraction process, a subsample of these records (n = 75) were compared.

Statistical AnalysisNon-FDA-approved ondansetron therapy, the primary outcome of interest, was compared with standard treat-ment (receipt of promethazine or prochlorperazine as first-line therapy). Descriptive statistics were used to describe the prevalence of ondansetron and standard antiemetic use in the study. Bivariate comparisons were made using independent sample t tests for continuous data (age and number of hospitalizations) and the chi-squared statistic for categorical covariates (gender, co-morbidities, admitting service, admitting and discharge diagnosis, and whether multiple antiemetic agents were prescribed at the time of admission and use of antiemetic in the ED). Covariates of interest were selected a priori using a conceptual framework and were entered into a multivariable logistic regression model to examine their association with ondansetron use. Results were reported as odds ratios (ORs) with corresponding 95% confidence intervals (CIs). Inter-rater reliability was calculated using the kappa statistic, which indicates the strength of agree-ment between raters. Statistical analysis was conducted using Stata version 11 (Stata, College Station, TX). All statistical tests were 2-tailed; P ≤ 0.05 was considered statistically significant. The University of Michigan in-stitutional review board provided ethical and regulatory approval for this study.

RESULTS

Between May 2008 and September 2009, we identified 4169 patients who received ondansetron and 750 patients who received either promethazine or prochlorperazine as first-line antiemetic agents. We conducted a review of medical records on a random sample (n = 475) of ondan-

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Figure.Flowdiagramillustratingcohortidentification.

Patientswhoreceivedondansetron

n = 4169

Randomsample

n = 475

Excluded:n = 73

•Antiemeticashomemedication

•Documentedallergytotreatment

•Pregnant•ICUadmission•Indicationotherthen

nausea/emesis

Admittedtoasurgicalservice

n = 227

Excluded:n = 17

•Ondansetronnotfirstantiemetic:4

•Receivedgeneralanesthesiapriortoantiemetictherapy:5

•Chemotherapyorradiation30dayspriortoantiemetictherapy:8

Patientsreceivingondansetronorpromethazineorprochlorperazineasfirstantiemeticagentatadmission(betweenMay2008andSeptember2009)

n = 4919

Patientswhoreceivedpromethazineorprochlorperazine

n = 750

Admittedtoamedicineservice

n = 175

Finalpopulation

n = 158

Randomsample

n = 248

Finalpopulation

n = 151

Excluded:n = 80

•Antiemeticashomemedication

•Documentedallergytotreatment

•Pregnant•ICUadmission•Indicationotherthen

nausea/emesis

Admittedtoasurgicalservice

n = 17

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setron recipients, of which 236 (49.7%) were admitted to an inpatient medicine service. After application of the exclusion criteria, 158 ondansetron patients (33.3%) were included in the analysis (Figure). We also conducted a review of medical records on a random sample (n = 248) of patients who received promethazine or prochlor-perazine during the same time period. After application of the exclusion criteria, 151 patients (60.9%) who had received either promethazine or prochlorperazine were included in the analysis (Figure). Inter-rater reliability for data abstraction between the 2 raters showed excellent agreement (k = 0.89).

A total of 90.2% (158/175) of the randomly selected sample of medical patients that received ondansetron

while admitted did not meet an FDA-approved indica-tion for such therapy. In addition, 20.2% (32/158) of these patients were given a prescription for ondansetron at the time of discharge. Characteristics associated with higher rates of non-FDA-approved ondansetron use included older age (54.6 years versus 48.8 years, P < 0.01), hypertension (50.6% versus 39.7%, P = 0.05), a cardiac discharge diagnosis (22.2% versus 12.6%, P = 0.04), and prescription of a single antiemetic at the time of admission (32.3% vs. 43.7%, P = 0.04) (Table 1). Conversely, gender, number of prior admissions, and comorbidities such as diabetes, cirrhosis, or renal failure were not associated with ondansetron use. No significant differences between the use of ondansetron or standard

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Table 1.DescriptiveCharacteristicsofStudyPopulation

Characteristic

Ondansetron

n = 158

Prochlorperazine / Promethazine

n = 151

P

Age,mean(SD) 54.6(18.3) 48.8(15.0) <0.01

Male,n(%) 56(35.4) 56(37.1) 0.76

No.ofadmissions,mean(SD) 1.0(2.5) 1.2(2.0) 0.44

Hypertension,n(%) 80(50.6) 60(39.7) 0.05

Diabetes,n(%) 40(25.3) 31(20.5) 0.32

Cirrhosis,n(%) 11(7.0) 6(4.0) 0.25

Renalinsufficiency,n(%) 26(16.5) 20(13.2) 0.43

Dischargediagnosis,n(%)

Cardiac 35(22.2) 19(12.6) 0.04

Endocrine 1(<1) 3(2.0) 0.36

Gastrointestinal 51(32.3) 51(33.8) 0.78

Hematologic 11(7.0) 10(6.6) 0.94

Infectiousdisease 16(10.1) 19(12.6) 0.50

Musculoskeletal 5(3.2) 4(2.6) 1.00

Neurological 3(1.9) 5(3.3) 0.49

Oncology 0(0) 7(4.6) <0.01

Other 13(8.2) 17(11.3) 0.37

Psychological 1(<1) 0(0) 1.00

Pulmonary 15(9.5) 12(8.0) 0.63

Renal 7(4.4) 4(2.6) 0.40

Admittingservice,n(%)

Generalmedicine 88(55.7) 88(58.3) 0.65

Hospitalistmedicine 61(38.6) 50(33.1) 0.31

Hematology/oncology 9(5.7) 13(8.6) 0.32

Dischargedonanantiemetic,n(%) 32(20.2) 35(23.2) 0.53

>1inpatientantiemeticordered,n(%) 51(32.3) 66(43.7) 0.04

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anti-nausea treatment were evident when admitting ser-vices were examined.

Although few statistically significant patient or pro-vider predictors of ondansetron therapy were observed, after adjustment patients who received prochlorperazine or promethazine as the first antiemetic in the ED were significantly less likely to receive ondansetron as the first antiemetic on admission (OR 0.27, 95% CI 0.11–0.66) (Table 2). Age, cirrhosis, number of admissions, admit-ting service, and treatment with ondansetron in the ED were not found to be significant predictors of inpatient ondansetron use.

DISCUSSION

Since its introduction in 1991 as the first of the 5-HT3-receptor antagonists, ondansetron use outside of con-sensus guidelines has been reported to be as high as 26% [5]. However, in this study, ondansetron was prescribed outside of FDA-approved indications in 90.2% of our sample of hospitalized adults on medical wards. This use is not explained by admission or diagnosis specific order sets, as all such order sets at our institution offer a selection of antiemetic agents. Therefore on a dose-by-dose basis, the inpatient use of ondansetron as an initial antiemetic outpaced that of promethazine or prochlorperazine fivefold, suggesting significant discre-tionary and preferential use as compared with standard therapy.

While studies conducted in pediatric EDs have dem-onstrated that ondansetron may be cost-effective and beneficial for treatment of nausea and emesis, (at times preventing admissions and reducing need for further care) [12–14], no such data exists for adults. In fact, a recent randomized controlled study of adults present-ing to the ED with vomiting found no difference in outcomes between patients treated with ondansetron versus prochlorperazine [15]. Despite this evidence gap, the use of ondansetron appears to be highly prevalent in hospitalized adult medical patients at our institution. Un-derstanding the rationale behind such use is important for several reasons. First, non-evidence-based therapies initiated in the ED may ultimately be nonhelpful, harm-ful, or cost-prohibitive [16]. Identifying and curbing such practices are important from both a cost and patient safety perspective. Second, hospitalist use of medications may have additional implications after discharge. For instance, the widespread inpatient use of proton-pump inhibitors has been shown to be associated with greater cost, increased risk of infections such as Clostridium difficile and pneumonia [17,18], and sequelae such as osteoporosis if continued beyond hospitalization [19].Indeed, in our study, approximately 20% of patients who received inpatient ondansetron for non-FDA-approved indications were discharged home on this treatment. In view of growing cardiovascular concerns associated with ondansetron [20,21], such therapy may have important clinical risks and consequences.

Although off-label, the use of ondansetron for non-FDA-approved conditions may have clinically relevant rationales. For example, older patients were more likely to receive ondansetron than standard treatment in our study (P < 0.01). An increased risk of neuropsychiatric side effects related to promethazine or prochlorperazine in the elderly may account for their less frequent use in this subset [22,23]. Similarly, we observed that hypertension and a cardiac discharge diagnosis were more prevalent in those who received ondansetron treatment (P = 0.05 and P = 0.04, respectively). Cardiovascular side effects associ-ated with promethazine and prochlorperazine may explain the tendency to prefer this agent in this context [24,25].

Importantly, we observed that receipt of standard anti-nausea treatment in the ED strongly reduced the odds of subsequent therapy with ondansetron as the first antiemetic after admission to the hospital. This finding highlights the importance of clinical decision making in the ED on subsequent inpatient care. Instinc-

Table 2.MultivariableLogisticRegressionResults

Predictor Variable

Odds Ratio

95% Confidence Interval

Age 1.02 1.00–1.03

Cirrhosis 1.51 0.54–4.27

Numberofadmissions 0.97 0.87–1.08

Admittingservice

Hematology/

oncology

0.54 0.21–1.36

Hospitalist 1.10 0.67–1.83

Other Reference

TreatmentinED

Ondansetron 1.04 0.60–1.80

Prochlorperazineorpromethazine

0.27 0.11–0.66

*Other admitting service includes Internal Medicine, Cardiology,FamilyMedicineandPulmonary.

*

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tively, this anchoring in decision-making appears logical: should an antiemetic provide relief from nausea in the ED, there is little reason for the prescribing clinician to alter treatment [26]. Thus, if ondansetron was the first agent prescribed and was effective in relief of symp-toms, it is conceivable that it will be continued in the inpatient setting. Conversely, should standard anti-nau-sea treatment prove efficacious at the outset, escalation or modification of therapy may be unnecessary. Our study thus provides insights into an important lever with which to influence inpatient practice: adoption of prescribing policies in the ED to influence the use of therapeutics during an ensuing hospitalization [27]. In the case of nausea and emesis specifically, one such paradigm may be a step-wise approach to anti-nausea treatment in EDs with use of ondansetron reserved for those that fail to respond to initial therapy. Given the cost of other 5-HT3 agents that still remain on patent ($10 to $20 per dose), important adverse effects associated with these agents, and the ubiquity of nausea and emesis as presenting complaints to EDs, these types of policies may have important implications for health care costs in this era.

Our study has several limitations. First, as with any retrospective study, our ability to draw inferences regarding patterns and predictors of ondansetron use was limited to observational administrative data, which may show correlation but does not prove causation. However, this is an important first step to understanding factors that may influence prescribing patterns and informs future research. Second, factors not specifically explored in our analysis may account for differences in nausea treat-ment. For instance, hospitalists may avoid promethazine or prochlorperazine due to concerns regarding dystonic reactions, neuropsychiatric side effects [23], or risk of tis-sue necrosis due to intravenous infiltration [28]. However, studies conducted in ED settings suggest that the rates of dystonic reactions, sedation, and akathesia are infrequent to support such concerns [2,29]. Alternatively, motivations centered on patient satisfaction or length of hospital stay may lead providers to use purportedly more efficacious agents in the hopes of prompt symptom resolution. Third, for feasibility, our study utilized a random selection of a larger sample of patients receiving ondansetron and thus may be statistically underpowered to robustly examine all predictors of ondansetron use. Fourth, as our analysis was limited to a single academic medical center, the applica-bility of our findings to different organizational/patient characteristics remains unknown.

However, our study also has important strengths. First, we identified ondansetron as an agent that is fre-quently prescribed for hospitalized adults in the absence of evidence supporting its use over other conventional therapies. Thus, the use of this agent may serve as a model through which to examine factors associated with non-evidence-based use of novel or costly therapeutics (eg, oral direct thrombin inhibitors), or those with high prevalence of inpatient use (eg, proton-pump inhibi-tors). Second, non-FDA-approved ondansetron therapy extended beyond hospitalization in 20.2% of patients in our study. This finding is important as it may have important cost and safety implications. Third, we found that ED use of promethazine or prochlorperazine was a powerful predictor of ondansetron nonuse. This find-ing has important implications as interventions prior to hospitalization are rarely considered when adopting or implementing policy changes in the inpatient setting. Although most have described anchoring in the context of clinical decision making, our findings suggest that a similar paradigm may also hold true for therapeutic prescribing. Prospective studies that specifically exam-ine whether or not treatment decisions made in the ED influence subsequent care in the hospital appear neces-sary. Such studies may help curtail the use of therapeutics that are costly, harmful or have little evidence supporting their use over other available treatments.

In conclusion, ondansetron use outside of FDA-approved indications is common among hospitalized medical patients. Interventions aimed at reining in such practice from both a cost and safety perspective are nec-essary. Policy changes to medication selection in the ED may provide a novel approach and be worthy of consider-ation in this regard.

Acknowledgments: The authors would like to thank Dr. Jennifer Griggs, MD, MPH, for her input and guidance during the initial design of this study.

Corresponding author: Sarah E. Hartley, MD, University of Michigan Health System, 1500 E. Medical Center Dr., SPC 5736, Ann Arbor, MI 48109, hartsara@med.umich.edu.

Funding/support: The project described was supported by the National Center for Research Resources, Grant UL1RR024986, and is now at the National Center for Advancing Translational Sciences, Grant 2UL1TR000433. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.

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Financial disclosures: None.

Author contributions: Author contributions: conception and design, SH, SV, NF, SLM, SS, VC; analysis and interpreta-tion of data, SH, LK, NF, KBD, SLM, SS, VC; drafting of article, SH, LK, SV, NF, KBD, SJ, SLM, SS, VC; critical revision of the article, SH, SV, NF, KBD, SJ, SLM, SS, VC; provision of study materials or patients, SH, SV, SS, VC; statistical expertise, LK, VC; obtaining of funding, SH, SV, SS, VC; administrative or technical support, SH, SV, KBD, SS, VC; collection and assembly of data, SH, KBD, SJ, VC.

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