Research Article Domperidone Prescribing Practices Exposed …downloads.hindawi.com/journals/cjgh/2016/2937678.pdf · 2019. 7. 30. · Research Article Domperidone Prescribing Practices

Research ArticleDomperidone Prescribing Practices ExposedPatients to Cardiac Risk despite a (Black Box) Warning:A Canadian Tertiary Care Center Study

Nauzer Forbes,1,2 Mohan Cooray,1 Raed Al-Dabbagh,1 Yuhong Yuan,3 Frances Tse,1

Louis W. C. Liu,4 and Ted Xenodemetropoulos1

1Division of Gastroenterology, McMaster University Department of Medicine, Hamilton, ON, Canada L8S 4K12Division of Gastroenterology, University of Calgary Therapeutic Endoscopy Training Program, Calgary, AB, Canada T2N 4Z63Farncombe Family Digestive Research Institute, Hamilton, ON, Canada L8S 4K14Division of Gastroenterology, University of Toronto Department of Medicine, Toronto, ON, Canada M5T 2S8

Correspondence should be addressed to Nauzer Forbes; [email protected]

Received 6 August 2015; Accepted 25 August 2015

Copyright © 2016 Nauzer Forbes et al. This is an open access article distributed under the Creative Commons Attribution License,which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Background. In 2012, Health Canada released a warning regarding domperidone use, based on associations with life-threateningarrhythmias and death. Objective. This study aimed to compare the appropriateness of domperidone prescribing patterns beforethe advisory to those afterward.Methods. Two retrospective reviews were conducted for patients prescribed domperidone duringquarters in 2005 and 2012. Outcomes included appropriateness of indication, dosing regimens, monitoring of electrolytes, baselineelectrocardiogram performance and characteristics, presence of left ventricular dysfunction, and coprescription of QT-prolongingmedications. Univariable andmultivariable logistic regression analyses were performed.𝑝 values< 0.05were considered significant.Results. 290 and 287 patients were analyzed in 2005 and 2012, respectively. Domperidone initiation in hospital decreased from 2005to 2012 (71.4% versus 39.4%, 𝑝 < 0.0001) as did prescriptions for nonapproved indications (84.8% versus 58.2%, 𝑝 < 0.0001).In-hospital initiation predicted prescription for nonapproved indications (OR = 7.01, 95% CI 4.52–10.87, 𝑝 < 0.0001). Use ofdomperidone as the sole GI drug predicted nonapproved indications (OR = 2.51, 95% CI 1.38–4.55, 𝑝 = 0.002). Conclusions. Theadvisory was associated with more appropriate domperidone initiation and compliance with recommended dosages. Our studysuggests the need for increased awareness of the dosing and monitoring of domperidone to ensure patient safety.

1. Introduction

Domperidone, a benzimidazole-derived dopamine receptorantagonist, exhibits both prokinetic and antiemetic prop-erties. Domperidone’s higher molecular weight and lowerlipophilicity are felt to contribute to its relative inabilityto cross the blood brain barrier and, thus, lesser inci-dence of central adverse effects in comparison to metoclo-pramide. Current Health Canada approved indications fordomperidone use are symptomatic management of uppergastrointestinal motility disorders associated with chronicand subacute gastritis, diabetic gastroparesis, and preventionof gastrointestinal symptoms associated with the use ofdopamine agonist anti-Parkinsonian agents.

In March of 2012, Health Canada issued an alert [1]regarding domperidone use, warning practitioners about therisk of ventricular tachyarrhythmias and sudden cardiacdeath with its use, particularly in doses exceeding 30mg/day,and in patients older than 60. This information was basedprimarily on two studies: a population-based case-controlstudy [2] that showed increased risk of sudden cardiac death,which was higher in patients using daily doses >30mg,with an adjusted OR = 11.4 (1.99–65.2), and a nested case-control study [3] that showed an increased risk of a compositeendpoint of sudden cardiac death and serious ventriculararrhythmia, which was higher in patients older than 60 yearsof age (adjusted OR 1.64, 1.31–2.05).

Hindawi Publishing CorporationCanadian Journal of Gastroenterology and HepatologyVolume 2016, Article ID 2937678, 5 pageshttp://dx.doi.org/10.1155/2016/2937678

2 Canadian Journal of Gastroenterology and Hepatology

Numerous unapproved or “off-label” clinical uses of dom-peridone exist, including gastroesophageal reflux disease(GERD), the induction and maintenance of adequate lac-tation in breast-feeding women [4], treatment of vaguedyspepsia symptoms, and treatment of nausea and/or emesis,especially in the postoperative or postchemotherapy settings.In the hospital environment, the drug is frequently usedin patients fed via nasogastric tube to promote kinesis andclear residual volumes. In spite of the potentially lethalconsequences of its use, data on the prescription practicesof domperidone by Canadian physicians are lacking in theliterature and thus need to be defined.

The objectives of this study were threefold. The first wasto review the appropriateness of domperidone prescriptionin relation to the approved indications in admitted patientsat 2 tertiary care hospitals within a single Canadian city. Thesecond was to compare domperidone prescribing patternsbefore the 2012 Health Canada advisory to those afterward,thereby assessing its impact. The final aim was to determinephysician compliance with regard to measuring baselinesafety parameters in patients prescribed domperidone.

2. Methods

2.1. Study Setting and Design. Hamilton Health Sciences(HHS) is a tertiary care hospital network serving over 2.3million residents of Hamilton and south central Ontarioand is the second largest hospital group in Ontario. HHSencompasses over 1100 inpatient beds; this includes patientsadmitted to medicine, surgery, and critical care services,all of which were considered for this study. Two retrospec-tive electronic medical record reviews were conducted forpatients at 3 centers (McMaster University Medical Centre,Hamilton General Hospital, and Juravinski Hospital) withinthe HHS network. The reviews were conducted for con-secutive hospital inpatients who received prescriptions fordomperidone over 4-month periods (April–July) in 2005 and2012, respectively. Ethics approval for the study was obtainedthrough the Hamilton Integrated Research Ethics Board atMcMaster University.

2.2. Study Patients. Study patients were compiled from thecentralized HHS pharmacy computer database and includedthose initially prescribed domperidone during their hospitaladmission as well as those with preexisting prescription priorto their hospital admission. Any patient aged 18 and overwho met the above criteria was included. Furthermore, thedose and duration of domperidone prescription were alsorecorded.

2.3. Outcomes. Consistency of domperidone indication withapproved indications was assessed, based on current HealthCanada recommendations. The medical records of all studypatients were reviewed for indications of domperidoneprescription that were either explicitly documented orinferred in the medical history. In addition, dosing regimenswere assessed, including any observed changes to dosages.Outcome measures assessed were derived from the mostrecent Health Canada document on Guidance for Product

Monograph Content for QT/QTc Interval Prolongation [5].This included whether or not an electrocardiogram wasperformed during the patient’s admission, as well as whetherthere was any evidence of corrected QT interval (QTc)prolongation, defined as a period equal to or greater than440msec. Further outcome measures included the monitor-ing of serum potassium (K+), magnesium (Mg+), and cal-cium (Ca2+) levels, either during the first 2 days of initialdomperidone prescription or on admission to hospital forpatients already on domperidone therapy prior to theiradmission. Finally, the presence of left ventricular (LV) dys-function by transthoracic echocardiogram and coprescrip-tion of other known QT-prolonging medications were alsoassessed. Potential QT-prolonging medications were cross-referenced and confirmed using updated drug databases [6].

2.4. Data Analysis. Data was analyzed using the StatisticalPackage for the Social Sciences (SPSS) software, version20. 𝜒2 test was used to assess significance of differences inproportions. A 𝑝 value of

Canadian Journal of Gastroenterology and Hepatology 3

Table 1: Baseline domperidone prescribing practices in 2005 and 2012 (after Health Canada advisory).

2005 2012𝑝 value

𝑛 = 290 𝑛 = 287

CharacteristicMean age 62.4 67.9

4 Canadian Journal of Gastroenterology and Hepatology

association with domperidone prescription, although therewas significant improvement in 2012 compared to 2005.

QT interval prolongation has been used as a surro-gate marker for predicting adverse and potentially lethalmedication-induced effect related to torsades de pointes, bothclinically and in research settings [7]. Domperidone has beenfrequently associated with both QT interval prolongationand ventricular tachyarrhythmia in the literature, with car-diotoxicity being described with both oral and intravenousadministration [2, 3, 8–10]. Domperidone’s risk of suddencardiac death may be comparable to cisapride, a prokineticmedication that has long been removed from the NorthAmerican pharmaceutical market following postmarketingsurveillance reports of elevated risk of QT interval prolon-gation and torsades de pointes, as well as arrhythmia-relatedfatality [11–13]. Therefore, dissemination of these concernsand resultant uptake of safer prescribing practices are crucial.

4.1. Strengths and Limitations. Our study design took advan-tage of the timing of the March 2012 Health Canada advisoryin order to compare tertiary care hospital-based prescribingpractices before and after the warning. Although our studycould not establish causality of the change in prescribing pat-tern of domperidone as a consequence of the disseminationof the 2012 Health Canada warning, it clearly demonstratedthe increased awareness of its appropriate use. Further studiesare required to confirm its impact on prescribing practices inoutpatient clinics and community hospitals.

Many inherent limitations apply to our retrospectivechart-review study. A proportion of the studied patientshad no clearly documented or inferable indication for dom-peridone prescription on available hospital records. Therewas also a subset of diabetic patients on domperidone withno clearly documented history of diabetic gastroparesis orobjective evidence of delayed gastric emptying. Althoughthese patients may indeed reflect the general trend of pre-scription of domperidone for unapproved therapeutic uses,it is possible that improper documentation overestimated theproportion of nonapproved indications in this study. Simi-larly, there was an inability to assess whether the electrolytemeasurements and ECGs performed during a given patient’shospital admission were directly related to the initiation ofdomperidone. Coincidental performance of these tests forother medical assessments could not be determined, whichmay overestimate the degree of safety with which domperi-done was prescribed. Furthermore, our study was unable toestablish causality between domperidone prescription andadverse outcomes such as cardiac arrhythmia or increasedmortality due to the retrospective design and relative samplesizes.

5. Conclusion

Our study demonstrates that heightened awareness ofthe appropriate use and monitoring of domperidone arerequired. The 2012 Health Canada advisory warning sig-nificantly improved the use of domperidone in terms ofappropriate indications, dosing, and monitoring. Furtherqualitative research employing a physician survey-based

design could be useful in establishing the causality betweenthe Health Canada advisory and changes in practice patterns.Increased in-hospital awareness of domperidone’s indicationsand adverse effects, through both active and passive tech-niques, could serve to enhance the impact of the HealthCanada advisory. Increased awareness of the indications,dosage, and adverse effects of domperidone will result inimproved patient safety, quality of care, and healthcareexpenditure.

Conflict of Interests

The authors declare that there is no conflict of interestsregarding the publication of this paper. Louis W. C. Liu is theSpeaker for Takeda Canada Inc., Forest Laboratories, Actavis,AbbVie, and Procter & Gamble; Advisory Board for TakedaCanada Inc., Forest Laboratories, Actavis, and AbbVie; andConsultant for Takeda Canada Inc. Ted Xenodemetropoulosis the Speaker for Actavis, Converge, Janssen, Pendopharm,Procter & Gamble, and Warner Chilcott (Actavis).

References

[1] Health Canada, “Domperidone Maleate—Association withSerious Abnormal Heart Rhythms and Sudden Death (CardiacArrest)—For Health Professionals,” 2012, http://www.healthy-canadians.gc.ca/recall-alert-rappel-avis/hc-sc/2012/15857a-eng.php.

[2] C. Van Noord, J. P. Dieleman, G. Van Herpen, K. Verhamme,and M. C. J. M. Sturkenboom, “Domperidone and ventriculararrhythmia or sudden cardiac death: a population-based case-control study in theNetherlands,”Drug Safety, vol. 33, no. 11, pp.1003–1014, 2010.

[3] C. B. Johannes, C. Varas-Lorenzo, L. J. McQuay, K. D. Midkiff,and D. Fife, “Risk of serious ventricular arrhythmia and suddencardiac death in a cohort of users of domperidone: a nestedcase-control study,” Pharmacoepidemiology and Drug Safety,vol. 19, no. 9, pp. 881–888, 2010.

[4] A. Osadchy, M. E. Moretti, and G. Koren, “Effect of domperi-done on insufficient lactation in puerperal women: a systematicreview and meta-analysis of randomized controlled trials,”Obstetrics and Gynecology International, vol. 2012, Article ID642893, 7 pages, 2012.

[5] QT/QTc Interval Prolongation: Guidance for ProductMonographContent, Health Canada, 2010, http://www.hc-sc.gc.ca/dhp-mps/prodpharma/applic-demande/guide-ld/qtqtc/qt pm mp-eng.php.

[6] CredibleMeds, “Combined List of All QTdrugs and the List ofDrugs to Avoid for Patients with Congenital Long QT Syn-drome,” 2015, https://www.crediblemeds.org/index.php/login/dlcheck.

[7] D. M. Roden, “Drug-induced prolongation of the QT interval,”The New England Journal of Medicine, vol. 350, no. 10, pp. 1013–1022, 2004.

[8] B. Drolet, G. Rousseau, P. Daleau, R. Cardinal, and J. Turgeon,“Domperidone should not be considered a no-risk alternative tocisapride in the treatment of gastrointestinalmotility disorders,”Circulation, vol. 102, no. 16, pp. 1883–1885, 2000.

[9] P. J. Kannankeril and D. M. Roden, “Drug-induced long QTand torsade de pointes: recent advances,” Current Opinion inCardiology, vol. 22, no. 1, pp. 39–43, 2007.

Canadian Journal of Gastroenterology and Hepatology 5

[10] C. M. G. Rocha and M. M. Barbosa, “QT interval prolongationassociated with the oral use of domperidone in an infant,”Pediatric Cardiology, vol. 26, no. 5, pp. 720–723, 2005.

[11] S. M. J. M. Straus, M. C. J. M. Sturkenboom, G. S. Bleumink etal., “Non-cardiac QTc-prolonging drugs and the risk of suddencardiac death,” EuropeanHeart Journal, vol. 26, no. 19, pp. 2007–2012, 2005.

[12] D. K.Wysowski, A. Corken, H. Gallo-Torres, L. Talarico, and E.M. Rodriguez, “Postmarketing reports of QT prolongation andventricular arrhythmia in association with cisapride and Foodand Drug Administration regulatory actions,” The AmericanJournal of Gastroenterology, vol. 96, pp. 1698–1703, 2001.

[13] W. Arnott, “Cisapride and the vanessa young inquest,” Cana-dian Medical Association Journal, vol. 165, no. 4, p. 395, 2001.

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Research Article Domperidone Prescribing Practices Exposed …downloads.hindawi.com/journals/cjgh/2016/2937678.pdf · 2019. 7. 30. · Research Article Domperidone Prescribing Practices