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Cardiovascular Toxicities Associated With Loperamide

2021; Lippincott Williams & Wilkins; Volume: 143; Issue: 4 Linguagem: Inglês

10.1161/circulationaha.120.050587

1524-4539

Pierre Ollitrault, Charles Dolladille, Basile Chrétien, Paul Milliez, Joachim Alexandre,

Pharmacovigilance and Adverse Drug Reactions

HomeCirculationVol. 143, No. 4Cardiovascular Toxicities Associated With Loperamide Free AccessLetterPDF/EPUBAboutView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissions ShareShare onFacebookTwitterLinked InMendeleyRedditDiggEmail Jump toFree AccessLetterPDF/EPUBCardiovascular Toxicities Associated With LoperamideAnalysis of the World Health Organization Pharmacovigilance Database Pierre Ollitrault, MD, MSc, Charles Dolladille, MD, MSc, Basile Chrétien, PharmD, MSc, Paul Milliez, MD, PhD and Joachim Alexandre, MD, PhD Pierre OllitraultPierre Ollitrault Pierre Ollitrault, MD, MSc, Department of Cardiology, Regional University Hospital, 14000, Caen, Normandy, France. Email E-mail Address: [email protected] https://orcid.org/0000-0002-2739-1967 Electrophysiology Unit, Department of Cardiology (P.O., P.M.), Caen University Hospital, France. Université Caen Normandie, France (P.O., C.D., B.C., P.M., J.A.). Search for more papers by this author , Charles DolladilleCharles Dolladille https://orcid.org/0000-0003-0449-6261 Pharmacoepidemiology Unit, Department of Pharmacology (C.D., B.C., J.A.), Caen University Hospital, France. Université Caen Normandie, France (P.O., C.D., B.C., P.M., J.A.). Search for more papers by this author , Basile ChrétienBasile Chrétien https://orcid.org/0000-0002-7483-2489 Pharmacoepidemiology Unit, Department of Pharmacology (C.D., B.C., J.A.), Caen University Hospital, France. EA 4650, Signalisation, Électrophysiologie et Imagerie des Lésions d’Ischémie-Reperfusion Myocardique, Normandie University (C.D., B.C., J.A.), Caen University Hospital, France. Université Caen Normandie, France (P.O., C.D., B.C., P.M., J.A.). Search for more papers by this author , Paul MilliezPaul Milliez Electrophysiology Unit, Department of Cardiology (P.O., P.M.), Caen University Hospital, France. Université Caen Normandie, France (P.O., C.D., B.C., P.M., J.A.). Search for more papers by this author and Joachim AlexandreJoachim Alexandre Pharmacoepidemiology Unit, Department of Pharmacology (C.D., B.C., J.A.), Caen University Hospital, France. EA 4650, Signalisation, Électrophysiologie et Imagerie des Lésions d’Ischémie-Reperfusion Myocardique, Normandie University (C.D., B.C., J.A.), Caen University Hospital, France. Université Caen Normandie, France (P.O., C.D., B.C., P.M., J.A.). Search for more papers by this author Originally published25 Jan 2021https://doi.org/10.1161/CIRCULATIONAHA.120.050587Circulation. 2021;143:403–405Loperamide is an over-the-counter opiate medication used worldwide for its antidiarrheal properties but also for recreational use because high-dose loperamide crosses the blood–brain barrier. In 2016, the US Food and Drug Administration released a safety announcement concerning a potential risk of loperamide-associated cardiovascular adverse drug reactions (CV-ADRs) based on several case reports.1 We aimed to assess the association between loperamide and CV-ADRs in a real-world population as well as the characteristics of loperamide-associated CV-ADRs.In this observational retrospective study, we used the World Health Organization pharmacovigilance database (VigiBase), encompassing >22 million reports from >130 countries, to compare CV-ADR reporting in patients who were taking loperamide with all other drugs in the full database. Association between loperamide and CV-ADRs was assessed using the information component (IC), an indicator value for disproportionate Bayesian reporting that compares observed and expected values to find associations between drugs and adverse drug reactions. The lower end of the IC’s 95% CI is IC025. A positive IC025 is deemed significant. These methods are similar to those used to study CV-ADRs related to various noncardiovascular medications.2 For each report, age, sex, coreported medications and conditions, seriousness, and concurrent adverse drug reactions were collected. The local ethics committee approved the use of confidential electronically processed patient data. All CV-ADRs were included, classified by group queries, according to MedDRA (the Medical Dictionary for Regulatory Activities, version 22.1), between November 14, 1979, and June 7, 2020. All data and materials are publicly available and can be accessed at http://www.vigiaccess.org/.We extracted 12 845 reports of adverse drug reactions associated with loperamide from the 22 278 731 reports in VigiBase. Of those, 792 (6.2%) were CV-ADRs, among which 257/792 (32%) were life-threatening and 144/792 (18%) were fatal. Reporters were mostly healthcare professionals (666/792 [84%]) from North America (636/792 [80%]) or Europe (125/792 [16%]). Reporting over time is detailed in the Figure.Download figureDownload PowerPointFigure. Loperamide-associated cardiovascular adverse drug reactions (CV-ADRs) over time, selected CV-ADRs significantly associated with loperamide, and intersection size for selected CV-ADRs.A, Loperamide-associated CV-ADRs over time (MedDRA [Medical Dictionary for Regulatory Activities] term “cardiac disorders”; last accessed June 7, 2020). Year of first CV-ADR report within VigiBase for loperamide was 1979. B, Selected CV-ADRs significantly associated with loperamide. The information component (IC) is an indicator for disproportionate Bayesian reporting that compares observed and expected values for a studied drug (ie, loperamide) vs the full database, to find associations between drugs and adverse reactions. C, Intersection size for selected CV-ADRs. Statistics: IC=log2[(Nobserved + 0.5)/(Nexpected + 0.5)], where Nexpected = (Ndrug × Nreaction)/Ntotal, Nexpected being the number of individual case safety reports (ICSRs) expected for the drug–CV-ADR combination; Nreaction being the actual number of ICSRs observed for the drug–CV-ADRs combination; Ndrug being the number of ICSRs for the drug, regardless of CV-ADR; Nreaction being the number of ICSRs for the CV-ADR, regardless of the drug; and Ntotal being the total number of ICSRs in the database. Ntotal=22.278.731 deduplicated ICSRs. BrS indicates Brugada ECG pattern; CRA, cardiorespiratory arrest; HF, heart failure; PR, PR interval prolongation; QRS, QRS complex prolongation; QT, QT interval prolongation; SB, sinus bradycardia; VA, ventricular arrhythmia; and VPC, ventricular premature complexes.Most CV-ADR reports were in middle-aged men (male sex, 481/792 [61%]; age 18 to 44 years, 443/792 [56%]). Drug overdose or misuse was a coreported term in 651/792 (82%) cases. Loperamide was the only reported drug in 576/792 (73%) cases. Coreported drugs were antidepressants or anticonvulsants (71/792 [9.0%]), antihistamines (55/792 [6.9%]), paracetamol (40/792 [5.1%]), opioids (34/792 [4.3%]), and aspirin (16/792 [2.0%]). The IC values for each CV-ADR significantly associated with loperamide and the intersecting cases are presented in the Figure. Ventricular arrhythmia (including ventricular tachycardia, fibrillation, and torsades de pointes) was the most frequently reported loperamide-associated CV-ADR (n=302, IC=4.1, IC025=4.0), followed by QT interval prolongation (n=277, IC=4.4, IC025=4.2) and ventricular premature contractions (n=192, IC=1.2, IC025=0.2). The strongest association was found between loperamide and Brugada ECG pattern (n=23, IC=5.1, IC025=4.5). Ventricular arrhythmia overlapped with QRS complex or QT interval prolongation in 49% (147/302) of reports (Figure).Using the largest cohort of loperamide-associated CV-ADRs, we found a strong association between ventricular arrhythmogenesis and loperamide. Drug misuse or abuse and preexisting risk factors for ventricular arrhythmias (such as primary inherited arrhythmia syndromes or drug-induced QT prolongation) might confer a higher risk of loperamide-associated CV-ADRs. The main limitation of our study is that the disproportionality analyses conducted in the present study cannot prove a definite causality between loperamide and CV-ADRs reported. However, our pharmacovigilance data are corroborated by recent case reports3 and in vitro studies that found that loperamide is an effective inhibitor of both sodium Nav1.5 and potassium hERG human cardiac ion channels.4,5 Potential confounders such as myocarditis, acute kidney injury, or metabolic disturbances (associated or not with diarrhea) were not coreported terms.The exact incidence of loperamide-associated CV-ADRs cannot be assessed directly using VigiBase. However, using the Medical Expenditure Panel Survey from the US Department of Health and Human Services between 2013 and 2016 (https://www.meps.ahrq.gov/mepsweb/), we found an incidence ranging between 2.44 and 3.46 per 100 000 prescriptions (2014 through 2016) in the United States. Since the January 2018 US Food and Drug Administration regulation on loperamide packaging, there has been a notable decrease in loperamide-associated CV-ADRs reporting in the United States. This encouraging trend needs to be confirmed in the future.In conclusion, there is notably high loperamide-associated CV-ADR reporting, especially in the United States. The risk of ventricular arrhythmia might be higher in case of drug misuse or abuse or when additional risk factors are present. Altogether, those data support an increased regulation of loperamide over-the-counter sales.Disclosures The data supplied from VigiBase come from various sources. The information does not represent the opinion of the World Health Organization. The authors report no conflicts.Footnoteshttps://www.ahajournals.org/journal/circPierre Ollitrault, MD, MSc, Department of Cardiology, Regional University Hospital, 14000, Caen, Normandy, France. Email [email protected]frReferences1. FDA Drug Safety Communication: FDA warns about serious heart problems with high doses of the antidiarrheal medicine loperamide (Imodium), including from abuse and misuse.Published 2016. Accessed July 24, 2020. https://www.fda.gov/drugs/drug-safety-and-availability/fda-drug-safety-communication-fda-warns-about-serious-heart-problems-high-doses-antidiarrheal.Google Scholar2. Salem JE, Yang T, Moslehi JJ, Waintraub X, Gandjbakhch E, Bachelot A, Hidden-Lucet F, Hulot JS, Knollmann BC, Lebrun-Vignes Bet al.. Androgenic effects on ventricular repolarization: a translational study from the international pharmacovigilance database to iPSC-cardiomyocytes.Circulation. 2019; 140:1070–1080. doi: 10.1161/CIRCULATIONAHA.119.040162LinkGoogle Scholar3. Sun C, Brice JA, Clark RF. Brugada-type pattern on electrocardiogram associated with high-dose loperamide abuse.J Emerg Med. 2018; 54:484–486. doi: 10.1016/j.jemermed.2017.12.040CrossrefMedlineGoogle Scholar4. Klein MG, Haigney MCP, Mehler PS, Fatima N, Flagg TP, Krantz MJ. Potent inhibition of hERG channels by the over-the-counter antidiarrheal agent loperamide.JACC Clin Electrophysiol. 2016; 2:784–789. doi: 10.1016/j.jacep.2016.07.008CrossrefMedlineGoogle Scholar5. Kang J, Compton DR, Vaz RJ, Rampe D. Proarrhythmic mechanisms of the common anti-diarrheal medication loperamide: revelations from the opioid abuse epidemic.Naunyn Schmiedebergs Arch Pharmacol. 2016; 389:1133–1137. doi: 10.1007/s00210-016-1286-7CrossrefMedlineGoogle Scholar Previous Back to top Next FiguresReferencesRelatedDetailsCited By Wu P and Juurlink D (2022) Loperamide Cardiac Toxicity: Pathophysiology, Presentation, and Management, Canadian Journal of Cardiology, 10.1016/j.cjca.2022.04.005, Online publication date: 1-Apr-2022. (2021) Reports of cardiovascular adverse drug reactions with loperamide, Reactions Weekly, 10.1007/s40278-021-90511-1, 1841:1, (9-9), Online publication date: 1-Feb-2021. Sarica A, Bor S, Orman M, Barajas-Martinez H, Juang J, Antzelevitch C and Hasdemir C (2021) Frequency of Irritable Bowel Syndrome in Patients with Brugada Syndrome and Drug-Induced Type 1 Brugada Pattern, The American Journal of Cardiology, 10.1016/j.amjcard.2021.04.010, 151, (51-56), Online publication date: 1-Jul-2021. January 26, 2021Vol 143, Issue 4Article InformationMetrics © 2021 American Heart Association, Inc.https://doi.org/10.1161/CIRCULATIONAHA.120.050587PMID: 33493030 Originally publishedJanuary 25, 2021 Keywordsloperamidedrug-related side effects and adverse reactionstoxicitypharmacovigilancePDF download Advertisement SubjectsArrhythmiasEpidemiologyHealth Services