Reported time to onset of neurological adverse drug reactions among different age and gender groups using metoclopramide: an analysis of the global database Vigibase®.
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Despite FDA and EMA warnings of long-term use, little is known regarding the time to onset (TTO) of neurological adverse drug reactions (ADR) for metoclopramide. The aims of this study were, first, to evaluate whether neurological ADRs are more commonly reported for metoclopramide than for other medications, and second, to describe how time to onset of neurological ADRs differs by age and gender.
All ADR reports with metoclopramide as the suspected/interacting drug were extracted from the WHOs Global ADR database Vigibase® between 1967 and May 2016. Cox proportional hazards models were fit using TTO of neurological ADRs as the outcome and age, gender, and type of ADR as predictors. Proportional Reporting Ratios (PRRs) for neurological ADRs were compared across age and gender. Lawyer reports were excluded in the analysis.
Over 47,000 ADR reports with metoclopramide were identified. Over one third (35.6%) of the reports came from lawyers. The majority of ADRs in general and neurological ADRs in specific occurred within the first 5 days of metoclopramide use (median 1 day). TTO increased with age. Neurological ADRs were reported two to four times as frequently for metoclopramide than for other drugs, with the highest PRRs observed in children (PRR = 4.24 for girls and 4.60 for boys).
Most adverse drug reactions occur within the first 5 days of treatment with metoclopramide. Patients requiring use of metoclopramide should be carefully monitored for neurological ADRs during the first days of treatment.
KeywordsMetoclopramide Vigibase Adverse drug reactions
The authors would like to thank the Uppsala Monitoring Centre (UMC), WHO’s Collaborating Centre for International Drug Monitoring that provided and gave permission to use the data analyzed in the present study. The opinions and conclusions, however, are not those of the UMC or of the WHO.
Compliance with ethical standards
Since the data received by the UMC is de-identified and furthermore the UMC did not provide any potentially identifiable variables such as narratives or patient initials, no ethical approval was needed.
The WHO database contains summary reports of individual suspected adverse reactions to medicines, received from national centers in countries participating in the WHO International Drug Monitoring Programme. No causality assessment is made at the Uppsala Monitoring Centre. Since these reports constitute suspicions of adverse drug reactions, further investigation and research is needed for a full interpretation of the data.
Conflict of interest
The authors declare they have no conflict of interest.
- 1.European Medicines Agency. Assessment report. Metoclopramide only containing procucts; December 2013. http://www.ema.europa.eu/docs/en_GB/document_library/Referrals_document/Metoclopramide_31/WC500160356.pdf (accessed 20 December 2016).
- 2.Food and Drug Administration. Medication Guide Reglan (REG-lan) Tablets (metoclopramide tablets). NDA 017854/S-052 NDA 021793/S-005, June 2009. http://www.accessdata.fda.gov/drugsatfda_docs/label/2009/017854s052,021793s005medguide.pdf (accessed 20 December 2016)
- 4.Pasricha PJ, Pehlivanov N, Sugumar A, Jankovic J (2006) Drug insight: from disturbed motility to disordered movement—a review of the clinical benefits and medicolegal risks of metoclopramide. Nat Clin Pract Gastroenterol Hepatol 3(3):138–148. https://doi.org/10.1038/ncpgasthep0442 CrossRefPubMedGoogle Scholar
- 9.Food and Drug Administration. Metoclopramide information. http://www.fda.gov/Drugs/DrugSafety/PostmarketDrugSafetyInformationforPatientsandProviders/ucm220099.htm (accessed 20 December 2016).
- 10.Heitmann K, Holst L, Lupattelli A, Maltepe C, Nordeng H (2015) Treatment of nausea in pregnancy: a cross-sectional multinational web-based study of pregnant women and new mothers. BMC pregnancy and childbirth 15(1):321. https://doi.org/10.1186/s12884-015-0746-2 CrossRefPubMedPubMedCentralGoogle Scholar
- 12.Matok I, Perlman A (2014) Metoclopramide in pregnancy: no association with adverse fetal and neonatal outcomes. Evid Based Med.:ebmed-2013-101654Google Scholar
- 14.WHO Collaborating Center for International Drug Monitoring. Caveat Document. Accompanying statment to data released from the Uppsala Monitoring Centre, WHO Collaboratoring Centre for International Drug Monitoring, Uppsala; 2015. [Available from: https://www.who-umc.org/media/1417/umc_caveat_201605.pdf] (accessed 5. October 2017).
- 15.Uppsala Monitoring Centre. Vigibase FAQs [Available from: https://www.who-umc.org/vigibase/vigibase/know-more-about-vigibase/]
- 16.Food and Drug Administration. FDA requires boxed warning and risk mitigation strategy for metoclopramide-containing drugs [press release]. February 2009. https://wayback.archive-it.org/7993/20170112033201/http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/2009/ucm149533.htm (accessed 15 April 2017)
- 17.European Medicines Agency. Guideline on the use of statistical signal detection methods on the eudravigilance data analysis system. EMEA/106464/2006 rev.1, London; 2008. http://www.ema.europa.eu/docs/en_GB/document_library/Regulatory_and_procedural_guideline/2009/11/WC500011434.pdf (accessed 20 December 2016)
- 19.Woerner MG, Correll CU, Alvir JM, Greenwald B, Delman H, Kane JM (2011) Incidence of tardive dyskinesia with risperidone or olanzapine in the elderly: results from a 2-year, prospective study in antipsychotic-naive patients. Neuropsychopharmacology 36(8):1738–1746. https://doi.org/10.1038/npp.2011.55 CrossRefPubMedPubMedCentralGoogle Scholar
- 20.Norwegian Prescription Database. Metoclopramide. Users per 1000 during 2015. http://www.norpd.no/Prevalens.aspx (accessed 20 December 2016).
- 21.The National Board of Health and Welfare. Statistical database. Metoclopramide. Users per 1000 during (2015) Stockholm:2016 http://www.socialstyrelsen.se/statistik/statistikdatabas/lakemedel (accessed 20 December 2016
- 22.Ehrenpreis ED, Deepak P, Sifuentes H, Devi R, Du H, Leikin JB (2013) The metoclopramide black box warning for tardive dyskinesia: effect on clinical practice, adverse event reporting, and prescription drug lawsuits. Am J Gastroenterol 108(6):866–872. https://doi.org/10.1038/ajg.2012.300 CrossRefPubMedGoogle Scholar
- 23.Ehrenpreis E, Krishnan A, Alexoff A, Smith D, Wilensky S (2015) A survey of lawsuits filed for the complaint of tardive dyskinesia following treatment with metoclopramide. Clin Pharmacol Biopharm 4:131Google Scholar
- 24.Sweden MPA (October 2016) Summary of product characteristics. Primperan tablet, Uppsala https://lakemedelsverket.se/LMF/Lakemedelsinformation/?nplid=19720825000013&type=product (accessed 20 December 2016
- 25.Fernandez HH, Friedman JH (2003) Classification and treatment of tardive syndromes. Neurologist 9(1):16–27. https://doi.org/10.1097/01.nrl.0000038585.58012.97 CrossRefPubMedGoogle Scholar
- 26.van Os J, Fahy T, Jones P, Harvey I, Toone B, Murray R (1997) Tardive dyskinesia: who is at risk? Acta Psychiatr Scand 96(3):206–216. https://doi.org/10.1111/j.1600-0447.1997.tb10153.x CrossRefPubMedGoogle Scholar
- 27.Wonodi I, Adami HM, Cassady SL, Sherr JD, Avila MT, Thaker GK (2004) Ethnicity and the course of tardive dyskinesia in outpatients presenting to the motor disorders clinic at the Maryland psychiatric research center. J Clin Psychopharmacol 24(6):592–598. https://doi.org/10.1097/01.jcp.0000144888.43449.54 CrossRefPubMedGoogle Scholar