title: Disproportionality analysis of buprenorphine transdermal system and cardiac arrhythmia using FDA and WHO postmarketing reporting system data.
abstract: OBJECTIVE
  Positive-controlled clinical studies have shown a dose dependent effect of buprenorphine transdermal system on QTc interval prolongation. This study provides assessment of the buprenorphine transdermal system and cardiac arrhythmia using US FDA and WHO postmarketing reporting databases.
  
  
  METHODS
  Disproportionality analysis of spontaneously reported adverse events to assess whether the reporting rate of cardiac arrhythmia events was disproportionately elevated relative to expected rates of reporting in both FDA and WHO databases. Cardiac arrhythmia events were identified using the standardized Medical Dictionary for Regulatory Activities query for torsade de pointes and/or QT prolongation (TdP/QTP). The threshold for a signal of disproportionate adverse event reporting was defined as the lower 90% confidence limit ≥ 2 of the Empiric Bayes geometric mean in FDA database and as the lower 95% confidence limit of the Informational Component >0 in WHO database.
  
  
  RESULTS
  There were 124 (<1%) and 77 (2%) cardiac arrhythmia event cases associated with buprenorphine transdermal as compared to 3206 (12%) and 2913 (14%) involving methadone in the FDA and WHO databases, respectively. In the FDA database methadone was associated with a signal of disproportionate reporting for TdP/QTP (EB05 3.26); however, buprenorphine transdermal was not (EB05 0.33). In the WHO database methadone was associated with a signal of disproportionate reporting for TdP/QTP (IC025 2.66); however, buprenorphine transdermal was not (IC025 -0.88). Similar trends were observed in sensitivity analyses by age, gender, and specific terms related to ventricular arrhythmia.
  
  
  CONCLUSIONS
  The signal identified in the transdermal buprenorphine thorough QTc study, which led to a dose limitation in its US label, does not translate into a signal of increased risk for cardiac arrhythmia in real world use, as assessed by this method of analyzing post-market surveillance data.
authors.affiliation: a Purdue Pharma L.P ., Stamford , CT , USA.
authors.forename: Nelson E
authors.initials: NE
authors.lastname: Sessler
authors.affiliation: a Purdue Pharma L.P ., Stamford , CT , USA.
authors.forename: Ekaterina
authors.initials: E
authors.lastname: Walker
authors.affiliation: a Purdue Pharma L.P ., Stamford , CT , USA.
authors.forename: Harsha
authors.initials: H
authors.lastname: Chickballapur
authors.affiliation: a Purdue Pharma L.P ., Stamford , CT , USA.
authors.forename: James
authors.initials: J
authors.lastname: Kacholakalayil
authors.affiliation: a Purdue Pharma L.P ., Stamford , CT , USA.|b University of Pennsylvania , Philadelphia , PA , USA.
authors.forename: Paul M
authors.initials: PM
authors.lastname: Coplan
mesh_terms: D000279:Administration, Cutaneous; D000293:Adolescent; D000328:Adult; D016907:Adverse Drug Reaction Reporting Systems / Q000706:statistics & numerical data*; D000368:Aged; D000369:Aged, 80 and over; D002047:Buprenorphine / Q000009:adverse effects* / Q000627:therapeutic use*; D002648:Child; D002675:Child, Preschool; D005260:Female; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D008297:Male; D008875:Middle Aged; D010146:Pain / Q000188:drug therapy*; D016171:Torsades de Pointes / Q000139:chemically induced* / Q000188:drug therapy*; D014481:United States; D014486:United States Food and Drug Administration / Q000706:statistics & numerical data*; D014944:World Health Organization; D055815:Young Adult
chemical_list: D002047:Buprenorphine
keywords: Opioid; QT prolongation; buprenorphine transdermal; torsade de pointes