Pharmacovigilance presents many challenges, particularly when managing unpredictable, rare conditions, eg, severe cutaneous adverse reactions (SCARs). Such rare events are often only detected from spontaneous reports, which present their own limitations, particularly during a prolonged global launch schedule. GlaxoSmithKline's routine pharmacovigilance includes regular reviews of global adverse event (AE) reports and aggregate data from a central safety database. Lamotrigine is one of the several antiepileptic drugs associated with SCARs. After identification of increased rates of fatal SCAR cases with lamotrigine in Japan between September and December 2014, this analysis investigated the global incidence of fatal SCARs with lamotrigine and explored whether known risk factors may have contributed to these cases. Global fatal SCAR cases reported with lamotrigine administration from launch until January 2015 were reviewed for evidence of temporal association with dosing and the presence of risk factors, including comorbidities, concomitant medications, and noncompliance with the prescribing information (PI). Worldwide, the estimated cumulative exposure to lamotrigine was >8.4 million patient-years. Globally, there were 54,513 AE reports for lamotrigine, of which 3,454 (6.3%) concerned SCARs. Of these, 122 (3.5%) had a fatal outcome (attributable and nonattributable to lamotrigine), equating to 0.01 fatal SCARs per 1,000 patient-years. In Japan (estimated cumulative exposure 141,000 patient-years), 17 fatal SCARs were reported (attributable and nonattributable), equating to 0.12 per 1,000 patient-years. Seventy-one percent of fatal SCAR cases in Japan showed evidence of noncompliance with the recommended dosing regimen; in 65% of the cases, a delay in discontinuation of lamotrigine after early signs of hypersensitivity was reported. Despite a number of limitations inherent in comparing spontaneous report data, this analysis highlights the need for adherence to the lamotrigine PI and emphasizes the importance of collaboration between global and local pharmacovigilance departments, to promptly identify and reduce the risk of rare and serious events, such as SCARs.