We ascertained a comprehensive list of postmarket safety outcomes, defined as a safety-related market withdrawal or an update to a safety-related section of product label for 278 new molecular entity drugs (NMEs) with a follow-up period of up to 13 years. At least one safety-related update was added to 195 (70.1%) labels of the drugs studied. Updates occurred as early as 160 days after approval and throughout the follow-up period. The period between the second and eighth postapproval year was the most active, with a slight attenuation thereafter. The times to the first safety outcome were significantly shorter for NMEs approved with a fast-track designation (P = 0.02) or under an accelerated approval using a surrogate endpoint (P = 0.03). Our findings underscore the importance of a robust safety surveillance system throughout a drug's lifecycle and for practitioners and patients to remain updated on drug safety profiles.