Clinical Consequences of Disseminating the Bortezomib Postmarketing Safety Alerts In Japan

In Japan, bortezomib (Velcade; Janssen Pharmaceutical Corporation, Tokyo, Japan) was approved on October 2006 for relapsed or refractory multiple myeloma, and sales began on the open market in December 2006. The approval process clarified potential risk for interstitial lung disease (ILD) among bortezomib-treated Japanese patients as we reported before (Blood 2006; 107:3492–4, Lancet Oncol 2008; 9:414–5). By 2007, various safety alerts were widely disseminated through the responsible pharmaceutical company, the media, the academic societies and the regulatory authority of Japan (Pharmaceuticals and Medical Devices Agency, PMDA) concerning the potential ILD risk of bortezomib (J Clin Oncol 2008; 26:5820–3). In this study, we investigated whether notification of patients and providers about these safety alerts influenced the clinical outcomes after bortezomib therapy in Japan.

We reviewed all bortezomib-related adverse drug reaction (ADR) reports available from open source database of PMDA from December 2006 to December 2009. The indication of bortezomib remained unchanged in this period. We compared the number of reported cases and their outcomes between the early postmarketing period (from December 2006 to December 2007) and the late period after the dissemination of the safety alerts concerning ILD (from January 2008 to December 2009).

In the study period, 419 ADR cases were identified after bortezomib therapy. The proportion of ILD to any ADR was 25.0% (9 of the 36 cases) in December 2006, 8.3% (13 of the 156 cases) in 2007, 12.0% (17 of the 142 cases) in 2008 and 7.1% (6 of the 85 cases) in 2009 (Table 1). When we compared the early postmarketing period before the safety alerts and the late period after the safety alerts, the death proportion of the cases with any ADRs seemed similar. Forty of the 192 cases (20.8%) died in the early period and 47 of the 227 cases (20.7%) in the late period. On the other hand, the death proportion among ILD cases appeared to decrease remarkably (Table 2). Nine of the 22 ILD cases (40.9%) died in the early period and 1 of the 23 ILD cases (4.3%) died in the late period (p=0.004, Fisher's exact test).

Notification of patients and providers about the safety alerts appeared to influence the clinical practice and to improve proportion of fatal outcomes for bortezomib-treated ILD patients. This study illusrates the importance of communicating drug safety information to the public.

Oshima:Sanofi-Aventis: Employment.