Safety Experience with Trisenox® (Arsenic Trioxide) Injection.

Introduction: Trisenox®(arsenic trioxide) injection was approved in the United States in Sept 2000 and in the EU in March 2002 for the treatment of patients (pts) with relapsed or refractory acute promyelocytic leukemia (APL). Aim: The aim of this analysis is to assess the safety profile of Trisenox®. Methods: Safety information was gathered from monitored clinical trials and from spontaneous postmarketing reports. Results : As of June 2004, approximately 3600 pts had received commercial drug for a variety of hematologic and nonhematologic cancers. In clinical trials or compassionate programs since the beginning of the Trisenox® development program, 808 pts [with APL (265), multiple myeloma (103), MDS (188), and other hematologic cancers or solid tumors (252)] have been treated. The overall safety experience for Trisenox® is therefore based on exposure of approximately 4400 pts. Postmarketing Experience: As of May 2004, 380 spontaneous postmarketing adverse event (AE) reports were received by CTI; 123 of these were serious AEs (SAEs), with 13 deaths, most due to disease progression or complications of the disease being treated. Trisenox® may have contributed to a death due to possible tumor lysis syndrome in a pt with MM, and 1 AML pt died with no cause reported. Most reported AEs are expected events that are listed in the Trisenox® product labeling. AEs reported for >15 pts were cytopenia (anemia, leukopenia, neutropenia, thrombocytopenia), pyrexia, prolonged QT interval, dyspnea, edema/wt gain, pain, hypotension, leukocytosis, rash, differentiation syndrome, nausea, asthenia/fatigue. Clinical Trial Experience : SAEs considered related to Trisenox® have been reported for 120 of 305 pts enrolled in clinical trials since US approval. This larger proportion of pts with SAEs likely reflects the monitored data in clinical trials compared to spontaneous postmarketing reports. Most of these SAEs are events listed in the Trisenox® label. AEs considered by investigators to be related to Trisenox® in 20% or more of the 233 pts with data received by CTI since US approval are pain (51%), nausea/vomiting (47%/23%), edema (43%), diarrhea (43%), fatigue/asthenia (37%/21%), pyrexia (36%), rash (34%), dyspnea (33%), gastrointestinal disorder (32%), headache (30%), cough (30%), upper respiratory symptoms (27%), abdominal pain (26%), anorexia (23%), lower respiratory disorders (22%), any cardiac arrhythmia (21%), hemorrhage (21%), viral infection (21%). As disease symptoms diminish, adverse events generally decrease in incidence and severity with continued use of Trisenox®. Few pts require interruption of therapy. A recent report of transient arrhythmias in pts continuously monitored during treatment with a non-Trisenox® formulation of arsenic trioxide (Unnikrishnan, Br J Haematol 2004;124:610–7) does not reflect the safety experience in pts treated with Trisenox® and managed in accordance with the product labeling. Conclusion : With >4400 pts exposed to Trisenox®, the postmarketing AEs reported are generally similar to those observed in clinical trials and listed in the product labeling. The risk/benefit profile of Trisenox® when pts are managed in accordance with the product label remains acceptable.