title: Risk evaluation and mitigation strategies: a focus on the mammalian target of rapamycin inhibitors.
abstract: OBJECTIVE
  To review the history of risk evaluation and mitigation strategies (REMS) with the mammalian target of rapamycin (mToR) inhibitors, evaluate their required REMS elements, and delineate the reasons for them being released from their REMS requirements.
  
  
  METHODS
  Articles were identified through a literature search of MEDLINE and EMBASE (January 2007-July 2012) using the search terms: risk evaluation and mitigation strategies, REMS, everolimus, sirolimus and organ transplant (individual organs also were searched). Information from the Federal Register, the Food and Drug Administration, and the manufacturers of the mToR inhibitors was also evaluated.
  
  
  RESULTS
  REMS are strategies implemented to manage known or potential risks associated with medications and to ensure ongoing pharmacovigilance throughout the life of a pharmaceutical product. The mToR inhibitors have been associated with several potential risks, including proteinuria, graft thrombosis, and wound-healing complications. The Food and Drug Administration approved REMS programs for both sirolimus and everolimus. The manufacturers of both medications complied with the components of their approved REMS, but after less than 2 years, both medications have been relieved of their REMS obligations.
  
  
  CONCLUSIONS
  The only element of the sirolimus REMS was a medication guide, whereas the everolimus REMS consisted of a medication guide and a communication plan. The sirolimus REMS was implemented more than 10 years after its initial approval by the Food and Drug Administration, but was released from its REMS requirement within 7 months of its implementation. The everolimus REMS was instituted upon initial approval and was removed approximately 2 years later. Both medications' REMS were always intended to educate health care providers and patients about the potential risks associated with this transplant immunosuppressant. Transplant practitioners should be familiar with the mToR inhibitors' associated risks and properly educate patients regarding the inhibitors' risk-benefit profiles.
authors: Brigham and Women's Hospital, Boston, MA, USA. sgabardi@partners.org
authors: Steven
authors: S
authors: Gabardi
mesh_terms: D000068338:Everolimus; D006291:Health Policy; D006801:Humans; D007166:Immunosuppressive Agents / Q000009:adverse effects* / Q000627:therapeutic use; D060735:Pharmacovigilance; D012308:Risk Management; D020123:Sirolimus / Q000009:adverse effects* / Q000031:analogs & derivatives / Q000627:therapeutic use; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors*; D014481:United States
chemical_list: D007166:Immunosuppressive Agents; D000068338:Everolimus; D058570:TOR Serine-Threonine Kinases; D020123:Sirolimus