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Important Drug Warning from the Manufacturer Vitex Inc. on PLAS+®SD

Date: 2000-10-20

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October 20, 2000

IMPORTANT DRUG WARNING

Dear Doctor or Pharmacist:

This letter is to advise you of a reported cluster of serious adverse events occurring at a single U.S. institution in patients receiving PLAS+®SD (Pooled Plasma, (Human) Solvent Detergent Treated) during orthotopic liver transplantation. In addition, as a separate update, to provide important information on the handling and storage of PLAS+®SD.

REPORTED SERIOUS ADVERSE EVENTS IN LIVER TRANSPLANT PATIENTS

VITEX has received reports of serious adverse events (thrombotic events or excessive bleeding) occurring in a cluster of six patients, who underwent orthotopic liver transplantation for end stage liver disease due to a variety of underlying disease processes. All patients received intra-operative PLAS+®SD along with multiple other blood components. The possible relationship between the use of PLAS+®SD and these reported adverse events is currently under investigation however, no causal relationship between the two has been established at this time. As a result, we ask that caution be exercised when using PLAS+®SD during liver transplant procedures. If PLAS+®SD is to be used during liver transplant, the coagulation status of the patients should be carefully monitored for evidence of thrombosis, excessive bleeding or exacerbation of disseminated intravascular coagulation (DIC).

Liver transplantation is a high-risk procedure with mortality rates in the U.S. varying between 20% and 40%. Thrombotic events with fatal outcomes have been associated with massive infusion of standard fresh frozen plasma in patients undergoing liver transplantation and those with thrombotic thrombocytopenic purpura. At the institution where the adverse events occurred, the mortality rate among liver transplant patients who received PLAS+®SD was 18.7%, a rate consistent with the overall U.S. mortality rate after liver transplantation.¹

The patients in this cluster received PLAS+®SD from 16 separate lots. All lots were tested by an independent laboratory and found to be within specification for release. All of the lots were released for sale in the U.S.

VITEX is continuing to monitor and investigate the occurrence of thrombotic events and determine if there is a relationship between the use of PLAS+®SD and the occurrence of thrombotic events.

STORAGE AND HANDLING OF PLAS+®SD

In addition to the serious adverse events related to the 6 liver transplant patients, there have also been reports of particulates in thawed PLAS+®SD. The reported particulates include strands of proteinaceous material, large, opaque protein aggregates, and translucent clots. The formation of such particulates may be related to improper handling or storage of PLAS+®SD. The storage and handling information provided below and in the product monograph must be strictly followed in order to minimize the potential for the formation of particulates in thawed PLAS+®SD. This information is being incorporated into the labelling for PLAS+®SD as follows:

• Always store PLAS+®SD at -18°C or colder during transport and prior to thawing. Do not use a bag of PLAS+®SD if the "freeze bar" indentation is not clearly visible.
  
  ALWAYS INSPECT THE BACK OF THE FROZEN PLAS+®SD PLASTIC BAG FOR THE PRESENCE OF AN INDENTED "FREEZE BAR" PRIOR TO THAWING. The "freeze bar" indentation is part of the freezing operation in the manufacturing process. If it is not clearly visible, it may be that thawing or partial thawing has taken place. Storage stability studies reveal maintenance of product coagulation factors when stored for 12 months at -18°C.
  
  
• Always thaw PLAS+®SD at 30-37°C.
  
  It is preferable to thaw product in a 30-37°C water bath with very gentle shaking. Prior to submerging in a water bath, the frozen bag of PLAS+®SD should be inserted into an outer plastic protective bag. Only thaw the number of PLAS+®SD bags that can adequately be accommodated by the bath and still maintain the 30-37°C water temperature throughout the thawing process. Time to thaw is dependent upon the number of bags to be thawed and the size of the water bath.
  
  
• Once thawed, only store PLAS+®SD at room temperature, not in the cold or on ice.
  
  PLAS+®SD may be used up to 24 hours after thawing. However, it is important that product be kept at room temperature and not stored in the cold (not in a refrigerator or on ice).

Healthcare professionals should report adverse events with VITEX Plas+®SD to INFOTRAC^® at 1-800-535-5053 and product complaints should be reported to Canadian Plasma Products at 1-705 897-6481. Alternatively, adverse events may be reported directly to Health Canada:

Adverse Reaction Review and Information Unit, Adverse Reaction and Medication Error Assessment Division, Bureau of Licensed Product Assessment, Therapeutic Products Programme, Health Canada, Finance Building Address Locator 0201C2, Ottawa, Ontario K1A 1B9.

ADR Report Forms can be found in The Canadian Compendium of Pharmaceutical and Specialties or by contacting the Adverse Reaction Review and Information Unit at tel.: (613) 957-0337 or fax (613) 957-0335.

The product monograph is currently being amended to reflect these concerns. Please refer, in future, to the updated version of the product monograph under sections warnings and adverse reactions.

Sincerely,

original signed by

Kathleen J. Beach, M.D.
Vice President, Clinical Research

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