IMPORTANT CORRECTION
OF DRUG INFORMATION
To AST and ASTS
Members Dear Health Care Provider: Recently you may have received a publication
from Galen Press as a part of the Protocols Series.
It had the title "Protocols Series Ð Guidelines from experts in transplantation:
Sirolimus for liver transplantation: Primary and rescue immunosuppression."
This publication was supported by an unrestricted educational grant from Wyeth.
This publication did not provide the following important information: °
The safety and efficacy of Rapamune ® (sirolimus) as immunosuppressive therapy
has not been established in liver transplant patients, and therefore, such use
is not recommended.
The prescribing information has been updated to include the following black
box WARNING.
Hepatic Artery Thrombosis: In two multicenter, randomized controlled studies
in de novo liver transplant recipients, the use of sirolimus in combination
with cyclosporine or tacrolimus was associated with an increase in hepatic artery
thrombosis. Most cases occurred within 30 days post-transplantation and most
led to graft loss or death. The safety and efficacy of Rapamune ® (sirolimus)
as immunosuppressive therapy have not been established in liver transplant patients,
and therefore, such use is not recommended.
° Wyeth Research has suspended enrollment in a Phase II clinical study comparing
sirolimus in combination with tacrolimus/ corticosteroids to tacrolimus/ corticosteroids
alone in de novo liver transplant patients. This action was prompted by an imbalance
in the observed rates of hepatic artery thrombosis with a rate of 5.5% (6/ 110)
in the sirolimus-tacrolimus treatment group, all of which occurred within 16
days post-liver transplantation, versus 0.9% (1/ 112) in the tacrolimus-treated
control arm.
° As of April 10, 2002, based on additional information, we have learned
that the use of sirolimus plus tacrolimus was associated with an excess rate
of death and graft loss in a liver transplant study. Many of these patients
had evidence of infection at or near the time of death. Additional revisions
will be made to the product labeling, which will be available at www. Wyeth.
com or 1-800-934-5556. A previous clinical trial in de novo liver transplant
patients in which RAPAMUNE was used in combination with cyclosporine and corticosteroids
revealed an excess of hepatic artery thrombosis in patients on the combination
regimen (10/ 112, 8.9%) as compared to the tacrolimus/ corticosteroid control
arm (2/ 52, 3.8%).
Prescribing Information ° RAPAMUNE is indicated for the prophylaxis of organ
rejection in patients receiving renal transplants. It is recommended that RAPAMUNE
be used in a regimen with cyclosporine and corticosteroids. Increased susceptibility
to infection and the possible development of lymphoma and malignancy, especially
of the skin, may result from immunosuppression. Only physicians experienced
in the use of immunosuppressive therapy and the management of transplant patients
should use RAPAMUNE. Patients receiving the drug should be managed in facilities
equipped and staffed with adequate laboratory and supportive medical resources.
The physician responsible for maintenance therapy should have complete information
requisite for the follow-up of the patient.
The following other changes have also been made to the Prescribing Information:
° In the Food effects subsection of CLINICAL PHARMACOLOGY, the kcal information
has been corrected regarding the nutritional information for the high-fat breakfast
used in this study and now reads:
"In 22 healthy volunteers receiving Rapamune Oral Solution, a high-fat
meal (861.8 kcal, 54.9% kcal from fat) altered the bioavailability characteristics
of sirolimus."
° In the Lipids subsection of PRECAUTIONS, the statement regarding concomitant
administration of RAPAMUNE and HMG-CoA reductase inhibitors and/ or fibrates
was revised to read:
"In clinical trials, the concomitant administration of Rapamune and HMG-CoA
reductase inhibitors and/ or fibrates appeared to be well tolerated. During
Rapamune therapy with cyclosporine, patients administered an HMG-CoA reductase
inhibitor and/ or fibrate should be monitored for the possible development of
rhabdomyolysis and other adverse effects as described in the respective labeling
for these agents."
° In the Other clinical experience subsection of ADVERSE REACTIONS, the
following has been added:
"Abnormal healing following transplant surgery has been reported, including
fascial dehiscence and anastomotic disruption (e. g., wound, vascular, airway,
ureteral, biliary)."
Serious adverse events or product problems should be reported to Wyeth Global
Safety Surveillance and Epidemiology by FAX at (610) 989-5544 or by mail to
GSSE, 201 King of Prussia Road, 6th Floor, Radnor, PA 19087.
A copy of the Prescribing Information for RAPAMUNE is enclosed for your reference.
Please contact Wyeth Medical Affairs at 1-800-934-5556 with any questions or
concerns.
Sincerely,
Victoria Kusiak, M. D.
Vice President, Global Medical Affairs North American Medical Director Wyeth
Pharmaceuticals