 FDA
Rezulin Papers
- October 24, 2000, FDA TO SCHEDULE PUBLIC DISCUSSION
OF REZULIN
- March 24, 2000, “FDA to Schedule Public
Discussion of Rezulin”
- March 22, 2000, REZULIN TO BE WITHDRAWN FROM
THE MARKET
- June 16, 1999, New Labeling and Use Changes
for Rezulin
- July 28, 1998, IMPORTANT DRUG WARNING
- December 1, 1997, Patient Testing and Labeling
Strengthened for Rezulin
- December 1, 1997, Dear Healthcare Professional
Letter
- November 3, 1997, Rezulin Labeling Changes
- October 28, 1997, Dear Healthcare Professional
Letter
October 24, 2000, FDA TO SCHEDULE PUBLIC
DISCUSSION OF REZULIN
FDA is announcing today that it plans to make a public presentation
of the data underlying and the rationale for its decision to request
the withdrawal of Rezulin (troglitazone) from the US market. This
presentation will be made to the next meeting of the Endocrine and
Metabolic Drugs Advisory Committee.
A general discussion of the matter with the committee will follow
the presentation. No specific questions are planned to be posed
to the committee at this time.
The meeting will also provide a public forum for all interested
parties to get detailed information about these data and the agency’s
decision-making processes.
The next meeting of the advisory committee is scheduled tentatively
for May 18 and 19th; however, that date could change based on availability
of committee members.
A formal Federal Register notice about this meeting and any other
items to be discussed at the meeting will be forthcoming.
top - Rezulin Lawsuit News
March 24, 2000, “FDA to Schedule
Public Discussion of Rezulin”
FDA is announcing today that it plans to make a public presentation
of the data underlying and the rationale for its decision to request
the withdrawal of Rezulin (troglitazone) from the US market. This
presentation will be made to the next meeting of the Endocrine and
Metabolic Drugs Advisory Committee.
A general discussion of the matter with the committee will follow
the presentation. No specific questions are planned to be posed
to the committee at this time.
The meeting will also provide a public forum for all interested
parties to get detailed information about these data and the agency’s
decision-making processes.
The next meeting of the advisory committee is scheduled tentatively
for May 18 and 19th; however, that date could change based on availability
of committee members.
A formal Federal Register notice about this meeting and any other
items to be discussed at the meeting will be forthcoming.
top - Rezulin Lawsuit News
March 22, 2000, REZULIN TO BE WITHDRAWN
FROM THE MARKET
FDA today asked the manufacturer of Rezulin (troglitazone) -- a
drug used to treat type 2 diabetes mellitus-- to remove the product
from the market. The drug's manufacturer, Parker-Davis/Warner-Lambert,
has agreed to FDA's request.
FDA took this action after its review of recent safety data on
Rezulin and two similar drugs, rosiglitazone (Avandia) and pioglitazone
(Actos), showed that Rezulin is more toxic to the liver than the
other two drugs. Data to date show that Avandia and Actos, both
approved in the past year, offer the same benefits as Rezulin without
the same risk.
"When considered as a whole, the pre-marketing clinical data
and post-marketing safety data from Rezulin as compared to similar,
alternative diabetes drugs indicate that continued use of Rezulin
now poses an unacceptable risk to patients," said Dr. Janet
Woodcock, Director of FDA's Center for Drug Evaluation and Research.
"We are now confident that patients have safer alternatives
in this important class of diabetes drugs," she added.
Severe liver toxicity has been known to occur with Rezulin since
1997. In consultation with FDA, Parke-Davis has strengthened the
drug’s labeling several times and has recommended close monitoring
of liver function in patients taking Rezulin.
In March 1999, FDA's Endocrine and Metabolic Drugs Advisory Committee
reviewed the status of Rezulin and its risk of liver toxicity and
recommended continued availability of this drug in a select group
of patients -- patients not well-controlled on other diabetes drugs.
Since then, FDA has continued to actively monitor adverse events
associated with Rezulin, as well as Avandia and Actos. After up
to nine months of marketing experience with these two newer drugs,
it has now become clear that these newer drugs have less risk of
severe liver toxicity than Rezulin.
Patients using Rezulin are urged to contact their physicians for
information about alternative treatments. Patients should not discontinue
taking Rezulin or other treatments for diabetes without discussing
alternative therapies with their physicians.
top - Rezulin Lawsuit News
June 16, 1999, New Labeling and Use Changes
for Rezulin
Significant new changes are being made to the labeling and recommended
uses for Rezulin (troglitazone) - a drug used to treat type 2 diabetes
mellitus (non-insulin dependent diabetes mellitus, or adult onset
diabetes). These changes are being made because new safety information
(i.e., further evidence of serious and sometimes fatal liver injury
in patients treated with Rezulin) indicates that the use of Rezulin
should be limited to patients not adequately controlled by other
therapy and should not be used as initial single agent therapy in
the treatment of type 2 diabetes. The labeling changes also include
recommendations for more extensive monitoring of liver function
in patients using Rezulin. A patient information sheet has been
added to the labeling and will be available for distribution to
patients by pharmacists with each Rezulin prescription.
FDA and Parke-Davis agreed to these changes after careful analyses
of the drug's safety profile, drawing upon clinical trials data,
post-marketing surveillance data and the recommendations made by
FDA's Endocrinologic and Metabolic Drugs Advisory Committee during
a March 26, 1999 meeting. The new labeling and other measures being
taken regarding Rezulin are in keeping with the recommendations
made by that panel of outside experts.
Parke-Davis is issuing a nationwide letter to healthcare professionals
notifying them of these modifications. The letter specifically notes
that:
- Rezulin is no longer indicated to be used as initial single
agent therapy.
- Prospective Rezulin patients need to have liver chemistries
tested before starting therapy, then monthly during the first
year of therapy (rather than just 10 times previously recommended).
After the first year of therapy patients should be tested quarterly
(rather than "periodically" as previously recommended).
- Within the next few weeks, the company will prepare a patient
information sheet with FDA-approved information about the safe
and effective use of Rezulin. This patient information sheet will
be available for distribution to patients by pharmacists with
each Rezulin prescription.
In addition to changes in labeling noted above, a new indication
will be added to Rezulin's labeling for its use in combination with
sulfonyureas and metformin in patients whose diabetes is not adequately
controlled by the combined use of just these other diabetes drugs.
This indication is based on new clinical data evaluated by the agency.
FDA urges patients to consult with their physicians before making
any changes in their use of Rezulin. Any adverse reactions associated
with the drug should be reported to the agency through MedWatch,
FDA's adverse reaction reporting system. Reports may be submitted
to FDA by telephone (800-332-1088), by fax (800-332-0178) or by
mail to MedWatch, HF-2, FDA, 5600 Fishers Lane, Rockville, Md. 20857.
Reports can also be filed via the Internet at www.fda.gov/medwatch.
Reports may also be filed directly to the manufacturer.
top - Rezulin Lawsuit News
July 28, 1998, IMPORTANT DRUG WARNING
Dear Healthcare Professional:
Importance of Monitoring Liver Function
This letter is to inform healthcare professionals about the modified
requirements relating to more stringent liver enzyme monitoring
as reflected in the new product labeling for Rezulin. These new
liver enzyme monitoring modifications are intended to reduce the
risk of rare but serious liver injury, including liver failure leading
to transplant or death. The labeling has also been changed to modify
the initial period of evaluation in monotherapy. This letter describes
these changes and includes new educational materials for your reference
and use with patients.
Modifications to Liver Function Monitoring Information
Liver enzyme monitoring recommendations were originally implemented
in November 1997. Since that time there have been few new cases
of severe hepatocellular events, primarily involving patients who
may not have been monitored as recommended in the labeling. Since
the introduction of Rezulin in March 1997, the reported rate of
death or transplant in patients receiving Rezulin is approximately
1 case in 60,000 patients. Although it appears to be rare, at least
one patient has exhibited a rapid elevation of alanine aminotransferase
(ALT). Therefore, it is very important to closely monitor patients
who exhibit even modest ALT elevations during their treatment with
Rezulin.
Accordingly, Parke-Davis, in consultation with the FDA, has modified
the prescribing information in the following way:
* Patients with moderately elevated ALT levels at the start of
therapy (greater than 1.5 times the upper limit of normal) should
not be initiated on Rezulin therapy.
* ALT levels should be measured at the start of Rezulin therapy
and monthly for eight months, then every two months for the remainder
of the first year of therapy and periodically thereafter.
* Patients whose ALT levels are found to be moderately elevated
(greated than 1.5 - 2 times the upper limit of normal) during Rezulin
therapy should have ALT levels retested within a week and then weekly
until they either return to normal levels or rise about 3 times
the upper limit of normal, at which point Rezulin should be discontinued.
For your information, during clinical trials with Rezulin in 2510
patient, 1.9% of patients treated with Rezulin have ALT >3 times
the upper limit of normal; overall about 5% of patients treated
with Rezulin in these clinical trials developed moderate ALT elevations
of greater than 1.5 times the upper limit of normal during the course
of therapy.
It should be emphasized that although serious hepatic events associated
with Rezulin are rare, all patients on Rezulin must be monitored
in accordance with the monitoring schedule described in the revised
prescribing information in order to reduce the occurrence of these
events.
Parke-Davis encourages healthcare providers to report any new cases
of severe adverse liver events or other adverse events to Parke-Davis
at 1-800-223-0432 or to the FDA MedWatch program at 1-800-FDA-1088
(Fax 1-800-FDA-0178).
Modifications to Monotherapy Prescribing Information
The recommendation for use as initial therapy has been modified
to the following:
* For patients not responding to 400 mg, the Rezulin dose should
be increased to 600 mg after one month. For patients not responding
adequately to 600 mg after one month, Rezulin should be discontinued
and alternative therapeutic options should be pursued.
New Educational Materials Available
Since its introduction in March 1997, Rezulin has been prescribed
for more than 1.1 million patients with type 2 diabetes. We are
committed to keeping you informed of important developments relating
to Rezulin so that your patients can achieve better control of their
type 2 diabetes. You will find enclosed items that explain the modifications
to the monitoring recommendations, as well as the new prescribing
information and other information that will help you to communicate
the importance of monitoring liver enzymes to your patients. In
addition, we will send similar items to pharmacists and diabetes
educators so that they can support your efforts in educating patients
about their therapy with Rezulin. We hope that this information
will help you and your patients.
Your Parke-Davis and Sankyo Parke Davis representatives will be
able to supply additional copies of these and other materials as
you require, as well as to respond to your questions or concerns.
Sincerely,
William R. Sigmund II, M.D., M.H.S., F.A.C.C.
Vice President, Medical and Scientific Affairs
top - Rezulin Lawsuit News
December 1, 1997, Patient Testing and Labeling
Strengthened for Rezulin
The U.S. Food and Drug Administration today announced that patients
taking the diabetes drug Rezulin (troglitazone) should be monitored
more frequently for signs of injury to the liver. In addition, warning
information about potential liver toxicity will be more prominently
featured in the drug's labeling.
These actions, taken with the full cooperation of the drug's manufacturer,
re-emphasize for health care providers and patients the importance
of monitoring patients taking Rezulin to ensure that it is used
in the safest manner.
Rezulin is used in combination with insulin or sulfonylurea in
patients with type II diabetes (adult-onset diabetes mellitus) whose
blood glucose levels are not adequately controlled by these other
therapies alone.
On November 3, FDA and the drug's manufacturer announced changes
in the prescribing information for Rezulin, including a new warning
and recommendations for monitoring liver function. In making these
changes, FDA was aware of approximately 35 post-marketing reports
of liver injury among U.S. and Japanese patients taking Rezulin,
including liver failure leading to one liver transplant and one
death.
At that time, FDA asked for reports on additional adverse events
associated with the use of Rezulin, and the agency has now received
a total of approximately 150 adverse event reports, including three
deaths from liver failure linked to the use of Rezulin in Japan.
Approximately 600,000 patients in the U.S. and 200,000 in Japan
have been treated with this drug. The deaths in Japan occurred in
patients treated before the stronger label
warning and recommendation for liver enzyme testing took effect
there.
FDA has concluded that liver enzyme levels should be measured in
patients taking Rezulin at the start of therapy, every month for
the first six months of treatment, every other month for the next
six months, and periodically thereafter. In addition, liver function
tests should be performed on any patient on Rezulin who develops
symptoms of liver dysfunction, such as nausea, vomiting, fatigue,
loss of appetite, or dark urine and
jaundice. The product's current labeling advises that patients
with significant elevation of these liver enzymes stop taking the
drug. Previously, liver enzyme testing was recommended during the
first two months of therapy and then every three months.
The increased monitoring of patients taking Rezulin is designed
to detect those few patients in whom use of the drug can lead to
serious liver damage. Warner-Lambert, the manufacturer of the drug,
will send a letter within the next week to U.S. health care professionals
to inform them of these changes.
While Rezulin was being studied in patients before FDA approval,
approximately two percent of all patients were found to develop
elevation of liver enzymes in the blood. These elevations, which
serve as markers of potential liver injury, were mostly mild, unassociated
with symptoms, and usually resolved when the drug was discontinued.
Although FDA will carefully monitor and evaluate reports of liver
problems associated with Rezulin, at present the agency continues
to find the benefits outweigh the risks for treating appropriately
selected and monitored type-2 diabetes patients with Rezulin.
Type 2 diabetes is a serious, life-threatening disease that affects
18 million Americans. It is a leading cause of coronary heart disease,
blindness, kidney failure, and limb amputation. Adequate control
of blood sugar appears to be the most important means of preventing
these complications.
top - Rezulin Lawsuit News
December 1, 1997, Dear Healthcare Professional
Letter
Dear Healthcare Professional:
As you will recall, on November 3 Warner-Lambert informed you about
a company-initiatied change in the prescribing information on Rezulin
(troglitazone) which specified the need for monitoring of liver
function with patients taking the drug. Rezulin has already been
prescribed for over 600,000 patients in the U.S. and heightened
awareness following the earlier labeling change has, as expected,
generated some additional reports of hepatic dysfunction. You may
also hear media reports or receive patient inquiries related to
Glaxo Wellcome's decision to temporarily suspend marketing of Romozin,
their brand of troglitazone in the U.K., pending their review of
worldwide safety data. Glaxo Wellcome recently received approval
of Romozin in the U.K. and has experience with only 5,000 patients.
This decision has no impact on the availability of Rezulin in the
United States.
Warner-Lambert and the FDA have already completed a thorough review
of the worldwide safety experience with Rezulin. On November 3 the
FDA asked physicians for reports on additional adverse events. You
will be reassured to know that the additional reports received since
early November do not indicate a greater frequency of liver injury
or potential for serious harm than had been previously estimated.
Rezulin has been shown to be very effective in helping patients
achieve glycemic control. The FDA continues to find a favorable
benefit to risk relationship for Rezulin therapy in appropriately
selected and monitored type 2 diabetics.
All therapies that are currently available to treat type 2 diabetes
have potentially serious side effects. Warner-Lambert and the FDA,
on the recent advice of experts, have decided to take additional
steps in an effort to assure that the potential for this rare liver
injury in Rezulin-treated patients is reduced to the absolute minimum.
This has resulted in a new recommendation that liver enzymes and
bilirubin levels of Rezulin-treated patients be measured at the
start of therapy and monthly for the first six months of therapy.
These tests should then be measured every two months for the remainder
of the first year of therapy, and periodically thereafter.
We trust that this information will be helpful to you in continuing
to effectively treat your type 2 diabetes patients with this important
therapy. Should you have questions regarding these changes, or if
you want to receive a copy of full prescribing information for Rezulin,
please call 1-800-223-0432 between 8:00 am and 8:00 pm EST Monday
through Friday, or contact your Parke-Davis or Sankyo Parke Davis
representative. Updated prescribing information for Rezulin will
be sent to you as soon as it's available.
Sincerely,
William Sigmund II, M.D., M.H.S., F.A.C.C.
Vice President, Medical and Scientific Affairs
top - Rezulin Lawsuit News
November 3, 1997, Rezulin Labeling Changes
The manufacturer of the diabetes drug Rezulin (troglitazone) is
changing prescribing information for the product and adding new
warning information to the labeling, in response to reports of liver
injury associated with use of the drug.
Rezulin is used in combination with insulin or sulfonylurea in
patients with type II diabetes (adult-onset diabetes mellitus) whose
blood glucose levels are not adequately controlled by these other
therapies alone.
About 500,000 patients in the United States have been treated with
Rezulin since it came on the market in January 1997; of those, approximately
85,000 have been taking the drug for six months or more. As of October
21, 1997, 35 post-marketing reports of liver injury of various degrees
have been received. These reports ranged from mildly elevated blood
levels of the liver transaminase enzymes to liver failure leading
to one liver transplant and one death. Whether the drug was solely
responsible for all of these reports of liver injury is as yet unknown,
due to confounding medical factors in some of the reported cases.
Based on these reports, FDA and the manufacturer are recommending
that serum transaminase levels in patients be checked routinely
within the first one to two months of Rezulin therapy, every three
months thereafter during the first year of treatment, and periodically
thereafter. In addition, liver function tests should be performed
on any patient on Rezulin who develops symptoms of liver dysfunction,
such as nausea, vomiting, abdominal pain, fatigue, loss of appetite,
or dark urine. Patients on Rezulin who develop jaundice or whose
laboratory results indicate liver injury should stop taking the
drug.
Based on clinical trials, approximately two percent of patients
on Rezulin can be expected to have to stop taking the drug because
of elevated liver enzymes. Few, if any,
The new prescribing information and labeling warning are designed
to give health care providers and patients the latest available
information about possible risks associated with Rezulin and recommendations
for safer use of the drug.
Health care providers are urged to report any Rezulin-related adverse
events, especially those suggestive of possible liver injury, to
the manufacturer, Parke Davis, at 1-800-223-0432, or FDA MedWatch
at (phone) 1-800-FDA-1088, (fax) 1-800-FDA-0178 or
(mail) FDA, HF-2, 5600 Fishers Lane, Rockville, MD 20857.
top - Rezulin Lawsuit News
October 28, 1997, Dear Healthcare Letter
Dear Healthcare Professional:
We are notifying you of a change in prescribing information initiated
by Parke-Davis to provide additional information regarding the incidence
of idiosyncratic hepatocellular injury in patients with type 2 diabetes
being treated with Rezulin (troglitazone) Tablets. The labeling
changes are in response to rare reports during marketed use (35
as of October 21, 1997) of such injury. These cases range from mild
elevations of serum transaminases to one liver transplant and one
death.
Based on this experience during marketed use, Parke-Davis is recommending
that serum transaminase levels be checked within the first one to
two months and then every three months during the first year of
troglitazone therapy, and periodically thereafter. Liver function
tests also should be obtained for patients at the first symptoms
suggestive of hepatic dysfunction, e.g., nausea, vomiting, abdominal
pain, fatigue, anorexia, dark urine. Rezulin should be discontinued
if the patient has jaundice or if laboratory measurements suggest
liver injury (e.g., ALT > 3 times the upper limit of normal).
As described in the Rezulin package insert, rare cases of jaundice,
which were reversible, were observed in the controlled clinical
studies that supported marketing approval. Approximately 650,000
patients (500,000 in the United States and 150,000 in Japan) have
been treated with Rezulin since its introduction in early 1997.
Of those 650,000 patients, approximately 85,000 in the United States
have been on Rezulin therapy for six months or more.
The changes to prescribing information include:
WARNINGS
Hepatic
RARE CASES OF SEVERE IDIOSYNCRATIC HEPATOCELLULAR INJURY HAVE BEEN
REPORTED DURING MARKETED USE (SEE ADVERSE REACTIONS, POSTINTRODUCTION
REPORTS). THE HEPATIC INJURY IS USUALLY REVERSIBLE, BUT VERY RARE
CASES OF HEPATIC FAILURE, INCLUDING DEATH, HAVE BEEN REPORTED. INJURY
HAS OCCURRED AFTER BOTH SHORT- AND LONG-TERM TROGLITAZONE TREATMENT.
During all clinical studies in North America, a total of 48 of
2510 (1.9%) Rezulin-treated patients and 3 of 475 (0.6%) placebo-treated
patients had ALT levels greater than 3 times the upper limit of
normal. Twenty of the Rezulin-treated and one of the placebo-treated
patients were withdrawn from treatment. Two of the 20 Rezulin-treated
patients developed reversible jaundice; one of these patients had
a liver biopsy which was consistent with an idiosyncratic drug reaction.
An additional Rezulin-treated patient had a liver biopsy which was
also consistent with an idiosyncratic drug reaction. (See ADVERSE
REACTIONS, Laboratory Abnormalities)
It is recommended that serum transaminase levels be checked within
the first one to two months and then every three months during the
first year of troglitazone therapy, and periodically thereafter.
Liver function tests also should be obtained for patients at the
first symptoms suggestive of hepatic dysfunction, e.g., nausea,
vomiting, abdominal pain, fatigue, anorexia, dark urine. Rezulin
should be discontinued if the patient has jaundice or laboratory
measurements suggest liver injury (e.g., ALT > 3 times the upper
limit of normal).
PRECAUTIONS
Information for Patients
Patients who develop nausea, vomiting, abdominal pain, fatigue,
anorexia, dark urine or other symptoms suggestive of hepatic dysfunction
or jaundice should immediately report these signs or symptoms to
their physician.
ADVERSE REACTIONS
Postintroduction Reports
Adverse Events associated with Rezulin that have been reported
since market introduction, that are not listed above, and for which
causal relationship to drug has not been established include the
following: jaundice, hepatitis, liver transplant, death. Also see
WARNINGS.
A full copy of the revised Package Insert is enclosed.
We trust that this information will be helpful to you in continuing
to effectively treat your type 2 diabetes patients with this important
therapy. For further information, please contact the Parke-Davis
Medical and Scientific Affairs Department at 1-800-223-0432.
Health care professionals are encouraged to report any unexpected
events suggestive of idiosyncratic hepatocellular injury directly
to the Parke-Davis Medical and Scientific Affairs Department or
FDA MedWatch program at 1-800-FDA-1088 (FAX 1-800-FDA-0178).
Rezulin is indicated for concomitant use with a sulfonylurea or
insulin to improve glycemic control. Rezulin, as monotherapy, is
indicated as an adjunct to diet and exercise to lower blood glucose
in patients with type 2 diabetes. Rezulin should not be used as
monotherapy in patients previously well-controlled on sulfonylurea
therapy. For patients inadequately controlled with a sulfonylurea
alone, Rezulin should be added to, not substituted for, the sulfonylurea.
Sincerely,
William R. Sigmund II, M.D., M.H.S., F.A.C.C.
Vice President, Medical and Scientific Affairs
top - Rezulin Lawsuit News
|
