FDA Meeting March 2003: Update on the Safety of New Drugs for Rheumatoid Arthritis
Part III: Safety and Efficacy Update on Leflunomide (Arava®)
The FDA Arthritis Advisory
Committee met on March 5, 2003, to discuss updated issues related to the safety
and efficacy of leflunomide (LEF). Information from the FDA meeting is available
Safety issues concerning LEF, particularly related to potential hepatotoxicity,
was the subject of an August 2001 ACR Hotline and a previous ACR President’s
Column from April 2002 (both available at www.rheumatology.org).
In March 2002, a citizen’s petition was submitted to the FDA by the group
Public Citizen requesting that the agency remove LEF from the market based primarily
in response to Medwatch reports of acute liver failure (reviewed in the April
2002 ACR President's Column). The March 2003 FDA meeting followed a yearlong
assessment by the Agency of the most recent safety data concerning LEF. In addition,
the committee considered data potentially supporting an additional indication
for LEF, for improving physical functioning of patients with rheumatoid arthritis.
The yearlong, comprehensive
review of safety data for LEF included analysis of the following databases:
- A database of 2,900
subjects on LEF in controlled clinical trials with a median exposure of over
- Three independent medical
claims databases comprising over 5,400 subjects treated with LEF for a mean
of over 12 months.
- Data from the National
Databank of Rheumatic Diseases on over 5,000 subjects treated with LEF for
a mean of over 12 months.
- A database of hospitalizations
for acute liver failure from a consortium of 17 liver transplant centers.
- The Adverse Event Reporting
System (AERS) that represents the database of all Medwatch reports received
by the FDA.
The FDA Division of Arthritis,
Analgesic and Ophthalmic Drug Products reached the following conclusions regarding
LEF and liver injury:
- LEF is associated with
a three-fold elevation of liver enzymes in 2-4% of subjects compared to 1-2%
in the placebo-treated groups as is currently identified in the drug label
- Hospitalization for
apparent drug-related hepatitis was identified in the databases at a rate
of approximately 0.02% or 1/5000 patients
- There were no cases
of hepatocellular necrosis with jaundice (an event with a mortality association
of greater than 10%) in the databases of 13,700 subjects
There are few cases of LEF-induced
serious liver injury or acute liver failure in postmarketing surveillance. Through
the Medwatch system, the FDA has received several reports of possible LEF-induced
acute hepatic failure. The majority of these reports were highly confounded
by the concomitant use of agents known to be potential hepatotoxins, co-morbidity
affecting the liver or otherwise inadequate case information so that no conclusions
about the relationship between these reports of serious liver injury or acute
liver failure and the use of LEF could be drawn.
The FDA presentation concluded
that the incidence of elevated liver function tests is in the range of 2-4%
but serious hepatotoxicity, such as hepatocellular jaundice and acute liver
failure, is rare based on:
- The small number of post-marketing
reports of acute liver failure
- The absence of acute
liver failure as well as a less severe degree of acute liver injury, (hepatocellular
necrosis with jaundice) in a database of over 13,000 subjects
- Data suggesting that
hospitalization for drug-induced liver injury may occur with a frequency of
well under 0.02%
- Review of the FDA Medwatch
database showing that the reporting rate for acute liver failure and fatal
hepatotoxicity associated with LEF is well below that for previously identified
drugs with serious hepatotoxicity such as INH, valproate, trovafloxacin bromfenac
The committee unanimously
voted to recommend that LEF remain on the market and commented that it continued
to represent a valuable therapeutic in the armamentarium for the treatment of
In addition, the committee
received data supporting the efficacy of LEF for the improvement of physical
function. Such data, based on assessments using the Health Assessment Questionnaire,
reflect symptomatic improvement. The committee voted to recommend that labeling
be updated to include information on the demonstrated improvement in physical
The FDA will review these
nonbinding recommendations forwarded by the Arthritis Advisory Committee.
The Bottom Line:
While elevations in liver
function tests are seen in 2-4% of LEF treated patients, serious hepatotoxicity
is extremely rare.
- The Arthritis Advisory
Committee of the FDA recommends that LEF remain on the market.
- LEF should receive additional
labeling for improvement in physical function in patients with RA.
Authors: Larry Goldkind,
MD, Lee S. Simon, MD
Editors: Arthur Kavanaugh, MD, Eric Matteson, MD, John J. Cush, MD
Drs. Goldkind and Simon
are in the Division of Analgesic, Anti-inflammatory, and Ophthalmologic drug
products of the Food and Drug Administration. Drs. Cush, Kavanaugh and Matteson
have performed clinical research studies for and/or served as consultants to
Aventis. Dr. Cush is a member of the FDA Arthritis Advisory Committee.
Hotline is provided by the
ACR Communications and Marketing Committee as a service to members. This Hotline
reflects the views of the authors, and does not represent a position statement
of the College.
© 2003 American
College of Rheumatology
Previous | Index | Next