Eli Lilly and Company would like to inform you of new safety information regarding
hepatotoxicity with Cymbalta® (duloxetine hydrochloride). This information comes
from postmarketing reports of hepatic injury (including hepatitis and cholestatic jaundice).
Some of these reports indicate that patients with preexisting liver disease who take
duloxetine may have an increased risk for further liver damage. The new labeling
extends the Precaution against using Cymbalta in patients with substantial alcohol use to
include those patients with chronic liver disease.
The following is updated language in the PRECAUTIONS of the Cymbalta package
insert, and will be reflected in other materials. The language that has been added is
underlined. Language that was deleted is shown in strikethrough.
Hepatotoxicity - Cymbalta increases the risk of elevation of serum transaminase
levels. Liver transaminase elevations resulted in the discontinuation of 0.4% (31/8454) of
Cymbalta-treated patients. In these patients, the median time to detection of the
transaminase elevation was about
two months. In controlled trials in MDD, elevations of
alanine transaminase (ALT) to >3 times the upper limit of normal occurred in
0.9% (8/930) of Cymbalta-treated patients and in 0.3% (2/652) of placebo-treated
patients. In controlled trials in DPN, elevations of ALT to >3 times the upper limit of
normal occurred in 1.68% (8/477) of Cymbalta-treated patients and in 0% (0/187) of
placebo-treated patients. In the full cohort of placebo-controlled trials in any indication,
1% (39/3732) of Cymbalta-treated patients had a >3 times the upper limit of normal
elevation of ALT compared to 0.2% (6/2568) of placebo-treated patients. In
placebo-controlled studies using a fixed-dose design, there was evidence of a
dose-response relationship for ALT and AST elevation of >3 times the upper limit of
normal and >5 times the upper limit of normal, respectively. Postmarketing reports have
described cases of hepatitis with abdominal pain, hepatomegaly and elevation of
transaminase levels to more than twenty times the upper limit of normal with or without
jaundice, reflecting a mixed or hepatocellular pattern of liver injury. Cases of cholestatic
jaundice with minimal elevation of transaminase levels have also been reported.
The combination of transaminase elevations and elevated bilirubin, without evidence of
obstruction, is generally recognized as an important predictor of severe liver injury. In
clinical trials, three Cymbalta patients had elevations of transaminases and bilirubin, but
also had elevation of alkaline phosphatase, suggesting an obstructive process; in these
patients, there was evidence of heavy alcohol use and this may have contributed to the
abnormalities seen. Two placebo-treated patients also had transaminase elevations with
elevated bilirubin. Severe elevations of li':er enzymes (> 10 times the upper limit of
normal) or liver injury '.'/ith a cholestatic or mixed pattern have been rarely reported, iFl
some cases associated '.'lith excessi':e alcohol use. Postmarketing reports indicate that
elevated transaminases, bilirubin and alkaline phosphatase have occurred in patients with
chronic liver disease or cirrhosis. Because it is possible that duloxetine and alcohol may
interact to cause liver injury or that duloxetine may aggravate pre-existing liver disease,
Cymbalta should ordinarily not be prescribed to patients with substantial alcohol use or
evidence of chronic liver disease.
Prior to approval, and as described in PRECAUTIONS of the previous package insert, it
was known that use of duloxetine was associated with mild to moderate and usually
transient elevation of hepatic enzymes that infrequently led to Cymbalta discontinuation.
In addition, some cases of severe hepatic injury in patients consuming large quantities of
alcohol were observed during duloxetine clinical trials, as is described in the original
Since approval on August 3,2004, approximately one million patients have taken
duloxetine. Among these, several cases of hepatic injury have been spontaneously
reported. Some of these patients had underlying liver disease. Review of these cases
suggests that patients with underlying chronic liver disease may be at increased risk of
hepatotoxicity with duloxetine. In addition to hepatocellular and mixed liver injury,
cases of cholestatic jaundice have been reported.Patients and prescribers should be aware of the signs and symptoms of liver damage
(pruritus, dark urine, jaundice, right upper quadrant tenderness, or unexplained "flu-like"
symptoms) and health care professionals are encouraged to investigate such symptoms
and signs promptly.
Should you have any questions or concerns regarding this important safety information,
please contact your Eli Lilly and Company sales representative or contact the Lilly
medical department at 1-800-Lilly-Rx. Please refer to the full prescribing information for
Cymbalta included with this letter. As always, we request that serious adverse events be
reported to Lilly at 1-800-Lilly-Rx or to the FDA MedWatch program by phone (1-800-
FDA-1088), by fax (1-800-FDA-0178) or by email (www.fda.gov/medwatch
G?3' ~ Paul Eisenberg, MD
Vice-President, Global Product Safety
Eli Lilly and Company