FDA Drug Safety Communication: New Boxed Warning for Severe Liver Injury with Arthritis Drug Arava (leflunomide)
The U.S. Food and Drug Administration (FDA) is
adding information on severe liver injury to the Boxed Warning of
Arava (leflunomide) – a drug used to treat rheumatoid
arthritis - to highlight the risk of severe liver injury in
patients using this drug and how this risk may be reduced. FDA
previously required a Boxed Warning stating that leflunomide was
contraindicated in pregnant women, or women of childbearing
potential who were not using reliable contraception.
The information on severe liver
injury now being added to the Boxed Warning states:
- Patients with pre-existing liver disease should not receive
- Patients with elevated liver enzymes (ALT greater than two
times the upper limit of normal) should not receive
- Caution should be used in patients who are taking other drugs
that can cause liver injury.
- Liver enzymes should be monitored at least monthly for three
months after starting leflunomide and at least quarterly
- If the ALT rises to greater than two times the upper limit of
normal while the patient is on leflunomide – leflunomide
should be stopped, cholestryamine washout begun to speed the
removal of leflunomide from the body and follow-up liver function
tests conducted at least weekly until the ALT value is within
Although a bolded warning statement
on severe liver injury was added to the leflunomide drug label in
2003, FDA determined that information on severe liver injury should
be included in the Boxed Warning to highlight the importance of
appropriate patient selection before starting treatment, and
monitoring once treatment has begun.
to add information on severe liver injury to the Boxed Warning was
based on FDA’s 2010 review of adverse event reports which
identified 49 cases of severe liver injury, including 14 cases of
fatal liver failure, between August 2002 and May 2009. In this
review, the greatest risk for liver injury was seen in patients
taking other drugs known to cause liver injury, and patients with
pre-existing liver disease (see
should know that severe liver injury is a rare, but
serious side effect of this drug. Patients who experience itching,
yellow eyes or skin, dark urine, loss of appetite, or light-colored
stools should contact their healthcare professional right
away—these may be signs of severe liver injury (see
Additional Information for Patients
- Be aware that cases of severe liver
injury have been reported in people taking leflunomide.
- Contact your healthcare professional
if you develop itching, yellow eyes or skin, dark urine, loss of
appetite, or light-colored stools. These may be signs of liver
- Talk to your healthcare professional
about any concerns you have with this medication.
- Report any side effects with
leflunomide to FDA’s MedWatch program using the information
at the bottom of the page in the “Contact Us” box.
- Cases of severe liver injury,
including fatal liver failure, have been reported in patients using
- Only patients for whom the anticipated
therapeutic benefit is expected to outweigh the risk of severe
liver injury should be considered for leflunomide treatment.
- Patients with pre-existing liver
disease (acute or chronic infection with hepatitis B or C virus),
or those with serum ALT greater than 2 times the upper limit of
normal before initiating treatment, should not be treated with
- Caution should be used when
leflunomide is given with other drugs that have the potential to
cause liver injury.
- ALT levels should be monitored at
least monthly for three months after starting leflunomide and at
least quarterly thereafter.
- If the ALT rises to greater than 2 x
the upper limit of normal while the patient is being treated with
leflunomide – leflunomide should be stopped, cholestryamine
washout begun, and follow-up liver function tests conducted at
least weekly until normalization.
In 2003, a bolded warning statement
about the risk of severe liver injury and a recommendation to
monitor liver function tests every 6 to 8 weeks were included in
the professional prescribing information for leflunomide. In 2009,
based on continued reports of severe liver injury, FDA conducted an
updated review of severe liver injury and leflunomide and
identified 49 cases, 36 which required hospitalization, reported
between August 2002 and May 2009.
The estimated duration of leflunomide
treatment before the occurrence of severe liver injury ranged from
9 days to 6 years, with the majority of patients developing severe
liver injury within the first 6 to 12 months of treatment.
Of the 49 cases, there were 14
deaths. An additional five patients required a liver transplant and
nine patients experienced a life-threatening event. Twenty-three
reports described jaundice at the time of diagnosis, 11 reported
coagulopathy (clotting disorder), and five reported encephalopathy.
Other presenting symptoms in these cases included vomiting, rash
and or itching, abdominal pain, and fever. Seventeen cases reported
normal liver enzymes prior to starting leflunomide.
Forty-six of the 49 patients were
also taking other medications that have been associated with liver
injury, including methotrexate, TNF-α blockers,
hydroxychloroquine, acetaminophen, non-steroidal anti-inflammatory
drugs, and statins. In addition, 14 patients had pre-existing liver
disease such as active or chronic hepatitis, and/or a history of
alcohol abuse. Although many patients who developed severe liver
injury were also taking other drugs that can damage the liver, or
had pre-existing liver disease, FDA concluded that use of
leflunomide was associated with the development of severe liver
injury in these patients.
To highlight the importance of
appropriate patient selection and monitoring in reducing the risk
of severe liver injury, the agency decided that specific
recommendations to ensure safe use of leflunomide needed to be
added to the Boxed Warning.
Posted: July 2010