FDA Drug Safety Communication: New boxed warning for severe liver injury with arthritis drug Arava (leflunomide)
Safety Announcement [07-13-2010]
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 leflunomide.
- Patients with elevated liver enzymes (ALT greater than two times the upper limit of normal) should not receive leflunomide.
- 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 thereafter.
- If the ALT rises to greater than two times the upper limit of normal while the patient is on leflunomide – leflunomide should be stopped, cholestyramine 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 normal range.
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.
The decision 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 Data Summary
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 injury.
- 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 leflunomide.
- 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 leflunomide.
- 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, cholestyramine 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.