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FDA Drug Safety Podcast for Healthcare Professionals: New boxed warning for severe liver injury with arthritis drug Arava (leflunomide)

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Welcome, my name is Catherine Chew, a pharmacist in the Division of Drug Information. I am updating you about a new boxed warning for severe liver injury with the arthritis drug Arava (leflunomide).

FDA is adding information on severe liver injury to the Boxed Warning of leflunomide 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, such as ALT greater than two times the upper limit of normal, should also not receive leflunomide.
  • Caution should be used in patients who are taking other drugs that 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, 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 normal range.

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.
 

At this time, FDA recommends that Healthcare Professionals be aware that:

1. Cases of severe liver injury, including fatal liver failure, have been reported in patients using leflunomide.

2. Only patients for whom the anticipated therapeutic benefit is expected to outweigh the risk of severe liver injury should be considered for leflunomide treatment.

3. Patients with pre-existing liver disease, such as 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.

4. Caution should be used when leflunomide is given with other drugs that have the potential to cause liver injury.

5. ALT levels should be monitored at least monthly for three months after starting leflunomide and at least quarterly thereafter.

6. 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.

7. Adverse events involving leflunomide can be reported to the FDA MedWatch program at www.fda.gov/medwatch.

 
Thank you for listening. The FDA is committed to keeping healthcare professionals informed of the latest safety information. If you have questions about this safety communication, you can reach us at the following email address: druginfo@fda.hhs.gov.
 

 

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