HIV/AIDS Update - Videx EC/Videx (didanosine) label change reflects potential for serious liver disorder

HIV/AIDS Update - Videx EC/Videx (didanosine) label change reflects potential for serious liver disorder

The Food and Drug Administration (FDA) is alerting healthcare professionals and patients about a rare, but serious, complication in the liver known as non-cirrhotic portal hypertension in patients using Videx or Videx EC (didanosine). Didanosine is a medication used to treat human immunodeficiency virus (HIV) infection.

Non-cirrhotic portal hypertension (portal hypertension that is not caused by cirrhosis of the liver) is rare in the United States. It occurs when blood flow in the major vein in the liver (the portal vein) slows down. This slowed blood flow can lead to the development of severely enlarged esophageal veins (varices) in the gastrointestinal system. Because esophageal varices are thin and portal hypertension increases the pressure of blood flow in these veins, esophageal varices can break open. This can result in serious bleeding and, in some cases, death.

FDA became aware of cases of non-cirrhotic portal hypertension through adverse event reports submitted to FDA's Adverse Event Reporting System (AERS). Based on these reports, FDA has revised the didanosine drug label to include information about non-cirrhotic portal hypertension to help ensure the safe use of this drug.

FDA believes the clinical benefits of didanosine for certain patients with HIV continue to outweigh its potential risks. The decision to use this drug, however, must be made on an individual basis between the treating physician and the patient.

Additional Information for Patients
Didanosine is a prescription medication used along with other drugs to treat patients who are infected with HIV, the virus that causes AIDS.
Didanosine works by reducing the growth of HIV.It belongs to a class of medications called nucleoside analogues.
Didanosine helps your body maintain its supply of immune cells called CD4 cells. These cells are important for fighting HIV and other infections.
Non-cirrhotic portal hypertension is a serious, but rare, side effect that has occurred in patients using didanosine.

Additional Information for Healthcare Professionals
Be aware that didanosine use has been associated with the development of non-cirrhotic portal hypertension.
Discuss with patients the clinical benefits and potential risks, including the risk of non-cirrhotic portal hypertension, with the use of didanosine.
Continue to monitor patients for the development of portal hypertension and esophageal varices.
Be aware that didanosine already has a Boxed Warning for lactic acidosis and hepatomegaly with steatosis.
Didanosine in combination with other antiretroviral agents as well as hydroxyurea or ribavirin has been associated with the development of liver toxicity.

Data Summary
FDA's decision to revise the drug label for didanosine is based on post-marketing reports of patients developing non-cirrhotic portal hypertension while using didanosine. Other liver adverse events such as lactic acidosis, hepatomegaly with steatosis, and liver failure have been reported with the use of didanosine alone and in combination with other antiviral drugs.
Of the 42 post-marketing cases of non-cirrhotic portal hypertension in patients using didanosine:
Twenty-six were males, 14 were females, and in two no gender was specified.
The ages ranged from 10 years to 66 years.
Duration of didanosine treatment ranged from months to years before development of non-cirrhotic portal hypertension.
Definitive cases of non-cirrhotic portal hypertension were confirmed by biopsy and had no alternative etiology for the diagnosis.
Medical interventions described in the reported cases included:
Banding/ligation of esophageal varices in 8 patients.
Transjugular intrahepatic portosystemic shunt (TIPSS) procedure in three patients.
Liver transplantation in 3 patients.
There were four deaths total in the 42 reported cases. The cause of death in the four patients was due to:
Hemorrhage from esophageal varices in two patients.
Progressive liver failure in one patient.
A combination of multi-organ failure, cerebral hemorrhage, sepsis, and lactic acidosis in one patient.

The only patients who have been reported as fully recovered are the three non-cirrhotic portal hypertension patients who received a liver transplant.

A causal association is difficult to determine from postmarketing reports alone. However, based on the number of well-documented cases and exclusion of other causes of portal hypertension such as alcohol-related cirrhosis or hepatitis C, FDA concludes there is an association between use of didanosine and development of non-cirrhotic portal hypertension. Because of the potential severity of portal hypertension, including death from hemorrhaging esophageal varices, FDA has revised the Warning and Precautions section of the didanosine drug label to assure safe use of the medication.

The Videx EC and Videx Pediatric Powder for Oral Solution were revised as follows:
In Highlights section of the package insert under Warnings and Precautions, the following was added:

Non-cirrhotic portal hypertension: Discontinue didanosine in patients with evidence of non-cirrhotic portal hypertension

In section 5 Warnings and Precautions the following new subsection was added:
5.4 Non-cirrhotic Portal Hypertension

Postmarketing cases of non-cirrhotic portal hypertension have been reported, including cases leading to liver transplantation or death. Cases of didanosine-associated non-cirrhotic portal hypertension were confirmed by liver biopsy in patients with no evidence of viral hepatitis. Onset of signs and symptoms ranged from months to years after start of didanosine therapy. Common presenting features included elevated liver enzymes, esophageal varices, hematemesis, ascites, and splenomegaly. Patients receiving Videx should be monitored for early signs of portal hypertension (eg. Thrombocytopenia and splenomegaly) during routine medical visits. Appropriate laboratory testing including liver enzymes, serum bilirubin, albumin, complete blood count, and international normalized ratio (INR) and ultrasonography should be considered. Videx should be discontinued in patients with evidence of non-cirrhotic portal hypertension

In section 17 Patient Counseling Information the following was added:
17.5 Non-cirrhotic Portal Hypertension
Patients should be informed that non-cirrhotic portal hypertension has been reported in patients taking Videx, including cases leading to liver transplantation or death.
Videx and VidexEC are Nucleoside Reverse Transcriptase Inhibitors (NRTIs), products of Bristol Myers-Squibb.

Richard Klein
Office of Special Health Issues
Food and Drug Administration
Kimberly Struble
Division of Antiviral Drug Products
Food and Drug Administration