Incorrect Dosing of Obeticholic Acid (OCALIVA) Could Be Fatal, FDA Warns

On Sept. 21, 2017, the Food and Drug Administration (FDA) warned that for some patients with moderate-to-severe decreases in liver function, taking a higherthan- approved dose of obeticholic acid (OCALIVA) may result in an increased risk of serious liver injury and death.[1] The drug was approved by the FDA in May 2016 as a second-line treatment of the liver disease primary biliary cholangitis (previously known as primary biliary cirrhosis).[2] To avoid serious harm, the FDA-approved dosage of obeticholic acid must not be exceeded.

Overview of primary biliary cholangitis

Primary biliary cholangitis is a rare, chronic liver disease that results from the gradual destruction of the small bile ducts in the liver.[3] Bile normally is produced by liver cells and travels via these bile ducts to the gallbladder, where it is stored between meals, and then to the small intestines, where it helps to digest fatty foods and absorb fat-soluble vitamins (A, D, E and K). When the bile ducts are destroyed, excess bile collects in the liver, causing inflammation and scarring. Progressive scarring of the liver can lead to cirrhosis and, eventually, liver failure.

Most patients with primary biliary cholangitis (90 to 95 percent) are women, and most are diagnosed during their 30s to 60s.[4] The cause of the disease is unknown, but it appears to involve the immune system attacking the bile ducts within the liver.[5]

Approximately 50 to 60 percent of patients with primary biliary cholangitis have no symptoms when they are first diagnosed with the disease. For patients who do have symptoms, fatigue and itching are the most common initial symptoms.[6]

The first-line drug for treating primary biliary cholangitis is ursodiol (URSO 250, URSO FORTE). The drug has been shown to delay the progression of the liver disease and to improve survival.[7]

Obeticholic acid should be reserved for patients who do not respond adequately to ursodiol alone or who do not tolerate ursodiol.[8] Unlike ursodiol, obeticholic acid has not been shown to improve survival or symptoms of primary biliary cholangitis. It received accelerated FDA approval based only on clinical trials that showed that the drug improves results of a blood test used to measure liver damage.

The FDA-approved starting dose of obeticholic acid is 5 milligrams (mg) once daily in patients with normal or mildly decreased liver function. The maximum dose in such patients is 10 mg daily. In patients with moderately or severely decreased liver function, however, the approved starting dose is 5 mg once weekly, which can be increased, over time, to a maximum dose of 10 mg twice weekly.

The FDA warning

The FDA based its September 2017 warning on reports of serious liver injury and death in patients with moderate or severe decreases in liver function who were incorrectly given obeticholic acid at a dose of 5 mg once daily, well above the approved maximum dose for such patients of 10 mg twice weekly.[9]

The agency therefore recommended that doctors check the liver function of all patients before starting treatment with obeticholic acid, and “frequently” thereafter, and follow the approved dosing regimen based on patients’ liver function.

Of note, the lower dosing regimen for patients with moderately or severely reduced liver function already was in the drug’s FDA-approved label and should have been followed by the affected patients’ doctors. It is therefore questionable whether the FDA’s safety communication on its own will result in safer prescribing without further actions by the agency, such as a monitored prescribing program.

It also should be noted that five cases of reported serious liver injury associated with obeticholic acid use occurred in patients with no or only mild decreases in liver function prior to starting the drug and who were given the FDA-approved dose of 5 mg once daily. At least two of these patients experienced improvement upon stopping the drug. Although it is difficult to determine whether obeticholic acid was, in fact, responsible for these patients’ liver injuries, such reports raise concern that obeticholic acid, even at the FDA-approved dose, may cause serious liver injury in patients without a history of significantly impaired liver function.

What You Can Do

If you have primary biliary cholangitis and do not respond adequately to ursodiol alone or do not tolerate ursodiol, your doctor should test your liver function before you start taking obeticholic acid and frequently thereafter. In addition, you should be alert for symptoms of possible liver toxicity even if you have normal or mildly decreased liver function.

Contact your doctor if you experience new or worsening skin itching while using obeticholic acid. You also should contact your health care provider immediately if you experience any of the following symptoms:

• New or worsening fatigue
• Diarrhea
• Weight loss
• Abdominal pain
• Decreased appetite
• Nausea and vomiting
• Change in behavior or confusion
• Vague symptoms such as anxiety or unease
• Abdominal swelling
• Yellow eyes or skin
• Bloody stools

References

[1] Food and Drug Administration. FDA drug safety communication: FDA warns about serious liver injury with Ocaliva (obeticholic acid) for rare chronic liver disease. September 21, 2017. https://www.fda.gov/Drugs/DrugSafety/ucm576656.htm. Accessed November 13, 2017.

[2] Intercept Pharmaceuticals. Label: obeticholic acid (OCALIVA). May 2017. https://dailymed.nlm.nih.gov/dailymed/getFile.cfm?setid=cdfbe0cd-eb15-45a1-ac17-531bcda21aec&type=pdf&name=cdfbe0cd-eb15-45a1-ac17-531bcda21aec. Accessed November 13, 2017.

[3] American Liver Foundation. Primary Biliary Cholangitis (PBC, previously Primary Biliary Cirrhosis). September 9, 2017. http://www.liverfoundation.org/abouttheliver/info/pbc/. Accessed November 13, 2017.

[4] Poupon R. Clinical manifestations, diagnosis, and prognosis of primary biliary cholangitis (primary biliary cirrhosis). Updated January 11, 2017. UpToDate. https://www.uptodate.com/contents/clinical-manifestations-diagnosis-and-prognosis-of-primary-biliary-cholangitis-primary-biliary-cirrhosis. Accessed November 13, 2017.

[5] Ibid.

[6] Ibid.

[7] Poupon R. Overview of the treatment of primary biliary cholangitis (primary biliary cirrhosis). Updated October 19, 2016. UpToDate. https://www.uptodate.com/contents/overview-of-the-treatment-of-primary-biliary-cholangitis-primary-biliary-cirrhosis. Accessed November 13, 2017.

[8] Intercept Pharmaceuticals. Label: obeticholic acid (OCALIVA). May 2017. https://dailymed.nlm.nih.gov/dailymed/getFile.cfm?setid=cdfbe0cd-eb15-45a1-ac17-531bcda21aec&type=pdf&name=cdfbe0cd-eb15-45a1-ac17-531bcda21aec. Accessed November 13, 2017.

[9] Food and Drug Administration. FDA drug safety communication: FDA warns about serious liver injury with Ocaliva (obeticholic acid) for rare chronic liver disease. November 13, 2017. https://www.fda.gov/Drugs/DrugSafety/ucm576656.htm. Accessed November 13, 2017.