FDA Adds Boxed Warning to Ocaliva to Reinforce Correct Dosing

Megan Brooks


February 01, 2018

The US Food and Drug Administration (FDA) has added a boxed warning and dosing table to the label of the liver disease drug obeticholic acid (Ocaliva, Intercept Pharmaceuticals) to reinforce appropriate dosing.

The action follows reports that obeticholic acid has been incorrectly dosed daily instead of weekly in patients with moderate to severe primary biliary cholangitis (PBC), increasing the risk for serious liver injury.

Ocaliva is being given to patients with PBC "more often than is recommended in the prescribing information, resulting in liver decompensation, liver failure, and sometimes death," the FDA said in a safety communication.

"To ensure correct dosing and reduce the risk of liver problems, FDA is clarifying the current recommendations for screening, dosing, monitoring, and managing PBC patients with moderate to severe liver disease taking Ocaliva," the agency said. 

In addition to the boxed warning and dosing table, the FDA is also requiring a medication guide for patients to inform them about this issue.

The FDA approved obeticholic acid in May 2016 for the treatment of PBC in combination with ursodeoxycholic acid (UDCA) in adults with an inadequate response to UDCA, or as monotherapy in adults unable to tolerate UDCA. PBC is a rare, progressive autoimmune disease that puts patients at risk for liver failure and death.

In September 2017, the FDA warned clinicians of an increased risk for serious liver injury or death with excessive doses of obeticholic acid.

The recommended starting dose for obeticholic acid is 5 mg daily, according to the FDA-approved label. The maximum dose is 10 mg daily. However, for patients with moderate or severe liver impairment, the recommended starting dose is 5 mg per week instead of 5 mg per day, and the dose should not exceed 10 mg twice a week. However, the FDA has found that some clinicians are prescribing 5 mg of obeticholic acid per day right off the bat for patients with moderate or severe liver impairment.

"Following extensive review of postmarketing data, we remain confident in Ocaliva's safety profile and the benefit it provides when used as directed in patients with PBC," Mark Pruzanski, MD, president and CEO of Intercept, said in statement issued today. "The focus of our label update is to aid physicians in identifying and appropriately dosing Ocaliva in the most vulnerable PBC patients with advanced cirrhosis."

FDA Advice to Clinicians

  • Follow the obeticholic acid dosing regimen in the drug label, which is based on calculating a Child-Pugh score in patients with PBC who are suspected of having  liver cirrhosis before treatment to determine their specific classification and starting dosage.

  • Routinely monitor all patients for biochemical response, tolerability, and PBC progression and re-evaluate Child-Pugh classification to determine whether dosage adjustment is needed.

  • Closely monitor patients at an increased risk for liver decompensation, including those with laboratory evidence of worsening liver function (eg, total bilirubin, international normalized ratio, albumin) or progression to cirrhosis.

  • Educate patients and caregivers on the symptoms of worsening liver function.

  • Temporarily stop obeticholic acid in patients with laboratory or clinical evidence of worsening liver function, which may indicate decompensation, and monitor the patient's liver function.

  • If a patient's condition returns to baseline, weigh the potential risks and benefits of restarting obeticholic acid. When restarting the drug, use the recommended starting dosage based on Child-Pugh classification.

  • Consider stopping obeticholic acid in patients who have experienced clinically significant liver-related adverse reactions.

To report any problems with obeticholic acid, contact MedWatch, the FDA's safety information and adverse event reporting program, by telephone at 1-800-FDA-1088; by fax at 1-800-FDA-0178; online at https://www.accessdata.fda.gov/scripts/medwatch/medwatch-online.htm; with postage-paid FDA form 3500, available at https://www.fda.gov/MedWatch/getforms.htm; or by mail to MedWatch, 5600 Fishers Lane, Rockville, Maryland 20852-9787.

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