Obeticholic acid FDA Alerts

Drug Safety Communication: Ocaliva (obeticholic acid) - Serious Liver Injury Being Observed in Patients without Cirrhosis

ISSUE: The FDA identified cases of serious liver injury among patients being treated for primary biliary cholangitis (PBC) with Ocaliva (obeticholic acid) who did not have cirrhosis of the liver. 

The original clinical trial showed a decrease in alkaline phosphatase (ALP) that supported FDA accelerated approval. FDA required the additional postmarket clinical trial to verify the clinical benefit of Ocaliva. FDA evaluated liver safety in the postmarket clinical trial in patients who were appropriate for Ocaliva treatment based on the approved indication in the prescribing information. Among these patients, the risk of both liver transplant and death were higher in patients receiving Ocaliva compared with those receiving placebo. Specifically, among patients for whom Ocaliva was indicated, which were those with a lower risk of progression to liver transplant or death, 7 of 81 who received Ocaliva needed a liver transplant compared to 1 of 68 patients who received placebo. (Note: The liver transplant case in the placebo group occurred after the patient switched to commercially available Ocaliva and was dosed with Ocaliva for two years prior to liver transplant; this case may also be related to Ocaliva treatment.) An additional four patients receiving Ocaliva died, compared to one receiving placebo. Analyses evaluating the risk of liver transplant and death resulted in a hazard ratio of 4.77 (95% confidence interval: 1.03, 22.09) for patients without advanced cirrhosis and not contraindicated from receiving the drug.

FDA is notifying health care professionals and patients of this new safety information, and that frequent liver test monitoring is necessary to identify worsening liver function and ensure appropriate discontinuation of Ocaliva. FDA will continue to monitor the medicine’s safety and will follow up if additional information becomes available.

BACKGROUND: Ocaliva is a prescription medicine approved in May 2016 that has been shown to improve a certain liver test called ALP in patients with PBC who have not responded well enough to another medicine called ursodeoxycholic acid. 

The FDA previously communicated about the risk of serious liver injury associated with Ocaliva in May 2021 (restriction of Ocaliva use in PBC patients with advanced cirrhosis). Additional communications about related safety issues for Ocaliva occurred in February 2018 (addition of Boxed Warning to highlight correct dosing of Ocaliva) and September 2017 (warning about serious liver injury with incorrect dosing).

RECOMMENDATIONS: 

Health Care Professionals:

• Should monitor liver tests frequently in patients being treated with Ocaliva to detect and address worsening liver function early. Based on the current data, it is not clear if this monitoring will be sufficient to address the risk of serious liver injury.

• Discontinue Ocaliva treatment with any evidence of liver disease progression or if efficacy is not established.

• Explain the signs and symptoms of worsening liver injury to patients receiving Ocaliva and direct them to contact you immediately if they develop any signs or symptoms of worsening liver injury.

Patients:

• Should talk to your health care professional about this safety risk and the benefits of continuing treatment with Ocaliva.

• Discuss any concerns you may have, including about possible alternative treatments. Contact your health care professional immediately if you develop any symptoms, which may indicate worsening liver injury.

• Contact your health care professional immediately if you develop any of the following symptoms which may indicate worsening liver injury.
  
  Any of these specific symptoms

  • Swollen belly

  • Yellow eyes or skin

  • Bloody or black stools

  • Coughing up or vomiting blood

  • Mental status changes such as confusion, slurred speech, mood swings, changes in personality, or increased sleepiness or difficulty waking up

Any of these general symptoms if they are severe or do not go away after a few days

• • Belly pain

  • Nausea, vomiting, or diarrhea

  • Loss of appetite or weight loss

  • New or worsening tiredness

  • Weakness

  • Fever and chills

  • Lightheadedness

  • Less frequent urination

Health care professionals and patients are encouraged to report adverse events or side effects related to the use of these products to the FDA's MedWatch Safety Information and Adverse Event Reporting Program:

• Complete and submit the report online.
• Download form or call 1-800-332-1088 to request a reporting form, then complete and return to the address on form, or submit by fax to 1-800-FDA-0178.

Source: FDA

FDA Restricts Use of Ocaliva (obeticholic acid) in Primary Biliary Cholangitis Patients with Advanced Cirrhosis Due to Risk of Serious Liver Injury

ISSUE: The FDA is restricting the use of the liver disease medicine Ocaliva (obeticholic acid) in patients having primary biliary cholangitis (PBC) with advanced cirrhosis of the liver because it can cause serious harm. Some PBC patients with cirrhosis who took Ocaliva, especially those with evidence of advanced cirrhosis, developed liver failure, sometimes requiring liver transplant. In the five years since Ocaliva’s accelerated approval, FDA identified 25 cases of serious liver injury leading to liver decompensation or liver failure associated with Ocaliva in PBC patients with cirrhosis, both in those without clinical signs of cirrhosis (compensated) or in those with clinical signs of cirrhosis (decompensated). Many of these PBC patients had advanced cirrhosis before starting Ocaliva.

FDA added a new Contraindication, FDA’s strongest warning, to the Ocaliva prescribing information and patient Medication Guide stating that Ocaliva should not be used in PBC patients with advanced cirrhosis. FDA also revised the Boxed Warning, our most prominent warning, to include this information along with related warnings about this risk.

Based on the original clinical trials, FDA believes the benefits of Ocaliva outweigh the risks for PBC patients who do not have advanced cirrhosis. FDA will continue to monitor and evaluate the clinical benefit and adverse events of Ocaliva and will communicate any new information to the public if it becomes available.

BACKGROUND: PBC is a rare, chronic disease affecting the ducts in the liver that carry bile, which helps with digestion.

RECOMMENDATIONS:

Patients:

• Patients with PBC who have cirrhosis and are taking Ocaliva should talk to your health care professional about these new warnings. Contact your prescriber immediately if you develop any symptoms, which may be signs of worsening liver injury or development of advanced cirrhosis.

Health Care Professionals:

• Health care professionals should determine before starting Ocaliva whether a patient with PBC has advanced cirrhosis as the medicine is contraindicated in these patients. Advanced cirrhosis is defined as cirrhosis with current or prior evidence of hepatic decompensation (e.g., encephalopathy, coagulopathy) or portal hypertension (e.g., ascites, gastroesophageal varices, persistent thrombocytopenia).
• Routinely monitor patients during Ocaliva treatment for progression of PBC with laboratory and clinical assessments to determine whether the medicine needs to be discontinued. Permanently discontinue Ocaliva in patients with cirrhosis who progress to advanced cirrhosis.
• Also monitor patients for clinically significant liver-related adverse reactions that may manifest as development of acute-on-chronic liver disease with nausea, vomiting, diarrhea, jaundice, scleral icterus, and/or dark urine. Permanently discontinue Ocaliva in patients developing these symptoms.

Health care professionals and patients are encouraged to report adverse events or side effects related to the use of these products to the FDA's MedWatch Safety Information and Adverse Event Reporting Program:

• Complete and submit the report online.

• Download form or call 1-800-332-1088 to request a reporting form, then complete and return to the address on form, or submit by fax to 1-800-FDA-0178.

[05/26/2021 - Drug Safety Communication - FDA] 

[02/01/2018 - Drug Safety Communication - FDA]

[09/21/2017 - Drug Safety Communication - FDA]

Drug Safety Communication: Ocaliva (obeticholic acid) - Boxed Warning Added To Highlight Correct Dosing

ISSUE: FDA is warning that the liver disease medicine Ocaliva (obeticholic acid) has been incorrectly dosed daily instead of weekly in patients with moderate to severe primary biliary cholangitis (PBC), a rare chronic liver disease, increasing the risk of serious liver injury. 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. FDA is adding a new Boxed Warning, FDA’s most prominent warning, to highlight this information in the prescribing information of the drug label. FDA is also requiring a Medication Guide for patients to inform them about this issue.

As a condition of approval, FDA required the manufacturer of Ocaliva, Intercept Pharmaceuticals, to continue studying the medicine in patients with advanced PBC. These clinical trials are currently ongoing and FDA expects to receive results in 2023. FDA is adding the additional warnings to the drug label after receiving reports that Ocaliva is being given to PBC patients with moderate to severe liver impairment more often than is recommended in the prescribing information, resulting in liver decompensation, liver failure, and sometimes death. FDA will continue to monitor this medicine and will update the public if new information becomes available.

BACKGROUND: This is an update to the MedWatch safety alert for Ocaliva (obeticholic acid) - Increased Risk of Serious Liver Injury, issued 09-21-2017.

RECOMMENDATION: Health care professionals should follow the Ocaliva dosing regimen in the drug label, which is based on calculating a Child-Pugh score in PBC patients with suspected liver cirrhosis before treatment to determine their specific classification and starting dosage (see Table for the Clarified Ocaliva Dosage Regimen and more detailed instructions).  Dosing higher than recommended in the drug label can increase the risk for liver decompensation, liver failure, and sometimes death. Routinely monitor all patients for biochemical response, tolerability, and PBC progression, and re-evaluate Child-Pugh classification to determine if dosage adjustment is needed.  Close monitoring is recommended for patients at an increased risk of liver decompensation, including those with laboratory evidence of worsening liver function (e.g., total bilirubin, INR, albumin) or progression to cirrhosis.
 
Educate patients and caregivers on the symptoms of worsening liver function. Temporarily stop Ocaliva in those with laboratory or clinical evidence of worsening liver function that 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 Ocaliva. Re-initiate, using the recommended starting dosage based on Child Pugh classification.  Consider discontinuing Ocaliva in patients who have experienced clinically significant liver-related adverse reactions.
 
Patients should be aware that your prescriber should do regular tests to check how well your liver is working while you are taking Ocaliva. If your liver problems get worse, your dose may need to be changed or stopped.  Report new or worsening severe skin itching to your health care professional. See the Drug Safety Communication for additional information.

Healthcare professionals and patients are encouraged to report adverse events or side effects related to the use of these products to the FDA's MedWatch Safety Information and Adverse Event Reporting Program:

• Complete and submit the report Online: www.accessdata.fda.gov/scripts/medwatch/index.cfm
• Download form or call 1-800-332-1088 to request a reporting form, then complete and return to the address on the pre-addressed form, or submit by fax to 1-800-FDA-0178

Drug Safety Communication: Ocaliva (obeticholic acid) - Increased Risk of Serious Liver Injury

ISSUE: FDA is warning that the liver disease medicine Ocaliva (obeticholic acid) is being incorrectly dosed in some patients with moderate to severe decreases in liver function, resulting in an increased risk of serious liver injury and death. These patients are receiving excessive dosing, particularly a higher frequency of dosing than is recommended in the drug label for them. Ocaliva may also be associated with liver injury in some patients with mild disease who are receiving the correct dose. The recommended dosing and monitoring for patients on Ocaliva are described in the current drug label. FDA is working with the drug manufacturer, Intercept Pharmaceuticals, to address these safety concerns.

BACKGROUND: Ocaliva is used to treat a rare, chronic liver disease known as primary biliary cholangitis (PBC). PBC causes the bile ducts in the liver to become inflamed, damaged and destroyed. This causes bile, a fluid that helps in digestion, to build up in the liver. This build-up damages the liver over time, eventually causing it to lose its ability to function. Ocaliva has been shown to improve a certain blood test that measures liver problems.

RECOMMENDATIONS:

Health care professionals

• Determine the patient’s baseline liver function prior to starting Ocaliva.
• Patients with moderate to severe liver impairment (Child-Pugh B and C) should be started on the approved dosing schedule of 5 mg once weekly, rather than the 5 mg daily dosing used for other PBC patients, and if needed, can be increased up to a maximum approved dose of 10 mg twice weekly.
• Health care professionals should monitor patients frequently for disease progression, and reduce the dosing frequency to once- or twice-weekly for patients who progress to moderate or severe liver impairment.
• In all patients treated with Ocaliva, monitor frequently for liver injury (e.g., worsened liver blood tests and adverse liver-related reactions that may be inconsistent with the patient’s extent of disease). If liver injury is suspected, discontinue Ocaliva. After the patient has stabilized, weigh the benefits against the risks when deciding whether to re-initiate treatment.
• Educate patients on the symptoms of potential liver injury.

Patients

• Contact your health care professional if you have questions or concerns about taking Ocaliva.
• Report new or worsening severe skin itching to your health care professional.
• Contact your health care professional immediately if you develop any of the following symptoms that may be signs of liver injury:
  • 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

Healthcare professionals and patients are encouraged to report adverse events or side effects related to the use of these products to the FDA's MedWatch Safety Information and Adverse Event Reporting Program:

• Complete and submit the report Online: www.accessdata.fda.gov/scripts/medwatch/index.cfm
• Download form or call 1-800-332-1088 to request a reporting form, then complete and return to the address on the pre-addressed form, or submit by fax to 1-800-FDA-0178

[09/21/2017 - Drug Safety Communication - FDA]