Ocaliva

OCALIVA- obeticholic acid tablet, film coated
Intercept Pharmaceuticals Inc

WARNING: HEPATIC DECOMPENSATION AND FAILURE IN PRIMARY BILIARY CHOLANGITIS PATIENTS WITH CIRRHOSIS

  • Hepatic decompensation and failure, sometimes fatal or resulting in liver transplant, have been reported with OCALIVA treatment in primary biliary cholangitis (PBC) patients with either compensated or decompensated cirrhosis [see Warnings and Precautions (5.1)].
  • OCALIVA is contraindicated in PBC patients with decompensated cirrhosis, a prior decompensation event, or with compensated cirrhosis who have evidence of portal hypertension [see Contraindications (4)].
  • Permanently discontinue OCALIVA in patients who develop laboratory or clinical evidence of hepatic decompensation; have compensated cirrhosis and develop evidence of portal hypertension; or experience clinically significant hepatic adverse reactions while on treatment [see Dosage and Administration (2.3), Warnings and Precautions (5.1)].

1 INDICATIONS AND USAGE

OCALIVA® is indicated for the treatment of adult patients with primary biliary cholangitis (PBC)

  • without cirrhosis or
  • with compensated cirrhosis who do not have evidence of portal hypertension,

either in combination with ursodeoxycholic acid (UDCA) with an inadequate response to UDCA or as monotherapy in patients unable to tolerate UDCA.

This indication is approved under accelerated approval based on a reduction in alkaline phosphatase (ALP) [see Clinical Studies (14)]. An improvement in survival or disease-related symptoms has not been established. Continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trials.

2 DOSAGE AND ADMINISTRATION

2.1 Important Dosage and Administration Instructions

Prior to the initiation of OCALIVA, healthcare providers should determine whether the patient has decompensated cirrhosis (e.g., Child-Pugh Class B or C), has had a prior decompensation event, or has compensated cirrhosis with evidence of portal hypertension (e.g., ascites, gastroesophageal varices, persistent thrombocytopenia) because OCALIVA is contraindicated in these patients [see Contraindications (4), Warnings and Precautions (5.1)].

2.2 Recommended Dosage Regimen

The recommended dosage of OCALIVA for PBC patients without cirrhosis or with compensated cirrhosis who do not have evidence of portal hypertension, who have not achieved an adequate biochemical response to an appropriate dosage of UDCA for at least 1 year or are intolerant to UDCA [see Clinical Studies (14)] follows below:

  • Start with a dosage of 5 mg once daily for the first 3 months.
  • After the first 3 months, for patients who have not achieved an adequate reduction in ALP and/or total bilirubin and who are tolerating OCALIVA, increase to a maximum dosage of 10 mg once daily.

2.3 Monitoring to Assess Safety, Need for OCALIVA Discontinuation

Routinely monitor patients during OCALIVA treatment for biochemical response, tolerability, and progression of PBC. Closely monitor patients with compensated cirrhosis, concomitant hepatic disease (e.g., autoimmune hepatitis, alcoholic liver disease), and/or severe intercurrent illness for new evidence of portal hypertension (e.g., ascites, gastroesophageal varices, persistent thrombocytopenia) or increases above the upper limit of normal in total bilirubin, direct bilirubin, or prothrombin time. Permanently discontinue OCALIVA in patients who develop laboratory or clinical evidence of hepatic decompensation, have compensated cirrhosis and develop evidence of portal hypertension, experience clinically significant hepatic adverse reactions, or develop complete biliary obstruction [see Contraindications (4), Warnings and Precautions (5.1)].

2.4 Management of Patients with Intolerable Pruritus on OCALIVA

For patients with intolerable pruritus on OCALIVA, consider one or more of the following management strategies:

  • Add an antihistamine or bile acid binding resin [see Dosage and Administration (2.5), Clinical Studies (14)].
  • Reduce the dosage of OCALIVA to:
    • 5 mg every other day, for patients intolerant to 5 mg once daily.
    • 5 mg once daily, for patients intolerant to 10 mg once daily.
  • Temporarily interrupt OCALIVA dosing for up to 2 weeks. Restart at a reduced dosage.

For patients whose dosage is reduced or interrupted, titrate the dosage based on biochemical response and tolerability [see Dosage and Administration (2.2)].

Consider discontinuing OCALIVA treatment in patients who continue to experience persistent, intolerable pruritus despite management strategies [see Warnings and Precautions (5.2)].

2.5 Administration Instructions

  • Take OCALIVA with or without food.
  • For patients taking a bile acid binding resin, take OCALIVA at least 4 hours before or 4 hours after taking the bile acid binding resin, or at as great an interval as possible [see Drug Interactions (7.1), Clinical Studies (14)].

3 DOSAGE FORMS AND STRENGTHS

OCALIVA is available as:

  • 5 mg tablet: Off white to yellow, round tablet debossed with “INT” on one side and “5” on the other side.
  • 10 mg tablet: Off white to yellow, triangular tablet debossed with “INT” on one side and “10” on the other side.

4 CONTRAINDICATIONS

OCALIVA is contraindicated in patients with:

  • decompensated cirrhosis (e.g., Child-Pugh Class B or C) or a prior decompensation event [see Warnings and Precautions (5.1)].
  • compensated cirrhosis who have evidence of portal hypertension (e.g., ascites, gastroesophageal varices, persistent thrombocytopenia) [see Warnings and Precautions (5.1)].
  • complete biliary obstruction.

5 WARNINGS AND PRECAUTIONS

5.1 Hepatic Decompensation and Failure in PBC Patients with Cirrhosis

Hepatic decompensation and failure, sometimes fatal or resulting in liver transplant, have been reported with OCALIVA treatment in PBC patients with cirrhosis, either compensated or decompensated. Among postmarketing cases reporting it, median time to hepatic decompensation (e.g., new onset ascites) was 4 months for patients with compensated cirrhosis; median time to a new decompensation event (e.g., hepatic encephalopathy) was 2.5 months for patients with decompensated cirrhosis.

Some of these cases occurred in patients with decompensated cirrhosis when they were treated with higher than the recommended dosage for that patient population; however, cases of hepatic decompensation and failure have continued to be reported in patients with decompensated cirrhosis even when they received the recommended dosage.

Hepatotoxicity was observed in the OCALIVA clinical trials. A dose-response relationship was observed for the occurrence of hepatic adverse reactions including jaundice, worsening ascites, and primary biliary cholangitis flare with dosages of OCALIVA of 10 mg once daily to 50 mg once daily (up to 5-times the highest recommended dosage), as early as one month after starting treatment with OCALIVA in two 3-month, placebo-controlled clinical trials in patients with primarily early stage PBC [see Overdosage (10)].

In a pooled analysis of three placebo-controlled clinical trials in patients with primarily early stage PBC, the exposure-adjusted incidence rates for all serious and otherwise clinically significant hepatic adverse reactions, and isolated elevations in liver biochemical tests, per 100 patient exposure years (PEY) were: 5.2 in the OCALIVA 10 mg group (highest recommended dosage), 19.8 in the OCALIVA 25 mg group (2.5-times the highest recommended dosage) and 54.5 in the OCALIVA 50 mg group (5-times the highest recommended dosage) compared to 2.4 in the placebo group.

Patient Management

Routinely monitor patients for progression of PBC, including hepatic adverse reactions, with laboratory and clinical assessments to determine whether drug discontinuation is needed [see Dosage and Administration (2.3)].

Closely monitor patients with compensated cirrhosis, concomitant hepatic disease (e.g., autoimmune hepatitis, alcoholic liver disease), and/or with severe intercurrent illness for new evidence of portal hypertension (e.g., ascites, gastroesophageal varices, persistent thrombocytopenia) or increases above the upper limit of normal in total bilirubin, direct bilirubin, or prothrombin time to determine whether drug discontinuation is needed [see Dosage and Administration (2.3)].

Permanently discontinue OCALIVA in patients who:

  • develop laboratory or clinical evidence of hepatic decompensation (e.g., ascites, jaundice, variceal bleeding, hepatic encephalopathy) [see Contraindications (4)].
  • have compensated cirrhosis and develop evidence of portal hypertension (e.g., ascites, gastroesophageal varices, persistent thrombocytopenia) [see Contraindications (4)].
  • experience clinically significant hepatic adverse reactions.
  • develop complete biliary obstruction [see Contraindications (4)].

If severe intercurrent illness occurs, interrupt treatment with OCALIVA and monitor the patient’s liver function. After resolution of the intercurrent illness, consider the potential risks and benefits of restarting OCALIVA treatment.

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