Drug Safety-related Labeling Changes (SrLC)

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OCALIVA (NDA-207999)

(OBETICHOLIC ACID)

Safety-related Labeling Changes Approved by FDA Center for Drug Evaluation and Research (CDER)

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02/01/2018 (SUPPL-3)

Approved Drug Label (PDF)

Boxed Warning

(Newly added section)

WARNING: HEPATIC DECOMPENSATION AND FAILURE IN INCORRECTLY DOSED PBC PATIENTS WITH CHILD-PUGH CLASS B OR C OR DECOMPENSATED CIRRHOSIS

  • In postmarketing reports, hepatic decompensation and failure, in some cases fatal, have been reported in patients with primary biliary cholangitis (PBC) with decompensated cirrhosis or Child-Pugh Class B or C hepatic impairment when OCALIVA was dosed more frequently than recommended.

  • The recommended starting dosage of OCALIVA is 5 mg once weekly for patients with Child-Pugh Class B or C hepatic impairment or a prior decompensation event.

5 Warnings and Precautions

5.1 Hepatic Decompensation and Failure in Incorrectly Dosed PBC Patients with Child-Pugh Class B or C or Decompensated Cirrhosis

(Subsection title has been added; additions and/or revisions are underlined)

In postmarketing reports, hepatic decompensation and failure, in some cases fatal, have been reported in PBC patients with decompensated cirrhosis or Child-Pugh Class B or C hepatic impairment when OCALIVA was dosed more frequently than the recommended starting dosage of 5 mg once weekly.

Reported cases typically occurred within 2 to 5 weeks after starting OCALIVA and were characterized by an acute increase in total bilirubin and/or ALP concentrations in association with clinical signs and symptoms of hepatic decompensation (e.g., ascites, jaundice, gastrointestinal bleeding, worsening of hepatic encephalopathy). A few cases reported improvement after OCALIVA discontinuation; however, some cases reported ongoing symptoms. Because postmarketing cases often contain limited clinical information, there was insufficient information to rule out confounding factors (e.g., concomitant medications) or the role of the patient’s underlying advanced disease in the events.

Patients who died due to liver-related complications generally had decompensated cirrhosis prior to treatment and were started on OCALIVA 5 mg once daily, which is 7-fold greater than the once weekly starting regimen in this population.

Patient Management

Routinely monitor patients for progression of PBC disease, including liver-related complications, with laboratory and clinical assessments. Dosage adjustment, interruption or discontinuation may be required.

Close monitoring is recommended for patients at an increased risk of hepatic decompensation. Severe intercurrent illnesses that may worsen renal function or cause dehydration (e.g., gastroenteritis), may exacerbate the risk of hepatic decompensation.

Interrupt treatment with OCALIVA in patients with laboratory or clinical evidence of worsening liver function indicating risk of decompensation, and monitor the patient’s liver function. Consider discontinuing OCALIVA in patients who have experienced clinically significant liver-related adverse reactions.

5.2 Liver-Related Adverse Reactions

(Additions and/or revisions are underlined)

In two 3-month, placebo-controlled clinical trials in patients with primarily early stage PBC disease, a dose-response relationship was observed for the occurrence of liver-related 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 a pooled analysis of three placebo-controlled trials in patients with primarily early stage PBC disease,…

Close monitoring is recommended for patients at an increased risk of hepatic decompensation. Interrupt treatment with OCALIVA in patients with laboratory or clinical evidence of worsening liver function indicating risk of decompensation, and monitor the patient’s liver function.

5.3 Severe Pruritus

(Additions and/or revisions are underlined)

Consider clinical evaluation of patients with new onset or worsening severe pruritus

6 Adverse Reactions

(Additions and/or revisions are underlined)

The following clinically significant adverse reactions are described elsewhere in labeling:

  • Hepatic Decompensation and Failure in Incorrectly Dosed PBC Patients with Child-Pugh Class B or C or Decompensated Cirrhosis

6.2 Postmarketing Experience

(Newly added subsection)

The following adverse reactions have been identified during post approval use of OCALIVA. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure, particularly in PBC patients who have progressive liver disease.

Hepatobiliary Disorders: liver failure, new onset cirrhosis, increased direct and total bilirubin, new or worsening of jaundice, ascites, worsening hepatic encephalopathy.

7 Drug Interactions

7.4 Inhibitors of Bile Salt Efflux Pump

(Newly added subsection)

Avoid concomitant use of inhibitors of the bile salt efflux pump (BSEP) such as cyclosporine. Concomitant medications that inhibit canalicular membrane bile acid transporters such as the BSEP may exacerbate accumulation of conjugated bile salts including taurine conjugate of obeticholic acid in the liver and result in clinical symptoms. If concomitant use is deemed necessary, monitor serum transaminases and bilirubin.

8 Use in Specific Populations

8.6 Hepatic Impairment

(Additions and/or revisions are underlined)

Hepatic decompensation and failure, in some cases fatal, have been reported postmarketing in PBC patients with decompensated cirrhosis or Child-Pugh B or C hepatic impairment when OCALIVA was dosed more frequently than recommended. In PBC clinical trials, a dose-response relationship was observed for the occurrence of liver-related adverse reactions with OCALIVA.

Prior to the initiation of OCALIVA determine the patient’s Child-Pugh classification to determine the starting dosage. Re-evaluate the dosing regimen periodically during treatment.

Dosage adjustment is required in patients with Child-Pugh Class B and C. Routinely monitor patients for progression of PBC disease with laboratory and clinical assessments. Dosage adjustment, interruption or discontinuation may be required.

17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)

17 PATIENT COUNSELING INFORMATION

(Additions and/or revisions are underlined)

Advise the patient to read the FDA-approved patient labeling (Medication Guide).

Hepatic Decompensation and Failure in Incorrectly Dosed PBC Patients with Child-Pugh Class B or C or Decompensated Cirrhosis

  • Instruct patients and caregivers to immediately contact their healthcare provider if they experience:

    • Symptoms of disease progression or worsening liver function, such as ascites, jaundice, gastrointestinal bleeding or worsening of liver disease to their healthcare provider immediately and hepatic encephalopathy.

    • Symptoms of complete biliary obstruction.

  • Instruct patients and caregivers to immediately contact their healthcare provider if they experience severe or persistent non-specific signs and symptoms of impaired health: nausea, vomiting, abdominal pain, diarrhea, weight loss, fever and chills, worsening or new fatigue, weakness, loss of appetite or dehydration.

  • Inform patients that they will need to undergo laboratory testing periodically while on OCALIVA treatment to assess liver function.


Severe Pruritus

Advise patients to contact their healthcare provider if they experience new onset or worsening severe pruritus.

MEDICATION GUIDE

(Newly added section; please refer to label)

Questions related to the drug data in these files should be directed to the Center for Drug Evaluation and Research, Division of Drug Information
druginfo@fda.hhs.gov.

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