Approved Drug Label (PDF)
4
Contraindications
(Additions
and/or revisions underlined)
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
(Extensive
changes; please refer to labeling)
8
Use in Specific Populations
8.4 Hepatic Impairment
(Additions
and/or revisions underlined)
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 [see Warnings and Precautions (5.1)]. OCALIVA is contraindicated
in patients with decompensated cirrhosis (e.g., Child-Pugh Class B
or C), in those with a prior decompensation event, or with
compensated cirrhosis who have evidence of portal hypertension (e.g., ascites,
gastroesophageal varices, persistent thrombocytopenia) [see Contraindications (4)].
In
PBC clinical trials, a dose-response relationship was observed for the
occurrence of hepatic adverse reactions with OCALIVA [see Warnings and Precautions (5.1)].
Plasma exposure to
obeticholic acid and its active conjugates, increases significantly in patients
with moderate to severe hepatic impairment [see
Clinical
Pharmacology (12.3)].
Routinely monitor
patients for progression of PBC with laboratory and clinical assessments. Closely monitor patients with compensated cirrhosis, concomitant hepatic 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 to determine whether
drug discontinuation is needed. 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. Interrupt treatment during severe intercurrent illness [see Dosage and
Administration (2.3), Warnings and
Precautions (5.1)].
17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)
17 PATIENT COUNSELING INFORMATION
(Additions
and/or revisions underlined)
Advise the patient
to read the FDA-approved patient labeling (Medication Guide). Hepatic
Decompensation and Failure in BC Patients with Cirrhosis
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:
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)
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