Hepatic decompensation and failure:
In postmarketing reports, hepatic decompensation and failure, in some cases fatal, have been reported in patients with primary biliary cholangitis with decompensated cirrhosis or Child-Pugh class B or C hepatic impairment when obeticholic acid was dosed more frequently than recommended.
The recommended starting dose is 5 mg once weekly for patients with Child-Pugh class B or C hepatic impairment or a prior decompensation event.
Excipient information presented when available (limited, particularly for generics); consult specific product labeling.
Ocaliva: 5 mg, 10 mg
Mechanism of Action
Obeticholic acid is a farnesoid X receptor agonist; activation of FXR suppresses de novo synthesis of bile acids from cholesterol and increases transport of bile acids out of the hepatocytes, limiting the overall size of the circulating bile acid pool while promoting choleresis.
Conjugated in the liver to active metabolites (glyco- and tauro-obeticholic acid; activity similar to parent drug) that undergo enterohepatic recirculation and conversion by intestinal microbiota back to obeticholic acid that is reabsorbed or excreted. A third metabolite, 3-glucuronide, has minimal pharmacologic activity.
Feces (~87%); urine (<3%)
Time to Peak
Plasma: Obeticholic acid: ~1.5 hours; glyco- and tauro-obeticholic acid: 10 hours
Use in Specific Populations
Special Populations: Hepatic Function Impairment
Mean AUC of total obeticholic acid (the sum of obeticholic acid and its 2 active conjugates) increased by 1.1-, 4-, and 17-fold in patients with mild, moderate, and severe hepatic impairment (Child-Pugh class A, B, and C), respectively.
Use: Labeled Indications
Primary biliary cholangitis: Treatment of primary biliary cholangitis (PBC) in combination with ursodiol (ursodeoxycholic acid) in adults with an inadequate response to ursodiol, or as monotherapy in adults unable to tolerate ursodiol.
Complete biliary obstruction
Canadian labeling: Additional contraindications (not in US labeling): Hypersensitivity to obeticholic acid or any component of the formulation.
Dosage and Administration
Note: Use in combination with ursodiol (ursodeoxycholic acid) in patients with an inadequate biochemical response to treatment with an appropriate dosage of ursodiol for ≥1 year; may be used as monotherapy in patients unable to tolerate ursodiol.
Primary biliary cholangitis: Oral:
Noncirrhotic or compensated Child-Pugh class A: Initial: 5 mg once daily; if an adequate reduction in alkaline phosphatase and/or total bilirubin has not been achieved after 3 months, increase to 10 mg once daily (maximum: 10 mg/day). Note: Prior to dose adjustment, re-calculate the Child-Pugh classification.
Child-Pugh class B or C or patients with a prior decompensation event (including gastroesophageal variceal bleeding, new or worsening jaundice, spontaneous bacterial peritonitis): Initial: 5 mg once weekly; if an adequate reduction in alkaline phosphatase and/or total bilirubin has not been achieved after 3 months, increase to 5 mg twice weekly (at least 3 days apart). May titrate to 10 mg twice weekly (at least 3 days apart) based on response and tolerability (maximum: 10 mg twice weekly [at least 3 days apart]). Note: Prior to dose adjustment, re-calculate the Child-Pugh classification. Based on expert opinion, use in patients with decompensated liver disease (Child-Pugh B or C) is uncertain and not recommended (AASLD [Lindor 2019]).
Refer to adult dosing.
Dosing: Adjustment for Toxicity
Noncirrhotic or compensated cirrhotic Child-Pugh class A: Reduce dose to 5 mg every other day (for patients intolerant to 5 mg once daily) or 5 mg once daily (for patients intolerant to 10 mg once daily) or may interrupt therapy for up to 2 weeks (and restart at a reduced dose). If re-initiating therapy after dose reduction or interruption, titrate the dose based on response and tolerability and adjust according to Child-Pugh classification.
Child-Pugh class B or C or patients with a prior decompensation event: Temporarily interrupt therapy for up to 2 weeks followed by reintroduction at a reduced dosage. Titrate the dose based on response and tolerability and according to Child-Pugh classification.
Persistent intolerable pruritus: Consider discontinuing therapy.
Oral: Administer with or without food. For patients taking a bile acid binding resin to manage intolerable pruritus, take obeticholic acid ≥4 hours before or 4 hours after taking the bile acid binding resin.
Store at 20ºC to 25ºC (68ºF to 77ºF); excursions permitted to 15ºC to 30ºC (59ºF to 86ºF).
Bile Acid Sequestrants: May decrease the serum concentration of Obeticholic Acid. Management: Administer obeticholic acid at least 4 hours before or at least 4 hours after the administration of bile acid sequestrants. Consider therapy modification
BSEP/ABCB11 Inhibitors: May increase serum concentrations of the active metabolite(s) of Obeticholic Acid. Management: Avoid concomitant use of obeticholic acid and bile salt efflux pump (BSEP) inhibitors if possible. If concomitant therapy is necessary, monitor patients for elevated liver transaminases and elevated bilirubin. Consider therapy modification
CloZAPine: CYP1A2 Inhibitors (Weak) may increase the serum concentration of CloZAPine. Management: Drugs listed as exceptions to this monograph are discussed in further detail in separate drug interaction monographs. Monitor therapy
Theophylline Derivatives: CYP1A2 Inhibitors (Weak) may increase the serum concentration of Theophylline Derivatives. Exceptions: Dyphylline. Monitor therapy
TiZANidine: CYP1A2 Inhibitors (Weak) may increase the serum concentration of TiZANidine. Management: Avoid these combinations when possible. If combined use is necessary, initiate tizanidine at an adult dose of 2 mg and increase in 2 to 4 mg increments based on patient response. Monitor for increased effects of tizanidine, including adverse reactions. Consider therapy modification
Warfarin: Obeticholic Acid may diminish the anticoagulant effect of Warfarin. Monitor therapy
Central nervous system: Fatigue (19% to 25%)
Dermatologic: Pruritus (56% to 70%; severe: 19% to 23%)
Endocrine & metabolic: Decreased HDL cholesterol (9% to 20%)
Gastrointestinal: Abdominal pain (19%)
1% to 10%:
Cardiovascular: Peripheral edema (7%), palpitations (3% to 7%)
Central nervous system: Dizziness (7%)
Dermatologic: Skin rash (10%), eczema (3% to 6%)
Endocrine & metabolic: Thyroid dysfunction (4% to 6%)
Gastrointestinal: Constipation (7%)
Neuromuscular & skeletal: Arthralgia (6% to 10%)
Respiratory: Oropharyngeal pain (7% to 8%)
Miscellaneous: Fever (≤7%)
Frequency not defined: Gastrointestinal: Cholangitis (worsening)
<1%, postmarketing and/or case reports: Ascites, hepatic cirrhosis (new onset), hepatic encephalopathy (worsening), hepatic failure, hepatic insufficiency, increased direct serum bilirubin, increased serum bilirubin, jaundice (new onset and worsening), liver decompensation
Concerns related to adverse effects:
- Hepatic effects: Dose-related hepatic adverse reactions (eg, jaundice, worsening ascites, primary biliary cholangitis [PBC] flare) have been reported in patients with primarily early stage PBC, as early as one month after initiating therapy. Monitor LFTs and for signs/symptoms of hepatic adverse reactions, especially for patients at increased risk of hepatic decompensation. Interrupt treatment in patients with laboratory or clinical evidence of worsening liver function indicating decompensation; consider discontinuation of therapy in patients who experience clinically significant liver-related adverse reactions. Permanently discontinue treatment in patients who develop complete biliary obstruction.
- Lipid effects: Dose-dependent reductions in high density lipoprotein-cholesterol (HDL-C) levels have been reported; monitor lipids during treatment. In patients who experience a reduction in HDL-C and do not respond to therapy after 1 year at the maximum dosage, consider the potential risks against the benefits of continuing obeticholic acid.
- Pruritus: Severe pruritus (ie, intense or widespread itching, interfering with activities of daily living, or causing severe sleep disturbance or intolerable discomfort, typically requiring medical interventions) has been reported. Consider clinical evaluation for patients with new-onset or worsening severe pruritus; dosage reduction, temporary interruption of dosing, and/or addition of bile acid resins or antihistamines may be used to manage severe pruritus.
- Hepatic decompensation and failure: [US Boxed Warning]: Hepatic decompensation and failure have been reported (including fatalities) in patients with PBC with decompensated cirrhosis or Child-Pugh class B or C hepatic impairment when obeticholic acid was dosed more frequently than the recommended starting dose. Cases were typically reported within 2 to 5 weeks after initiation of therapy and were characterized by an acute increase in total bilirubin and/or alkaline phosphatase concentrations with clinical signs and symptoms of hepatic decompensation. Some cases improved after discontinuation of therapy; patients who died due to liver-related complications generally had decompensated cirrhosis prior to treatment and were initiated on daily dosing instead of weekly dosing. Monitor patients for progression of PBC, including liver-related complications; dosage adjustment, interruption, or discontinuation may be necessary. Close monitoring is recommended for patients at increased risk of hepatic decompensation; severe intercurrent illnesses that may worsen renal function or cause dehydration (eg, gastroenteritis) may exacerbate the risk of hepatic decompensation. Monitor LFTs and interrupt treatment in patients with laboratory or clinical evidence of worsening liver function; consider discontinuation of therapy in patients who have experienced clinically significant liver-related adverse reactions. Discontinue use in patients who develop complete biliary obstruction. Dosage adjustment is recommended in patients with Child-Pugh class B and C.
Concurrent drug therapy issues:
- Drug-drug interactions: Potentially significant interactions may exist, requiring dose or frequency adjustment, additional monitoring, and/or selection of alternative therapy. Consult drug interactions database for more detailed information.
LFTs, including alkaline phosphatase and bilirubin, lipid profile; signs/symptoms of hepatic adverse reactions and/or pruritus; progression of PBC (laboratory and clinical assessments).
Adverse events have not been observed in animal reproduction studies.
- Discuss specific use of drug and side effects with patient as it relates to treatment. (HCAHPS: During this hospital stay, were you given any medicine that you had not taken before? Before giving you any new medicine, how often did hospital staff tell you what the medicine was for? How often did hospital staff describe possible side effects in a way you could understand?)
- Patient may experience loss of strength or energy, abdominal pain, joint pain, throat pain, dizziness, constipation, or eczema. Have patient report immediately to prescriber signs of liver problems (dark urine, fatigue, lack of appetite, nausea, abdominal pain, light-colored stools, vomiting, or yellow skin), signs of thyroid problems (change in weight without trying, anxiety, feeling restless, feeling very weak, hair thinning, depression, neck swelling, difficulty focusing, inability handling heat or cold, menstrual changes, tremors, or sweating), severe itching, swelling in the arms or legs, or abnormal heartbeat (HCAHPS).
- Educate patient about signs of a significant reaction (eg, wheezing; chest tightness; fever; itching; bad cough; blue skin color; seizures; or swelling of face, lips, tongue, or throat). Note: This is not a comprehensive list of all side effects. Patient should consult prescriber for additional questions.
Intended Use and Disclaimer: Should not be printed and given to patients. This information is intended to serve as a concise initial reference for health care professionals to use when discussing medications with a patient. You must ultimately rely on your own discretion, experience, and judgment in diagnosing, treating, and advising patients.