Hepatic decompensation and failure, sometimes fatal or resulting in liver transplant, have been reported with obeticholic acid treatment in primary biliary cholangitis (PBC) patients with either compensated or decompensated cirrhosis.
Obeticholic acid is contraindicated in PBC patients with decompensated cirrhosis, a prior decompensation event, or with compensated cirrhosis who have evidence of portal hypertension.
Permanently discontinue obeticholic acid 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.
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: 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, recalculate the Child-Pugh classification.
Dosage adjustment for concomitant therapy: Significant drug interactions exist, requiring dose/frequency adjustment or avoidance. Consult drug interactions database for more information.
There are no dosage adjustments provided in the manufacturer's labeling.
Hepatic impairment prior to treatment initiation: Decompensated cirrhosis (eg, Child-Pugh class B or C), prior decompensation event, or compensated cirrhosis with evidence of portal hypertension (eg, ascites, gastroesophageal varices, persistent thrombocytopenia): Use is contraindicated.
Hepatotoxicity during treatment:
Biliary obstruction (complete): Permanently discontinue treatment.
Hepatic decompensation to Child-Pugh class B or C: Permanently discontinue treatment.
Hepatic adverse reactions (clinically significant): Permanently discontinue treatment.
Portal hypertension: Permanently discontinue treatment.
Refer to adult dosing.
Intolerable pruritus: 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 reinitiating therapy after dose reduction or interruption, titrate the dose based on response and tolerability.
Persistent intolerable pruritus: Consider discontinuing therapy.
Severe intercurrent illness: Interrupt treatment and monitor liver function. If condition returns to baseline, restart treatment after weighing risk versus benefits.
Excipient information presented when available (limited, particularly for generics); consult specific product labeling.
Tablet, Oral:
Ocaliva: 5 mg, 10 mg
No
Excipient information presented when available (limited, particularly for generics); consult specific product labeling.
Tablet, Oral:
Ocaliva: 5 mg, 10 mg
An FDA-approved patient medication guide, which is available with the product information and as follows, must be dispensed with this medication:
Ocaliva: https://www.accessdata.fda.gov/drugsatfda_docs/label/2021/207999s007lbl.pdf#page=22
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.
Primary biliary cholangitis: Treatment of adults with primary biliary cholangitis without cirrhosis or with compensated cirrhosis who do not have evidence of portal hypertension, either in combination with ursodiol (ursodeoxycholic acid) in patients with an inadequate response to ursodiol, or as monotherapy in patients unable to tolerate ursodiol.
The following adverse drug reactions and incidences are derived from product labeling unless otherwise specified.
>10%:
Dermatologic: Pruritus (56% to 70%; severe: 19% to 23%)
Endocrine & metabolic: Decreased HDL cholesterol (9% to 20%)
Gastrointestinal: Abdominal distress (≤19%), abdominal pain (≤19%)
Nervous system: Fatigue (19% to 25%)
1% to 10%:
Cardiovascular: Palpitations (3% to 7%), peripheral edema (7%)
Dermatologic: Eczema (3% to 6%), skin rash (10%)
Endocrine & metabolic: Thyroid dysfunction (4% to 6%)
Gastrointestinal: Constipation (7%)
Hepatic: Ascites (1%), hepatic encephalopathy (1%)
Nervous system: Dizziness (7%)
Neuromuscular & skeletal: Arthralgia (6% to 10%)
Respiratory: Oropharyngeal pain (7% to 8%)
Miscellaneous: Fever (7%)
Frequency not defined:
Gastrointestinal: Cholangitis (worsening)
Hepatic: Hepatotoxicity
Postmarketing: Hepatic: Decompensated liver disease, hepatic cirrhosis (new onset), hepatic failure, hepatic insufficiency (FDA 2017), increased direct serum bilirubin, increased serum bilirubin, jaundice (new onset and worsening)
Decompensated cirrhosis (eg, Child-Pugh class B or C) or a prior decompensation event; compensated cirrhosis with evidence of portal hypertension (eg, ascites, gastroesophageal varices, persistent thrombocytopenia); complete biliary obstruction.
Canadian labeling: Additional contraindications (not in US labeling): Hypersensitivity to obeticholic acid or any component of the formulation.
Concerns related to adverse effects:
• Hepatic effects: Cases of hepatic decompensation, some fatal or requiring liver transplant, have occurred and were typically reported at 2.5 months (median time) for a new decompensation event (eg, hepatic encephalopathy) in patients with decompensated cirrhosis and at 4 months (median time) for hepatic decompensation (eg, new-onset ascites) with compensated cirrhosis. Cases reported in patients with decompensated cirrhosis have occurred in patients receiving recommended doses while in other cases higher than recommended dosages were used. Additionally, dose-related (dose range: 10 mg once daily [maximum approved dose] to 50 mg once daily [5 times highest recommended dose]) hepatotoxicity (eg, jaundice, worsening ascites, primary biliary cholangitis [PBC] flare) has been reported in patients with primarily early stage PBC, as early as 1 month after initiating therapy. Monitor patients for progression of PBC, hepatic injury (increased bilirubin, PT), or new evidence of portal hypertension (eg, ascites, gastroesophageal varices, persistent thrombocytopenia); discontinuation of therapy may be necessary.
• 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.
Inhibits CYP1A2 (weak)
Note: Interacting drugs may not be individually listed below if they are part of a group interaction (eg, individual drugs within “CYP3A4 Inducers [Strong]” are NOT listed). For a complete list of drug interactions by individual drug name and detailed management recommendations, use the Lexicomp drug interactions program by clicking on the “Launch drug interactions program” link above.
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. Risk D: 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. Risk D: Consider therapy modification
CloZAPine: CYP1A2 Inhibitors (Weak) may increase the serum concentration of CloZAPine. Risk C: Monitor therapy
Theophylline Derivatives: CYP1A2 Inhibitors (Weak) may increase the serum concentration of Theophylline Derivatives. Risk C: 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. Risk D: Consider therapy modification
Warfarin: Obeticholic Acid may diminish the anticoagulant effect of Warfarin. Risk C: Monitor therapy
Adverse events have not been observed in animal reproduction studies.
It is not known if obeticholic acid is present in breast milk. According to the manufacturer, the decision to breastfeed during therapy should take into account the risk of exposure to the infant and the benefits of treatment to the mother.
LFTs, including alkaline phosphatase and bilirubin, platelet count (baseline and every 3 to 6 months [Lindor 2019] or when clinically indicated); PT (annually [Lindor 2019] or when clinically indicated); lipid profile (baseline and periodically thereafter); signs/symptoms of portal hypertension, and/or pruritus; progression of primary biliary cholangitis (laboratory and clinical assessments).
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.
Distribution: 618 L
Protein binding: >99%
Metabolism: 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.
Time to peak, plasma: Obeticholic acid: ~1.5 hours; glyco- and tauro-obeticholic acid: 10 hours
Excretion: Feces (~87%); urine (<3%)
Altered kidney function: Following a single dose of obeticholic acid 25 mg, mean AUC of total obeticholic acid increased by ~1.4- to 1.6-fold in patients with mild (eGFR 60 to 89 mL/minute/1.73 m2), moderate (eGFR 30 to 59 mL/minute/1.73 m2), and severe (eGFR 15 to 29 mL/minute/1.73 m2) kidney impairment compared to subjects with normal kidney function.
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.
Tablets (Ocaliva Oral)
5 mg (per each): $321.78
10 mg (per each): $321.78
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