Brand name: Ocaliva
Drug class: Cholelitholytic Agents

Medically reviewed by Drugs.com on Jan 10, 2025. Written by ASHP.

Introduction

A farnesoid X receptor (FXR) agonist; bile acid-regulating drug.

Uses for Obeticholic Acid

Primary Biliary Cholangitis

Management of primary biliary cholangitis (previously called primary biliary cirrhosis ) in patients who do not have cirrhosis or who have compensated cirrhosis without evidence of portal hypertension (designated an orphan drug by FDA for use in this condition ).

Used in combination with ursodiol (ursodeoxycholic acid) in patients not responding adequately to ursodiol therapy or used alone in those intolerant of ursodiol.

Accelerated approval based on reduction in alkaline phosphatase concentration; clinical benefit (e.g., improvement in disease-related symptoms, increased survival) not demonstrated. Continued approval may be contingent on verification and description of clinical benefit in confirmatory studies.

Obeticholic Acid Dosage and Administration

General

Pretreatment Screening

• Evaluate patients for presence of decompensated cirrhosis (e.g., Child-Pugh class B or C), history of decompensation event, or compensated cirrhosis with evidence of portal hypertension (e.g., ascites, gastroesophageal varices, persistent thrombocytopenia) since these conditions are contraindications to use.

Patient Monitoring

• Monitor patients routinely during therapy for biochemical response and to assess tolerability, disease progression, and need for discontinuance.

• Closely monitor those 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 in total or direct bilirubin concentration or prothrombin time that exceed the upper limit of normal (ULN) to determine need for discontinuance. (See Hepatic Effects under Cautions.)

• Monitor patients for changes in lipid concentrations during therapy. For patients experiencing reductions in HDL-cholesterol concentrations with obeticholic acid, assess response to therapy after 1 year to evaluate whether to continue therapy. (See Lipid Effects under Cautions.)

Administration

Oral Administration

Administer orally without regard to meals.

Dosage

Adults

Primary Biliary Cholangitis

Without Cirrhosis or With Compensated Cirrhosis but Without Evidence of Portal Hypertension

Oral

Initially, 5 mg once daily for the first 3 months in combination with ursodiol or as monotherapy.

For patients who are tolerating the drug but having an inadequate reduction in alkaline phosphatase and/or total bilirubin concentrations after 3 months of initial therapy, increase to 10 mg once daily. Initial dosage of 10 mg once daily not recommended because of increased risk of pruritus.

Permanently discontinue therapy in patients who develop laboratory or clinical evidence of hepatic decompensation (e.g., ascites, jaundice, variceal bleeding, hepatic encephalopathy), have compensated cirrhosis and develop evidence of portal hypertension (e.g., ascites, gastroesophageal varices, persistent thrombocytopenia), experience clinically important adverse hepatic reactions, or experience complete biliary obstruction.

Dosage Modification for Severe Pruritus

Oral

Consider addition of antihistamine or bile acid sequestrant. Administer obeticholic acid at least 4 hours (or as long an interval as possible) before or after administration of a bile acid sequestrant. (See Specific Drugs under Interactions.)

Also consider dosage reduction of obeticholic acid with or without temporary interruption of therapy. For patients intolerant of obeticholic acid 5 mg once daily, reduce dosage to 5 mg every other day. For patients intolerant of 10 mg once daily, reduce dosage to 5 mg once daily. Therapy may be held for up to 2 weeks before restarting drug at reduced dosage.

For patients with intolerable pruritus whose dosage is reduced or interrupted, adjust dosage based on biochemical response and tolerability.

For patients continuing to experience persistent, intolerable pruritus despite dosage modification, consider drug discontinuance.

Prescribing Limits

Adults

Primary Biliary Cholangitis

Oral

Maximum 10 mg daily.

Special Populations

Hepatic Impairment

Primary Biliary Cholangitis

Oral

Compensated cirrhosis without evidence of portal hypertension: Dosage adjustment not necessary.

Contraindicated in those with decompensated cirrhosis (e.g., Child-Pugh class B or C), a prior decompensation event, or compensated cirrhosis with evidence of portal hypertension (e.g., ascites, gastroesophageal varices, persistent thrombocytopenia). (See Hepatic Impairment under Cautions.)

Renal Impairment

No specific dosage recommendations at this time. (See Renal Impairment under Cautions.)

Geriatric Patients

No specific dosage recommendations at this time. (See Geriatric Use under Cautions.)

Cautions for Obeticholic Acid

Contraindications

• Decompensated cirrhosis (e.g., Child-Pugh class B or C) or a prior decompensation event.

• Compensated cirrhosis with evidence of portal hypertension (e.g., ascites, gastroesophageal varices, persistent thrombocytopenia).

• Complete biliary obstruction.

Warnings/Precautions

Warnings

Hepatic Effects

Hepatic decompensation and failure (sometimes fatal or requiring liver transplantation) reported during postmarketing experience with obeticholic acid in patients with primary biliary cholangitis having either compensated or decompensated cirrhosis. Although some cases in patients with decompensated cirrhosis occurred at higher than recommended dosages, other cases occurred at previously recommended dosage. (See Boxed Warning.)

Median time to hepatic decompensation (e.g., new-onset ascites) in those with compensated cirrhosis was 4 months (range: 2 weeks to 10 months); median time to a new decompensation event (e.g., hepatic encephalopathy) in those with decompensated cirrhosis was 2.5 months (range: 10 days to 8 months).

FDA and the manufacturer issued alerts in September 2017 describing the increased risk of serious hepatic injury, liver decompensation, hepatic failure, and death in some patients with hepatic impairment receiving obeticholic acid, particularly those receiving the drug more frequently than recommended.

Dose-related adverse hepatic effects (e.g., jaundice, worsening ascites, primary biliary cholangitis flare) also reported during clinical trials.

From May 27, 2016 through January 18, 2021, FDA identified 25 cases of serious hepatic injury leading to hepatic decompensation or failure in patients receiving obeticholic acid for the treatment of primary biliary cholangitis; all 25 patients (18 with compensated cirrhosis [including 10 with evidence or suspicion of portal hypertension] and 7 with decompensated cirrhosis at baseline) were receiving recommended dosages prior to the initial adverse hepatic event. In May 2021, FDA warned that obeticholic acid should not be used for management of primary biliary cholangitis in patients with advanced cirrhosis.

Routinely monitor patients during therapy for disease progression, including adverse hepatic effects, with laboratory and clinical assessments. Closely monitor those 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 in total or direct bilirubin concentration or prothrombin time that exceed the ULN.

Permanently discontinue therapy in patients who develop laboratory or clinical evidence of hepatic decompensation (e.g., ascites, jaundice, variceal bleeding, hepatic encephalopathy), have compensated cirrhosis and develop evidence of portal hypertension (e.g., ascites, gastroesophageal varices, persistent thrombocytopenia), experience clinically important adverse hepatic reactions, or experience complete biliary obstruction.

Interrupt therapy in patients who experience a severe intercurrent illness and monitor hepatic function. Following resolution of the intercurrent illness, weigh potential risks and benefits of resuming obeticholic acid therapy.

Other Warnings and Precautions

Severe Pruritus

Severe pruritus reported. Dose-related increases in incidence and severity of pruritus observed, particularly at dosages >10 mg daily.

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

For patients experiencing severe pruritus, consider addition of antihistamine or bile acid sequestrant. (See Specific Drugs under Interactions.)

Dosage reduction of obeticholic acid with or without temporary interruption of therapy also may be considered. (See Dosage Modification for Severe Pruritus under Dosage and Administration.)

Lipid Effects

Reductions in HDL-cholesterol concentration observed.

Monitor patients for changes in serum lipid concentrations. For patients experiencing reductions in HDL-cholesterol concentrations without an adequate response to obeticholic acid at the highest recommended, maximally tolerated dosage after 1 year of therapy, weigh potential benefits of drug against possible risks of continuing treatment.

Specific Populations

Pregnancy

Limited data on obeticholic acid use during pregnancy inadequate to inform of drug-associated risk.

No evidence of developmental abnormalities or fetal harm in animal studies.

Lactation

Not known whether obeticholic acid distributes into human milk; effects of drug on breast-fed infants or milk production also not known.

Consider benefits of breast-feeding and the woman's clinical need for the drug; also consider potential adverse effects on breast-fed infant from drug or underlying maternal condition.

Pediatric Use

Safety and efficacy not established in children <18 years of age.

Geriatric Use

No overall differences in safety or efficacy relative to younger adults, but increased sensitivity cannot be ruled out.

Hepatic Impairment

Hepatic decompensation and failure (sometimes fatal or requiring liver transplantation) reported during postmarketing experience with obeticholic acid in patients with primary biliary cholangitis having either compensated or decompensated cirrhosis. (See Boxed Warning and also see Hepatic Effects under Cautions.)

Dose-response relationship observed with this drug and occurrence of adverse hepatic reactions. Increased exposure in patients with moderate or severe hepatic impairment (Child-Pugh class B or C). (See Absorption: Special Populations, under Pharmacokinetics.)

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 in total or direct bilirubin concentration or prothrombin time that exceed the ULN. Interrupt therapy during severe intercurrent illnesses and permanently discontinue therapy in patients who develop laboratory or clinical evidence of hepatic decompensation, have compensated cirrhosis and develop evidence of portal hypertension, or experience clinically important adverse hepatic reactions during therapy.

Use contraindicated in patients with decompensated cirrhosis (e.g., Child-Pugh class B or C), a prior decompensation event, compensated cirrhosis with evidence of portal hypertension (e.g., ascites, gastroesophageal varices, persistent thrombocytopenia), or complete biliary obstruction.

Renal Impairment

Population analysis indicates that pharmacokinetics not altered by estimated GFR >50 mL/minute per 1.73 m². (See Elimination: Special Populations, under Pharmacokinetics.)

Not studied in patients with moderate or severe renal impairment (estimated GFR <60 mL/minute per 1.73 m²).

Common Adverse Effects

Pruritus, fatigue, nasopharyngitis, abdominal pain/discomfort, rash, arthralgia, oropharyngeal pain, dizziness, constipation, peripheral edema, palpitations, pyrexia, thyroid function abnormality, eczema.

Drug Interactions

In vitro studies suggest obeticholic acid not metabolized to any clinically relevant extent by CYP isoenzymes.

In vitro studies indicate that obeticholic acid can inhibit CYP3A4; however, an in vivo study did not indicate inhibition of CYP3A4 by obeticholic acid at the recommended dosage. Concentration-dependent down-regulation of messenger RNA (mRNA) for CYP1A2 and 3A4 by obeticholic acid and its conjugates observed. Obeticholic acid not expected to inhibit CYP2B6, 2C8, 2C9, 2C19, or 2D6 or induce CYP1A2, 2B6, 2C8, 2C9, 2C19, or 3A4 at the recommended dosage.

In vitro studies indicate that obeticholic acid and its conjugates do not have potential to inhibit P-glycoprotein (P-gp), breast cancer resistance protein (BCRP), organic anion transporter (OAT) 1 and 3, organic cation transporter (OCT) 2, and multidrug and toxin extrusion (MATE) transporter at the recommended dosage.

Drugs Metabolized by Hepatic Microsomal Enzymes

Substrates of CYP1A2: Possible increased exposure to the substrate drug. Therapeutic monitoring of CYP1A2 substrates with narrow therapeutic index recommended with such concomitant use.

Drugs Affecting or Affected by Bile Acid Transport

Inhibitors of canalicular membrane bile acid transporters (e.g., the bile salt export pump [BSEP]): Possible exacerbated, symptomatic accumulation of conjugated bile salts in the liver. Avoid concomitant use. If concomitant use is necessary, monitor AST, ALT, and bilirubin concentrations.

Drugs Affecting or Affected by Organic Anion Transport Proteins

In vitro studies indicate that obeticholic acid and its conjugates have potential to inhibit organic anion transport protein (OATP) 1B1 and 1B3 at the recommended dosage. Clinical importance of these potential interactions not known.

Specific Drugs

Obeticholic Acid Pharmacokinetics

Absorption

Bioavailability

Following oral administration, peak plasma concentrations of obeticholic acid and its active conjugates attained after approximately 1.5 and 10 hours, respectively.

Food

Extent of absorption unaltered under fed conditions.

Special Populations

In patients with mild, moderate, or severe hepatic impairment (Child-Pugh class A, B, or C), mean AUC increased 1.1-, 4-, and 17-fold, respectively, compared with those having normal hepatic function following 10-mg single dose oral administration.

Distribution

Extent

Not known if distributed into milk. (See Lactation under Cautions.)

Plasma Protein Binding

>99%.

Elimination

Metabolism

Conjugated with glycine and taurine in the liver; secreted into bile.

Elimination Route

Fecal excretion via biliary secretion (87%) and urinary excretion (<3%).

Half-life

Obeticholic acid: Effective half-life about 24 hours.

Total obeticholic acid (sum of obeticholic acid and its active conjugates): Predicted to be approximately 4 days.

Special Populations

Patients with estimated GFR >50 mL/minute per 1.73 m²: Population analysis indicates no clinically important effect on pharmacokinetics of obeticholic acid or its conjugates.

Not studied in patients with moderate or severe renal impairment (estimated GFR <60 mL/minute per 1.73 m²).

Stability

Storage

Oral

Tablets

20–25°C (may be exposed to 15–30°C).

Actions

• FXR agonist and a bile acid-regulating drug.

• FXR is a nuclear hormone receptor expressed at high concentrations in the liver and intestines that regulates bile acid synthesis and transport in addition to inflammatory, fibrotic, and metabolic pathways.

• Selective, steroidal FXR agonist with approximately 100-fold greater potency in activating the FXR than its endogenous ligand, human chenodeoxycholic acid, from which obeticholic acid is derived.

• Activation of FXR through binding of obeticholic acid decreases bile acid concentrations in hepatocytes by suppressing their de novo synthesis and by increasing transport of bile acids out of hepatocytes; as a result, overall size of bile acid pool is limited and bile secretion is promoted, reducing hepatic exposure to bile acids.

Advice to Patients

• Importance of instructing patients to read the medication guide prior to therapy initiation and each time prescription is refilled.

• Importance of advising patients to report immediately to their clinician any signs or symptoms of worsening liver function (e.g., ascites, jaundice, variceal bleeding, worsening of hepatic encephalopathy) or of complete biliary obstruction. Periodic laboratory testing may be warranted to assess liver function and/or monitor for changes in serum lipid concentrations.

• Importance of advising patients to report immediately to their clinician any severe and/or persistent nonspecific signs or symptoms of impaired health (e.g., nausea, vomiting, abdominal pain, diarrhea, weight loss, fever and chills, new or worsening fatigue, weakness, loss of appetite, dehydration, behavioral changes such as confusion).

• Importance of advising patients to contact their clinician if they experience new or worsening severe pruritus.

• Importance of informing patients that obeticholic acid may be taken without regard to meals.

• Importance of taking obeticholic acid at least 4 hours (or as long an interval as possible) before or after taking a bile acid sequestrant.

• Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription (e.g., bile acid sequestrants, warfarin) and OTC drugs and dietary or herbal supplements, as well as any concomitant illnesses (e.g., hepatic impairment).

• Importance of advising women to inform clinicians if they are or plan to become pregnant or plan to breast-feed.

• Importance of informing patients of other important precautionary information. (See Cautions.)

Additional Information

The American Society of Health-System Pharmacists, Inc. represents that the information provided in the accompanying monograph was formulated with a reasonable standard of care, and in conformity with professional standards in the field. Readers are advised that decisions regarding use of drugs are complex medical decisions requiring the independent, informed decision of an appropriate health care professional, and that the information contained in the monograph is provided for informational purposes only. The manufacturer’s labeling should be consulted for more detailed information. The American Society of Health-System Pharmacists, Inc. does not endorse or recommend the use of any drug. The information contained in the monograph is not a substitute for medical care.

Preparations

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.

Distribution of obeticholic acid is restricted. Contact Interconnect Support Services for specific ordering and availability information (844-622-4278 or [Web]).

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