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Obeticholic Acid

Class: GI Drugs, Miscellaneous
Chemical Name: (3α,5β,6α,7α)-6-Ethyl-3,7-dihydroxy-cholan-24-oic acid
Molecular Formula: C26H44O4
CAS Number: 459789-99-2
Brands: Ocaliva

Medically reviewed by Drugs.com on March 8, 2021. Written by ASHP.

Warning

  • Following administration of obeticholic acid at shorter than recommended dosing intervals, hepatic decompensation and failure (sometimes fatal) reported in patients with primary biliary cholangitis who had decompensated cirrhosis or moderate or severe (Child-Pugh class B or C) hepatic impairment. (See Hepatic Effects under Cautions.)

  • Recommended initial dosage of obeticholic acid is 5 mg once weekly in patients with moderate or severe (Child-Pugh class B or C) hepatic impairment or a history of hepatic decompensation. (See Dosage Modification in Hepatic Impairment Progressing to Moderate or Severe under Dosage and Administration.)

Introduction

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

Uses for Obeticholic Acid

Primary Biliary Cholangitis

Used for management of primary biliary cholangitis (previously called primary biliary cirrhosis) (designated an orphan drug by FDA for this use).

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

  • Prior to therapy initiation, evaluate baseline hepatic function to determine Child-Pugh classification and to select appropriate initial dosage. Refer to manufacturer's prescribing information for instructions on calculating the Child-Pugh score for patients with suspected cirrhosis and to determine Child-Pugh classification.

  • Monitor patients routinely during therapy for biochemical response, tolerability, and disease progression. Reevaluate Child-Pugh classification periodically to determine need for dosage adjustment.

  • Monitor patients frequently during therapy for disease progression and hepatic injury based on worsening of liver function tests and/or development of adverse hepatic effects potentially inconsistent with the extent of hepatic impairment. (See Hepatic Effects under Cautions.)

  • Measure alkaline phosphatase and total bilirubin concentrations after 3 months to assess response to therapy.

  • 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.)

Restricted Distribution Program

  • Obtain through a specialty pharmacy. Contact Interconnect Support Services for specific ordering and availability information (844-622-4278 or [Web]).

Administration

Oral Administration

Administer orally without regard to meals.

Dosage

Adults

Primary Biliary Cholangitis
Noncirrhotic Hepatic Disease and No or Mild Hepatic Impairment
Oral

Recommended initial dosage and dosage titration regimen are dependent on disease stage.

For patients with noncirrhotic hepatic disease or in those with no or mild (Child-Pugh class A) hepatic impairment, recommended initial dosage is 5 mg once daily for the first 3 months in combination with ursodiol or as monotherapy.

Prior to any dosage adjustment, reevaluate the patient's Child-Pugh classification. Reduce dosage from once daily to once or twice weekly as appropriate in patients progressing from mild (Child-Pugh class A) to moderate or severe (Child-Pugh class B or C) hepatic impairment. (See Dosage Modification in Hepatic Impairment Progressing to Moderate or Severe under Dosage and Administration.)

For patients with noncirrhotic hepatic disease or in those with no or mild (Child-Pugh class A) hepatic impairment and 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.

Dosage Modification in Hepatic Impairment Progressing to Moderate or Severe
Oral

Reduce dosage of obeticholic acid from once daily to once or twice weekly as appropriate in patients with hepatic impairment progressing from Child-Pugh class A to Child-Pugh class B or C.

For patients with moderate or severe (Child-Pugh class B or C) hepatic impairment or history of hepatic decompensation events, including gastroesophageal variceal bleeding, new or worsening jaundice, or spontaneous bacterial peritonitis, recommended initial dosage is 5 mg once weekly for the first 3 months in combination with ursodiol or as monotherapy.

Prior to any dosage adjustment, reevaluate the patient's Child-Pugh classification.

For patients with moderate or severe hepatic impairment (Child-Pugh class B or C) or history of hepatic decompensation and 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 dosage to 5 mg twice weekly (at least 3 days apart) and titrate to 10 mg twice weekly (at least 3 days apart) based on response and tolerability.

Maximum dosage is 10 mg twice weekly (at least 3 days apart) in patients with moderate or severe hepatic impairment (Child-Pugh class B or C) or in those with a history of hepatic decompensation.

Routinely monitor patients for disease progression with laboratory and clinical assessments to determine need for dosage adjustment. Closely monitor patients at increased risk for hepatic decompensation, including those with laboratory evidence of worsening hepatic function (based on total bilirubin or albumin concentrations, INR) and/or those with progression to cirrhosis.

Interrupt therapy in patients with laboratory or clinical evidence of worsening hepatic function indicating risk of hepatic decompensation; continue to monitor the patient's hepatic function.

Consider potential risks and benefits of restarting therapy with obeticholic acid if patient's condition returns to baseline. If therapy is reinitiated, use the recommended initial dosage with adjustment based on patient's Child-Pugh score.

Consider discontinuance of therapy in patients experiencing clinically important adverse hepatic effects.

Dosage Modification for Severe Pruritus
Oral

For all patients with severe, intolerable pruritus with noncirrhotic or compensated cirrhotic mild (Child-Pugh class A) hepatic impairment as well as those with moderate or severe (Child-Pugh class B or C) hepatic impairment with a history of hepatic decompensation, 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.)

Dosage reduction of obeticholic acid with or without temporary interruption of therapy also may be considered.

For patients with noncirrhotic or compensated cirrhotic Child-Pugh class A hepatic impairment, and who are 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 moderate or severe (Child-Pugh class B or C) hepatic impairment with a history of hepatic decompensation and who are intolerant of obeticholic acid, interrupt therapy for up to 2 weeks; restart at reduced dosage if applicable.

For all patients with severe, intolerable pruritus whose dosage is reduced or interrupted, adjust dosage based on biochemical response, tolerability, and patient's Child-Pugh classification.

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

Mild hepatic impairment (Child-Pugh class A): Dosage adjustment not necessary.

Moderate or severe hepatic impairment (Child-Pugh class B or C): Initially, 5 mg once weekly. Increase dosage to 5 mg twice weekly (administered at least 3 days apart) if patient tolerates drug and if clinical response based on alkaline phosphatase and/or total bilirubin concentrations inadequate after 3 months. Increase dosage further to a maximum of 10 mg twice weekly (administered at least 3 days apart) based on patient tolerance and response. (See Hepatic Impairment under Cautions.)

Monitor patients frequently during therapy for disease progression and hepatic injury. For patients who progress from mild (Child-Pugh class A) to moderate or severe (Child-Pugh class B or C) hepatic impairment, reduce dosing frequency from daily administration to once or twice weekly. If hepatic injury is suspected, discontinue obeticholic acid and other potentially hepatotoxic drugs; perform a thorough evaluation of causality. Upon stabilization of the patient, weigh risks of therapy against potential benefits of the drug when considering reinitiation of therapy. (See Hepatic Effects 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

  • Complete biliary obstruction.

Warnings/Precautions

Hepatic Effects

Hepatic decompensation and failure (sometimes fatal) reported during postmarketing experience with obeticholic acid when given at shorter than recommended dosing intervals in patients with primary biliary cholangitis having decompensated cirrhosis or Child-Pugh class B or C hepatic impairment. (See Boxed Warning.)

Reported cases typically occurred within 2–5 weeks following initiation of therapy and were characterized by an acute increase in total bilirubin and/or alkaline phosphatase concentrations in association with clinical signs and symptoms of hepatic decompensation (e.g., ascites, jaundice, GI bleeding, worsening of hepatic encephalopathy). Some patients experienced improvement following discontinuance of therapy, but others reported continuing symptoms. Data were insufficient to rule out confounding factors (e.g., concomitant medications) or the role of the patient's underlying advanced disease state in these cases. Deaths resulting from liver-related complications generally occurred in those with decompensated cirrhosis prior to therapy initiation who received an initial obeticholic acid dosage of 5 mg once daily rather than the recommended dosage of 5 mg once weekly.

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.

Determine baseline hepatic function prior to therapy initiation based on classification of patients as Child-Pugh class A, B, or C; select appropriate initial dosage of obeticholic acid.

Monitor patients frequently during therapy for disease progression and hepatic injury (e.g., worsening of liver function tests and/or development of adverse hepatic effects potentially inconsistent with the extent of hepatic impairment). In patients experiencing clinically important hepatic effects (e.g., ascites, hepatic encephalopathy), weigh potential benefits of drug against possible risks.

Do not exceed maximum recommended dosage of 10 mg daily. Adjust dosage in patients with moderate or severe hepatic impairment. For patients who progress to advanced disease (i.e., from Child-Pugh class A to Child-Pugh class B or C) during therapy, reduce dosing frequency from once daily to once or twice weekly. (See Special Populations under Dosage and Administration.)

In patients experiencing clinically important adverse hepatic effects, consider discontinuance of therapy. Discontinue drug in patients who develop complete biliary obstruction. (See Contraindications under Cautions.)

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) reported during postmarketing experience with obeticholic acid when given at shorter than recommended dosing intervals in patients with primary biliary cholangitis having decompensated cirrhosis or Child-Pugh class B or C hepatic impairment. (See Boxed Warning.)

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.)

Prior to therapy initiation, determine the patient's Child-Pugh classification and select appropriate initial dosage of the drug. Reevaluate the patient's Child-Pugh classification and dosage regimen periodically during therapy.

Dosage adjustment is required in patients with moderate or severe hepatic impairment (Child-Pugh class B or C) or history of hepatic decompensation. Dosage interruption or discontinuance of therapy also may be required in such patients depending on response. (See Dosage Modification in Hepatic Impairment Progressing to Moderate or Severe under Dosage and Administration.)

Monitor all patients routinely for biochemical response, tolerability, and disease progression with laboratory and clinical assessments.

Use contraindicated in patients with 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.

Interactions for Obeticholic Acid

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

Drug

Interaction

Comments

Bile acid sequestrants (e.g., cholestyramine, colesevelam, colestipol)

Possible reduced absorption, exposure, and efficacy of obeticholic acid

Administer obeticholic acid at least 4 hours (or as long an interval as possible) before or after administering a bile acid sequestrant

Caffeine

Peak plasma concentration and AUC of caffeine increased by 6 and 42%, respectively

Cyclosporine

Possible exacerbation of accumulation of conjugated bile salts in the liver

Avoid concomitant use; if concomitant use necessary, monitor serum ALT, AST, bilirubin concentrations

Dextromethorphan

Peak plasma concentration and AUC of dextromethorphan decreased by 12 and 11%, respectively

Not considered clinically important

Digoxin

Peak plasma concentration of digoxin decreased by 3% and AUC increased by 1%

Not considered clinically important

Midazolam

Peak plasma concentration and AUC of midazolam increased by 2% each

Not considered clinically important

Omeprazole

Peak plasma concentration and AUC of omeprazole increased by 33 and 32%, respectively

Exposure of obeticholic acid increased by <1.2-fold

Clinical importance of increased omeprazole exposure unknown

Effect on obeticholic acid exposure not considered clinically important

Rosuvastatin

Peak plasma concentration and AUC of rosuvastatin increased by 27 and 22%, respectively

Not considered clinically important

Theophylline

Possible increased exposure to theophylline (CYP1A2 substrate)

Therapeutic monitoring of theophylline recommended

Tizanidine

Possible increased exposure to tizanidine (CYP1A2 substrate)

Therapeutic monitoring of tizanidine recommended

Warfarin

Exposure to S-warfarin increased by 13% and maximum INR decreased by 11%

Monitor INR and adjust warfarin dosage as needed

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, GI 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.)

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. (See Restricted Distribution Program under Dosage and Administration.)

Obeticholic Acid

Routes

Dosage Forms

Strengths

Brand Names

Manufacturer

Oral

Tablets, film-coated

5 mg

Ocaliva

Intercept

10 mg

Ocaliva

Intercept

AHFS DI Essentials™. © Copyright 2021, Selected Revisions March 18, 2018. American Society of Health-System Pharmacists, Inc., 4500 East-West Highway, Suite 900, Bethesda, Maryland 20814.

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