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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

Warning(s)

Special Alerts:

[Posted 09/21/2017]

AUDIENCE: Pharmacy, Hepatology, Gastroenterology

ISSUE: FDA is warning that the liver disease medicine obeticholic acid (Ocaliva) is being incorrectly dosed in some patients with moderate to severe decreases in liver function, resulting in an increased risk of serious liver injury and death. These patients are receiving excessive dosing, particularly a higher frequency of dosing than is recommended in the drug label for them. Obeticholic acid may also be associated with liver injury in some patients with mild disease who are receiving the correct dose. The recommended dosing and monitoring for patients on obeticholic acid are described in the current drug label. FDA is working with the drug manufacturer, Intercept Pharmaceuticals, to address these safety concerns.

BACKGROUND: Obeticholic acid is used to treat a rare, chronic liver disease known as primary biliary cholangitis (PBC). PBC causes the bile ducts in the liver to become inflamed, damaged and destroyed. This causes bile, a fluid that helps in digestion, to build up in the liver. This build-up damages the liver over time, eventually causing it to lose its ability to function. Obeticholic acid has been shown to improve a certain blood test that measures liver problems.

RECOMMENDATIONS:

Health care professionals

  • Determine the patient's baseline liver function prior to starting obeticholic acid.

  • Patients with moderate to severe liver impairment (Child-Pugh B and C) should be started on the approved dosing schedule of 5 mg once weekly, rather than the 5 mg daily dosing used for other PBC patients, and if needed, can be increased up to a maximum approved dose of 10 mg twice weekly.

  • Health care professionals should monitor patients frequently for disease progression, and reduce the dosing frequency to once- or twice-weekly for patients who progress to moderate or severe liver impairment.

  • In all patients treated with obeticholic acid, monitor frequently for liver injury (e.g., worsened liver blood tests and adverse liver-related reactions that may be inconsistent with the patient's extent of disease). If liver injury is suspected, discontinue obeticholic acid. After the patient has stabilized, weigh the benefits against the risks when deciding whether to re-initiate treatment.

  • Educate patients on the symptoms of potential liver injury.

Patients

  • Contact your health care professional if you have questions or concerns about taking obeticholic acid.

  • Report new or worsening severe skin itching to your health care professional.

  • Contact your health care professional immediately if you develop any of the following symptoms that may be signs of liver injury:

    • New or worsening fatigue

    • Diarrhea

    • Weight loss

    • Abdominal pain

    • Decreased appetite

    • Nausea and vomiting

    • Change in behavior or confusion

    • Vague symptoms such as anxiety or unease

    • Abdominal swelling

    • Yellow eyes or skin

    • Bloody stools

For more information visit the FDA website at: and .

Introduction

A farnesoid X receptor (FXR) agonist; bile acid-regulating drug.1 3

Uses for Obeticholic Acid

Pending revision, the material in this section should be considered in light of more recently available information in the MedWatch notification at the beginning of this monograph.

Primary Biliary Cholangitis

Used for management of primary biliary cholangitis1 3 11 (previously called primary biliary cirrhosis)13 (designated an orphan drug by FDA for this use).2

Used in combination with ursodiol (ursodeoxycholic acid) for patients not responding adequately to ursodiol therapy or alone in those intolerant of ursodiol.1

Accelerated approval based on reduction in alkaline phosphatase concentration; clinical benefit (e.g., improvement in disease-related symptoms, increased survival) not demonstrated.1 Continued approval may be contingent on verification and description of clinical benefit in confirmatory studies.1

Obeticholic Acid Dosage and Administration

General

  • Measure alkaline phosphatase and total bilirubin concentrations after 3 months to assess response to therapy.1

  • Monitor patients for elevations in liver function tests, development of adverse hepatic effects, and changes in serum lipid concentrations during therapy.1

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

Restricted Distribution Program

  • Obtain through a specialty pharmacy.12 Contact Interconnect Support Services for specific ordering and availability information (844-622-4278 or ).12

Administration

Oral Administration

Administer orally without regard to meals.1

Dosage

Pending revision, the material in this section should be considered in light of more recently available information in the MedWatch notification at the beginning of this monograph.

Adults

Primary Biliary Cholangitis
Oral

Initially, 5 mg once daily in combination with ursodiol or as monotherapy.1

Increase to 10 mg once daily if patient tolerates drug and if response in alkaline phosphatase and/or total bilirubin concentrations inadequate after 3 months.1 Initial dosage of 10 mg once daily not recommended because of increased risk of pruritus.1 3

Dosage Modification for Severe Pruritus
Oral

For patients experiencing severe, intolerable pruritus, consider addition of antihistamine or bile acid sequestrant.1 Administer obeticholic acid at least 4 hours (or as long an interval as possible) before or after administration of a bile acid sequestrant.1 (See Specific Drugs under Interactions.)

Dosage reduction of obeticholic acid with or without temporary interruption of therapy also may be considered.1

For patients intolerant of obeticholic acid 5 mg once daily, reduce dosage to 5 mg every other day.1 For patients intolerant of 10 mg once daily, reduce dosage to 5 mg once daily.1 Therapy may be held for up to 2 weeks before restarting drug at reduced dosage.1

For patients continuing to experience persistent, intolerable pruritus, consider drug discontinuance.1

Prescribing Limits

Adults

Primary Biliary Cholangitis
Oral

Maximum 10 mg daily.1

Special Populations

Hepatic Impairment

Primary Biliary Cholangitis
Oral

Mild hepatic impairment (Child-Pugh class A): Dosage adjustment not necessary.1

Moderate or severe hepatic impairment (Child-Pugh class B or C): Initially, 5 mg once weekly.1 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.1 Increase dosage further to 10 mg twice weekly (administered at least 3 days apart) based on patient tolerance and response.1 (See Hepatic Impairment under Cautions.)

Renal Impairment

No specific dosage recommendations at this time.1 (See Renal Impairment under Cautions.)

Geriatric Patients

No specific dosage recommendations at this time.1 (See Geriatric Use under Cautions.)

Cautions for Obeticholic Acid

Contraindications

Pending revision, the material in this section should be considered in light of more recently available information in the MedWatch notification at the beginning of this monograph.

  • Complete biliary obstruction.1

Warnings/Precautions

Hepatic Effects

Dose-related adverse hepatic effects (e.g., jaundice, worsening ascites, primary biliary cholangitis flare) reported.1

Monitor patients for elevations in liver function tests and development of adverse hepatic effects.1 In patients experiencing clinically important hepatic effects (e.g., ascites, hepatic encephalopathy), weigh potential benefits of drug against possible risks.1

Do not exceed maximum recommended dosage of 10 mg daily.1 Adjust dosage in patients with moderate or severe hepatic impairment.1 (See Special Populations under Dosage and Administration.) Discontinue drug in patients who develop complete biliary obstruction.1 (See Contraindications under Cautions.)

Severe Pruritus

Severe pruritus reported.1 Dose-related increases in incidence and severity of pruritus observed, particularly at dosages >10 mg daily.3

For patients experiencing severe pruritus, consider addition of antihistamine or bile acid sequestrant.1 (See Specific Drugs under Interactions.)

Dosage reduction of obeticholic acid with or without temporary interruption of therapy also may be considered.1 (See Dosage Modification for Severe Pruritus under Dosage and Administration.)

Lipid Effects

Reductions in HDL-cholesterol concentration observed.1 3

Monitor patients for changes in serum lipid concentrations.1 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.1

Specific Populations

Pregnancy

Limited data on obeticholic acid use during pregnancy inadequate to inform of drug-associated risk.1

No evidence of developmental abnormalities or fetal harm in animal studies.1

Lactation

Not known whether obeticholic acid distributes into human milk; effects of drug on breast-fed infants or milk production also not known.1

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.1

Pediatric Use

Safety and efficacy not established in children <18 years of age.1

Geriatric Use

No overall differences in safety or efficacy relative to younger adults, but increased sensitivity cannot be ruled out.1

Hepatic Impairment

Increased exposure in patients with moderate or severe hepatic impairment (Child-Pugh class B or C).1 (See Absorption: Special Populations, under Pharmacokinetics.)

Use contraindicated in patients with complete biliary obstruction.1

Renal Impairment

Population analysis indicates that pharmacokinetics not altered by estimated GFR >50 mL/minute per 1.73 m2.1 (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).1

Common Adverse Effects

Pruritus,1 3 fatigue,1 3 nasopharyngitis,3 abdominal pain/discomfort,1 rash,1 arthralgia,1 3 oropharyngeal pain,1 dizziness,1 constipation,1 peripheral edema,1 palpitations,1 pyrexia,1 thyroid function abnormality,1 eczema.1

Interactions for Obeticholic Acid

In vitro studies suggest obeticholic acid not metabolized to any clinically relevant extent by CYP isoenzymes.1

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.1 Concentration-dependent down-regulation of messenger RNA (mRNA) for CYP1A2 and 3A4 by obeticholic acid and its conjugates observed.1 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.1

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.1 7

Drugs Metabolized by Hepatic Microsomal Enzymes

Substrates of CYP1A2: Possible increased exposure to the substrate drug.1 Therapeutic monitoring of CYP1A2 substrates with narrow therapeutic index recommended with such concomitant use.1

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.1 Clinical importance of these potential interactions not known.1

Specific Drugs

Drug

Interaction

Comments

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

Possible reduced absorption, exposure, and efficacy of obeticholic acid1

Administer obeticholic acid at least 4 hours (or as long an interval as possible) before or after administering a bile acid sequestrant1

Caffeine

Peak plasma concentration and AUC of caffeine increased by 6 and 42%, respectively1

Dextromethorphan

Peak plasma concentration and AUC of dextromethorphan decreased by 12 and 11%, respectively1

Not considered clinically important1

Digoxin

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

Not considered clinically important1

Midazolam

Peak plasma concentration and AUC of midazolam increased by 2% each1

Not considered clinically important1

Omeprazole

Peak plasma concentration and AUC of omeprazole increased by 33 and 32%, respectively1

Exposure of obeticholic acid increased by <1.2-fold1

Clinical importance of increased omeprazole exposure unknown1

Effect on obeticholic acid exposure not considered clinically important1

Rosuvastatin

Peak plasma concentration and AUC of rosuvastatin increased by 27 and 22%, respectively1

Not considered clinically important1

Theophylline

Possible increased exposure to theophylline (CYP1A2 substrate)1

Therapeutic monitoring of theophylline recommended1

Tizanidine

Possible increased exposure to tizanidine (CYP1A2 substrate)1

Therapeutic monitoring of tizanidine recommended1

Warfarin

Exposure to S-warfarin increased by 13% and maximum INR decreased by 11%1

Monitor INR and adjust warfarin dosage as needed1

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.1

Food

Extent of absorption unaltered under fed conditions.1

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.1

Distribution

Extent

Not known if distributed into milk.1 (See Lactation under Cautions.)

Plasma Protein Binding

>99%.1

Elimination

Metabolism

Conjugated with glycine and taurine in the liver; secreted into bile.1

Elimination Route

Fecal excretion via biliary secretion (87%) and urinary excretion (<3%).1

Half-life

Obeticholic acid: Effective half-life about 24 hours.6

Total obeticholic acid (sum of obeticholic acid and its active conjugates): Predicted to be approximately 4 days.6

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.1

Not studied in patients with moderate or severe renal impairment (estimated GFR <60 mL/minute per 1.73 m2).1

Stability

Storage

Oral

Tablets

20–25°C (may be exposed to 15–30°C).1

Actions

  • FXR agonist and a bile acid-regulating drug.1 3

  • 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.1 6 9 10

  • 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.3 9

  • 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;1 10 as a result, overall size of bile acid pool is limited and bile secretion is promoted, reducing hepatic exposure to bile acids.1

Advice to Patients

Pending revision, the material in this section should be considered in light of more recently available information in the MedWatch notification at the beginning of this monograph.

  • Importance of advising patients to report immediately to their clinician any symptoms of worsening liver disease or symptoms of complete biliary obstruction.1 Periodic laboratory testing may be warranted to assess liver function and/or monitor for changes in serum lipid concentrations.1

  • Importance of advising patients to contact their clinician if they experience pruritus or an increase in severity of pruritus.1

  • Importance of informing patients that obeticholic acid may be taken without regard to meals.1

  • Importance of taking obeticholic acid at least 4 hours (or as long an interval as possible) before or after taking a bile acid sequestrant.1

  • 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).1

  • Importance of advising women to inform clinicians if they are or plan to become pregnant or plan to breast-feed.1

  • Importance of informing patients of other important precautionary information.1 (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.12 (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 2017, Selected Revisions September 21, 2017. American Society of Health-System Pharmacists, Inc., 4500 East-West Highway, Suite 900, Bethesda, Maryland 20814.

References

1. Intercept Pharmaceuticals, Inc. Ocaliva (obeticholic acid) tablets prescribing information. New York, NY; 2016 May.

2. Food and Drug Administration. Search Orphan Drug Designations and Approvals. Silver Spring, MD. From FDA website. Accessed 2016 Aug 18.

3. Nevens F, Andreone P, Mazzella G et al. A Placebo-Controlled Trial of Obeticholic Acid in Primary Biliary Cholangitis. N Engl J Med. 2016; 375:631-43. [PubMed 27532829]

4. Jones D, Kowdley K, Chapman R et al. OP02 The first new monotherapy therapeutic PBC study in a decade? An international study evaluating the first farnesoid X receptor agonist obeticholic acid in PBC. Oral presentation at the British Association for the Study of the Liver (BASL) 2011 Annual Meeting. London: 2011 Sep 8. Abstract.

5. Kowdley KV, Jones D, Luketic V et al. The OCA PBC study group. An international study evaluating the farnesoid X receptor agonist obeticholic acid as monotherapy in PBC. Oral presentation at the European Association for the Study of the Liver 2011 Annual Meeting. Berlin: 2011 Mar 31. Abstract.

6. Food and Drug Administration. Center for Drug Evaluation and Research. Application number: 207999Orig1s000: Medical review(s). From FDA website

7. Food and Drug Administration. Center for Drug Evaluation and Research. Application number: 207999Orig1s000: Clinical pharmacology and biopharmaceutics review(s). From FDA website.

8. Lindor KD, Gershwin ME, Poupon R et al. Primary biliary cirrhosis. Hepatology. 2009; 50:291-308. [PubMed 19554543]

9. Bowlus CL. Obeticholic acid for the treatment of primary biliary cholangitis in adult patients: clinical utility and patient selection. Hepat Med. 2016; 8:89-95. [PubMed 27621676]

10. Ali AH, Carey EJ, Lindor KD. Recent advances in the development of farnesoid X receptor agonists. Ann Transl Med. 2015; 3:5. [PubMed 25705637]

11. Pratt DS. Primary Biliary Cholangitis--A New Name and a New Treatment. N Engl J Med. 2016; 375:685-7. [PubMed 27532836]

12. Intercept Pharmaceuticals, Inc. Enrollment form. From Interconnect Support Services website. Accessed 2016 Nov 17.

13. Beuers U, Gershwin ME, Gish RG et al. Changing nomenclature for PBC: From 'cirrhosis' to 'cholangitis'. Hepatology. 2015; 62:1620-2. [PubMed 26372460]

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