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Obeticholic Acid

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

Introduction

Obeticholic acid, a farnesoid X receptor (FXR) agonist, is a bile acid regulating drug.

Uses for Obeticholic Acid

Obeticholic acid has the following uses:

Obeticholic acid, a farnesoid X receptor (FXR) agonist, is indicated for the treatment of primary biliary cholangitis (PBC) in combination with ursodiol (ursodeoxycholic acid [UDCA]) in adults with an inadequate response to ursodiol, or as monotherapy in adults unable to tolerate ursodiol. 1

This indication is approved under accelerated approval based on a reduction in alkaline phosphatase (ALP). An improvement in survival or disease-related symptoms has not been established. Continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trials.1

Obeticholic Acid Dosage and Administration

General

Obeticholic acid is available in the following dosage form(s) and strength(s):

Tablets: 5 mg, 10 mg1

Dosage

It is essential that the manufacturer's labeling be consulted for more detailed information on dosage and administration of this drug. Dosage summary:

  • Starting Dosage: The recommended starting dosage of obeticholic acid is 5 mg orally once daily in adults who have not achieved an adequate response to an appropriate dosage of ursodiol for at least 1 year or are intolerant to ursodiol.1

  • Dosage Titration: If adequate reduction in alkaline phosphatase (ALP) and/or total bilirubin has not been achieved after 3 months of obeticholic acid 5 mg once daily and the patient is tolerating obeticholic acid, increase dosage to 10 mg once daily.1

  • Maximum Dosage: 10 mg once daily.1

  • Management of Patients with Intolerable Pruritus: See full prescribing information for management options.1

  • Hepatic Impairment: See full prescribing information for dosage adjustment in patients with moderate or severe hepatic impairment (Child-Pugh Class B or C).1

  • Administration Instructions
  • Take with or without food.1

  • For patients taking bile acid binding resins, take obeticholic acid at least 4 hours before or 4 hours after taking a bile acid binding resin, or at as great an interval as possible.1

Cautions for Obeticholic Acid

Contraindications

Patients with complete biliary obstruction.1

Warnings/Precautions

Liver-related Adverse Reactions

In two 3-month, placebo-controlled clinical trials, a dose-response relationship was observed for the occurrence of liver-related adverse reactions including jaundice, worsening ascites and primary biliary cholangitis flare with dosages of obeticholic acid of 10 mg once daily to 50 mg once daily (up to 5-times the highest recommended dosage), as early as one month after starting treatment with obeticholic acid. 1

In a pooled analysis of three placebo-controlled trials in patients with primary biliary cholangitis (PBC), the exposure-adjusted incidence rates for all serious and otherwise clinically significant liver-related adverse reactions, and isolated elevations in liver biochemical tests, per 100 patient exposure years (PEY) were 5.2 in the obeticholic acid 10 mg group (highest recommended dosage), 19.8 in the obeticholic acid 25 mg group (2.5 times the highest recommended dosage) and 54.5 in the obeticholic acid 50 mg group (5 times the highest recommended dosage) compared to 2.4 in the placebo group.1

Monitor patients during treatment with obeticholic acid for elevations in liver biochemical tests and for the development of liver-related adverse reactions. Weigh the potential risks against the benefits of continuing treatment with obeticholic acid in patients who have experienced clinically significant liver-related adverse reactions. The maximum recommended dosage of obeticholic acid is 10 mg once daily. Adjust the dosage for patients with moderate or severe hepatic impairment.1

Discontinue obeticholic acid in patients who develop complete biliary obstruction.1

Severe Pruritus

Severe pruritus was reported in 23% of patients in the obeticholic acid 10 mg arm, 19% of patients in the obeticholic acid titration arm, and 7% of patients in the placebo arm in Trial 1, a 12-month double-blind randomized controlled trial of 216 patients. Severe pruritus was defined as intense or widespread itching, interfering with activities of daily living, or causing severe sleep disturbance, or intolerable discomfort, and typically requiring medical interventions. In the subgroup of patients in the obeticholic acid titration arm who increased their dosage from 5 mg once daily to 10 mg once daily after 6 months of treatment (n=33), the incidence of severe pruritus was 0% from months 0 to 6 and 15% from months 6 to 12. The median time to onset of severe pruritus was 11, 158, and 75 days for patients in the obeticholic acid 10 mg, obeticholic acid titration, and placebo arms, respectively. 1

Management strategies include the addition of bile acid resins or antihistamines, obeticholic acid dosage reduction, and/or temporary interruption of obeticholic acid dosing.1

Reduction in HDL-C

Patients with PBC generally exhibit hyperlipidemia characterized by a significant elevation in total cholesterol primarily due to increased levels of high density lipoprotein-cholesterol (HDL-C). In Trial 1, dose-dependent reductions from baseline in mean HDL-C levels were observed at 2 weeks in obeticholic acid-treated patients, 20% and 9% in the 10 mg and titration arms, respectively, compared to 2% in the placebo arm. At month 12, the reduction from baseline in mean HDL-C level was 19% in the obeticholic acid 10 mg arm, 12% in the obeticholic acid titration arm, and 2% in the placebo arm. Nine patients in the obeticholic acid 10 mg arm, 6 patients in the obeticholic acid titration arm, versus 3 patients in the placebo arm had reductions in HDL-C to less than 40 mg/dL.1

Monitor patients for changes in serum lipid levels during treatment. For patients who do not respond to obeticholic acid after 1 year at the highest recommended dosage that can be tolerated (maximum of 10 mg once daily), and who experience a reduction in HDL-C, weigh the potential risks against the benefits of continuing treatment.1

Specific Populations

Pregnancy

Risk Summary: The limited available human data on the use of obeticholic acid during pregnancy are not sufficient to inform a drug-associated risk. In animal reproduction studies, no developmental abnormalities or fetal harm was observed when pregnant rats or rabbits were administered obeticholic acid during the period of organogenesis at exposures approximately 13 times and 6 times human exposures, respectively, at the maximum recommended human dose (MRHD) of 10 mg. 1

The estimated background risks of major birth defects and miscarriage for the indicated population are unknown. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively. 1

Animal Data: In an embryo-fetal development study in rats, obeticholic acid was administered orally during the period of organogenesis at doses of 5, 25, and 75 mg/kg/day. At 25 mg/kg/day (a dose that produced systemic exposures approximately 13 times those in humans at the MRHD of 10 mg), there was no maternal or developmental toxicity. At 75 mg/kg/day (approximately 40 times the human exposure at the MRHD), decreased fetal body weights and increased numbers of early or late resorptions and nonviable fetuses were observed. In maternal animals, mortality, fetal loss, decreased body weight and food consumption as well as decreased body weight gain were observed at 75 mg/kg/day. Thus, the developmental toxicity observed at this dose may be secondary to maternal toxicity. In rabbits, obeticholic acid was administered orally during the period of organogenesis at doses of 3, 9, and 20 mg/kg/day. Obeticholic acid administered at doses up to 20 mg/kg/day (approximately 6 times the human exposure at the MRHD) was not teratogenic and did not produce any evidence of fetal harm.1

In a pre- and post-natal development study, administration of obeticholic acid in rats during organogenesis through lactation at doses of 5, 25, and 40 mg/kg/day did not produce effects on pregnancy, parturition or postnatal development at any dose (the 40 mg/kg/day dose is approximately 21 times the human exposure at the MRHD). 1

Obeticholic acid exposure margins were calculated using systemic exposure (AUC) values of obeticholic acid plus obeticholic acid's active metabolite conjugates (tauro-obeticholic acid and glyco-obeticholic acid) in animals (at the indicated doses) and in humans at the MRHD of 10 mg.1

Lactation

There is no information on the presence of obeticholic acid in human milk, the effects on the breast-fed infant or the effects on milk production. The developmental and health benefits of breastfeeding should be considered along with the mother's clinical need for obeticholic acid and any potential adverse effects on the breastfed infant from obeticholic acid or from the underlying maternal condition.1

Pediatric Use

The safety and effectiveness of obeticholic acid in pediatric patients have not been established.1

Geriatric Use

Of the 201 patients in clinical trials of obeticholic acid who received the recommended dosage (5 mg or 10 mg once daily), 41 (20%) were 65 years of age and older, while 9 (4%) were 75 years of age and older. No overall differences in safety or effectiveness were observed between these subjects and subjects less than 65 years of age, but greater sensitivity of some older individuals cannot be ruled out.1

Hepatic Impairment

Plasma exposure to obeticholic acid and its active conjugates increases significantly in patients with moderate to severe hepatic impairment (Child-Pugh Classes B and C). 1

Monitor patients during treatment with obeticholic acid for elevations in liver biochemical tests and for the development of liver-related adverse reactions. Dosage adjustment of obeticholic acid is recommended for patients with moderate and severe hepatic impairment. No dosage adjustment is needed in patients with mild hepatic impairment (Child-Pugh Class A).1

Common Adverse Effects

Most common adverse reactions (≥ 5%) are pruritus, fatigue, abdominal pain and discomfort, rash, oropharyngeal pain, dizziness, constipation, arthralgia, thyroid function abnormality, and eczema.1

Drug Interactions

Specific Drugs

It is essential that the manufacturer's labeling be consulted for more detailed information on interactions with this drug, including possible dosage adjustments. Interaction highlights:

  • Bile Acid Binding Resins: Bile acid binding resins such as cholestyramine, colestipol, or colesevelam adsorb and reduce bile acid absorption and may reduce the absorption, systemic exposure, and efficacy of obeticholic acid. If taking a bile acid binding resin, take obeticholic acid at least 4 hours before or 4 hours after taking the bile acid binding resin, or at as great an interval as possible.1

  • Warfarin: Potential for decreased INR; monitor INR and adjust the dosage of warfarin, as needed, to maintain the target INR range.1

  • CYP1A2 Substrates with Narrow Therapeutic Index (e.g., theophylline and tizanidine): Potential for increased exposure to CYP1A2 substrates; monitor drug concentrations of CYP1A2 substrates with narrow therapeutic index.1

Actions

Obeticholic acid is an agonist for farnesoid X receptor (FXR), a nuclear receptor expressed in the liver and intestine. FXR is a key regulator of bile acid, inflammatory, fibrotic, and metabolic pathways. FXR activation decreases the intracellular hepatocyte concentrations of bile acids by suppressing de novo synthesis from cholesterol as well as by increased transport of bile acids out of the hepatocytes. These mechanisms limit the overall size of the circulating bile acid pool while promoting choleresis, thus reducing hepatic exposure to bile acids.1

Advice to Patients

Liver-Related Adverse Reactions

Advise patients to report any symptoms of worsening of liver disease to their healthcare provider immediately and that they may need to undergo laboratory testing periodically while on obeticholic acid treatment to assess liver function. 1

Advise patients who develop symptoms of complete biliary obstruction to report to their healthcare provider immediately.1

Severe Pruritus

Advise patients to contact their healthcare provider if they experience pruritus or an increase in the severity of pruritus. 1

Reduction in HDL-C

Advise patients that they may need to undergo laboratory testing to check for changes in lipid levels while on treatment with obeticholic acid. 1

Administration

Advise patients to take obeticholic acid with or without food.1 Also advise patients to take obeticholic acid at least 4 hours before or 4 hours after taking a bile acid binding resin, or at as great an interval as possible.1

Additional Information

AHFS First Release. For additional information until a more detailed monograph is developed and published, the manufacturer's labeling should be consulted. It is essential that the manufacturer's labeling be consulted for more detailed information on usual uses, dosage and administration, cautions, precautions, contraindications, potential drug interactions, laboratory test interferences, and acute toxicity.

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.

Obeticholic Acid

Routes

Dosage Forms

Strengths

Brand Names

Manufacturer

Oral

Tablet, Film Coated

5 mg

Ocaliva

Intercept Pharmaceuticals Inc

10 mg

Ocaliva

Intercept Pharmaceuticals Inc

AHFS Drug Information. © Copyright 2016, Selected Revisions September 12, 2016. American Society of Health-System Pharmacists, Inc., 7272 Wisconsin Avenue, Bethesda, Maryland 20814.

References

1. Intercept Pharmaceuticals Inc. Ocaliva (Obeticholic Acid) ORAL prescribing information. 2016 May.

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