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Obeticholic Acid

Pronunciation

(oh bet i KOE lik AS id)

Dosage Forms

Excipient information presented when available (limited, particularly for generics); consult specific product labeling.

Tablet, Oral:

Ocaliva: 5 mg, 10 mg

Brand Names: U.S.

  • Ocaliva

Pharmacologic Category

  • Farnesoid X Receptor Agonist

Pharmacology

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

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.

Excretion

Feces (~87%); urine (<3%)

Time to Peak

Plasma: Obeticholic acid: ~1.5 hours; glyco- and tauro- obeticholic acid: 10 hours

Protein Binding

>99%

Special Populations: 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.

Use: Labeled Indications

Primary biliary cholangitis: Treatment of primary biliary cholangitis (PBC) in combination with ursodiol (ursodeoxycholic acid) in adults with an inadequate response to ursodiol, or as monotherapy in adults unable to tolerate ursodiol.

Contraindications

Complete biliary obstruction.

Dosing: Adult

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 ALP and/or total bilirubin has not been achieved after 3 months, increase to 10 mg once daily (maximum: 10 mg/day).

Dosing: Geriatric

Refer to adult dosing.

Dosing: Renal Impairment

There are no dosage adjustments provided in the manufacturer′s labeling (has not been studied in patients with eGFR <60 mL/minute/1.73 m2).

Dosing: Hepatic Impairment

Mild impairment (Child- Pugh class A): No dosage adjustment necessary.

Moderate and severe impairment (Child-Pugh class B and C): Initial: 5 mg once weekly. If adequate reduction in ALP and/or total bilirubin has not been achieved after 3 months, increase to 5 mg twice weekly (at least 3 days apart) and subsequently to 10 mg twice weekly (at least 3 days apart) based on response and tolerability.

Dosing: Adjustment for Toxicity

Intolerable pruritus: Consider reducing dose to 5 mg every other day (patients intolerant to 5 mg once daily) or 5 mg once daily (patients intolerant to 10 mg once daily). May also interrupt dosing for up to 2 weeks followed by reintroduction at a reduced dosage. To achieve optimal response, increase to 10 mg once daily, as tolerated.

Persistent intolerable pruritus: Consider discontinuing therapy.

Administration

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.

Storage

Store at 20ºC to 25ºC (68ºF to 77ºF); excursions permitted to 15ºC to 30ºC (59ºF to 86ºF).

Drug Interactions

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. Consider therapy modification

CloZAPine: CYP1A2 Inhibitors (Weak) may increase the serum concentration of CloZAPine. Monitor therapy

CYP1A2 Substrates: Obeticholic Acid may increase the serum concentration of CYP1A2 Substrates. Monitor therapy

TiZANidine: CYP1A2 Inhibitors (Weak) may increase the serum concentration of TiZANidine. Management: Avoid these combinations when possible. If combined use cannot be avoided, initiate tizanidine at an adult dose of 2 mg and increase in 2-4 mg increments based on patient response. Monitor for increased effects of tizanidine, including adverse reactions. Consider therapy modification

Warfarin: Obeticholic Acid may diminish the anticoagulant effect of Warfarin. Monitor therapy

Adverse Reactions

>10%:

Central nervous system: Fatigue (19% to 25%)

Dermatologic: Pruritus (56% to 70%; severe: 19% to 23%)

Endocrine & metabolic: Decreased HDL cholesterol (9% to 20%)

Gastrointestinal: Abdominal pain (19%)

1% to 10%:

Cardiovascular: Peripheral edema (7%), palpitations (3% to 7%)

Central nervous system: Dizziness (7%)

Dermatologic: Skin rash (10%), eczema (3% to 6%)

Endocrine & metabolic: Thyroid dysfunction (4% to 6%)

Gastrointestinal: Constipation (7%)

Neuromuscular & skeletal: Arthralgia (6% to 10%)

Respiratory: Oropharyngeal pain (7% to 8%)

Miscellaneous: Fever (7%)

Frequency not defined::

Gastrointestinal: Cholangitis (primary biliary)

Hepatic: Ascites (worsening), jaundice

Warnings/Precautions

Concerns related to adverse effects:

• Hepatic effects: Dose-related hepatic adverse reactions (eg, jaundice, worsening ascites, primary biliary cholangitis flare) have been reported, as early as one month after initiating therapy. Monitor LFTs and for signs/symptoms of hepatic adverse reactions; in patients who develop clinically significant hepatic-related adverse reactions, weigh the potential risks against the benefits of continuing treatment. Discontinue use in patients who develop complete biliary obstruction.

• 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 dosage reduction, temporary interruption of dosing, and/or addition of bile acid resins or antihistamines to manage severe pruritus.

Disease-related concerns:

• Hepatic impairment: Use with caution in patients with moderate to severe hepatic impairment (Child-Pugh classes B and C); exposure increases significantly; dosage adjustment recommended.

Concurrent drug therapy issues:

• Drug-drug interactions: Potentially significant interactions may exist, requiring dose or frequency adjustment, additional monitoring, and/or selection of alternative therapy. Consult drug interactions database for more detailed information.

Monitoring Parameters

LFTs, including alkaline phosphatase and bilirubin, lipid profile; signs/symptoms of hepatic adverse reactions and/or pruritus.

Pregnancy Considerations

Adverse events have not been observed in animal reproduction studies.

Patient Education

• Discuss specific use of drug and side effects with patient as it relates to treatment. (HCAHPS: During this hospital stay, were you given any medicine that you had not taken before? Before giving you any new medicine, how often did hospital staff tell you what the medicine was for? How often did hospital staff describe possible side effects in a way you could understand?)

• Patient may experience loss of strength or energy, abdominal pain, joint pain, throat pain, dizziness, constipation, or eczema. Have patient report immediately to prescriber signs of liver problems (dark urine, fatigue, lack of appetite, nausea, abdominal pain, light-colored stools, vomiting, or jaundice), signs of thyroid problems (change in weight without trying, anxiety, feeling restless, feeling very weak, hair thinning, depression, neck swelling, difficulty focusing, inability handling heat or cold, menstrual changes, tremors, or sweating), severe itching, swelling in the arms or legs, or abnormal heartbeat (HCAHPS).

• Educate patient about signs of a significant reaction (eg, wheezing; chest tightness; fever; itching; bad cough; blue skin color; seizures; or swelling of face, lips, tongue, or throat). Note: This is not a comprehensive list of all side effects. Patient should consult prescriber for additional questions.

Intended Use and Disclaimer: Should not be printed and given to patients. This information is intended to serve as a concise initial reference for health care professionals to use when discussing medications with a patient. You must ultimately rely on your own discretion, experience, and judgment in diagnosing, treating, and advising patients.

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