obeticholic acid (Rx)

Brand and Other Names:Ocaliva
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Dosing & Uses

AdultPediatricGeriatric

Dosage Forms & Strengths

tablet

  • 5mg
  • 10mg

Primary Biliary Cholangitis

Indicated for primary biliary cholangitis (PBC) without cirrhosis or with compensated cirrhosis who do not have evidence of portal hypertension either in combination with ursodeoxycholic acid (UDCA) in adults with an inadequate response to UDCA for at least 1 yr or as monotherapy in adults intolerant to UDCA

Before initiating, determine if patient has the following:

  • Decompensated cirrhosis (eg, Child-Pugh class B or C)
  • Had prior decompensation event
  • Compensated cirrhosis with evidence of portal hypertension (eg, ascites, gastroesophageal varices, persistent thrombocytopenia)

Dosage regimen

  • 5 mg PO qDay for first 3 months
  • After 3 months, for patients tolerating drug, but have an inadequate reduction in alkaline phosphatase (ALP) and/or total bilirubin (TB), may increase dose up to 10 mg/day

Dosage Modifications

Intolerable pruritus

  • Consider 1 or more of the following options:
    • Add an antihistamine or bile-acid binding resin
    • Reduce dosage to 5 mg every other day if intolerant to 5 mg qDay OR 5 mg qDay if intolerant to 10 mg qDay
    • Temporarily interrupt dosing for up to 2 weeks, restart at reduced dosage
    • For patients whose dosage is reduced or interrupted, titrate dosage based on biochemical response and tolerability
    • Consider discontinuing treatment in patients who continue to experience persistent, intolerable pruritus despite management strategies

Renal impairment

  • eGFR >50 mL/min/1.73 m2: No meaningful effect observed on obeticholic acid and its conjugated metabolites
  • Moderate-to-severe (eGFR <60 mL/min/1.73 m2): Not studied

Hepatic impairment

  • Contraindicated in
    • Moderate-to-severe (Child-Pugh B or C)
    • Prior decompensated hepatic event
    • Compensated cirrhosis with evidence of portal hypertension (eg, ascites, gastroesophageal varices, persistent thrombocytopenia)
  • Closely monitor
    • Compensated cirrhosis
    • Concomitant hepatic disease
    • Severe intercurrent illness for new evidence of portal hypertension

Safety and efficacy not established

No overall differences in safety or effectiveness were observed between subjects older than 65 yr, but sensitivity in some older individuals cannot be ruled out

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Interactions

Interaction Checker

and obeticholic acid

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    No Interactions Found
    Interactions Found

    Contraindicated

      Serious - Use Alternative

        Significant - Monitor Closely

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            Contraindicated (0)

              Serious - Use Alternative (0)

                Monitor Closely (6)

                • cholestyramine

                  cholestyramine will decrease the level or effect of obeticholic acid by drug binding in GI tract. Modify Therapy/Monitor Closely. Administer obeticholic acid at least 4 hr before or 4 hr after taking a bile acid binding resins.

                • colesevelam

                  colesevelam will decrease the level or effect of obeticholic acid by drug binding in GI tract. Modify Therapy/Monitor Closely. Administer obeticholic acid at least 4 hr before or 4 hr after taking a bile acid binding resins.

                • colestipol

                  colestipol will decrease the level or effect of obeticholic acid by drug binding in GI tract. Modify Therapy/Monitor Closely. Administer obeticholic acid at least 4 hr before or 4 hr after taking a bile acid binding resins.

                • theophylline

                  obeticholic acid will increase the level or effect of theophylline by affecting hepatic enzyme CYP1A2 metabolism. Modify Therapy/Monitor Closely. CYP1A2 substrates that have a narrow therapeutic index should be monitored closely and the dose adjusted accordingly.

                • tizanidine

                  obeticholic acid will increase the level or effect of tizanidine by affecting hepatic enzyme CYP1A2 metabolism. Modify Therapy/Monitor Closely. CYP1A2 substrates that have a narrow therapeutic index should be monitored closely and the dose adjusted accordingly.

                • warfarin

                  obeticholic acid decreases effects of warfarin by unknown mechanism. Modify Therapy/Monitor Closely. Coadministration has been shown to increase S-warfarin exposure by 13%, but lowered INR by 11%. Monitor INR and adjust warfarin dose accordingly.

                Minor (0)

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                  Adverse Effects

                  >10%

                  Pruritus (56-70%)

                  Fatigue (19-25%)

                  Severe pruritus (19-23%)

                  Reduced HDL-C (9-20%)

                  Abdominal pain and discomfort (10-19%)

                  1-10%

                  Rash (7-10%)

                  Arthralgia (6-10%)

                  Oropharyngeal pain (7-8%)

                  Dizziness (7%)

                  Constipation (7%)

                  Peripheral edema (3-7%)

                  Palpitations (3-7%)

                  Pyrexia (7%)

                  Thyroid function abnormality (4-6%)

                  Eczema (3-6%)

                  Postmarketing Reports

                  Hepatobiliary disorders: Liver failure, new onset cirrhosis, increased direct and total bilirubin, new or worsening of jaundice

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                  Warnings

                  Black Box Warnings

                  Hepatic decompensation and failure in primary biliary cholangitis with cirrhosis

                  • Hepatic decompensation and failure, in some cases fatal or resulting in liver transplant, reported in patients with primary biliary cholangitis (PBC) with either compensated or decompensated cirrhosis
                  • Contraindicated in PBC with decompensated cirrhosis, prior decompensation event, or with compensated cirrhosis in patients who have evidence of portal hypertension
                  • Permanently discontinue in patients who develop laboratory or clinical evidence of hepatic decompensation, have compensated cirrhosis and develop evidence of portal hypertension, or experience clinically significant hepatic adverse reactions during treatment

                  Contraindications

                  Complete biliary obstruction

                  Decompensated cirrhosis (eg, Child-Pugh Class B or C) or a prior decompensation event

                  Compensated cirrhosis with evidence of portal hypertension (eg, ascites, gastroesophageal varices, persistent thrombocytopenia)

                  Cautions

                  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); monitor for reduction in HDL-C; for patients who do not respond after 1 yr at the highest recommended dosage that can be tolerated (ie, 10 mg/day), and who experience a reduction in HDL-C, weigh the potential risks against the benefits of continuing treatment

                  Severe pruritus reported; evaluate patients with new onset or worsening pruritus; consider treatment with bile acid binding resins, antihistamines, dose reduction, and/or temporary dose interruption

                  Hepatic impairment

                  • Closely monitor patients with compensated cirrhosis, concomitant hepatic disease, and/or severe intercurrent illness for new evidence of portal hypertension (eg, ascites, gastroesophageal varices, persistent thrombocytopenia) or increases above the upper limit of normal in total bilirubin, direct bilirubin, or prothrombin time to determine whether drug discontinuation is needed
                  • 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 significant hepatic adverse reactions while on treatment; interrupt treatment during severe intercurrent illness

                  Hepatic decompensation and failure

                  • Hepatic decompensation and failure, sometimes fatal or resulting in liver transplant, reported with treatment in PBC patients with cirrhosis, either compensated or decompensated
                  • Routinely monitor patients for progression of PBC, including hepatic adverse reactions, with laboratory and clinical assessments to determine whether drug discontinuation is needed
                  • Closely monitor with compensated cirrhosis, concomitant hepatic disease (eg, autoimmune hepatitis, alcoholic liver disease), and/or with severe intercurrent illness for new evidence of portal hypertension (eg, ascites, gastroesophageal varices, persistent thrombocytopenia) or increases above the upper limit of normal in total bilirubin, direct bilirubin, or prothrombin time to determine whether drug discontinuation is needed
                  • If severe intercurrent illness occurs, interrupt treatment and monitor the patient’s liver function; after resolution of the intercurrent illness, consider the potential risks and benefits of restarting treatment
                  • Permanently discontinue therapy in the following patients who:
                    • Develop laboratory or clinical evidence of hepatic decompensation (eg, ascites, jaundice, variceal bleeding, hepatic encephalopathy)
                    • Have compensated cirrhosis and develop evidence of portal hypertension (eg, ascites, gastroesophageal varices, persistent thrombocytopenia)
                    • Experience clinically significant hepatic adverse reactions.
                    • Develop complete biliary obstruction

                  FDA MedWatch alert

                  • On May 26, 2021, FDA restricted use of obeticholic acid in patients having PBC with advanced liver cirrhosis because it can cause serious harm
                  • Some PBC patients with cirrhosis (especially advanced cirrhosis) developed liver failure and some requiring liver transplant
                  • FDA identified 25 serious liver injury cases leading to liver decompensation or liver failure associated with obeticholic acid in PBC patients with cirrhosis, both in those without clinical signs of cirrhosis (compensated) or in those with clinical signs of cirrhosis (decompensated)
                  • Advanced cirrhosis is defined as cirrhosis with current or prior evidence of hepatic decompensation (eg, encephalopathy, coagulopathy) or portal hypertension (eg, ascites, gastroesophageal varices, persistent thrombocytopenia)
                  • Advise patients to contact prescriber immediately if any symptoms develop
                  • Monitor for clinically significant liver-related adverse reactions that may manifest as development of acute-on-chronic liver disease with nausea, vomiting, diarrhea, jaundice, scleral icterus, and/or dark urine; permanently discontinue if these symptoms develop

                  Drug interaction overview

                  • CYP3A4 inhibitor
                  • Downregulation of mRNA was observed in a concentration-dependent fashion for CYP1A2 and CYP3A4 by obeticholic acid and its glycine and taurine conjugate
                  • Bile-acid binding resins
                    • Separate obeticholic acid dosing from bile-acid resins
                    • Bile-acid binding resins may reduce the absorption, systemic exposure, and efficacy of obeticholic acid
                  • Warfarin
                    • Monitor INR and adjust warfarin dose accordingly
                    • Coadministration of warfarin and obeticholic acid has been shown to decrease the INR
                  • CYP1A2 substrates with narrow therapeutic index
                    • Monitor CYP1A2 substrates with narrow therapeutic index
                    • Obeticholic acid may increase exposure of CYP1A2 substrates
                  • Bile salt efflux pump (BSEP) inhibitors
                    • Avoid coadministration
                    • BSEP inhibitors may exacerbate accumulation of conjugated bile salts in the liver and result in clinical symptoms
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                  Pregnancy

                  Pregnancy

                  Limited available human data on the use of obeticholic acid during pregnancy are not sufficient to inform a drug-associated risk

                  Lactation

                  There is no information on presence in human milk, effects on breastfed infants, or effects on milk production

                  Consider developmental and health benefits of breastfeeding along with the mother’s clinical need for the drug, and any potential adverse effects on the breastfed infant from the drug or from the underlying maternal condition

                  Pregnancy Categories

                  A: Generally acceptable. Controlled studies in pregnant women show no evidence of fetal risk.

                  B: May be acceptable. Either animal studies show no risk but human studies not available or animal studies showed minor risks and human studies done and showed no risk.

                  C: Use with caution if benefits outweigh risks. Animal studies show risk and human studies not available or neither animal nor human studies done.

                  D: Use in LIFE-THREATENING emergencies when no safer drug available. Positive evidence of human fetal risk.

                  X: Do not use in pregnancy. Risks involved outweigh potential benefits. Safer alternatives exist.

                  NA: Information not available.

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                  Pharmacology

                  Mechanism of Action

                  Farnesoid X receptor (FXR) agonist

                  FXR is a nuclear receptor expressed in the liver, intestine, kidney, and adipose tissue that regulates a wide variety of target genes critically involved in the control of bile acid synthesis and transport, lipid metabolism, and glucose homeostasis

                  FXR activation suppresses de novo synthesis of bile acids in hepatocytes as well as increasing transport of bile acids out of hepatocytes, thereby reducing exposure of the hepatocytes to bile acid

                  Absorption

                  Peak plasma concentration

                  • Obeticholic acid: 1.5 hr
                  • Active metabolites: 10 hr

                  Distribution

                  Protein bound: >99%

                  Vd: 618 L

                  Metabolism

                  Obeticholic acid is conjugated with glycine or taurine in the liver then secreted into bile

                  Conjugates are converted back to obeticholic acid and either reabsorbed in the small intestine for enterohepatic recirculation or excreted in feces

                  Elimination

                  Excretion: ~87% feces; <3% urine

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                  Administration

                  Oral Administration

                  May take with or without food

                  Coadministration with bile-acid binding resin: Separate obeticholic acid dose by at least 4 hr before or after the bile-acid binding resin, or at as great an interval as possible

                  Storage

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

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                  Patient Handout

                  A Patient Handout is not currently available for this monograph.
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                  Formulary

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                  The above information is provided for general informational and educational purposes only. Individual plans may vary and formulary information changes. Contact the applicable plan provider for the most current information.

                  Tier Description
                  1 This drug is available at the lowest co-pay. Most commonly, these are generic drugs.
                  2 This drug is available at a middle level co-pay. Most commonly, these are "preferred" (on formulary) brand drugs.
                  3 This drug is available at a higher level co-pay. Most commonly, these are "non-preferred" brand drugs.
                  4 This drug is available at a higher level co-pay. Most commonly, these are "non-preferred" brand drugs or specialty prescription products.
                  5 This drug is available at a higher level co-pay. Most commonly, these are "non-preferred" brand drugs or specialty prescription products.
                  6 This drug is available at a higher level co-pay. Most commonly, these are "non-preferred" brand drugs or specialty prescription products.
                  NC NOT COVERED – Drugs that are not covered by the plan.
                  Code Definition
                  PA Prior Authorization
                  Drugs that require prior authorization. This restriction requires that specific clinical criteria be met prior to the approval of the prescription.
                  QL Quantity Limits
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                  Drugs that have step therapy associated with each prescription. This restriction typically requires that certain criteria be met prior to approval for the prescription.
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                  Medscape prescription drug monographs are based on FDA-approved labeling information, unless otherwise noted, combined with additional data derived from primary medical literature.