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) in combination with ursodeoxycholic acid (UDCA) in adults with an inadequate response to UDCA for at least 1 yr or as monotherapy in adults unable to tolerate UDCA

Before initiating obeticholic acid in patients with suspected cirrhosis, determine patient’s Child-Pugh classification (A, B, or C) using nomogram (provided below) and determine the appropriate starting dosage

Child-Pugh nomogram

  • Calculate Child-Pugh class before initiating
  • Routinely monitor during treatment for biochemical response, tolerability, progression of PBC disease, and reevaluate Child-Pugh classification to determine if dosage adjustment needed
  • Reduce dose frequency from once daily to once weekly as appropriate for patients who progress to advanced disease (ie, from Child-Pugh Class A to Child-Pugh Class B or C)
  • Encephalopathy grade
    • Grade 0: 1 point
    • Grade 1 or 2: 2 points
    • Grade 3 or 4: 3 points
  • Ascites
    • Absent: 1 point
    • Slight: 2 points
    • Moderate: 3 points
  • Serum bilirubin (mg/dL)
    • <2: 1 point
    • 2-3: 2 points
    • >3: 3 points
  • Serum albumin (g/dL)
    • >3.5: 1 point
    • 2.8-3.5: 2 points
    • <2.8: 3 points
  • INR
    • <1.7: 1 point
    • 1.7-2.2: 2 points
    • >2.2: 3 points
  • Child-Pugh class (sum of all points)
    • Child-Pugh Class is obtained by adding the points from all 5 parameters to derive a total score, which can range from 5-15 points
    • Child-Pugh Class A: 5-6 points
    • Child-Pugh Class B: 7-9 points
    • Child-Pugh Class C: 10-15 points

Starting dose and titration

  • Noncirrhotic or compensated Child-Pugh class A
    • Starting dose: 5 mg PO qDay
    • Dosage titration: If an adequate response has not been achieved after 3 months at 5 mg/day, and obeticholic acid is being tolerated, increase dose to 10 mg qDay
    • Not to exceed 10 mg/day
  • Child-Pugh class B or C, or prior decompensation event
    • Starting dose: 5 mg PO once weekly
    • Dosage titration: If an adequate response has not been achieved after 3 months at 5 mg once weekly, and obeticholic acid is being tolerated, increase dose to 5 mg twice weekly (at least 3 days apart)
    • May titrate to 10 mg twice weekly (at least 3 days apart) based on response and tolerability

Dosage Modifications

Intolerable pruritus

  • Consider 1 or more of the following options:
  • Noncirrhotic or compensated cirrhotic Child-Pugh class A
    • Add an antihistamine or bile-acid binding resin
    • Temporarily interrupt treatment for up to 2 weeks, followed by restarting at reduced dosage
    • If intolerant to 5 mg/day, decrease to 5 mg every other day
    • If intolerant to 10 mg/day, decrease to 5 mg/day
    • For patients whose dosage is reduced or interrupted, titrate the dosage based on biochemical response, tolerability and adjust according to Child-Pugh classification
  • Child-Pugh class B or C or prior decompensation event
    • Add an antihistamine or bile-acid binding resin
    • Temporarily interrupt treatment for up to 2 weeks, followed by restarting at reduced dosage if applicable; titrate the dosage based on biochemical response, tolerability and adjust according to Child-Pugh classification
  • Treatment discontinuation
    • Consider discontinuing treatment in patients who continue to experience intolerable pruritus

Hepatic impairment

  • See adult dosing for dose recommendations based on Child-Pugh class
  • Contraindicated with complete biliary obstruction

Dosing Considerations

Indication is approved under accelerated approval based on a reduction in alkaline phosphatase; continued approval for this indication may be contingent on verification and description of clinical benefit in confirmatory trials

Monitor closely for patients at increased risk of hepatic decompensation, including those with laboratory evidence of worsening liver function (ie, total bilirubin, INR, albumin) and/or progression to cirrhosis

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

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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%)

            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%)

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            Warnings

            Black Box Warnings

            Hepatic decompensation and failure with incorrect dose for patients with Child-Pugh B or C

            • In postmarketing reports, hepatic decompensation and failure, in some cases fatal, have been reported in patients with primary biliary cholangitis (PBC) with decompensated cirrhosis or Child-Pugh Class B or C hepatic impairment when obeticholic acid was dosed more frequently than recommended
            • Recommended starting dosage is 5 mg PO once weekly for patients with Child-Pugh Class B or C hepatic impairment or a prior decompensation event

            Contraindications

            Complete biliary obstruction

            Cautions

            Hepatic decompensation and failure, in some cases fatal, reported in patients with PBC who have decompensated cirrhosis or Child-Pugh Class B or C hepatic impairment when obeticholic acid was dosed more frequently than the recommended starting dosage of 5 mg once weekly (see Black Box Warnings and Adult Dosing)

            Monitor patients for elevations in liver enzymes and risks for hepatic decompensation (eg, worsening renal function, dehydration)

            Dose response relationship observed in clinical trials for liver-related adverse reactions, including jaundice, worsening ascites, and primary biliary cholangitis flare (doses ≥10 mg/day)

            Discontinue therapy if complete biliary obstruction occurs (see Contraindications)

            Management strategies for severe pruritus include antihistamines, bile acid resins, and temporary treatment interruption (see Dosage Modifications); discontinue therapy if persistent intolerable pruritus occurs

            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

            Drug interaction overview

            • Bile-acid binding resins may reduce the absorption, systemic exposure, and efficacy of obeticholic acid
            • Coadministration of warfarin and obeticholic acid has been shown to decrease the INR; monitor the INR and adjust warfarin dose accordingly
            • Coadministration with CYP1A2 substrates (eg, theophylline, tizanidine) may increase exposure of CYP1A2 substrates; monitor CYP1A2 substrates with narrow therapeutic index
            • Avoid concomitant use of inhibitors of the bile salt efflux pump (BSEP) (eg, cyclosporine); 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

            Unknown if distributed in human breast milk

            Consider the 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

            The 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

            Concomitant bile-acid binding resin: Separate obeticholic acid dose by at least 4 hr

            Storage

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

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            Formulary

            FormularyPatient Discounts

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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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