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  • CLASSES

    Farnesoid X Receptor (FXR) Agonists

    DEA CLASS

    Rx

    DESCRIPTION

    Farnesoid X receptor (FXR) agonist
    For primary biliary cirrhosis, as monotherapy in adults unable to tolerate ursodeoxycholic acid or in combination with ursodeoxycholic acid in adults with inadequate response to ursodeoxycholic acid
    FDA Medwatch: Obeticholic acid is being incorrectly dosed in some patients with moderate to severe hepatic impairment, resulting in an increased risk of serious liver injury and death; obeticholic acid may also be associated with liver injury in some patients with mild hepatic impairment who are receiving the correct dose

    COMMON BRAND NAMES

    OCALIVA

    HOW SUPPLIED

    OCALIVA Oral Tab: 5mg, 10mg

    DOSAGE & INDICATIONS

    For the treatment of primary biliary cholangitis / primary biliary cirrhosis (PBC) in combination with ursodeoxycholic acid (UDCA) in patients with an inadequate response to UDCA, or as monotherapy in patients unable to tolerate UDCA.
    Oral dosage
    Adults

    5 mg PO orally once daily is the recommended starting dose in patients who have not achieved adequate response to UDCA for at least 1 year or for those intolerant to UDCA. May increase to 10 mg PO once daily if adequate reduction in ALP and/or total bilirubin has not been achieved after 3 months and the patient is tolerating the 5 mg dose. This indication is approved under accelerated approval based on reduction in alkaline phosphatase (ALP). An improvement in survival or disease-related symptoms has not been established.

    MAXIMUM DOSAGE

    Adults

    10 mg PO once daily.

    Geriatric

    10 mg PO once daily.

    Adolescents

    Safety and efficacy have not been established.

    Children

    Safety and efficacy have not been established.

    Infants

    Safety and efficacy have not been established.

    Neonates

    Safety and efficacy have not been established.

    DOSING CONSIDERATIONS

    Hepatic Impairment

    Treatment with obeticholic acid in patients with moderate to severe hepatic impairment should be initiated and monitored by a healthcare provider with experience managing primary biliary cholangitis / primary biliary cirrhosis (PBC). No dosage adjustment is recommended for patients with mild (Child-Pugh Class A) hepatic impairment. For patients with moderate (Child-Pugh Class B) and severe (Child-Pugh Class C) hepatic impairment, start at a dose of 5 mg PO once weekly. If adequate reduction in ALP and/or total bilirubin has not been achieved after 3 months, and the patient is tolerating treatment, increase the dose to 5 mg PO twice weekly (at least 3 days apart) and subsequently to the maximum approved dose of 10 mg PO twice weekly (at least 3 days apart) depending on response and tolerability. Serious hepatic injury and death has occurred in some patients with moderate to severe hepatic impairment who were receiving excessive dosing, particularly a higher frequency of dosing than is recommended in the drug label for them. Healthcare professionals should adhere to the recommended dosing and monitoring in the current drug label. Monitor patients frequently for disease progression and  hepatic-related adverse reactions; reduce the dosing frequency to once- or twice-weekly for patients who progress to moderate or severe liver impairment. . Weigh the potential risks and benefits of continuing treatment in patients who experience clinically significant liver-related adverse reactions.

    Renal Impairment

    Specific guidelines for dosage adjustments in renal impairment are not available; it appears that no dosage adjustments are needed as there is minimal renal excretion.
     
    Management of Patients with Intolerable Pruritus
    For patients with intolerable pruritus with obeticholic acid, consider one or more interventions including adding an antihistamine or bile acid binding resin (administered 4 hours before or after obeticholic acid). A dose reduction may also be considered. Reduce the dose to 5 mg PO every other day for patients intolerant to 5 mg PO daily or reduce the dose to 5 mg PO daily for patients intolerant to 10 mg PO daily. Additionally, consider temporarily interrupting therapy for up to 2 weeks and then restarting at a reduced dosage. Increase the dosage to 10 mg PO once daily, as tolerated, to achieve optimal response. Consider discontinuing obeticholic acid treatment in patients who continue to experience persistent, intolerable pruritus.

    ADMINISTRATION

    Oral Administration

    Take obeticholic acid orally with or without food.
    For patients 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.

    STORAGE

    OCALIVA :
    - Store between 68 to 77 degrees F, excursions permitted 59 to 86 degrees F

    CONTRAINDICATIONS / PRECAUTIONS

    Biliary obstruction, hepatic disease

    Obeticholic acid is contraindicated in patients with complete biliary obstruction. Additionally, use caution in patients with hepatic disease as dosage adjustment is necessary for patients with moderate (Child-Pugh Class B) or severe (Child-Pugh Class C) hepatic impairment. In September 2017, the FDA warned that treatment with obeticholic acid has resulted in an increased risk of serious hepatic injury and death in some patients with moderate to severe hepatic impairment who were 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 hepatic injury in some patients with mild hepatic impairment who are receiving the correct dose. Healthcare professionals should adhere to the recommended dosing and monitoring in the current drug label. The FDA is working with the manufacturer to address these safety concerns. Baseline liver function should be determined prior to initiating therapy; 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 hepatic injury (e.g., worsened liver blood tests and adverse hepatic-related reactions that may be inconsistent with the patient’s extent of disease). If hepatic 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 hepatic injury.

    Pregnancy

    The limited available human data on the use of obeticholic acid during pregnancy are not sufficient to inform a drug-associated risk. In animal studies, no developmental abnormalities or fetal harm was noted.

    Breast-feeding

    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. Consider the benefits of breast-feeding, the risk of potential infant drug exposure, and the risk of an untreated or inadequately treated condition. If a breast-feeding infant experiences an adverse effect related to a maternally administered drug, healthcare providers are encouraged to report the adverse effect to the FDA.

    ADVERSE REACTIONS

    Severe

    eczema vaccinatum / Delayed / 3.0-6.0
    hepatic encephalopathy / Delayed / 0-1.0
    biliary obstruction / Delayed / Incidence not known

    Moderate

    decreased HDL cholesterol (HDL-C) concentration / Delayed / 9.0-20.0
    constipation / Delayed / 7.0-7.0
    peripheral edema / Delayed / 3.0-7.0
    palpitations / Early / 3.0-7.0
    hypothyroidism / Delayed / 0-6.0
    ascites / Delayed / 0-1.0
    jaundice / Delayed / Incidence not known
    cholangitis / Delayed / Incidence not known
    elevated hepatic enzymes / Delayed / Incidence not known

    Mild

    pruritus ani / Early / 0-70.0
    ocular pruritus / Rapid / 0-70.0
    pruritus / Rapid / 56.0-70.0
    asthenia / Delayed / 0-25.0
    fatigue / Early / 19.0-25.0
    abdominal pain / Early / 10.0-19.0
    maculopapular rash / Early / 0-10.0
    urticaria / Rapid / 0-10.0
    rash (unspecified) / Early / 7.0-10.0
    arthralgia / Delayed / 6.0-10.0
    syncope / Early / 0-7.0
    dizziness / Early / 7.0-7.0
    fever / Early / 7.0-7.0

    DRUG INTERACTIONS

    Acetaminophen; Aspirin, ASA; Caffeine: (Moderate) Obeticholic acid may increase the exposure to concomitant drugs that are CYP1A2 substrates, such as caffeine. Concomitant administration of 200 mg caffeine as a single dose with obeticholic acid 10 mg once daily resulted in a 42% increase in caffeine AUC and a 6% increase in caffeine Cmax. Therapeutic monitoring is recommended with coadministration. No specific management is recommended except in patients who complain of caffeine-related side effects like nausea, tremor, or palpitations. In such patients, the dosage of caffeine-containing medications or the ingestion of caffeine-containing products may need to be reduced.
    Acetaminophen; Butalbital; Caffeine: (Moderate) Obeticholic acid may increase the exposure to concomitant drugs that are CYP1A2 substrates, such as caffeine. Concomitant administration of 200 mg caffeine as a single dose with obeticholic acid 10 mg once daily resulted in a 42% increase in caffeine AUC and a 6% increase in caffeine Cmax. Therapeutic monitoring is recommended with coadministration. No specific management is recommended except in patients who complain of caffeine-related side effects like nausea, tremor, or palpitations. In such patients, the dosage of caffeine-containing medications or the ingestion of caffeine-containing products may need to be reduced.
    Acetaminophen; Butalbital; Caffeine; Codeine: (Moderate) Obeticholic acid may increase the exposure to concomitant drugs that are CYP1A2 substrates, such as caffeine. Concomitant administration of 200 mg caffeine as a single dose with obeticholic acid 10 mg once daily resulted in a 42% increase in caffeine AUC and a 6% increase in caffeine Cmax. Therapeutic monitoring is recommended with coadministration. No specific management is recommended except in patients who complain of caffeine-related side effects like nausea, tremor, or palpitations. In such patients, the dosage of caffeine-containing medications or the ingestion of caffeine-containing products may need to be reduced.
    Acetaminophen; Caffeine; Dihydrocodeine: (Moderate) Obeticholic acid may increase the exposure to concomitant drugs that are CYP1A2 substrates, such as caffeine. Concomitant administration of 200 mg caffeine as a single dose with obeticholic acid 10 mg once daily resulted in a 42% increase in caffeine AUC and a 6% increase in caffeine Cmax. Therapeutic monitoring is recommended with coadministration. No specific management is recommended except in patients who complain of caffeine-related side effects like nausea, tremor, or palpitations. In such patients, the dosage of caffeine-containing medications or the ingestion of caffeine-containing products may need to be reduced.
    Acetaminophen; Caffeine; Magnesium Salicylate; Phenyltoloxamine: (Moderate) Obeticholic acid may increase the exposure to concomitant drugs that are CYP1A2 substrates, such as caffeine. Concomitant administration of 200 mg caffeine as a single dose with obeticholic acid 10 mg once daily resulted in a 42% increase in caffeine AUC and a 6% increase in caffeine Cmax. Therapeutic monitoring is recommended with coadministration. No specific management is recommended except in patients who complain of caffeine-related side effects like nausea, tremor, or palpitations. In such patients, the dosage of caffeine-containing medications or the ingestion of caffeine-containing products may need to be reduced.
    Acetaminophen; Caffeine; Phenyltoloxamine; Salicylamide: (Moderate) Obeticholic acid may increase the exposure to concomitant drugs that are CYP1A2 substrates, such as caffeine. Concomitant administration of 200 mg caffeine as a single dose with obeticholic acid 10 mg once daily resulted in a 42% increase in caffeine AUC and a 6% increase in caffeine Cmax. Therapeutic monitoring is recommended with coadministration. No specific management is recommended except in patients who complain of caffeine-related side effects like nausea, tremor, or palpitations. In such patients, the dosage of caffeine-containing medications or the ingestion of caffeine-containing products may need to be reduced.
    Aliskiren; Valsartan: (Moderate) Obeticholic acid may increase the exposure to valsartan. Valsartan is a substrate of OATP1B1 and obeticholic acid inhibits OAT1B1 in vitro. Caution and close monitoring is advised if these drugs are used together.
    Alosetron: (Major) Obeticholic acid may increase the exposure to concomitant drugs that are CYP1A2 substrates, such as alosetron. Therapeutic monitoring is recommended with coadministration. Elevated alosetron concentrations may cause severe constipation.
    Alprazolam: (Moderate) Obeticholic acid may increase the exposure to concomitant drugs that are CYP1A2 substrates, such as alprazolam. Therapeutic monitoring is recommended with coadministration.
    Amlodipine; Hydrochlorothiazide, HCTZ; Valsartan: (Moderate) Obeticholic acid may increase the exposure to valsartan. Valsartan is a substrate of OATP1B1 and obeticholic acid inhibits OAT1B1 in vitro. Caution and close monitoring is advised if these drugs are used together.
    Amlodipine; Valsartan: (Moderate) Obeticholic acid may increase the exposure to valsartan. Valsartan is a substrate of OATP1B1 and obeticholic acid inhibits OAT1B1 in vitro. Caution and close monitoring is advised if these drugs are used together.
    Amoxicillin; Clarithromycin; Omeprazole: (Minor) Concurrent administration of 20 mg omeprazole as a single dose with obeticholic acid 10 mg once daily resulted in a 32% increase in omeprazole AUC and a 33% increase in omeprazole Cmax. The clinical significance of this interaction is unknown. Even though omeprazole is a CYPC19 substrate, obeticholic acid is not expected to inhibit the CYPC19 isoenzyme. The mechanism of this interaction has not been described.
    Anagrelide: (Moderate) Obeticholic acid may increase the exposure to concomitant drugs that are CYP1A2 substrates, such as anagrelide. Therapeutic monitoring is recommended with coadministration.
    Asenapine: (Moderate) Obeticholic acid may increase the exposure to concomitant drugs that are CYP1A2 substrates, such as asenapine. Therapeutic monitoring is recommended with coadministration. Elevated asenapine concentrations may lead to adverse events such as extrapyramidal symptoms.
    Aspirin, ASA; Butalbital; Caffeine: (Moderate) Obeticholic acid may increase the exposure to concomitant drugs that are CYP1A2 substrates, such as caffeine. Concomitant administration of 200 mg caffeine as a single dose with obeticholic acid 10 mg once daily resulted in a 42% increase in caffeine AUC and a 6% increase in caffeine Cmax. Therapeutic monitoring is recommended with coadministration. No specific management is recommended except in patients who complain of caffeine-related side effects like nausea, tremor, or palpitations. In such patients, the dosage of caffeine-containing medications or the ingestion of caffeine-containing products may need to be reduced.
    Aspirin, ASA; Butalbital; Caffeine; Codeine: (Moderate) Obeticholic acid may increase the exposure to concomitant drugs that are CYP1A2 substrates, such as caffeine. Concomitant administration of 200 mg caffeine as a single dose with obeticholic acid 10 mg once daily resulted in a 42% increase in caffeine AUC and a 6% increase in caffeine Cmax. Therapeutic monitoring is recommended with coadministration. No specific management is recommended except in patients who complain of caffeine-related side effects like nausea, tremor, or palpitations. In such patients, the dosage of caffeine-containing medications or the ingestion of caffeine-containing products may need to be reduced.
    Aspirin, ASA; Caffeine; Dihydrocodeine: (Moderate) Obeticholic acid may increase the exposure to concomitant drugs that are CYP1A2 substrates, such as caffeine. Concomitant administration of 200 mg caffeine as a single dose with obeticholic acid 10 mg once daily resulted in a 42% increase in caffeine AUC and a 6% increase in caffeine Cmax. Therapeutic monitoring is recommended with coadministration. No specific management is recommended except in patients who complain of caffeine-related side effects like nausea, tremor, or palpitations. In such patients, the dosage of caffeine-containing medications or the ingestion of caffeine-containing products may need to be reduced.
    Aspirin, ASA; Omeprazole: (Minor) Concurrent administration of 20 mg omeprazole as a single dose with obeticholic acid 10 mg once daily resulted in a 32% increase in omeprazole AUC and a 33% increase in omeprazole Cmax. The clinical significance of this interaction is unknown. Even though omeprazole is a CYPC19 substrate, obeticholic acid is not expected to inhibit the CYPC19 isoenzyme. The mechanism of this interaction has not been described.
    Axitinib: (Minor) Monitor patients for increased axitinib-related adverse events if coadministration with obeticholic acid occurs. Axitinib is primarily metabolized by CYP3A4, and to a lesser extent by CYP1A2, CYP2C19, and UGT1A1. Obeticholic acid is a CYP1A2 inhibitor. Obeticholic acid increased the AUC and Cmax of caffeine, another CYP1A2 substrate, by 42% and 6%, respectively. Theoretically, exposure to axitinib may be increased.
    Bendamustine: (Major) Obeticholic acid may increase the exposure to concomitant drugs that are CYP1A2 substrates, such as bendamustine. Caution should be exercised, or alternative treatments considered with coadministration.
    Bupivacaine; Lidocaine: (Moderate) Obeticholic acid may increase the exposure to concomitant drugs that are CYP1A2 substrates, such as lidocaine. Lidocaine is extensively metabolized in the liver into two active compounds, monoethylglycinexylidide (MEGX) and glycinexylidide (GX). The major metabolic pathway, sequential N-deethylation to MEGX and GX, is primarily mediated by CYP1A2 with a minor role of CYP3A4. Therapeutic monitoring is recommended with coadministration.
    Caffeine: (Moderate) Obeticholic acid may increase the exposure to concomitant drugs that are CYP1A2 substrates, such as caffeine. Concomitant administration of 200 mg caffeine as a single dose with obeticholic acid 10 mg once daily resulted in a 42% increase in caffeine AUC and a 6% increase in caffeine Cmax. Therapeutic monitoring is recommended with coadministration. No specific management is recommended except in patients who complain of caffeine-related side effects like nausea, tremor, or palpitations. In such patients, the dosage of caffeine-containing medications or the ingestion of caffeine-containing products may need to be reduced.
    Caffeine; Ergotamine: (Moderate) Obeticholic acid may increase the exposure to concomitant drugs that are CYP1A2 substrates, such as caffeine. Concomitant administration of 200 mg caffeine as a single dose with obeticholic acid 10 mg once daily resulted in a 42% increase in caffeine AUC and a 6% increase in caffeine Cmax. Therapeutic monitoring is recommended with coadministration. No specific management is recommended except in patients who complain of caffeine-related side effects like nausea, tremor, or palpitations. In such patients, the dosage of caffeine-containing medications or the ingestion of caffeine-containing products may need to be reduced.
    Cholestyramine: (Moderate) Bile acid binding resins such as cholestyramine absorb and reduce bile acid absorption and may reduce the absorption, systemic exposure, and efficacy of obeticholic acid. If used together, take obeticholic acid at least 4 hours before or 4 hours after taking the bile acid resin, or at as great an interval as possible.
    Cinacalcet: (Moderate) Obeticholic acid may increase the exposure to concomitant drugs that are CYP1A2 substrates, such as cinacalcet. Therapeutic monitoring is recommended with coadministration.
    Clomipramine: (Moderate) Obeticholic acid may increase the exposure to concomitant drugs that are CYP1A2 substrates, such as clomipramine. Therapeutic monitoring is recommended with coadministration.
    Clozapine: (Major) Caution is advisable during concurrent use of obeticholic acid and clozapine. Obeticholic acid may increase the exposure to concomitant drugs that are CYP1A2 substrates, such as clozapine. Treatment with clozapine has been associated with QT prolongation, torsade de pointes (TdP), cardiac arrest, and sudden death. Elevated plasma concentrations of clozapine occurring through CYP inhibition may potentially increase the risk of life-threatening arrhythmias or other adverse effects. According to the manufacturer, patients receiving clozapine in combination with a weak to moderate CYP1A2 inhibitor should be monitored for adverse reactions. Consideration should be given to reducing the clozapine dose if necessary.
    Cobicistat; Elvitegravir; Emtricitabine; Tenofovir Alafenamide: (Minor) Obeticholic acid may increase the exposure to tenofovir alafenamide. Tenofavir alafenamide is a substrate of OATP1B1 and OATP1B3 and obeticholic acid inhibits OAT1B1 and OATP1B3 in vitro. Caution and close monitoring is advised if obeticholic acid is coadministered with tenofovir alafenamide.
    Colesevelam: (Moderate) Bile acid binding resins such as colesevelam absorb and reduce bile acid absorption and may reduce the absorption, systemic exposure, and efficacy of obeticholic acid. If used together, take obeticholic acid at least 4 hours before or 4 hours after taking the bile acid resin, or at as great an interval as possible.
    Colestipol: (Moderate) Bile acid binding resins such as colestipol absorb and reduce bile acid absorption and may reduce the absorption, systemic exposure, and efficacy of obeticholic acid. If used together, take obeticholic acid at least 4 hours before or 4 hours after taking the bile acid resin, or at as great an interval as possible.
    Cyclobenzaprine: (Minor) Obeticholic acid may increase the exposure to concomitant drugs that are CYP1A2 substrates, such as cyclobenzaprine. Therapeutic monitoring is recommended with coadministration. Observe the patient for enhanced side effects, such as CNS depression, if these drugs are coadministered.
    Dasabuvir; Ombitasvir; Paritaprevir; Ritonavir: (Moderate) Obeticholic acid may increase the exposure to paritaprevir. Paritaprevir is a substrate of OATP1B1 and OATP1B3 and obeticholic acid inhibits OAT1B1 and OATP1B3 in vitro. Caution and close monitoring is advised if obeticholic acid is administered with products containing paritaprevir.
    Elbasvir; Grazoprevir: (Severe) Concurrent administration of elbasvir; grazoprevir with obeticholic acid is contraindicated. Use of these drugs together is expected to significantly increase the plasma concentrations of grazoprevir, and may result in adverse effects (i.e., elevated ALT concentrations). Obeticholic acid is an inhibitor of the organic anion transporting polypeptide (OATP1B1/3) in vitro; grazoprevir is an OATP1B1/3 substrate.
    Eluxadoline: (Major) When administered concurrently with obeticholic acid, the dose of eluxadoline must be reduced to 75 mg PO twice daily, and the patient should be closely monitored for eluxadoline-related adverse effects (i.e., decreased mental and physical acuity). Eluxadoline is a substrate of the organic anion-transporting peptide (OATP1B1); obeticholic acid is an in vitro inhibitor of OATP1B1 and 1B3. Advise patients against driving or operating machinery until the combine effects of these drugs on the individual patient is known.
    Emtricitabine; Rilpivirine; Tenofovir alafenamide: (Minor) Obeticholic acid may increase the exposure to tenofovir alafenamide. Tenofavir alafenamide is a substrate of OATP1B1 and OATP1B3 and obeticholic acid inhibits OAT1B1 and OATP1B3 in vitro. Caution and close monitoring is advised if obeticholic acid is coadministered with tenofovir alafenamide.
    Emtricitabine; Tenofovir alafenamide: (Minor) Obeticholic acid may increase the exposure to tenofovir alafenamide. Tenofavir alafenamide is a substrate of OATP1B1 and OATP1B3 and obeticholic acid inhibits OAT1B1 and OATP1B3 in vitro. Caution and close monitoring is advised if obeticholic acid is coadministered with tenofovir alafenamide.
    Ezetimibe; Simvastatin: (Moderate) Obeticholic acid may increase the exposure to simvastatin. Simvastatin is a substrate of OATP1B1 and OATP1B3 and obeticholic acid inhibits OAT1B1 and OATP1B3 in vitro. Caution and close monitoring is advised if these drugs are used together.
    Fluoxetine; Olanzapine: (Moderate) Obeticholic acid may increase the exposure to concomitant drugs that are CYP1A2 substrates, such as olanzapine. Decreased metabolism of olanzapine may lead to clinically important adverse reactions such as extrapyramidal symptoms, sedation, or orthostatic hypotension. In addition, olanzapine is associated with a possible risk for QT prolongation and TdP. Therapeutic monitoring is recommended with coadministration.
    Flutamide: (Moderate) Obeticholic acid may increase the exposure to concomitant drugs that are CYP1A2 substrates, such as flutamide. Therapeutic monitoring is recommended with coadministration.
    Fluvoxamine: (Minor) Obeticholic acid may increase the exposure to concomitant drugs that are CYP1A2 substrates, such as fluvoxamine. Therapeutic monitoring is recommended with coadministration.
    Hydrochlorothiazide, HCTZ; Triamterene: (Minor) Obeticholic acid may increase the exposure to concomitant drugs that are CYP1A2 substrates, such as triamterene. Therapeutic monitoring is recommended with coadministration.
    Hydrochlorothiazide, HCTZ; Valsartan: (Moderate) Obeticholic acid may increase the exposure to valsartan. Valsartan is a substrate of OATP1B1 and obeticholic acid inhibits OAT1B1 in vitro. Caution and close monitoring is advised if these drugs are used together.
    Imipramine: (Moderate) Obeticholic acid may increase the exposure to concomitant drugs that are CYP1A2 substrates, such as imipramine. Therapeutic monitoring is recommended with coadministration.
    Lidocaine: (Moderate) Obeticholic acid may increase the exposure to concomitant drugs that are CYP1A2 substrates, such as lidocaine. Lidocaine is extensively metabolized in the liver into two active compounds, monoethylglycinexylidide (MEGX) and glycinexylidide (GX). The major metabolic pathway, sequential N-deethylation to MEGX and GX, is primarily mediated by CYP1A2 with a minor role of CYP3A4. Therapeutic monitoring is recommended with coadministration.
    Melatonin: (Moderate) Obeticholic acid may increase the exposure to concomitant drugs that are CYP1A2 substrates, such as melatonin. Therapeutic monitoring is recommended with coadministration.
    Mexiletine: (Moderate) Obeticholic acid may increase the exposure to concomitant drugs that are CYP1A2 substrates, such as mexiletine. Therapeutic monitoring is recommended with coadministration.
    Nebivolol; Valsartan: (Moderate) Obeticholic acid may increase the exposure to valsartan. Valsartan is a substrate of OATP1B1 and obeticholic acid inhibits OAT1B1 in vitro. Caution and close monitoring is advised if these drugs are used together.
    Niacin; Simvastatin: (Moderate) Obeticholic acid may increase the exposure to simvastatin. Simvastatin is a substrate of OATP1B1 and OATP1B3 and obeticholic acid inhibits OAT1B1 and OATP1B3 in vitro. Caution and close monitoring is advised if these drugs are used together.
    Olanzapine: (Moderate) Obeticholic acid may increase the exposure to concomitant drugs that are CYP1A2 substrates, such as olanzapine. Decreased metabolism of olanzapine may lead to clinically important adverse reactions such as extrapyramidal symptoms, sedation, or orthostatic hypotension. In addition, olanzapine is associated with a possible risk for QT prolongation and TdP. Therapeutic monitoring is recommended with coadministration.
    Ombitasvir; Paritaprevir; Ritonavir: (Moderate) Obeticholic acid may increase the exposure to paritaprevir. Paritaprevir is a substrate of OATP1B1 and OATP1B3 and obeticholic acid inhibits OAT1B1 and OATP1B3 in vitro. Caution and close monitoring is advised if obeticholic acid is administered with products containing paritaprevir.
    Omeprazole: (Minor) Concurrent administration of 20 mg omeprazole as a single dose with obeticholic acid 10 mg once daily resulted in a 32% increase in omeprazole AUC and a 33% increase in omeprazole Cmax. The clinical significance of this interaction is unknown. Even though omeprazole is a CYPC19 substrate, obeticholic acid is not expected to inhibit the CYPC19 isoenzyme. The mechanism of this interaction has not been described.
    Omeprazole; Sodium Bicarbonate: (Minor) Concurrent administration of 20 mg omeprazole as a single dose with obeticholic acid 10 mg once daily resulted in a 32% increase in omeprazole AUC and a 33% increase in omeprazole Cmax. The clinical significance of this interaction is unknown. Even though omeprazole is a CYPC19 substrate, obeticholic acid is not expected to inhibit the CYPC19 isoenzyme. The mechanism of this interaction has not been described.
    Pimozide: (Major) Obeticholic acid may increase the exposure to concomitant drugs that are CYP1A2 substrates, such as pimozide. Elevated pimozide concentrations can lead to QT prolongation, ventricular arrhythmias, and sudden death.
    Pirfenidone: (Major) Avoid concomitant administration of obeticholic acid and pirfenidone because coadministration may increase exposure to pirfenidone. If concurrent use cannot be avoided, closely monitor for adverse effects of pirfenidone, like elevated hepatic enzymes, arthralgia, or nausea. Dosage reduction, interruption of therapy, or discontinuation may be necessary. Obeticholic acid may increase the exposure to concomitant drugs that are CYP1A2 substrates, such as pirfenidone.
    Pomalidomide: (Major) Avoid the concomitant use of pomalidomide and obeticholic acid; significantly increased pomalidomide exposure may occur increasing the risk of pomalidomide adverse events. If concomitant use is unavoidable, decrease the pomalidomide dose by 50% and monitor for pomalidomide adverse events. Pomalidomide is a CYP1A2 substrate and obeticholic acid is a strong CYP1A2 inhibitor. In healthy volunteers, the Cmax and AUC values for pomalidomide were increased by 24% and 125%, respectively, when pomalidomide was co-administered with a strong CYP1A2 inhibitor.
    Propafenone: (Moderate) Obeticholic acid may increase the exposure to concomitant drugs that are CYP1A2 substrates, such as propafenone. Therapeutic monitoring is recommended with coadministration.
    Ramelteon: (Major) Ramelteon should be administered with caution to patients taking CYP1A2 inhibitors. Strong CYP1A2 inhibitors have been shown to have significant interactions with ramelteon, leading to elevated AUC of ramelteon > 190-fold and Cmax > 70-fold. Obeticholic acid may increase the exposure to concomitant drugs that are CYP1A2 substrates, such as ramelton. Co-administer ramelteon with caution and monitor for ramelteon-associated side effects.
    Rasagiline: (Major) Rasagiline plasma concentrations may increase up to 2 fold in patients using concomitant CYP1A2 inhibitors, resulting in the potential for increased adverse events from rasagiline. Dosage adjustments of rasagiline are required when CYP1A2 inhibitors are started in combination with rasagiline. Rasagiline does not have an alternate metabolic pathway other than CYP1A2 and thus these drug interactions may be of clinical significance; closely monitor for increased adverse effects including postural hypotension, hallucinations, dyskinesias, weight loss or xerostomia. Obeticholic acid may increase the exposure to concomitant drugs that are CYP1A2 substrates, such as rasagiline. Additionally, if therapy with a CYP1A2 inhibitor is halted, the rasagiline dosage may require adjustment to attain appropriate clinical outcomes.
    Rifaximin: (Moderate) Obeticholic acid may increase the exposure to rifaximin. Rifaximin is a substrate of OATP1B1 and OATP1B3 and obeticholic acid inhibits OAT1B1 and OATP1B3 in vitro. Caution and close monitoring is advised if these drugs are used together.
    Riluzole: (Moderate) Obeticholic acid may increase the exposure to concomitant drugs that are CYP1A2 substrates, such as riluzole. Therapeutic monitoring is recommended with coadministration.
    Roflumilast: (Moderate) Obeticholic acid may increase the exposure to concomitant drugs that are CYP1A2 substrates, such as roflumilast. Therapeutic monitoring is recommended with coadministration.
    Ropinirole: (Moderate) Obeticholic acid may increase the exposure to concomitant drugs that are CYP1A2 substrates, such as ropinirole. If these drugs are coadministered, adjustment of ropinirole dose may be required. Therapeutic monitoring is recommended with coadministration.
    Ropivacaine: (Moderate) Obeticholic acid may increase the exposure to concomitant drugs that are CYP1A2 substrates, such as ropivacaine. Clinical monitoring for adverse effects, such as hypotension, bradycardia or GI effects, is recommended during coadministration.
    Rosuvastatin: (Moderate) Obeticholic acid may increase the exposure to rosuvastatin. Rosuvastatin is a substrate of OATP1B1 and OATP1B3 and obeticholic acid inhibits OAT1B1 and OATP1B3 in vitro. Caution and close monitoring is advised if these drugs are used together.
    Sacubitril; Valsartan: (Moderate) Obeticholic acid may increase the exposure to valsartan. Valsartan is a substrate of OATP1B1 and obeticholic acid inhibits OAT1B1 in vitro. Caution and close monitoring is advised if these drugs are used together.
    Simeprevir: (Minor) Obeticholic acid may increase the exposure to simeprevir. Simeprevir is a substrate of OATP1B1 and OATP1B3 and obeticholic acid inhibits OAT1B1 and OATP1B3 in vitro. Caution and close monitoring is advised if these drugs are used together.
    Simvastatin: (Moderate) Obeticholic acid may increase the exposure to simvastatin. Simvastatin is a substrate of OATP1B1 and OATP1B3 and obeticholic acid inhibits OAT1B1 and OATP1B3 in vitro. Caution and close monitoring is advised if these drugs are used together.
    Simvastatin; Sitagliptin: (Moderate) Obeticholic acid may increase the exposure to simvastatin. Simvastatin is a substrate of OATP1B1 and OATP1B3 and obeticholic acid inhibits OAT1B1 and OATP1B3 in vitro. Caution and close monitoring is advised if these drugs are used together.
    Sofosbuvir; Velpatasvir; Voxilaprevir: (Major) Avoid concurrent administration of voxilaprevir and obeticholic acid. Taking these medications together may increase voxilaprevir plasma concentrations, potentially increasing the risk for adverse events. Voxilaprevir is a substrate for the drug transporter Organic Anion Transporting Polypeptides 1B1/1B3 (OATP1B1/1B3). Obeticholic acid is an in vitro inhibitor of OATP1B1/1B3.
    Tasimelteon: (Moderate) Obeticholic acid may increase the exposure to concomitant drugs that are CYP1A2 substrates, such as tasimelteon. Therapeutic monitoring is recommended with coadministration.
    Tenofovir Alafenamide: (Minor) Obeticholic acid may increase the exposure to tenofovir alafenamide. Tenofavir alafenamide is a substrate of OATP1B1 and OATP1B3 and obeticholic acid inhibits OAT1B1 and OATP1B3 in vitro. Caution and close monitoring is advised if obeticholic acid is coadministered with tenofovir alafenamide.
    Tenofovir Alafenamide: (Minor) Obeticholic acid may increase the exposure to tenofovir alafenamide. Tenofavir alafenamide is a substrate of OATP1B1 and OATP1B3 and obeticholic acid inhibits OAT1B1 and OATP1B3 in vitro. Caution and close monitoring is advised if obeticholic acid is coadministered with tenofovir alafenamide.
    Theophylline, Aminophylline: (Moderate) Obeticholic acid may increase the exposure to concomitant drugs that are CYP1A2 substrates, such as theophylline, aminophylline. Since the therapeutic range is narrow, it is prudent to monitor theophylline serum concentrations upon initiation, dosage adjustment, or discontinuation of medications that may alter the function of CYP1A2.
    Thiabendazole: (Moderate) Obeticholic acid may increase the exposure to concomitant drugs that are CYP1A2 substrates, such as thiabendazole. Therapeutic monitoring is recommended with coadministration.
    Thiothixene: (Moderate) Obeticholic acid may increase the exposure to concomitant drugs that are CYP1A2 substrates, such as thiothixene. Therapeutic monitoring is recommended with coadministration.
    Tizanidine: (Moderate) Obeticholic acid may increase the exposure to concomitant drugs that are CYP1A2 substrates, such as tizanidine. Therapeutic monitoring is recommended with coadministration as there is the potential for enhanced hypotensive and sedative effects.
    Triamterene: (Minor) Obeticholic acid may increase the exposure to concomitant drugs that are CYP1A2 substrates, such as triamterene. Therapeutic monitoring is recommended with coadministration.
    Valsartan: (Moderate) Obeticholic acid may increase the exposure to valsartan. Valsartan is a substrate of OATP1B1 and obeticholic acid inhibits OAT1B1 in vitro. Caution and close monitoring is advised if these drugs are used together.
    Warfarin: (Moderate) Monitor INR results with coadministration of warfarin and obeticholic acid. Concomitant use of 25 mg warfarin as a single dose with obeticholic acid 10 mg once daily resulted in a 13% increase in systemic exposure to S-warfarin and an 11% decrease in maximum INR.
    Zileuton: (Moderate) Obeticholic acid may increase the exposure to concomitant drugs that are CYP1A2 substrates, such as zileuton. Therapeutic monitoring is recommended with coadministration.
    Zolmitriptan: (Moderate) Obeticholic acid may increase the exposure to concomitant drugs that are CYP1A2 substrates, such as zolmitriptan. Therapeutic monitoring is recommended with coadministration.

    PREGNANCY AND LACTATION

    Pregnancy

    The limited available human data on the use of obeticholic acid during pregnancy are not sufficient to inform a drug-associated risk. In animal studies, no developmental abnormalities or fetal harm was noted.

    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. Consider the benefits of breast-feeding, the risk of potential infant drug exposure, and the risk of an untreated or inadequately treated condition. If a breast-feeding infant experiences an adverse effect related to a maternally administered drug, healthcare providers are encouraged to report the adverse effect to the FDA.

    MECHANISM OF ACTION

    Obeticholic acid is an agonist for 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 circulation bile acid pool while promoting choleresis, thus reducing hepatic exposure to bile acids.
     
    In clinical trials, alkaline phosphatase (ALP) reduction was observed to plateau at approximately 3 months in most patients treated with obeticholic acid 5 mg PO daily. Increasing the dose based on tolerability and response provided additional reduction in ALP in the majority of patients. Administration of 10 mg PO daily was associated with a 173% increase in concentrations of FGF-19, and FXR-inducible enterokine involved in bile acid homeostasis, from baseline to month 12. Concentrations of cholic acid and chenodeoxycholic acid were reduced 2.7 micromolar 1.4 micromolar, respectively, from baseline to month 12. The clinical relevance of these findings is unknown.

    PHARMACOKINETICS

    Obeticholic acid is administered orally. Plasma binding of obeticholic acid and its conjugates is greater than 99%. The volume of distribution of obeticholic acid is 618 L. The volumes of distribution of the conjugates have not been determined.
     
    Obeticholic acid is conjugated with glycine or taurine in the liver to glyco-obeticholic acid and tauro-obeticholic acid and secreted into bile. The glycine and taurine conjugates are absorbed in the small intestine leading to enterohepatic recirculation. The conjugated can be deconjugated in the ileum and colon by intestinal microbiota, leading to the conversion to obeticholic acid than can be reabsorbed or excreted in the feces, the principal route of elimination. After daily administration, there is accumulation of the conjugates, which have in vitro pharmacological activities similar to the parent drug. A third metabolite, 3-glucuronide, is formed, but is considered to have minimal pharmacologic activity. About 87% of the obeticholic acid dose is excreted in the feces through biliary secretion. Less than 3% of the dose is excreted in the urine with no detection of obeticholic acid.
     
    Affected cytochrome P450 isoenzymes: CYP1A2, OATP1B1, OATP1B3
    Obeticholic acid may increase exposure to concomitant drugs that are CYP1A2 substrates. Therapeutic monitoring of CYP1A2 substrates with a narrow therapeutic index is recommended. Down-regulation of mRNA was observed ina concentration-dependent fashion for CYP1A2 and CYP3A4 by obeticholic acid and its conjugates.  In vitro studies suggest obeticholic acid can inhibit CYP3A4; however, in vivo studies indicate no inhibition of CYP3A4. In vitro studies suggest there is potential of obeticholic acid and its conjugates to inhibit OATP1B1, and OATP1B3 (the clinical significance of which is unknown), but not P-glycoprotein (P-gp), BCRP, OAT1, OAT3, OCT2, and MATE transporters. Obeticholic acid is not expected to inhibit CYP enzymes 2B6, 2C8, 2C9, 2C19, or 2D6, nor induce CYP enzymes 1A2, 2B6, 2C8, 2C9, 2C19, and 3A4 at recommended doses.

    Oral Route

    After multiple doses of obeticholic acid 10 mg PO once daily, peak plasma concentrations (Cmax) occurred at a median time (Tmax) of approximately 1.5 hours. The median Tmax for both glyco- and tauro-conjugates was 10 hours. Coadministration with food did not alter the extent of obeticholic acid absorption.  After multiple doses of 5, 10, and 25 mg PO once daily for 14 days, the systemic exposures of obeticholic acid increased dose proportionally. Exposures to the conjugates and total obeticholic acid (the sum of obeticholic acid and its 2 active conjugates) increase more than proportionally with the dose.