CLASSES

Farnesoid X Receptor (FXR) Agonists

BOXED WARNING

Patients who are taking obeticholic acid for primary biliary cirrhosis/cholangitis (PBC) and have hepatic biliary cirrhosis with symptoms of hepatic decompensation such as ascites, jaundice, variceal GI bleeding, hepatic encephalopathy, or certain abnormalities in liver function tests (LFTs) should talk to their health care provider to see if this medication should be stopped. Obeticholic acid is contraindicated in patients with complete biliary obstruction or advanced cirrhosis, defined as cirrhosis with current (e.g., Child-Pugh Class B or C) or prior evidence of hepatic decompensation (e.g., hepatic encephalopathy, coagulopathy) or portal hypertension (e.g., ascites, gastro- or esophageal varices, persistent thrombocytopenia). In postmarketing reports, hepatotoxicity such as hepatic decompensation and hepatic failure (some cases fatal or resulting in liver transplant), have been reported with obeticholic acid treatment in patients with primary biliary cholangitis (PBC) with cirrhosis, either compensated or decompensated. The median time to hepatic decompensation (e.g., new onset ascites) was 4 months for patients with compensated cirrhosis; median time to a new decompensation event (e.g., hepatic encephalopathy) was 2.5 months for patients with decompensated cirrhosis. Some of these cases occurred in patients with decompensated cirrhosis when they were treated with higher than the recommended dosage for that patient population; however, cases of hepatic decompensation and liver failure have continued to be reported in patients with decompensated cirrhosis even when they received the recommended dosage. The FDA identified 25 cases of primary biliary cirrhosis/cholangitis (PBC) patients with cirrhosis (compensated or decompensated) taking obeticholic acid at recommended dosages prior to the initial liver-related adverse event. Eighteen of 25 cases occurred in PBC patients with compensated cirrhosis who experienced liver injury (hepatotoxicity) that led to decompensation; although the disease in these PBC patients was not expected to progress rapidly, they experienced accelerated deterioration in clinical status within months of starting obeticholic acid. Four PBC patients with compensated cirrhosis required a liver transplant within 1.3 years after starting obeticholic acid, and 1 PBC patient with compensated cirrhosis died from liver failure. The other 7 cases occurred in PBC patients with decompensated cirrhosis, 2 of whom died. Although there was a temporal relationship between obeticholic acid initiation and liver injury, it is difficult to distinguish a drug-induced effect from disease progression in the patients with advanced baseline liver disease. The median time to a new decompensation event (e.g., hepatic encephalopathy) after initiating obeticholic acid was 2.5 months, ranging from 10 days to 8 months. In addition to liver transplant, evidence for liver decompensation included events such as new-onset ascites, variceal GI bleeding, hepatorenal syndrome, and worsening synthetic function. The most common associated liver-related adverse event among the 25 cases was worsening total bilirubin. Hepatotoxicity was observed in the obeticholic acid clinical trials. A dose-response relationship was observed for the occurrence of hepatic 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 in two 3-month, placebo-controlled clinical trials in patients with primarily early stage PBC. Routinely monitor patients for biochemical response, tolerability, disease progression of PBC. Closely monitor patients with compensated cirrhosis, concomitant hepatic disease (e.g., autoimmune hepatitis, alcoholic liver disease), and/or severe intercurrent illness for new evidence of portal hypertension (e.g., ascites, gastroesophageal varices, persistent thrombocytopenia) or increases above the upper limit of normal in total bilirubin, direct bilirubin, or prothrombin time. Permanently discontinue obeticholic acid in patients who develop laboratory or clinical evidence of hepatic decompensation, have compensated cirrhosis and develop evidence of portal hypertension, experience clinically significant hepatic adverse reactions, or develop complete biliary obstruction. Also monitor patients 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 obeticholic acid in patients developing these symptoms. If severe intercurrent illness occurs, interrupt treatment with obeticholic acid and monitor the patient's liver function. After resolution of the intercurrent illness, consider the potential risks and benefits of restarting obeticholic acid treatment.

DEA CLASS

Rx

DESCRIPTION

Farnesoid X receptor (FXR) agonist
For primary biliary cholangitis (PBC) in patients without cirrhosis or who have compensated cirrhosis without evidence of portal hypertension; used as monotherapy in adults unable to tolerate ursodeoxycholic acid (UDCA) or in combination with UDCA in adults with inadequate response to UDCA alone
Boxed warning for hepatic decompensation and failure in PBC patients with cirrhosis; contraindicated in PBC patients with decompensated cirrhosis, a prior decompensation event, or with compensated cirrhosis and portal hypertension

COMMON BRAND NAMES

OCALIVA

HOW SUPPLIED

OCALIVA Oral Tab: 5mg, 10mg

DOSAGE & INDICATIONS

MAXIMUM DOSAGE

10 mg PO once daily.

10 mg PO once daily.

Safety and efficacy have not been established.

Safety and efficacy have not been established.

Safety and efficacy have not been established.

Safety and efficacy have not been established.

DOSING CONSIDERATIONS

Treatment with obeticholic acid should be initiated and monitored by a health care provider with experience managing primary biliary cholangitis/primary biliary cirrhosis (PBC). Routinely monitor patients for progression of PBC with laboratory and clinical assessments. Permanently discontinue obeticholic acid 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. Plasma exposure to obeticholic acid and its active conjugates increases significantly in patients with increasing hepatic impairment, whichis associate with an increased risk for adverse hepatic events.
Mild hepatic impairment (Child-Pugh Class A): No dosage adjustment is recommended; carefully monitor patients as recommended.
Moderate to severe hepatic impairment (Child-Pugh Class B or C and others): Contraindicated in patients with decompensated cirrhosis (e.g., Child-Pugh Class B or C), in those with a prior decompensation event, or with compensated cirrhosis who have evidence of portal hypertension (e.g., ascites, gastroesophageal varices, persistent thrombocytopenia).

No dosage adjustment is recommended as there is minimal renal excretion of the drug.

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

Patients who are taking obeticholic acid for primary biliary cirrhosis/cholangitis (PBC) and have hepatic biliary cirrhosis with symptoms of hepatic decompensation such as ascites, jaundice, variceal GI bleeding, hepatic encephalopathy, or certain abnormalities in liver function tests (LFTs) should talk to their health care provider to see if this medication should be stopped. Obeticholic acid is contraindicated in patients with complete biliary obstruction or advanced cirrhosis, defined as cirrhosis with current (e.g., Child-Pugh Class B or C) or prior evidence of hepatic decompensation (e.g., hepatic encephalopathy, coagulopathy) or portal hypertension (e.g., ascites, gastro- or esophageal varices, persistent thrombocytopenia). In postmarketing reports, hepatotoxicity such as hepatic decompensation and hepatic failure (some cases fatal or resulting in liver transplant), have been reported with obeticholic acid treatment in patients with primary biliary cholangitis (PBC) with cirrhosis, either compensated or decompensated. The median time to hepatic decompensation (e.g., new onset ascites) was 4 months for patients with compensated cirrhosis; median time to a new decompensation event (e.g., hepatic encephalopathy) was 2.5 months for patients with decompensated cirrhosis. Some of these cases occurred in patients with decompensated cirrhosis when they were treated with higher than the recommended dosage for that patient population; however, cases of hepatic decompensation and liver failure have continued to be reported in patients with decompensated cirrhosis even when they received the recommended dosage. The FDA identified 25 cases of primary biliary cirrhosis/cholangitis (PBC) patients with cirrhosis (compensated or decompensated) taking obeticholic acid at recommended dosages prior to the initial liver-related adverse event. Eighteen of 25 cases occurred in PBC patients with compensated cirrhosis who experienced liver injury (hepatotoxicity) that led to decompensation; although the disease in these PBC patients was not expected to progress rapidly, they experienced accelerated deterioration in clinical status within months of starting obeticholic acid. Four PBC patients with compensated cirrhosis required a liver transplant within 1.3 years after starting obeticholic acid, and 1 PBC patient with compensated cirrhosis died from liver failure. The other 7 cases occurred in PBC patients with decompensated cirrhosis, 2 of whom died. Although there was a temporal relationship between obeticholic acid initiation and liver injury, it is difficult to distinguish a drug-induced effect from disease progression in the patients with advanced baseline liver disease. The median time to a new decompensation event (e.g., hepatic encephalopathy) after initiating obeticholic acid was 2.5 months, ranging from 10 days to 8 months. In addition to liver transplant, evidence for liver decompensation included events such as new-onset ascites, variceal GI bleeding, hepatorenal syndrome, and worsening synthetic function. The most common associated liver-related adverse event among the 25 cases was worsening total bilirubin. Hepatotoxicity was observed in the obeticholic acid clinical trials. A dose-response relationship was observed for the occurrence of hepatic 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 in two 3-month, placebo-controlled clinical trials in patients with primarily early stage PBC. Routinely monitor patients for biochemical response, tolerability, disease progression of PBC. Closely monitor patients with compensated cirrhosis, concomitant hepatic disease (e.g., autoimmune hepatitis, alcoholic liver disease), and/or severe intercurrent illness for new evidence of portal hypertension (e.g., ascites, gastroesophageal varices, persistent thrombocytopenia) or increases above the upper limit of normal in total bilirubin, direct bilirubin, or prothrombin time. Permanently discontinue obeticholic acid in patients who develop laboratory or clinical evidence of hepatic decompensation, have compensated cirrhosis and develop evidence of portal hypertension, experience clinically significant hepatic adverse reactions, or develop complete biliary obstruction. Also monitor patients 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 obeticholic acid in patients developing these symptoms. If severe intercurrent illness occurs, interrupt treatment with obeticholic acid and monitor the patient's liver function. After resolution of the intercurrent illness, consider the potential risks and benefits of restarting obeticholic acid treatment.

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.

ADVERSE REACTIONS

eczema vaccinatum / Delayed / 3.0-6.0
hepatic encephalopathy / Delayed / 0-1.0
hepatic failure / Delayed / Incidence not known
hepatotoxicity / Delayed / Incidence not known
biliary obstruction / Delayed / Incidence not known
hepatic decompensation / Delayed / Incidence not known
GI bleeding / Delayed / Incidence not known

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

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
rash / Early / 7.0-10.0
maculopapular rash / Early / 0-10.0
urticaria / Rapid / 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
vomiting / Early / Incidence not known
nausea / Early / Incidence not known

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; 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; 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; Pyrilamine: (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.
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; 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; Hydrochlorothiazide, HCTZ: (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: (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; Orphenadrine: (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.
Atogepant: (Major) Limit the dose of atogepant to 10 or 30 mg PO once daily for episodic migraine or 30 mg PO once daily for chronic migraine if coadministered with obeticholic acid. Concurrent use may increase atogepant exposure and the risk of adverse effects. Atogepant is a substrate of OATP1B1 and OATP1B3 and obeticholic acid is an OATP inhibitor. Coadministration with an OATP1B1/3 inhibitor resulted in a 2.85-fold increase in atogepant overall exposure and a 2.23-fold increase in atogepant peak concentration.
Bendamustine: (Major) Consider the use of an alternative therapy if obeticholic acid treatment is needed in patients receiving bendamustine. Obeticholic acid may increase bendamustine exposure, which may increase the risk of adverse reactions (e.g., myelosuppression, infection, hepatotoxicity). Bendamustine is a CYP1A2 substrate and obeticholic acid is a CYP1A2 inhibitor.
Bictegravir; 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.
Brincidofovir: (Moderate) Postpone the administration of obeticholic acid for at least three hours after brincidofovir administration and increase monitoring for brincidofovir-related adverse reactions (i.e., elevated hepatic enzymes and bilirubin, diarrhea, other gastrointestinal adverse events) if concomitant use of brincidofovir and obeticholic acid is necessary. Brincidofovir is an OATP1B1/3 substrate and obeticholic acid is an OATP1B1/3 inhibitor. In a drug interaction study, the mean AUC and Cmax of brincidofovir increased by 374% and 269%, respectively, when administered with another OATP1B1/3 inhibitor.
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.
Butalbital; Acetaminophen; 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.
Butalbital; Acetaminophen; 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.
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; Sodium Benzoate: (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.
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.
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.
Cyclosporine: (Major) Avoid coadministration of obeticholic acid, an inhibitor of the bile salt efflux pump (BSEP) with other BSEP inhibitors, such as cyclosporine; if coadministration is necessary, monitor serum transaminases and bilirubin. Concomitant medications that inhibit canalicular membrane bile acid transporters such as the BSEP may exacerbate accumulation of conjugated bile salts including taurine conjugate of obeticholic acid in the liver and result in clinical symptoms.
Darunavir; Cobicistat; 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.
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.
Elagolix: (Contraindicated) Use of elagolix and strong OATP1B1 inhibitors is contraindicated due to increased elagolix AUC and risk for serious side effects, such as loss of bone mineral density. Use of elagolix with drugs that inhibit OATP1B1 may increase elagolix plasma concentrations. Elagolix is a substrate of CYP3A, P-gp, and OATP1B1. In vitro studies suggest that obeticholic acid and its glycine and taurine conjugates may inhibit OATP1B1 (the clinical significance of this inhibitiion has not been studied and is unknown), Consider alternative therapy.
Elagolix; Estradiol; Norethindrone acetate: (Contraindicated) Use of elagolix and strong OATP1B1 inhibitors is contraindicated due to increased elagolix AUC and risk for serious side effects, such as loss of bone mineral density. Use of elagolix with drugs that inhibit OATP1B1 may increase elagolix plasma concentrations. Elagolix is a substrate of CYP3A, P-gp, and OATP1B1. In vitro studies suggest that obeticholic acid and its glycine and taurine conjugates may inhibit OATP1B1 (the clinical significance of this inhibitiion has not been studied and is unknown), Consider alternative therapy.
Elbasvir; Grazoprevir: (Contraindicated) 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.
Elvitegravir; Cobicistat; 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.
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.
Ergotamine; 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.
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.
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.
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.
Lidocaine; Epinephrine: (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.
Lidocaine; Prilocaine: (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.
Maraviroc: (Moderate) Use caution and closely monitor for increased adverse effects during concurrent administration of maraviroc and obeticholic acid as increased maraviroc concentrations may occur. Maraviroc is a substrate of organic anion-transporting polypeptide (OATP1B1); obeticholic acid is an inhibitor of OATP1B1. The effects of this transporter on the concentrations of maraviroc are unknown, although an increase in concentrations and thus, toxicity, are possible.
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.
Olanzapine; Fluoxetine: (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.
Olanzapine; Samidorphan: (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; Amoxicillin; Rifabutin: (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.
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) Do not exceed a rasagiline dose of 0.5 mg once daily when coadministered with obeticholic acid. Coadministration may result in increased rasagiline concentrations. Rasagiline is primarily metabolized by CYP1A2; obeticholic acid is a moderate CYP1A2 inhibitor. When rasagiline was administered with a strong CYP1A2 inhibitor, the AUC of rasagiline increased by 83%.
Revefenacin: (Major) Coadministration of revefenacin is not recommended with obeticholic acid because it could lead to an increase in systemic exposure of the active metabolite of revefenacin and an increased potential for anticholinergic adverse effects. The active metabolite of revefenacin is a substrate of OATP1B1 and OATP1B3; obeticholic acid and its conjugates appear to inhibit OATP1B1 and OATP1B3 (the clinical significance of which is unknown).
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.
Rosuvastatin; Ezetimibe: (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.
Sodium Phenylbutyrate; Taurursodiol: (Major) Avoid coadministration of sodium phenylbutyrate; taurursodiol and obeticholic acid. Concomitant use may increase plasma concentrations of sodium phenylbutyrate; taurursodiol. Sodium phenylbutyrate; taurursodiol is an OATP1B3 substrate and obeticholic acid is an OATP1B3 inhibitor.
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.
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.
Triamterene; Hydrochlorothiazide, HCTZ: (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.
Valsartan; Hydrochlorothiazide, HCTZ: (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) Closely monitor the INR if coadministration of warfarin with obeticholic acid is necessary as concurrent use may increase the exposure of warfarin leading to increased bleeding risk. Obeticholic acid is a CYP1A2 inhibitor and the R-enantiomer of warfarin is a CYP1A2 substrate. The S-enantiomer of warfarin exhibits 2 to 5 times more anticoagulant activity than the R-enantiomer, but the R-enantiomer generally has a slower clearance. 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

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 and drug transporters: CYP1A2, OATP1B1, OATP1B3, BSEP
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 in a 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. In vitro studies showed that obeticholic acid and its glycine and taurine conjugates inhibit the bile salt efflux pump (BSEP) in a dose dependent manner. However, an in vivo drug interaction due to inhibition of BSEP in patients using the recommended dosage regimen appears unlikely. Induction of BSEP can occur by FXR activation by obeticholic acid and its conjugates, which are FXR agonists.