Understanding Primary Biliary Cholangitis

What is PBC?

PBC is a chronic liver disease that results from the destruction of the intrahepatic bile ducts in the liver.1 Formerly called primary biliary cirrhosis, PBC can cause inflammation and scarring of the liver, eventually leading to cirrhosis.1 Typically, PBC appears during middle age and affects mostly women.2

Disease Progression

PBC progression is highly variable from patient to patient, although early-stage diagnosis has increased in recent decades.3-5

Alkaline phosphatase (ALP) and bilirubin are important markers in PBC progression6,7

Monitor ALP as a diagnostic marker

  • The first indicator of PBC may be elevated ALP levels as measured by routine blood tests.8
  • Elevations in ALP are associated with cholestasis, ongoing bile duct destruction, and disease progression.6,9,10
  • Lower ALP is associated with longer transplant-free survival.7
  • Intervention in the early disease stages has been shown to lower ALP levels.3,6

Elevated bilirubin is a marker of advanced PBC and an early indicator of cirrhosis and portal hypertension12-14

  • Bilirubin levels are an important predictor of survival in PBC.3,6,7
  • Bilirubin elevations usually occur late in the disease progression, when treatment options are limited.3,6
  • While bilirubin does not normally become elevated during the early stages of PBC, even mild elevations put patients at risk for developing extensive fibrosis or cirrhosis.3,6
  • A total serum bilirubin level exceeding 2 mg/dL, based on 2 successive samples taken 6 months apart, is associated with a late stage of PBC.13

Even ALP showing modest, above normal elevations can increase risk

Graph is adapted from Lammers, Gastroenterology (2014).

This indication is approved under accelerated approval based on a reduction in alkaline phosphatase (ALP). An improvement in survival of disease-related symptoms has not been established. Continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trials.

Roughly 40% of patients are at an increased risk of disease progression due to an inadequate response to UDCA.14 As ALP increases, so does the risk of transplantation or death.7

Based on an analysis of nearly 5,000 patients with PBC, 85% of whom were treated with UDCA alone, when ALP was >1x ULN, patients were twice as likely to reach transplant or death than patients whose ALP was <1x ULN.7 Similarly, patients with bilirubin >1x ULN were found to be 5x more likely to reach transplant or death than patients with bilirubin <1x ULN.7

Risk factors for disease progression should be evaluated in all patients, even those with only slight elevations in ALP.8,14,15

Other factors associated with PBC disease progression include:

  • Elevated bilirubin.4,8
  • Development of fibrosis.6,8
  • Signs of liver failure and portal hypertension (eg, ascites and hepatic encephalopathy).14
  • Liver stiffness greater than 9.6 kPa.6

Managing PBC for your patients

Some patients being treated with UDCA may have an inadequate response, and others may not be able to tolerate UDCA treatment at all. 6,16-19

Treatment with UDCA can result in improvement in liver function tests, including ALP.6 In patients with PBC who present abnormal ALP, 90% of liver function improvements as a result of treatment with UDCA occur within 6 months.6

About 3 to 6 months after initiating treatment with UDCA, monitor patients to determine whether they are achieving adequate lowering of ALP. Continue to monitor them every 3 to 6 months.6

OCALIVA is indicated for the treatment of PBC in combination with UDCA in adults with an inadequate response to UDCA, or as monotherapy in adults unable to tolerate UDCA, to take PBC treatment further.

See Mechanism of Action

Additional Resources

References

  1. American Liver Foundation. Primary Biliary Cholangitis. American Liver Foundation website. https://liverfoundation.org/for-patients/about-the-liver/diseases-of-the-liver/primary-biliary-cholangitis/. 2017. Accessed July 10, 2019.
  2. Cheung AC; Canadian PBC Society. Primary Biliary Cholangitis. National Organization for Rare Disorders website. https://rarediseases.org/rare-diseases/primary-biliary-cholangitis/3/. Updated 2016. Accessed July 10, 2019.
  3. Poupon R. Primary biliary cirrhosis: a 2010 update. J Hepatol. 2010;52(5):745-758. doi:10.1016/j.jhep.2009.11.027.
  4. Lammers WJ, Kowdley KV, van Buuren HR. Predicting outcome in primary biliary cirrhosis. Ann Hepatol. 2014;13(4):316-326. doi:10.1016/S1665-2681(19)30838-5.
  5. Sclair SN, Little E, Levy C. Current concepts in primary biliary cirrhosis and primary sclerosing cholangitis. Clin Transl Gastroenterol. 2015;6(8):e109. doi:10.1038/ctg.2015.33.
  6. Lindor KD, Bowlus CL, Boyer J, Levy C, Mayo M. Primary biliary cholangitis: 2018 practice guidance from the American Association for the Study of Liver Diseases. Hepatology. 2019;69(1):394-419. doi:10.1002/hep.30145.
  7. Lammers WJ, van Buuren HR, Hirschfield GM, et al; on behalf of the Global PBC Study Group. Levels of alkaline phosphatase and bilirubin are surrogate end points of outcomes of patients with primary biliary cirrhosis: an international follow-up study. Gastroenterology. 2014;147(6):1338-1349. doi:10.1053/j.gastro.2014.08.029.
  8. European Association for the Study of the Liver. EASL clinical practice guidelines: the diagnosis and management of patients with primary biliary cholangitis. J Hepatol. 2017;67(1):145-172. doi:10.1016/j.jhep.2017.03.022.
  9. Poupon R. Liver alkaline phosphatase: a missing link between choleresis and biliary inflammation. Hepatology. 2015;61(6):2080-2090. doi:10.1002/hep.27715.
  10. Bonheur JL, Ells PF, Talavera F, Anand BS, Minocha A, Kapoor VK. Biliary Obstruction Workup. Medscape website. https://emedicine.medscape.com/article/187001-workup. Updated November 7, 2018. Accessed July 10, 2019.
  11. Corpechot C, Poujol-Robert A, Wendum D, et al. Biochemical markers of liver fibrosis and lymphocytic piecemeal necrosis in UDCA-treated patients with primary biliary cirrhosis. Liver Int. 2004;24(3):187-193. doi:10.1111/j.1478-3231.2004.0918.x.
  12. Poupon R, Chazouillères O, Balkau B, Poupon RE. Clinical and biochemical expression of the histopathological lesions of primary biliary cirrhosis. UDCA-PBC Group. J Hepatol. 1999;30(3):408-412. doi:10.1016/S0168-8278(99)80098-1.
  13. Shapiro JM, Smith H, Schaffner F. Serum bilirubin: a prognostic factor in primary biliary cirrhosis. Gut. 1979;20(2):137-140. doi:10.1136/gut.20.2.137.
  14. Parés A, Rodés J. Natural history of primary biliary cirrhosis. Clin Liver Dis. 2003;7(4):779-794. doi:10.1016/S1089-3261(03)00100-4.
  15. Brostoff JM, Rashid S, McCrea D. Primary biliary cirrhosis with a normal alkaline phosphatase: a case report. Cases J. 2008;1(1):33. doi:10.1186/1757-1626-1-33.
  16. Parés A, Caballería L, Rodés J. Excellent long-term survival in patients with primary biliary cirrhosis and biochemical response to ursodeoxycholic acid. Gastroenterology. 2006;130(3):715-720. doi:10.1053/j.gastro.2005.12.029.
  17. Kuiper EMM, Hansen BE, de Vries RA, et al. Improved prognosis of patients with primary biliary cirrhosis that have a biochemical response to ursodeoxycholic acid. Gastroenterology. 2009;136(4):1281-1287. doi:10.1053/j.gastro.2009.01.003.
  18. Corpechot C, Chazouillères O, Poupon R. Early primary biliary cirrhosis: biochemical response to treatment and prediction of long-term outcome. J Hepatol. 2011;55(6):1361-1367. doi:10.1016/j.jhep.2011.02.031.
  19. Jorgensen RA, Dickson ER, Hofmann AF, Rossi SS, Lindor KD. Characterisation of patients with a complete biochemical response to ursodeoxycholic acid. Gut. 1995;36(6):935-938. doi:10.1136/gut.36.6.935.

INDICATION AND IMPORTANT SAFETY INFORMATION

WARNING: HEPATIC DECOMPENSATION AND FAILURE IN INCORRECTLY DOSED PBC PATIENTS WITH CHILD-PUGH CLASS B OR C OR DECOMPENSATED CIRRHOSIS

  • In postmarketing reports, hepatic decompensation and failure, in some cases fatal, have been reported in patients with Primary Biliary Cholangitis (PBC) with decompensated cirrhosis or Child-Pugh Class B or C hepatic impairment when OCALIVA was dosed more frequently than recommended.
  • The recommended starting dosage of OCALIVA is 5 mg once weekly for patients with Child-Pugh Class B or C hepatic impairment or a prior decompensation event.

INDICATION

OCALIVA is indicated for the treatment of primary biliary cholangitis (PBC) in combination with ursodeoxycholic acid (UDCA) in adults with an inadequate response to UDCA, or as monotherapy in adults unable to tolerate UDCA.

This indication is approved under accelerated approval based on a reduction in alkaline phosphatase (ALP). An improvement in survival or disease-related symptoms has not been established. Continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trials.

Contraindications

OCALIVA is contraindicated in patients with complete biliary obstruction.

Warnings and Precautions

Hepatic Decompensation and Failure in Incorrectly Dosed PBC Patients with Child-Pugh Class B or C or Decompensated Cirrhosis

In postmarketing reports, hepatic decompensation and failure, in some cases fatal, have been reported in patients with decompensated cirrhosis or Child-Pugh B or C hepatic impairment when OCALIVA was dosed more frequently than the recommended starting dosage of 5 mg once weekly. Reported cases typically occurred within 2 to 5 weeks after starting OCALIVA and were characterized by an acute increase in total bilirubin and/or ALP concentrations in association with clinical signs and symptoms of hepatic decompensation (e.g., ascites, jaundice, gastrointestinal bleeding, worsening of hepatic encephalopathy). Patients who died due to liver-related complications generally had decompensated cirrhosis prior to treatment and were started on OCALIVA 5 mg once daily, which is 7-fold greater than the once-weekly starting regimen in this population.

Routinely monitor patients for progression of PBC disease, including liver-related complications, with laboratory and clinical assessments. Dosage adjustment, interruption or discontinuation may be required. Close monitoring is recommended for patients at an increased risk of hepatic decompensation. Severe intercurrent illnesses that may worsen renal function or cause dehydration (e.g., gastroenteritis), may exacerbate the risk of hepatic decompensation. Interrupt treatment with OCALIVA in patients with laboratory or clinical evidence of worsening liver function indicating risk of decompensation, and monitor the patient’s liver function. Consider discontinuing OCALIVA in patients who have experienced clinically significant liver-related adverse reactions. Discontinue OCALIVA in patients who develop complete biliary obstruction.

Liver-Related Adverse Reactions

Dose-related, liver-related adverse reactions including jaundice, worsening ascites and primary biliary cholangitis flare have been observed in clinical trials, as early as one month after starting treatment with OCALIVA 10 mg once daily up to 50 mg once daily (up to 5-times the highest recommended dosage). Monitor patients during treatment with OCALIVA for elevations in liver biochemical tests and for the development of liver-related adverse reactions.

Severe Pruritus

Severe pruritus was reported in 23% of patients in the OCALIVA 10 mg arm, 19% of patients in the OCALIVA titration arm, and 7% of patients in the placebo arm in a 12-month double-blind randomized controlled trial of 216 patients. Severe pruritus was defined as intense or widespread itching, interfering with activities of daily living, or causing severe sleep disturbance, or intolerable discomfort, and typically requiring medical interventions. Consider clinical evaluation of patients with new onset or worsening severe pruritus. Management strategies include the addition of bile acid resins or antihistamines, OCALIVA dosage reduction, and/or temporary interruption of OCALIVA dosing.

Reduction in HDL-C

Patients with PBC generally exhibit hyperlipidemia characterized by a significant elevation in total cholesterol primarily due to increased levels of high-density lipoprotein-cholesterol (HDL-C). Dose-dependent reductions from baseline in mean HDL-C levels were observed at 2 weeks in OCALIVA-treated patients, 20% and 9% in the 10 mg and titration arms, respectively, compared to 2% in the placebo arm. Monitor patients for changes in serum lipid levels during treatment. For patients who do not respond to OCALIVA after 1 year at the highest recommended dosage that can be tolerated (maximum of 10 mg once daily), and who experience a reduction in HDL-C, weigh the potential risks against the benefits of continuing treatment.

Adverse Reactions

The most common adverse reactions occurring in ≥5% of subjects taking OCALIVA were pruritus, fatigue, abdominal pain and discomfort, rash, oropharyngeal pain, dizziness, constipation, arthralgia, thyroid function abnormality, and eczema.

Drug Interactions

Bile Acid Binding ResinsBile acid binding resins such as cholestyramine, colestipol, or colesevelam adsorb and reduce bile acid absorption and may reduce the absorption, systemic exposure, and efficacy of OCALIVA. If taking a bile acid binding resin, take OCALIVA at least 4 hours before or 4 hours after taking the bile acid binding resin, or at as great an interval as possible.

WarfarinThe International Normalized Ratio (INR) decreased following coadministration of warfarin and OCALIVA. Monitor INR and adjust the dose of warfarin, as needed, to maintain the target INR range when coadministering OCALIVA and warfarin.

CYP1A2 Substrates with Narrow Therapeutic IndexObeticholic acid, the active ingredient in OCALIVA, may increase the exposure to concomitant drugs that are CYP1A2 substrates. Therapeutic monitoring of CYP1A2 substrates with a narrow therapeutic index (e.g. theophylline and tizanidine) is recommended when coadministered with OCALIVA.

Inhibitors of Bile Salt Efflux PumpAvoid concomitant use of inhibitors of the bile salt efflux pump (BSEP) such as cyclosporine. 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. If concomitant use is deemed necessary, monitor serum transaminases and bilirubin.

Please see Full Prescribing Information, including Boxed WARNING for OCALIVA.

To report SUSPECTED ADVERSE REACTIONS, contact Intercept Pharmaceuticals, Inc. at 1-844-782-ICPT or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

INDICATION AND IMPORTANT SAFETY INFORMATION

WARNING: HEPATIC DECOMPENSATION AND FAILURE IN INCORRECTLY DOSED PBC PATIENTS WITH CHILD-PUGH CLASS B OR C OR DECOMPENSATED CIRRHOSIS

  • In postmarketing reports, hepatic decompensation and failure, in some cases fatal, have been reported in patients with Primary Biliary Cholangitis (PBC) with decompensated cirrhosis or Child-Pugh Class B or C hepatic impairment when OCALIVA was dosed more frequently than recommended.
  • The recommended starting dosage of OCALIVA is 5 mg once weekly for patients with Child-Pugh Class B or C hepatic impairment or a prior decompensation event.

INDICATION

OCALIVA is indicated for the treatment of primary biliary cholangitis (PBC) in combination with ursodeoxycholic acid (UDCA) in adults with an inadequate response to UDCA, or as monotherapy in adults unable to tolerate UDCA.

This indication is approved under accelerated approval based on a reduction in alkaline phosphatase (ALP). An improvement in survival or disease-related symptoms has not been established. Continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trials.

Contraindications

OCALIVA is contraindicated in patients with complete biliary obstruction.

Warnings and Precautions

Hepatic Decompensation and Failure in Incorrectly Dosed PBC Patients with Child-Pugh Class B or C or Decompensated Cirrhosis

In postmarketing reports, hepatic decompensation and failure, in some cases fatal, have been reported in patients with decompensated cirrhosis or Child-Pugh B or C hepatic impairment when OCALIVA was dosed more frequently than the recommended starting dosage of 5 mg once weekly. Reported cases typically occurred within 2 to 5 weeks after starting OCALIVA and were characterized by an acute increase in total bilirubin and/or ALP concentrations in association with clinical signs and symptoms of hepatic decompensation (e.g., ascites, jaundice, gastrointestinal bleeding, worsening of hepatic encephalopathy). Patients who died due to liver-related complications generally had decompensated cirrhosis prior to treatment and were started on OCALIVA 5 mg once daily, which is 7-fold greater than the once-weekly starting regimen in this population.

Routinely monitor patients for progression of PBC disease, including liver-related complications, with laboratory and clinical assessments. Dosage adjustment, interruption or discontinuation may be required. Close monitoring is recommended for patients at an increased risk of hepatic decompensation. Severe intercurrent illnesses that may worsen renal function or cause dehydration (e.g., gastroenteritis), may exacerbate the risk of hepatic decompensation. Interrupt treatment with OCALIVA in patients with laboratory or clinical evidence of worsening liver function indicating risk of decompensation, and monitor the patient’s liver function. Consider discontinuing OCALIVA in patients who have experienced clinically significant liver-related adverse reactions. Discontinue OCALIVA in patients who develop complete biliary obstruction.

Liver-Related Adverse Reactions

Dose-related, liver-related adverse reactions including jaundice, worsening ascites and primary biliary cholangitis flare have been observed in clinical trials, as early as one month after starting treatment with OCALIVA 10 mg once daily up to 50 mg once daily (up to 5-times the highest recommended dosage). Monitor patients during treatment with OCALIVA for elevations in liver biochemical tests and for the development of liver-related adverse reactions.

Severe Pruritus

Severe pruritus was reported in 23% of patients in the OCALIVA 10 mg arm, 19% of patients in the OCALIVA titration arm, and 7% of patients in the placebo arm in a 12-month double-blind randomized controlled trial of 216 patients. Severe pruritus was defined as intense or widespread itching, interfering with activities of daily living, or causing severe sleep disturbance, or intolerable discomfort, and typically requiring medical interventions. Consider clinical evaluation of patients with new onset or worsening severe pruritus. Management strategies include the addition of bile acid resins or antihistamines, OCALIVA dosage reduction, and/or temporary interruption of OCALIVA dosing.

Reduction in HDL-C

Patients with PBC generally exhibit hyperlipidemia characterized by a significant elevation in total cholesterol primarily due to increased levels of high-density lipoprotein-cholesterol (HDL-C). Dose-dependent reductions from baseline in mean HDL-C levels were observed at 2 weeks in OCALIVA-treated patients, 20% and 9% in the 10 mg and titration arms, respectively, compared to 2% in the placebo arm. Monitor patients for changes in serum lipid levels during treatment. For patients who do not respond to OCALIVA after 1 year at the highest recommended dosage that can be tolerated (maximum of 10 mg once daily), and who experience a reduction in HDL-C, weigh the potential risks against the benefits of continuing treatment.

Adverse Reactions

The most common adverse reactions occurring in ≥5% of subjects taking OCALIVA were pruritus, fatigue, abdominal pain and discomfort, rash, oropharyngeal pain, dizziness, constipation, arthralgia, thyroid function abnormality, and eczema.

Drug Interactions

Bile Acid Binding ResinsBile acid binding resins such as cholestyramine, colestipol, or colesevelam adsorb and reduce bile acid absorption and may reduce the absorption, systemic exposure, and efficacy of OCALIVA. If taking a bile acid binding resin, take OCALIVA at least 4 hours before or 4 hours after taking the bile acid binding resin, or at as great an interval as possible.

WarfarinThe International Normalized Ratio (INR) decreased following coadministration of warfarin and OCALIVA. Monitor INR and adjust the dose of warfarin, as needed, to maintain the target INR range when coadministering OCALIVA and warfarin.

CYP1A2 Substrates with Narrow Therapeutic IndexObeticholic acid, the active ingredient in OCALIVA, may increase the exposure to concomitant drugs that are CYP1A2 substrates. Therapeutic monitoring of CYP1A2 substrates with a narrow therapeutic index (e.g. theophylline and tizanidine) is recommended when coadministered with OCALIVA.

Inhibitors of Bile Salt Efflux PumpAvoid concomitant use of inhibitors of the bile salt efflux pump (BSEP) such as cyclosporine. 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. If concomitant use is deemed necessary, monitor serum transaminases and bilirubin.

Please see Full Prescribing Information, including Boxed WARNING for OCALIVA.

To report SUSPECTED ADVERSE REACTIONS, contact Intercept Pharmaceuticals, Inc. at 1-844-782-ICPT or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.