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For adults with primary biliary cholangitis (PBC)1

For adults with primary biliary cholangitis (PBC)1

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Established Safety Profile

OCALIVA has been approved since 20161

OCALIVA has a well-established safety profile, studied in a total of 432 patients with PBC in 3 placebo-controlled trials.1

MOST COMMON ADVERSE REACTIONS IN POISE 12-MONTH TRIAL (N=216)1,a,b

Adverse Reaction OCALIVA + UDCA Placebo + UDCA Group (n=73)
5 mg →10 mg Titration Group (n=70)c 10 mg Group (n=73)
Pruritusd 56% 70% 38%
Fatiguee 19% 25% 15%
Abdominal pain and discomfortf 19% 10% 14%
Rashg 7% 10% 8%
Arthralgia 6% 10% 4%
Oropharyngeal pain 7% 8% 1%
Dizzinessh 7% 7% 5%
Constipation 7% 7% 5%
Peripheral edema 3% 7% 3%
Palpitations 3% 7% 1%
Pyrexia 0% 7% 1%
Thyroid function abnormalityi 6% 4% 3%
Eczema 6% 3% 0%

The 10 mg arm studied in POISE is not representative of the current recommended dose schedule for OCALIVA.

aA total of 16 patients (7%) who were intolerant did not receive concomitant UDCA: 6 patients (8%) in the OCALIVA 10 mg arm, 5 patients (7%) in the OCALIVA 5 mg→10 mg titration arm, and 5 patients (7%) in the placebo arm.1

bOccurring in ≥5% of patients in either OCALIVA treatment arm and at an incidence ≥1% higher than in the placebo treatment arm.1

cPatients randomized to OCALIVA titration received OCALIVA 5 mg for the initial 6-month period. At month 6, patients who did not achieve the composite endpoint and did not have evidence of tolerability issues were titrated from 5 mg to 10 mg for the final 6 months of the trial.1

dIncludes skin eruptions, prurigo, pruritus, generalized pruritus, eye pruritus, ear pruritus, anal pruritus, vulvovaginal pruritus, and pruritic rash.1

eIncludes fatigue, tiredness, and asthenia.1

fIncludes upper abdominal pain, abdominal pain, abdominal discomfort, lower abdominal pain, abdominal tenderness, and gastrointestinal pain.1

gIncludes urticaria, rash, macular rash, papular rash, macro-papular rash, heat rash, and urticaria cholinergic.1

hIncludes dizziness, syncope, and presyncope.1

iIncludes decreased free thyroxine, increased thyroid stimulating hormone (blood), and hypothyroidism.1

97% of patients who completed the double-blind phase chose to continue OCALIVA
treatment in the long-term OLE2

Adverse events

  • The most common adverse events were pruritus (70% of patients), fatigue (28%), and nasopharyngitis (27%)3

Discontinuations

  • Of 34 patients who discontinued during the POISE OLE, reasons included3:
    • Clinical or laboratory adverse events (n=9); pruritus (n=4); withdrew consent (n=9); lost to follow-up (n=5); death (n=1); major protocol violation/noncompliance (n=1); other (n=5)

Prevalence and severity of pruritus

  • Sixty-three percent of patients who entered the POISE open-label extension study had a history of PBC-related pruritus (at baseline, 56% had pruritus)4
  • Throughout treatment, more pruritus days were mild than moderate or severe3

Frequency and Severity of Pruritus

Frequency and severity of pruritus - graph

Study limitations: A maximum dose of OCALIVA 10 mg is presented, excluding data points as subjects titrated to greater than 10 mg daily.5 As this was a post hoc analysis, these results are exploratory, and no clinical conclusions should be made.

2% (4/193) discontinuation rate due to pruritus in the POISE OLE3

Pruritus is a concern for many patients with PBC, but there are modifications you can suggest to help them manage it.5

OCALIVA Drug-to-Drug Interactions1

Interaction Recommendation
Bile acid binding resins (eg, cholestryamine, colestipol, or colesevelam) adsorb and reduce bile acid absorption and may reduce the absorption, systemic exposure, and efficacy of OCALIVA If taking bile acid binding resins, instruct patients to take OCALIVA at least 4 hours before or 4 hours after (or at as great an interval as possible) taking a bile acid binding resin
International normalized ratio (INR) is decreased following co-administration of warfarin and OCALIVA Monitor INR and adjust the dosage of warfarin, as needed, to maintain target INR range when co-administering OCALIVA and warfarin
Obeticholic acid may increase exposure to concomitant drugs that are CYP1A2 substrates with a narrow therapeutic index (eg, theophylline and tizanidine) Therapeutic monitoring of CYP1A2 substrates with a narrow therapeutic index (eg, theophylline and tizanidine) is recommended when co-administered with OCALIVA
Inhibitors of bile salt efflux pump (BSEP) may exacerbate accumulation of conjugated bile salts including taurine conjugate of obeticholic acid in the liver and result in clinical symptoms Avoid concomitant use of inhibitors of BSEP, such as cyclosporine. If concomitant use is deemed necessary, monitor serum transaminases and bilirubin

Routinely monitor patients for biochemical response, tolerability, and progression of PBC, including hepatic adverse reactions, during treatment.1

HDL-C, high-density lipoprotein cholesterol; OLE, open-label extension; UDCA, ursodeoxycholic acid.

References

  1. OCALIVA full prescribing information. Morristown, NJ: Intercept Pharmaceuticals, Inc; 2022.
  2. Nevens F, Andreone P, Mazzella G, et al; for the POISE Study Group. A placebo-controlled trial of obeticholic acid in primary biliary cholangitis. N Engl J Med. 2016;375(7):631-643. doi:10.1056/NEJMoa1509840
  3. Data on file: INT-PB-MED-00009.
  4. Trauner M, Nevens F, Shiffman M, et al. Long-term efficacy and safety of obeticholic acid for patients with primary biliary cholangitis: 3-year results of an international open-label extension study. Lancet Gastroenterol Hepatol. 2019;4(6):445-453. doi:10.1016/S2468-1253(19)30094-9
  5. Onofrio FQ, Hirschfield GM, Gulamhusein AF. A practical review of primary biliary cholangitis for the gastroenterologist. Gastroenterol Hepatol. 2019;15(3):145-154.

INDICATION AND IMPORTANT SAFETY INFORMATION

WARNING: HEPATIC DECOMPENSATION AND FAILURE IN PRIMARY BILIARY CHOLANGITIS PATIENTS WITH CIRRHOSIS

  • Hepatic decompensation and failure, sometimes fatal or resulting in liver transplant, have been reported with OCALIVA treatment in primary biliary cholangitis (PBC) patients with either compensated or decompensated cirrhosis.
  • OCALIVA is contraindicated in PBC patients with decompensated cirrhosis, a prior decompensation event, or with compensated cirrhosis who have evidence of portal hypertension.
  • Permanently discontinue OCALIVA 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.

INDICATION

OCALIVA, a farnesoid X receptor (FXR) agonist, is indicated for the treatment of adult patients with primary biliary cholangitis (PBC)

  • without cirrhosis or
  • with compensated cirrhosis who do not have evidence of portal hypertension,

either in combination with ursodeoxycholic acid (UDCA) with an inadequate response to UDCA or as monotherapy in patients 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:

  • decompensated cirrhosis (e.g., Child-Pugh Class B or C) or a prior decompensation event.
  • compensated cirrhosis who have evidence of portal hypertension (e.g., ascites, gastroesophageal varices, persistent thrombocytopenia).
  • complete biliary obstruction.

Warnings and Precautions

Hepatic Decompensation and Failure in PBC Patients with Cirrhosis

Hepatic decompensation and failure, sometimes fatal or resulting in liver transplant, have been reported with OCALIVA treatment in PBC patients with cirrhosis, either compensated or decompensated. Among postmarketing cases reporting it, 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 failure have continued to be reported in patients with decompensated cirrhosis even when they received the recommended dosage.

Hepatotoxicity was observed in the OCALIVA 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 OCALIVA 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 OCALIVA in two 3-month, placebo-controlled clinical trials in patients with primarily early stage PBC.

Routinely monitor patients for progression of PBC, including hepatic adverse reactions, with laboratory and clinical assessments to determine whether drug discontinuation is needed. Closely monitor patients with compensated cirrhosis, concomitant hepatic disease (e.g., autoimmune hepatitis, alcoholic liver disease), and/or with 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 to determine whether drug discontinuation is needed. Permanently discontinue OCALIVA in patients who develop laboratory or clinical evidence of hepatic decompensation (e.g., ascites, jaundice, variceal bleeding, hepatic encephalopathy), have compensated cirrhosis and develop evidence of portal hypertension (e.g., ascites, gastroesophageal varices, persistent thrombocytopenia), experience clinically significant hepatic adverse reactions, or develop complete biliary obstruction. If severe intercurrent illness occurs, interrupt treatment with OCALIVA and monitor the patient’s liver function. After resolution of the intercurrent illness, consider the potential risks and benefits of restarting OCALIVA treatment.

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 clinical 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 binding 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 (≥5%) are: pruritus, fatigue, abdominal pain and discomfort, rash, oropharyngeal pain, dizziness, constipation, arthralgia, thyroid function abnormality, and eczema.

Drug Interactions

  • Bile Acid Binding Resins
    Bile 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.
  • Warfarin
    The 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 co-administering OCALIVA and warfarin.
  • CYP1A2 Substrates with Narrow Therapeutic Index
    Obeticholic acid 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 co-administered with OCALIVA.
  • Inhibitors of Bile Salt Efflux Pump
    Avoid 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 click here for Full Prescribing Information, including Boxed WARNING.

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.

If you have questions or would like more information about OCALIVA, contact Intercept Medical Information.