2.1 Important Dosage and Administration Instructions

• Prior to the initiation of OCALIVA in patients with suspected cirrhosis, use the nomogram (see Table 1) to calculate the patient's score to determine their Child-Pugh classification (A, B, or C) and determine the appropriate starting dosage (see Table 2) [see Dosage and Administration (2.2), Warnings and Precautions (5.1)].

• Routinely monitor patients during OCALIVA treatment for biochemical response, tolerability, progression of PBC disease, and re-evaluate Child-Pugh classification to determine if dosage adjustment is needed.
• Reduce the dosing frequency from once daily to once weekly as appropriate for patients who progress to advanced disease (i.e., from Child-Pugh Class A to Child-Pugh Class B or C) [see Dosage and Administration (2.2)].

2.2 Recommended Dosage Regimen

The recommended starting dose and titration dosage regimen of OCALIVA for patients who have not achieved an adequate biochemical response to an appropriate dosage of UDCA for at least 1 year or are intolerant to UDCA [see Clinical Studies (14)] is dependent upon disease stage, as shown in Table 2:

• Non-cirrhotic patients or compensated cirrhotic patients with no or mild hepatic impairment (Child-Pugh Class A) are dosed once daily.
• Cirrhotic patients with moderate or severe hepatic impairment (Child-Pugh Class B or C) or patients who have previously experienced a decompensation event are dosed initially once weekly and not more than twice weekly.

2.3 Monitoring to Assess Safety, Treatment Interruption or Discontinuation

Routinely monitor patients during OCALIVA treatment for progression of PBC disease with laboratory and clinical assessments to determine whether dosage adjustment is needed. Reduce the dosing frequency for patients who progress from Child-Pugh Class A to Child-Pugh Class B or C (see Table 2 above). Close monitoring is recommended for patients at an increased risk of hepatic decompensation, including those with laboratory evidence of worsening liver function (i.e., total bilirubin, INR, albumin) and/or progression to cirrhosis [see Warnings and Precautions (5.1)].

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.

If the patient's condition returns to baseline, weigh the potential risks and benefits of restarting OCALIVA treatment. If OCALIVA is re-initiated, use the recommended starting dosage with adjustment for Child-Pugh classification [see Dosage and Administration (2.2)].

Consider discontinuing OCALIVA in patients who have experienced clinically significant liver-related adverse reactions.

2.4 Management of Patients with Intolerable Pruritus on OCALIVA

For patients with intolerable pruritus on OCALIVA, consider one or more of the following management strategies:

2.5 Administration Instructions

• Take OCALIVA with or without food.
• For patients 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 [see Drug Interactions (7.1), Clinical Studies (14)].

5.1 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 PBC patients with decompensated cirrhosis or Child-Pugh Class 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). A few cases reported improvement after OCALIVA discontinuation; however, some cases reported ongoing symptoms. Because postmarketing cases often contain limited clinical information, there was insufficient information to rule out confounding factors (e.g., concomitant medications) or the role of the patient's underlying advanced disease in the events [see Adverse Reactions (6.2)].

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 [see Dosage and Administration (2.2)].

5.2 Liver-Related Adverse Reactions

In two 3-month, placebo-controlled clinical trials in patients with primarily early stage PBC disease, a dose-response relationship was observed for the occurrence of liver-related 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 [see Overdosage (10)].

In a pooled analysis of three placebo-controlled trials in patients with primarily early stage PBC disease, the exposure-adjusted incidence rates for all serious and otherwise clinically significant liver-related adverse reactions, and isolated elevations in liver biochemical tests, per 100 patient exposure years (PEY) were: 5.2 in the OCALIVA 10 mg group (highest recommended dosage), 19.8 in the OCALIVA 25 mg group (2.5 times the highest recommended dosage) and 54.5 in the OCALIVA 50 mg group (5 times the highest recommended dosage) compared to 2.4 in the placebo group.

Monitor patients during treatment with OCALIVA for elevations in liver biochemical tests and for the development of liver-related adverse reactions. Close monitoring is recommended for patients at an increased 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 [see Dosage and Administration (2.2, 2.3), Warnings and Precautions (5.1)].

5.3 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 Trial 1, a 12-month double-blind randomized controlled trial of 216 patients [see Adverse Reactions (6.1)]. 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. In the subgroup of patients in the OCALIVA titration arm who increased their dosage from 5 mg once daily to 10 mg once daily after 6 months of treatment (n=33), the incidence of severe pruritus was 0% from Months 0 to 6 and 15% from Months 6 to 12. The median time to onset of severe pruritus was 11, 158, and 75 days for patients in the OCALIVA 10 mg, OCALIVA titration, and placebo arms, respectively.

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 [see Dosage and Administration (2.4)].

5.4 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). In Trial 1, 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. At month 12, the reduction from baseline in mean HDL-C level was 19% in the OCALIVA 10 mg arm, 12% in the OCALIVA titration arm, and 2% in the placebo arm. Nine patients in the OCALIVA 10 mg arm, 6 patients in the OCALIVA titration arm, versus 3 patients in the placebo arm had reductions in HDL-C to less than 40 mg/dL.

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.

6.1 Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

A total of 432 patients with PBC were studied in three double-blind placebo-controlled trials. Of these patients, 290 were treated with OCALIVA for at least 6 months, 232 were treated for at least 12 months, and 70 were treated for at least 2 years. There were 131 patients who received OCALIVA 10 mg once daily and 70 who received OCALIVA 5 mg once daily.

In Trial 1, 216 patients were randomized (1:1:1) to receive either:

• OCALIVA 10 mg once daily for the entire 12 months of the trial (n=73);
• OCALIVA titration (5 mg once daily for the initial 6 months, with the option to increase to 10 mg once daily for the last 6 months, in patients who were tolerating OCALIVA, but had ALP 1.67-times ULN or greater, and/or total bilirubin greater than ULN, or less than 15% ALP reduction) (n=70); or
• placebo (n=73).

During the trial, OCALIVA or placebo was administered in combination with UDCA in 93% of patients and as monotherapy in 7% of patients who were unable to tolerate UDCA. The overall discontinuation rate was 12% in the OCALIVA 10 mg arm, 10% in the OCALIVA titration arm, and 4% in the placebo arm.

The recommended starting dosage of OCALIVA is 5 mg orally once daily for 3 months with titration to 10 mg once daily based upon tolerability and response [see Dosage and Administration (2.2)]. Initiation of therapy with OCALIVA 10 mg once daily is not recommended due to an increased risk of pruritus.

The most common adverse reactions in Trial 1 occurring in at least 5% of patients in either OCALIVA treatment arm and at an incidence at least 1% higher than the placebo treatment arm are shown in Table 3.

6.2 Postmarketing Experience

The following adverse reactions have been identified during post approval use of OCALIVA. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure, particularly in PBC patients who have progressive liver disease.

Hepatobiliary Disorders: liver failure, new onset cirrhosis, increased direct and total bilirubin, new or worsening of jaundice, ascites, worsening hepatic encephalopathy [see Warnings and Precautions (5.1)].

7.1 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 [see Dosage and Administration (2.5)].

7.2 Warfarin

The International Normalized Ratio (INR) decreased following coadministration of warfarin and OCALIVA [see Clinical Pharmacology (12.3)]. Monitor INR and adjust the dosage of warfarin, as needed, to maintain the target INR range when co-administering OCALIVA and warfarin.

7.3 CYP1A2 Substrates with Narrow Therapeutic Index

Obeticholic acid may increase the exposure to concomitant drugs that are CYP1A2 substrates [see Clinical Pharmacology (12.3)]. Therapeutic monitoring of CYP1A2 substrates with a narrow therapeutic index (e.g. theophylline and tizanidine) is recommended when co-administered with OCALIVA.

7.4 Inhibitors of Bile Salt Efflux Pump

Avoid concomitant use of inhibitors of the bile salt efflux pump (BSEP) such as cyclosporine [see Clinical Pharmacology (12.3)]. 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.

8.1 Pregnancy

8.2 Lactation

8.4 Pediatric Use

The safety and effectiveness of OCALIVA in pediatric patients have not been established.

8.5 Geriatric Use

Of the 201 patients in clinical trials of OCALIVA who received the recommended dosage (5 mg or 10 mg once daily), 41 (20%) were 65 years of age and older, while 9 (4%) were 75 years of age and older. No overall differences in safety or effectiveness were observed between these subjects and subjects less than 65 years of age, but greater sensitivity of some older individuals cannot be ruled out.

8.6 Hepatic Impairment

Hepatic decompensation and failure, in some cases fatal, have been reported postmarketing in PBC patients with decompensated cirrhosis or Child-Pugh B or C hepatic impairment when OCALIVA was dosed more frequently than recommended. In PBC clinical trials, a dose-response relationship was observed for the occurrence of liver-related adverse reactions with OCALIVA [see Warnings and Precautions (5.2)].

Plasma exposure to obeticholic acid and its active conjugates, increases significantly in patients with moderate to severe hepatic impairment (Child-Pugh Classes B and C) [see Clinical Pharmacology (12.3)].

Prior to the initiation of OCALIVA determine the patient's Child-Pugh classification to determine the starting dosage. Re-evaluate the dosing regimen periodically during treatment.

Dosage adjustment is required in patients with Child-Pugh Class B and C. Routinely monitor patients for progression of PBC disease with laboratory and clinical assessments. Dosage adjustment, interruption or discontinuation may be required [see Dosage and Administration (2.1, 2.2, 2.3)].

12.1 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 circulating bile acid pool while promoting choleresis, thus reducing hepatic exposure to bile acids.

12.2 Pharmacodynamics

12.3 Pharmacokinetics

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

Carcinogenic potential of obeticholic acid was assessed in carcinogenicity studies of up to 2 years in duration in mice and rats. In mice, there were no drug-related neoplastic findings at doses up to 25 mg/kg/day obeticholic acid, a dose that produced systemic exposures approximately 12 times those in humans at the MRHD of 10 mg. In rats, obeticholic acid was administered at doses of 2, 7, and 20 mg/kg/day. At 20 mg/kg/day (approximately 12 times the human exposure at the MRHD), obeticholic acid caused an increase in the incidence of benign granulosa cell tumors in the ovaries and benign granular cell tumors in the cervix and vagina of female rats. There were no drug-related neoplastic findings in male rats.

Obeticholic acid was not genotoxic in the Ames test, a human peripheral blood lymphocyte chromosomal aberration test, and a mouse micronucleus test. The glycine conjugate of obeticholic acid was also not genotoxic in an Ames test and human peripheral blood lymphocyte chromosome aberration test. The taurine conjugate of obeticholic acid was not genotoxic in an Ames test, and was negative in a human peripheral blood lymphocyte chromosomal aberration test in the presence of metabolic activation; the findings of the chromosomal aberration assay in the absence of metabolic activation were inconclusive.

Obeticholic acid, administered at oral doses of 5, 25 and 50 mg/kg/day to male rats for 28 days before mating and throughout the mating period, and to female rats from 14 days before mating through mating and until gestation day 7, did not alter male or female fertility or early embryonic development at any dose (the 50 mg/kg/day dose is approximately 13 times the human exposure at the MRHD).

Mean Reduction in ALP

Figure 1 shows the mean reductions in ALP in OCALIVA-treated patients compared to placebo. Reductions were observed as early as Week 2, plateaued by Month 3 and were maintained through Month 12 for patients who were maintained on the same dosage throughout 12 months. Although Trial 1 studied titration at 6 months, these data are supportive of titration of OCALIVA after 3 months [see Dosage and Administration (2.2)]. For patients in the OCALIVA titration arm whose OCALIVA dosage was increased from 5 mg once daily to 10 mg once daily, additional reductions in ALP were observed at Month 12 in the majority of patients [see Clinical Pharmacology (12.2)].

Figure 1: Mean ALP over 12 Months in Trial 1 by Treatment Arm with or without UDCAa

Mean Reduction in GGT

The mean (95% CI) reduction in gamma-glutamyl transferase (GGT) was 178 (137, 219) U/L in the OCALIVA 10 mg arm, 138 (102, 174) U/L in the OCALIVA titration arm, and 8 (-32, 48) U/L in the placebo arm.

OCALIVA Monotherapy

Fifty-one PBC patients with baseline ALP 1.67-times ULN or greater and/or total bilirubin greater than ULN were evaluated for a biochemical response to OCALIVA as monotherapy (24 patients received OCALIVA 10 mg once daily and 27 patients received placebo) in a pooled analysis of data from Trial 1 and from a randomized, double-blind, placebo-controlled, 3-month trial. At Month 3, 9 (38%) OCALIVA-treated patients achieved a response to the composite endpoint, compared to 1 (4%) placebo-treated patient. The mean (95% CI) reduction in ALP in OCALIVA-treated patients was 246 (165, 327) U/L compared to an increase of 17 (-7, 42) U/L in the placebo-treated patients.

5 mg Tablets

OCALIVA tablets are available as off-white to yellow, round tablets debossed with INT on one side and 5 on the other side. Each tablet contains 5 mg of obeticholic acid.

• NDC 69516-005-30           5 mg tablets in a bottle (30 count)

10 mg Tablets

OCALIVA tablets are available as off-white to yellow, triangular tablets debossed with INT on one side and 10 on the other side. Each tablet contains 10 mg of obeticholic acid.

• NDC 69516-010-30           10 mg tablets in a bottle (30 count)

Storage and Handling

Store at 20ºC-25ºC (68ºF-77ºF); excursions permitted to 15ºC- 30ºC (59ºF -86ºF) [See USP Controlled Room Temperature].

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

• Instruct patients and caregivers to immediately contact their healthcare provider if they experience:
  • Symptoms of disease progression or worsening liver function, such as ascites, jaundice, gastrointestinal bleeding or worsening of hepatic encephalopathy.
  • Symptoms of complete biliary obstruction [see Warnings and Precautions (5.1), Contraindications (4)].
• Instruct patients and caregivers to immediately contact their healthcare provider if they experience severe or persistent non-specific signs and symptoms of impaired health: nausea, vomiting, abdominal pain, diarrhea, weight loss, fever and chills, worsening or new fatigue, weakness, loss of appetite or dehydration.
• Inform patients that they will need to undergo laboratory testing periodically while on OCALIVA treatment to assess liver function.

Severe Pruritus

• Advise patients to contact their healthcare provider if they experience new onset or worsening severe pruritus [see Warnings and Precautions (5.3)].

Reduction in HDL-C

• Advise patients that they may need to undergo laboratory testing to check for changes in lipid levels while on treatment with OCALIVA [see Warnings and Precautions (5.4)].

Administration

Advise patients to take:

• OCALIVA with or without food.
• OCALIVA at least 4 hours before or 4 hours after taking a bile acid binding resin, or at as great an interval as possible [see Drug Interactions (7.1)].