Ocaliva: Package Insert and Label Information

OCALIVA- obeticholic acid tablet, film coated
Intercept Pharmaceuticals Inc

1 INDICATIONS AND USAGE

OCALIVA^® 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) [see Clinical Studies (14)]. 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.

2 DOSAGE AND ADMINISTRATION

2.1 Important Dosage and Administration Instructions

Prior to the initiation of OCALIVA, healthcare providers should determine whether the patient has decompensated cirrhosis (e.g., Child-Pugh Class B or C), has had a prior decompensation event, or has compensated cirrhosis with evidence of portal hypertension (e.g., ascites, gastroesophageal varices, persistent thrombocytopenia) because OCALIVA is contraindicated in these patients [see Contraindications (4), Warnings and Precautions (5.1)].

2.2 Recommended Dosage Regimen

The recommended dosage of OCALIVA for PBC patients without cirrhosis or with compensated cirrhosis who do not have evidence of portal hypertension, 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)] follows below:

• Start with a dosage of 5 mg once daily for the first 3 months.
• After the first 3 months, for patients who have not achieved an adequate reduction in ALP and/or total bilirubin and who are tolerating OCALIVA, increase to a maximum dosage of 10 mg once daily.

2.3 Monitoring to Assess Safety, Need for OCALIVA Discontinuation

Routinely monitor patients during OCALIVA treatment for biochemical response, tolerability, and 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 OCALIVA 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 [see Contraindications (4), Warnings and Precautions (5.1)].

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:

• Add an antihistamine or bile acid binding resin [see Dosage and Administration (2.5), Clinical Studies (14)].
• Reduce the dosage of OCALIVA to:
  • 5 mg every other day, for patients intolerant to 5 mg once daily.
  • 5 mg once daily, for patients intolerant to 10 mg once daily.
• Temporarily interrupt OCALIVA dosing for up to 2 weeks. Restart at a reduced dosage.

For patients whose dosage is reduced or interrupted, titrate the dosage based on biochemical response and tolerability [see Dosage and Administration (2.2)].

Consider discontinuing OCALIVA treatment in patients who continue to experience persistent, intolerable pruritus despite management strategies [see Warnings and Precautions (5.2)].

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)].

3 DOSAGE FORMS AND STRENGTHS

OCALIVA is available as:

• 5 mg tablet: Off white to yellow, round tablet debossed with “INT” on one side and “5” on the other side.
• 10 mg tablet: Off white to yellow, triangular tablet debossed with “INT” on one side and “10” on the other side.

4 CONTRAINDICATIONS

OCALIVA is contraindicated in patients with:

• decompensated cirrhosis (e.g., Child-Pugh Class B or C) or a prior decompensation event [see Warnings and Precautions (5.1)].
• compensated cirrhosis who have evidence of portal hypertension (e.g., ascites, gastroesophageal varices, persistent thrombocytopenia) [see Warnings and Precautions (5.1)].
• complete biliary obstruction.

5 WARNINGS AND PRECAUTIONS

5.1 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 [see Overdosage (10)].

In a pooled analysis of three placebo-controlled clinical trials in patients with primarily early stage PBC, the exposure-adjusted incidence rates for all serious and otherwise clinically significant hepatic 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.

Patient Management

Routinely monitor patients for progression of PBC, including hepatic adverse reactions, with laboratory and clinical assessments to determine whether drug discontinuation is needed [see Dosage and Administration (2.3)].

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 [see Dosage and Administration (2.3)].

Permanently discontinue OCALIVA in patients who:

• develop laboratory or clinical evidence of hepatic decompensation (e.g., ascites, jaundice, variceal bleeding, hepatic encephalopathy) [see Contraindications (4)].
• have compensated cirrhosis and develop evidence of portal hypertension (e.g., ascites, gastroesophageal varices, persistent thrombocytopenia) [see Contraindications (4)].
• experience clinically significant hepatic adverse reactions.
• develop complete biliary obstruction [see Contraindications (4)].

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.

5.2 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 clinical 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 binding resins or antihistamines, OCALIVA dosage reduction, and/or temporary interruption of OCALIVA dosing [see Dosage and Administration (2.4)].

5.3 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 ADVERSE REACTIONS

The following clinically significant adverse reactions are described elsewhere in labeling:

• Hepatic Decompensation and Failure in PBC Patients with Cirrhosis [see Warnings and Precautions (5.1)]
• Severe Pruritus [see Warnings and Precautions (5.2)]
• Reduction in HDL-C [see Warnings and Precautions (5.3)]

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 clinical 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 1.

Table 1: Most Common Adverse Reactions in Adult Patients with PBC in Trial 1 by Treatment Arm with or without UDCA *

			Placebo N=73%
Adverse Reaction †	OCALIVA 10 mgN=73%	OCALIVA Titration ‡N=70%
* In the trial there were 16 patients (7%) who were intolerant and did not receive concomitant UDCA: 6 patients (8%) in the OCALIVA 10 mg arm, 5 patients (7%) in the OCALIVA titration arm, and 5 patients (7%) in the placebo arm. † Occurring in greater than or equal to 5% of patients in either OCALIVA treatment arm and at an incidence greater than or equal to1% higher than in the placebo treatment arm. ‡ Patients randomized to OCALIVA titration received OCALIVA 5 mg once daily for the initial 6-month period. At Month 6, patients who were tolerating OCALIVA, but had an ALP 1.67-times ULN or greater, and/or total bilirubin greater than ULN, or less than 15% ALP reduction were eligible for titration from 5 mg once daily to 10 mg once daily for the final 6 months of the trial. § Includes skin eruptions, prurigo, pruritus, pruritus generalized, eye pruritus, ear pruritus, anal pruritus, vulvovaginal pruritus, rash pruritic. ¶ Includes fatigue, tiredness, asthenia. # Includes abdominal pain upper, abdominal pain, abdominal discomfort, abdominal pain lower, abdominal tenderness, gastrointestinal pain. Þ Includes urticaria, rash, rash macular, rash papular, rash maculo-papular, heat rash, urticaria cholinergic. ß Includes dizziness, syncope, presyncope. à Includes thyroxine free decreased, blood thyroid stimulating hormone increased, hypothyroidism.
Pruritus §	70	56	38
Fatigue ¶	25	19	15
Abdominal pain and discomfort #	10	19	14
Rash Þ	10	7	8
Arthralgia	10	6	4
Oropharyngeal pain	8	7	1
Dizziness ß	7	7	5
Constipation	7	7	5
Peripheral Edema	7	3	3
Palpitations	7	3	1
Pyrexia	7	0	1
Thyroid function abnormality à	4	6	3
Eczema	3	6	0

Hepatic Adverse Reactions

In Trial 1, the following serious or otherwise clinically significant hepatic adverse reactions were reported at the recommended dosage of OCALIVA: one patient in the OCALIVA 10 mg treatment arm experienced ascites; one patient in the OCALIVA titration treatment arm experienced two episodes of ascites and four episodes of hepatic encephalopathy; one patient in the placebo treatment arm experienced variceal bleeding.

Pruritus

Approximately 60% of patients had a history of pruritus upon enrollment in Trial 1. Treatment-emergent pruritus, including all the terms described in Table 1, generally started within the first month following the initiation of treatment with OCALIVA.

The incidence of pruritus was higher in patients who started on OCALIVA 10 mg once daily relative to the OCALIVA titration arm, 70% and 56%, respectively. Discontinuation rates due to pruritus were also higher in patients who started on OCALIVA 10 mg once daily relative to the OCALIVA titration arm, 10% and 1%, respectively.

The number of patients with pruritus who required an intervention (e.g., dosage adjustment, treatment interruption, or initiation of bile acid binding resin or antihistamine) was 30 of 51 patients (59%) in the OCALIVA 10 mg arm, 24 of 39 patients (62%) in the OCALIVA titration arm, and 14 of 28 patients (50%) in the placebo arm.