4.1. Therapeutic indications

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.

4.2. Posology and method of administration

Posology

Prior to initiation of treatment with obeticholic acid the patient's hepatic status must be known. Whether the patient has decompensated cirrhosis (including Child-Pugh Class B or C) or has had a prior decompensation event should be determined prior to initiation of treatment because obeticholic acid is contraindicated in these patients (see sections 4.3 and 4.4).

The starting dose of obeticholic acid is 5 mg once daily for the first 6 months.

After the first 6 months, for patients who have not achieved an adequate reduction in alkaline phosphatase (ALP) and/or total bilirubin and who are tolerating obeticholic acid, increase to a maximum dose of 10 mg once daily.

No dose adjustment of concomitant UDCA is required in patients receiving obeticholic acid.

Management and dose adjustment for severe pruritus

Management strategies include the addition of bile acid binding resins or antihistamines.

For patients experiencing severe intolerability due to pruritus, one or more of the following should be considered:

• The dose of obeticholic acid may be reduced 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

• The dose of obeticholic acid may be temporarily interrupted for up to 2 weeks followed by restarting at a reduced dose.

• The dose may be increased to 10 mg once daily, as tolerated, to achieve optimal response.

Discontinuing treatment with obeticholic acid may be considered for patients who continue to experience persistent, intolerable pruritus.

Bile acid binding resins

For patients taking bile acid binding resins, obeticholic acid should be administered at least 4 to 6 hours before or 4 to 6 hours after taking a bile acid binding resin, or at as great an interval as possible (see section 4.5).

Missed dose

If a dose is missed, the missed dose should be skipped and the normal schedule should be resumed for the following dose. A double dose should not be taken to make up for the missed dose.

Special populations

Hepatic impairment

Obeticholic acid is contraindicated in patients with decompensated cirrhosis (e.g., Child-Pugh Class B or C) or a prior decompensation event (see sections 4.3 and 4.4).

Elderly ( ≥ 65 years)

Limited data exists in elderly patients. No dose adjustment is required for elderly patients (see section 5.2).

Renal impairment

No dose adjustment is required for patients with renal impairment (see section 5.2).

Paediatric population

There is no relevant use of obeticholic acid in the paediatric population in the treatment of PBC.

Method of administration

The tablet should be taken orally with or without food.

4.3. Contraindications

• Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.

• Patients with decompensated cirrhosis (e.g., Child-Pugh Class B or C) or a prior decompensation event (see section 4.4).

• Patients with complete biliary obstruction.

4.4. Special warnings and precautions for use

Hepatic adverse events

Hepatic failure, sometimes fatal or resulting in liver transplant, has been reported with obeticholic acid treatment in PBC patients with either compensated or decompensated cirrhosis.

Some of these cases occurred in patients with decompensated cirrhosis when they were treated with higher than the recommended dose 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 dose.

Elevations in alanine amino transferase (ALT) and aspartate aminotransferase (AST) have been observed in patients taking obeticholic acid. Clinical signs and symptoms of hepatic decompensation have also been observed. These events have occurred as early as within the first month of treatment. Hepatic adverse events have primarily been observed at doses higher than the maximum recommended dose of 10 mg once daily (see section 4.9).

All patients should be routinely monitored for progression of PBC, including hepatic adverse reactions, with laboratory and clinical assessments to determine whether obeticholic acid treatment discontinuation is needed. Patients at increased risk of hepatic decompensation, including those with elevated bilirubin levels, evidence of portal hypertension (e.g., ascites, gastroesophageal varices, persistent thrombocytopenia), concomitant hepatic disease (e.g., autoimmune hepatitis, alcoholic liver disease), and/or severe intercurrent illness should be closely monitored to determine whether obeticholic acid treatment discontinuation is needed.

Treatment with obeticholic acid in patients with laboratory or clinical evidence of hepatic decompensation (e.g., ascites, jaundice, variceal bleeding, hepatic encephalopathy), including progression to Child-Pugh Class B or C, should be permanently discontinued (see section 4.3).

Treatment with obeticholic acid should be interrupted during severe intercurrent illness or in patients who experience clinically significant hepatic adverse reactions and the patient's liver function should be monitored. After resolution and if there is no laboratory or clinical evidence of hepatic decompensation, the potential risks and benefits of restarting obeticholic acid treatment should be considered.

Severe pruritus

Severe pruritus was reported in 23% of patients treated with obeticholic acid 10 mg arm, 19% of patients in the obeticholic acid titration arm, and 7% of patients in the placebo arms. The median time to onset of severe pruritus was 11, 158, and 75 days for patients in the obeticholic acid 10 mg, obeticholic acid titration, and placebo arms, respectively. Management strategies include the addition of bile acid binding resins or antihistamines, dose reduction, reduced dosing frequency, and/or temporary dose interruption (see sections 4.2 and 4.8).

Excipients

This medicinal product contains less than 1 mmol sodium (23 mg) per tablet, that is to say essentially 'sodium-free'.

4.5. Interaction with other medicinal products and other forms of interaction

Effect of other medicinal products on obeticholic acid

Bile acid binding resins

Bile acid binding resins such as cholestyramine, colestipol, or colesevelam adsorb and reduce bile acid absorption and may reduce efficacy of obeticholic acid. When concomitant bile acid binding resins are administered, obeticholic acid should be taken at least 4 to 6 hours before or 4 to 6 hours after taking a bile acid binding resin, or at as great an interval as possible.

Effect of obeticholic acid on other medicinal products

Warfarin

International normalised ratio (INR) is decreased following co-administration of warfarin and obeticholic acid. INR should be monitored and the dose of warfarin adjusted, if needed, to maintain the target INR range when co-administering obeticholic acid and warfarin.

Interaction with CYP1A2 substrates with narrow therapeutic index

Obeticholic acid may increase the exposure to concomitant medicinal products that are CYP1A2 substrates. Therapeutic monitoring of CYP1A2 substrates with narrow therapeutic index (e.g., theophylline and tizanidine) is recommended.

4.6. Fertility, pregnancy and lactation

Pregnancy

There are no data on the use of obeticholic acid in pregnant women. Animal studies do not indicate direct or indirect harmful effects with respect to reproductive toxicity (see section 5.3). As a precautionary measure, it is preferable to avoid the use of Ocaliva during pregnancy.

Breast-feeding

It is unknown whether obeticholic acid is excreted in human milk. Based on animal studies and intended pharmacology, obeticholic acid is not expected to interfere with breast-feeding or the growth or development of a breast-fed child (see section 5.3). A decision must be made whether to discontinue breast-feeding or to discontinue/abstain from Ocaliva therapy taking into account the benefit of breast-feeding for the child and the benefit of therapy for the woman.

Fertility

No fertility data is available in humans. Animal studies do not indicate any direct or indirect effects on fertility or reproduction (see section 5.3).

4.7. Effects on ability to drive and use machines

Ocaliva has no or negligible influence on the ability to drive and use machines.

4.8. Undesirable effects

Summary of the safety profile

The most commonly reported adverse reactions were pruritus (63%) and fatigue (22%). The most common adverse reaction leading to discontinuation was pruritus. The majority of pruritus occurred within the first month of treatment and tended to resolve over time with continued dosing.

Tabulated list of adverse reactions

The adverse reactions reported with obeticholic acid are listed in the table below by MedDRA system organ class and by frequency. Frequencies are defined as: very common (≥ 1/10), common (≥ 1/100 to < 1/10), uncommon (≥ 1/1,000 to < 1/100), rare (≥ 1/10,000 to < 1/1,000), very rare (< 1/10,000) and not known (cannot be estimated from the available data).

Table 1. Frequency of adverse reactions in PBC patients

System organ class

Very common

Common

Not known

Endocrine disorders

Thyroid function abnormality

Nervous system disorders

Dizziness

Cardiac disorders

Palpitations

Respiratory, thoracic and mediastinal disorders

Oropharyngeal pain

Gastrointestinal disorders

Abdominal pain and discomfort

Constipation

Hepatobiliary disorders

Hepatic failure, Blood bilirubin increased, Jaundice, Hepatic cirrhosis

Skin and subcutaneous tissue disorders

Pruritus

Eczema, Rash

Musculoskeletal and connective tissue disorders

Arthralgia

General disorders and administration site conditions

Fatigue

Oedema peripheral, Pyrexia

Description of selected adverse reactions

Discontinuation of treatment

Adverse reactions leading to discontinuation of treatment were 1% (pruritus) in the obeticholic acid titration arm and 11% (pruritus and fatigue) in the obeticholic acid 10 mg arm.

Pruritus

Approximately 60% of patients had a history of pruritus upon enrollment in the phase III study. Treatment-emergent pruritus generally started within the first month following the initiation of treatment.

Relative to patients who started on 10 mg once daily in the obeticholic acid 10 mg arm, patients in the obeticholic acid titration arm had a lower incidence of pruritus (70% and 56%, respectively) and a lower discontinuation rate due to pruritus (10% and 1%, respectively).

The percentages of patients who required interventions (i.e., dose adjustments, treatment interruptions, or initiation of antihistamines or bile acid binding resins) were 41% in the obeticholic acid 10 mg arm, 34% in the obeticholic acid titration group, and 19% in the placebo group.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the Yellow Card Scheme Website: www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store.

4.9. Overdose

The highest single dose exposure of obeticholic acid in healthy volunteers has been at the 500 mg dose. Repeated doses of 250 mg have been administered for 12 consecutive days and some subjects experienced pruritus and reversible transaminase liver elevations. In the clinical trials, PBC patients who received obeticholic acid 25 mg once daily (2.5-times the highest recommended dose) or 50 mg once daily (5-times the highest recommended dose), experienced a dose-dependent increase in the incidence of hepatic adverse reactions (e.g., ascites, primary biliary cholangitis flare, new onset jaundice), and transaminase and bilirubin elevations (up to greater than 3-times upper limit of normal [ULN]). In the case of overdose, patients should be carefully observed and supportive care administered, as appropriate.