Ocaliva

Posology Prior to initiation of treatment with obeticholic acid the patient’s hepatic status must be known. 4). The starting dose of obeticholic acid is 5 mg once daily for the first 6 months. Medicinal product no longer authorised 3 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. 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. 4). Elderly (≥ 65 years) Limited data exists in elderly patients.

2). 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. Medicinal product no longer authorised 4

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).

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.

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. , autoimmune hepatitis, alcoholic liver disease), and/or severe intercurrent illness should be closely monitored to determine whether obeticholic acid treatment discontinuation is needed.

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.

1. 4). • Patients with complete biliary obstruction.