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.

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:

1  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.

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’.

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.

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).

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

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

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 national reporting system listed below.

To report any side effect(s):

·        Saudi Arabia:

·         Other GCC States:

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.

Pharmacotherapeutic group: Bile and liver therapy, bile acids and derivatives. ATC code: A05AA04

Mechanism of action

Obeticholic acid is a selective and potent agonist for the farnesoid X receptor (FXR), a nuclear receptor expressed at high levels in the liver and intestine. FXR is thought to be 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 increasing 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.

Clinical efficacy and safety

A phase III, randomised, double-blind, placebo-controlled, parallel-group, 12-month study (POISE) evaluated the safety and efficacy of obeticholic acid in 216 patients with PBC who were taking UDCA for at least 12 months (stable dose for ≥ 3 months) or who were unable to tolerate UDCA and did not receive UDCA for ≥ 3 months.

Patients were included in the trial if the alkaline phosphatase (ALP) was greater than or equal to 1.67 times upper limit of normal (ULN) and/or if total bilirubin was greater than 1 × ULN but less 2 × ULN. Patients were randomised (1:1:1) to receive once daily placebo, obeticholic acid 10 mg, or obeticholic acid titration (5 mg titrated to 10 mg at 6 months dependent on therapeutic response/tolerability). The majority (93%) of patients received treatment in combination with UDCA and a small number of patients (7%) unable to tolerate UDCA received placebo, obeticholic acid (10 mg) or obeticholic acid titration (5 mg to 10 mg) as monotherapy. ALP and total bilirubin were assessed as categorical variables in the primary composite endpoint, as well as continuous variables over time.

The study population was predominantly female (91%) and white (94%). The mean age was 56 years, with the majority of patients less than 65 years old. Mean baseline ALP values ranged from 316 U/L to 327 U/L. Mean baseline total bilirubin values ranged from 10 μmol/L to 12 μmol/L across treatment arms, with 92% of patients within normal range.

Treatment with obeticholic acid 10 mg or obeticholic acid titration (5 mg to 10 mg) resulted in clinically and statistically significant increases (p<0.0001) relative to placebo in the number of patients achieving the primary composite endpoint at all study time points (see table 2). Responses occurred as early as 2 weeks and were dose dependent (obeticholic acid 5 mg compared with 10 mg at 6 months, p=0.0358).

Table 2. Percentage of PBC patients achieving the primary composite endpoint^a at month 6 and month 12 with or without UDCA^b

^a Percentage of subjects achieving a response, defined as an ALP less than 1.67-times the ULN, total bilirubin within the normal range, and an ALP decrease of at least 15%. Missing values were considered a non-response. The Fisher’s exact test was used to calculate the 95% confidence intervals (CIs).

^b In the trial there were 16 patients (7%) who were intolerant and did not receive concomitant UDCA: 6 patients (8%) in the obeticholic acid 10 mg arm, 5 patients (7%) in the obeticholic acid titration arm, and 5 patients (7%) in the placebo arm.

^c Patients were randomised (1:1:1) to receive obeticholic acid 10 mg once daily for the entire 12 months of the trial, or obeticholic acid 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, if the patient was tolerating obeticholic acid but had ALP 1.67-times the ULN or greater, and/or total bilirubin above the ULN, or less than 15% ALP reduction) or placebo.

^d Obeticholic acid titration and obeticholic acid 10 mg versus placebo. P-values are obtained using the Cochran-Mantel-Haenszel General Association test stratified by intolerance to UDCA and pre-treatment ALP greater than 3-times ULN and/or AST greater than 2-times ULN and/or total bilirubin greater than ULN.

^e Response rates were calculated based on the observed case analysis (i.e., [n=observed responder]/[N=intention to treat (ITT) population]); percentage of patients with month 12 values are 86%, 91% and 96% for the obeticholic acid 10 mg, obeticholic acid titration and placebo arms, respectively.

^f The mean baseline total bilirubin value was 0.65 mg/dL, and was within the normal range (i.e., less than or equal to the ULN) in 92% of the enrolled patients.

Mean reduction in ALP

Mean reductions in ALP were observed as early as week 2 and were maintained through month 12 for patients who were maintained on the same dose throughout 12 months. For patients in the obeticholic acid titration arm whose obeticholic acid dose 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.

Mean reduction in gamma-glutamyl transferase (GGT)

The mean (95% CI) reduction in GGT was 178 (137, 219) U/L in the obeticholic acid 10 mg arm, 138 (102, 174) U/L in the obeticholic acid titration arm, and

8 (-32, 48) U/L in the placebo arm.

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 obeticholic acid as monotherapy (24 patients received obeticholic acid 10 mg once daily and 27 patients received placebo) in a pooled analysis of data from the phase III randomised, double-blind, placebo-controlled 12-month study (POISE) and from a randomised, double-blind, placebo-controlled, 3-month study. At month 3, 9 (38%) obeticholic acid-treated patients achieved a response to the composite endpoint,

compared to 1 (4%) placebo-treated patient. The mean (95% CI) reduction in ALP in obeticholic acid-treated patients was 246 (165, 327) U/L compared to an increase of 17 (-7, 42) U/L in the placebo-treated patients.

Paediatric population

The European Medicines Agency has waived the obligation to submit the results of studies with Ocaliva in all subsets of the paediatric population in PBC (see section 4.2 for information on paediatric use).

This medicinal product has been authorised under a so-called ‘conditional approval’ scheme. This means that further evidence on this medicinal product is awaited.

The European Medicines Agency will review any new information on this medicinal product at least every year and this SmPC will be updated as necessary.

Absorption

Obeticholic acid is absorbed with peak plasma concentrations (Cmax) occurring at a median time (tmax) of approximately 2 hours. Co-administration with food does not alter the extent of absorption of obeticholic acid.

Distribution

Human plasma protein binding of obeticholic acid and its conjugates is greater than 99%. The volume of distribution of obeticholic acid is 618 L. The volumes of distribution of glyco- and tauro-obeticholic acid have not been determined.

Biotransformation

Obeticholic acid is conjugated with glycine or taurine in the liver and secreted into bile. These glycine and taurine conjugates of obeticholic acid are absorbed in the small intestine leading to enterohepatic recirculation. The conjugates can be deconjugated in the ileum and colon by intestinal microbiota, leading to the

conversion to obeticholic acid that can be reabsorbed or excreted in faeces, the principal route of elimination.

After daily administration of obeticholic acid, there was accumulation of the glycine and taurine conjugates of obeticholic acid which have in vitro pharmacological activities similar to the parent drug. The metabolite-to-parent ratios of the glycine and taurine conjugates of obeticholic acid were 13.8 and 12.3, respectively, after daily administration. An additional third obeticholic acid metabolite, 3-glucuronide is formed but is considered to have minimal pharmacologic activity.

Elimination

After administration of radiolabeled obeticholic acid, greater than 87% is excreted in faeces. Urinary excretion is less than 3%.

Dose/Time proportionality

Following multiple-dose administration of 5, 10, and 25 mg once daily for 14 days, systemic exposures of obeticholic acid increased dose proportionally. Exposures of glyco- and tauro-obeticholic acid, and total obeticholic acid increase more than proportionally with dose.

Special populations

Elderly

There are limited pharmacokinetic data in elderly patients (≥ 65 years). Population pharmacokinetic analysis, developed using data from patients up to 65 years old, indicated that age is not expected to significantly influence obeticholic acid clearance from the circulation.

Paediatric population

No pharmacokinetic studies were performed with obeticholic acid in patients less than 18 years of age.

Gender

Population pharmacokinetic analysis indicated that gender does not influence obeticholic acid pharmacokinetics.

Race

Population pharmacokinetic analysis indicated that race is not expected to influence obeticholic acid pharmacokinetics.

Renal impairment

In a dedicated single-dose pharmacokinetic study using 25 mg of obeticholic acid, plasma exposures to obeticholic acid and its conjugates were increased by

approximately 1.4- to 1.6-fold in subjects with mild (modification of diet in renal disease [MDRD] eGFR ≥ 60 and < 90 mL/min/1.73 m²), moderate (MDRD eGFR

≥ 30 and < 60 mL/min/1.73 m²) and severe (MDRD eGFR ≥ 15 and

< 30 mL/min/1.73 m²) renal impairment compared to subjects with normal renal function. This modest increase is not considered to be clinically meaningful.

Hepatic impairment

Obeticholic acid is metabolised in the liver and intestines. The systemic exposure of obeticholic acid, its active conjugates, and endogenous bile acids is increased in patients with moderate and severe hepatic impairment (Child-Pugh Class B and C, respectively) when compared to healthy controls (see sections 4.2, 4.3 and 4.4).

The impact of mild hepatic impairment (Child-Pugh Class A) on the pharmacokinetics of obeticholic acid was negligible, therefore, no dose adjustment is necessary for patients with mild hepatic impairment.

In subjects with mild, moderate and severe hepatic impairment (Child-Pugh Class A, B, and C, respectively), mean AUC of total obeticholic acid, the sum of obeticholic acid and its two active conjugates, increased by 1.13-, 4- and 17-fold, respectively, compared to subjects with normal hepatic function following single-dose administration of 10 mg obeticholic acid.

Nonclinical data reveal no special hazard for humans based on conventional studies of safety pharmacology, repeated dose toxicity, genotoxicity, carcinogenic potential, and toxicity to fertility, reproduction and development.

Oral administration of obeticholic acid above the NOAEL to mice, rats, and dogs in pivotal, repeat dose toxicity studies resulted primarily in effects on the hepatobiliary system. These included increased liver weights, alterations in serum chemistry parameters (ALT, AST, LDH, ALP, GGT, and/or bilirubin), and macroscopic/microscopic alterations. All changes were reversible with discontinued dosing, and are consistent with and predict the dose-limiting toxicity in humans (systemic exposure at NOAEL was up to 24-fold higher than that seen at the maximum recommended human dose). In a pre- and post-natal toxicity study in rats, the tauro-conjugate of obeticholic acid was found in pups nursing from dams dosed with obeticholic acid.

Tablet core

Microcrystalline cellulose (E 460) Sodium starch glycolate (Type A) Magnesium stearate

Tablet coating

Poly(vinyl alcohol), partially hydrolysed (E 1203) Titanium dioxide (E 171)

Macrogol (3350) (E 1521) Talc (E 553b)

Iron oxide yellow (E 172)

Not applicable.

 Do not store above 30 °C

High‑density polyethylene (HDPE) bottles with a child resistant polypropylene closure and an aluminium foil induction seal.

Pack size:  30 or 100 film‑coated tablets.

Not all pack sizes may be marketed.

Any unused medicinal product or waste material should be disposed of in accordance with local requirements.