OCALIVA 5mg tablets medication leaflet

Ocaliva 5 mg film-coated tablets

Ocaliva 10 mg film-coated tablets

Ocaliva 5 mg film-coated tablets

Each film-coated tablet contains 5 mg of obeticholic acid.

Ocaliva 10 mg film-coated tablets

Each film-coated tablet contains 10 mg of obeticholic acid.

For the full list of excipients, see section 6.1.

Film-coated tablet.

Ocaliva 5 mg film-coated tablets

Yellow, 8 mm round tablet debossed with ‘INT’ on one side and ‘5’ on the other side.

Ocaliva 10 mg film-coated tablets

Yellow, 8 mm × 7 mm triangular tablet debossed with ‘INT’ on one side and ‘10’ on the other side.

Ocaliva is indicated for the treatment of primary biliary cholangitis (PBC) in combination withursodeoxycholic acid (UDCA) in adults with an inadequate response to UDCA or as monotherapy inadults unable to tolerate UDCA.

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 aprior decompensation event should be determined prior to initiation of treatment because obeticholicacid 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 alkalinephosphatase (ALP) and/or total bilirubin and who are tolerating obeticholic acid, increase to amaximum 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 beconsidered:

* 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 byrestarting 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 toexperience persistent, intolerable pruritus.

Bile acid binding resins

For patients taking bile acid binding resins, obeticholic acid should be administered at least 4 to6 hours before or 4 to 6 hours after taking a bile acid binding resin, or at as great an interval aspossible (see section 4.5).

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

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

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

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

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

The tablet should be taken orally with or without food.

* 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 priordecompensation event (see section 4.4).

* Patients with complete biliary obstruction.

Hepatic adverse events

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

Some of these cases occurred in patients with decompensated cirrhosis when they were treated withhigher than the recommended dose for that patient population; however, cases of hepaticdecompensation and failure have continued to be reported in patients with decompensated cirrhosiseven when they received the recommended dose.

Elevations in alanine amino transferase (ALT) and aspartate aminotransferase (AST) have beenobserved in patients taking obeticholic acid. Clinical signs and symptoms of hepatic decompensationhave 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 maximumrecommended dose of 10 mg once daily (see section 4.9).

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

Treatment with obeticholic acid in patients with laboratory or clinical evidence of hepaticdecompensation (e.g., ascites, jaundice, variceal bleeding, hepatic encephalopathy), includingprogression 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 patientswho experience clinically significant hepatic adverse reactions and the patient’s liver function shouldbe monitored. After resolution and if there is no laboratory or clinical evidence of hepaticdecompensation, the potential risks and benefits of restarting obeticholic acid treatment should beconsidered.

Severe pruritus

Severe pruritus was reported in 23% of patients treated with obeticholic acid 10 mg arm, 19% ofpatients in the obeticholic acid titration arm, and 7% of patients in the placebo arms. The median timeto 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 additionof bile acid binding resins or antihistamines, dose reduction, reduced dosing frequency, and/ortemporary dose interruption (see sections 4.2 and 4.8).

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 acidabsorption and may reduce efficacy of obeticholic acid. When concomitant bile acid binding resins areadministered, obeticholic acid should be taken at least 4 to 6 hours before or 4 to 6 hours after taking abile acid binding resin, or at as great an interval as possible.

Effect of obeticholic acid on other medicinal products

International normalised ratio (INR) is decreased following co-administration of warfarin andobeticholic acid. INR should be monitored and the dose of warfarin adjusted, if needed, to maintainthe 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 CYP1A2substrates. Therapeutic monitoring of CYP1A2 substrates with narrow therapeutic index (e.g.,theophylline and tizanidine) is recommended.

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

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

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

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

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

The adverse reactions reported with obeticholic acid are listed in the table below by MedDRA systemorgan 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) andnot 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 Oropharyngeal painmediastinal disorders

Gastrointestinal disorders Abdominal pain and Constipationdiscomfort

Hepatobiliary disorders Hepatic failure, Bloodbilirubin increased,

Jaundice, Hepatic cirrhosis

Skin and subcutaneous tissue Pruritus Eczema, Rashdisorders

Musculoskeletal and Arthralgiaconnective tissue disorders

General disorders and Fatigue Oedema peripheral, Pyrexiaadministration site conditions

Adverse reactions leading to discontinuation of treatment were 1% (pruritus) in the obeticholic acidtitration 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 oftreatment.

Relative to patients who started on 10 mg once daily in the obeticholic acid 10 mg arm, patients in theobeticholic acid titration arm had a lower incidence of pruritus (70% and 56%, respectively) and alower 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 suspected adverse reactions after authorisation of the medicinal product is important. Itallows continued monitoring of the benefit/risk balance of the medicinal product. Healthcareprofessionals are asked to report any suspected adverse reactions via the national reporting systemlisted in Appendix V.

The highest single dose exposure of obeticholic acid in healthy volunteers has been at the 500 mgdose. Repeated doses of 250 mg have been administered for 12 consecutive days and some subjectsexperienced pruritus and reversible transaminase liver elevations. In the clinical trials, PBC patientswho received obeticholic acid 25 mg once daily (2.5-times the highest recommended dose) or 50 mgonce daily (5-times the highest recommended dose), experienced a dose-dependent increase in theincidence of hepatic adverse reactions (e.g., ascites, primary biliary cholangitis flare, new onsetjaundice), 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 careadministered, as appropriate.

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

Obeticholic acid is a selective and potent agonist for the farnesoid X receptor (FXR), a nuclearreceptor expressed at high levels in the liver and intestine. FXR is thought to be a key regulator of bileacid, inflammatory, fibrotic, and metabolic pathways. FXR activation decreases the intracellularhepatocyte 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 ofthe circulating bile acid pool while promoting choleresis, thus reducing hepatic exposure to bile acids.

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 UDCAfor at least 12 months (stable dose for ≥ 3 months) or who were unable to tolerate UDCA and did notreceive 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 wasgreater than 1 × ULN but less 2 × ULN. Patients were randomised (1:1:1) to receive once dailyplacebo, obeticholic acid 10 mg, or obeticholic acid titration (5 mg titrated to 10 mg at 6 monthsdependent on therapeutic response/tolerability). The majority (93%) of patients received treatment incombination with UDCA and a small number of patients (7%) unable to tolerate UDCA receivedplacebo, obeticholic acid (10 mg) or obeticholic acid titration (5 mg to 10 mg) as monotherapy. ALPand total bilirubin were assessed as categorical variables in the primary composite endpoint, as well ascontinuous 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/Lto 327 U/L. Mean baseline total bilirubin values ranged from 10 μmol/L to 12 μmol/L across treatmentarms, with 92% of patients within normal range.

Treatment with obeticholic acid 10 mg or obeticholic acid titration (5 mg to 10 mg) resulted inclinically and statistically significant increases (p<0.0001) relative to placebo in the number of patientsachieving the primary composite endpoint at all study time points (see Table 2). Responses occurredas early as 2 weeks and were dose dependent (obeticholic acid 5 mg compared with 10 mg at6 months, p=0.0358).

Table 2. Percentage of PBC patients achieving the primary composite endpointa at month 6 andmonth 12 with or without UDCAb

Obeticholic acid Obeticholic acid10 mgc Titrationc Placebo(N=73) (N=70) (N=73)

Month 6

Responders, n (%) 37 (51) 24 (34) 5 (7)

Corresponding 95% CI 39%, 62% 23%, 45% 1%, 13%p-valued <0.0001 <0.0001 NA

Month 12

Responders, n (%) 35 (48) 32 (46) 7 (10)

Corresponding 95% CI 36%, 60% 34%, 58% 4%, 19%p-valued <0.0001 <0.0001 NA

Components of primary endpointe

ALP less than 1.67-times

ULN, n (%) 40 (55) 33 (47) 12 (16)

Decrease in ALP of at least15%, n (%) 57 (78) 54 (77) 21 (29)

Total bilirubin less than orequal to 1-times ULNf, n (%) 60 (82) 62 (89) 57 (78)a Percentage of subjects achieving a response, defined as an ALP less than 1.67-times the ULN, total bilirubinwithin 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 thetrial, or obeticholic acid titration (5 mg once daily for the initial 6 months, with the option to increase to 10 mgonce daily for the last 6 months, if the patient was tolerating obeticholic acid but had ALP 1.67-times the ULNor 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 ALPgreater 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=intentionto treat (ITT) population]); percentage of patients with month 12 values are 86%, 91% and 96% for theobeticholic 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 orequal 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 forpatients who were maintained on the same dose throughout 12 months. For patients in the obeticholicacid titration arm whose obeticholic acid dose was increased from 5 mg once daily to 10 mg oncedaily, 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.

Fifty-one PBC patients with baseline ALP 1.67-times ULN or greater and/or total bilirubin greaterthan ULN were evaluated for a biochemical response to obeticholic acid as monotherapy (24 patientsreceived obeticholic acid 10 mg once daily and 27 patients received placebo) in a pooled analysis ofdata from the phase III randomised, double-blind, placebo-controlled 12-month study (POISE) andfrom a randomised, double-blind, placebo-controlled, 3-month study. At month 3, 9 (38%) obeticholicacid-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 was246 (165, 327) U/L compared to an increase of 17 (-7, 42) U/L in the placebo-treated patients.

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 onpaediatric use).

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

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

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 ofobeticholic acid.

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

Obeticholic acid is conjugated with glycine or taurine in the liver and secreted into bile. These glycineand taurine conjugates of obeticholic acid are absorbed in the small intestine leading to enterohepaticrecirculation. 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 principalroute of elimination.

After daily administration of obeticholic acid, there was accumulation of the glycine and taurineconjugates of obeticholic acid which have in vitro pharmacological activities similar to the parentdrug. The metabolite-to-parent ratios of the glycine and taurine conjugates of obeticholic acid were13.8 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.

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

Dose/Time proportionality

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

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

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

Population pharmacokinetic analysis indicated that gender does not influence obeticholic acidpharmacokinetics.

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

In a dedicated single-dose pharmacokinetic study using 25 mg of obeticholic acid, plasma exposures toobeticholic acid and its conjugates were increased by approximately 1.4- to 1.6-fold in subjects withmild (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 modestincrease is not considered to be clinically meaningful.

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 severehepatic impairment (Child-Pugh Class B and C, respectively) when compared to healthy controls (seesections 4.2, pct. 4.3 and 4.4).

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

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 activeconjugates, increased by 1.13-, 4- and 17-fold, respectively, compared to subjects with normal hepaticfunction following single-dose administration of 10 mg obeticholic acid.

Nonclinical data reveal no special hazard for humans based on conventional studies of safetypharmacology, 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, repeatdose toxicity studies resulted primarily in effects on the hepatobiliary system. These includedincreased liver weights, alterations in serum chemistry parameters (ALT, AST, LDH, ALP, GGT,and/or bilirubin), and macroscopic/microscopic alterations. All changes were reversible withdiscontinued 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 recommendedhuman dose). In a pre- and post-natal toxicity study in rats, the tauro-conjugate of obeticholic acid wasfound in pups nursing from dams dosed with obeticholic acid.

Microcrystalline cellulose (E 460)

Sodium starch glycolate (Type A)

Magnesium stearate

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.

4 years

This medicinal product does not require any special storage conditions.

High-density polyethylene (HDPE) bottles with a child resistant polypropylene closure and analuminium foil induction seal.

Pack sizes: 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 localrequirements.

ADVANZ PHARMA Limited

Suite 17, Northwood House,

Northwood Avenue, Santry,

Dublin 9

Ireland

EU/1/16/1139/001

EU/1/16/1139/002

EU/1/16/1139/003

EU/1/16/1139/004

Date of first authorisation: 12 December 2016

Date of latest renewal: 15 November 2023

Detailed information on this medicinal product is available on the website of the European Medicines

Agency http://www.ema.europa.eu.