Consumer medicine information

Ocaliva

Obeticholic acid

BRAND INFORMATION

Brand name

Ocaliva

Active ingredient

Obeticholic acid

Schedule

S4

 

Consumer medicine information (CMI) leaflet

Please read this leaflet carefully before you start using Ocaliva.

What is in this leaflet

This leaflet answers some common questions about OCALIVA. It does not contain all the available information. It does not take the place of talking to your doctor or pharmacist.

All medicines have risks and benefits. Your doctor has weighed the risks of you taking OCALIVA against the benefits they expect it will have for you.

If you have any concerns about taking this medicine, ask your doctor or pharmacist.

Keep this leaflet with the medicine. You may need to read it again.

What OCALIVA is used for

OCALIVA contains the active substance obeticholic acid (farnesoid X-receptor agonist) which helps to improve how your liver works by reducing the production and build-up of bile in the liver and also reducing inflammation.

This medicine is used to treat adult patients with a type of liver disease known as primary biliary cholangitis (PBC), either by itself or together with another medicine, ursodeoxycholic acid.

Ask your doctor if you have any questions about why this medicine has been prescribed for you. Your doctor may have prescribed it for another reason.

This medicine is available only with a doctor's prescription.

Before you take OCALIVA

When you must not take it

Do not take OCALIVA:

  • if you have or ever have had severe liver-related problems such as fluid in the belly, yellowing of the skin and/or eyes, or confusion (decompensated liver cirrhosis)
  • if you have a complete blockage of the biliary tract (liver, gall bladder and bile ducts).

Do not take OCALIVA if you have an allergy to:

  • any medicine containing obeticholic acid
  • any of the ingredients listed at the end of this leaflet.

Some of the symptoms of an allergic reaction may include:

  • shortness of breath
  • wheezing or difficulty breathing
  • swelling of the face, lips, tongue or other parts of the body
  • rash, itching or hives on the skin.

Do not give this medicine to a child or adolescent under the age of 18 years.

Do not take this medicine after the expiry date printed on the pack or if the packaging is torn or shows signs of tampering. If the medicine has expired or is damaged, return it to your pharmacist for disposal.

If you are not sure whether you should start taking this medicine, talk to your doctor.

Before you start to take it

Tell your doctor if you have allergies to any other medicines, foods, preservatives or dyes.

Before you start OCALIVA, and during your treatment with OCALIVA, your doctor will do tests to check your liver. These tests will help your doctor decide if it is safe for you to start taking OCALIVA and safe for you to continue taking OCALIVA.

If you have worsening liver problems, your dose of OCALIVA may be stopped for a period of time or stopped completely by your doctor.

Worsening of liver problems, liver failure, in some cases leading to liver transplant or death, has happened in people with PBC with liver cirrhosis when taking OCALIVA.

Tell your doctor right away if you have any of the following symptoms of worsening liver problems during treatment with OCALIVA:

  • swelling of your stomach-area from a build-up of fluid
  • yellowing of your skin or the whites of your eyes
  • black, tarry, or bloody stools
  • coughing up or vomiting blood, or your vomit looks like “coffee grounds”
  • mental changes such as confusion, sleepier than usual or harder to wake up, slurred speech, mood swings, or changes in personality.

Tell your doctor if you are pregnant or plan to become pregnant or are breast-feeding. Your doctor can discuss with you the risks and benefits involved.

There is little information about the effects of OCALIVA in pregnancy. As a precautionary measure, you should not take OCALIVA if you are pregnant.

It is not known if this medicine passes into human milk.

Your doctor will determine whether you should discontinue breast-feeding or discontinue/abstain from OCALIVA therapy taking into account the benefit of breast-feeding for the child and the benefit of therapy for you.

If you have not told your doctor about any of the above, tell him/her before you start taking OCALIVA.

Taking other medicines

Tell your doctor or pharmacist if you are taking any other medicines, including any that you get without a prescription from your pharmacy, supermarket or health food shop.

Some medicines and OCALIVA may interfere with each other.

These include:

  • bile acid binding resins (cholestyramine, colestipol, colesevelam) used to lower blood cholesterol levels as they may lessen the effect of OCALIVA. If you take any of these medicines, take OCALIVA at least 4-6 hours before or 4-6 hours after taking bile acid binding resin, giving as much time as possible.
  • theophylline (a medicine to help breathing) as levels of this medicine may be increased and will need to be monitored by your doctor while taking OCALIVA.
  • warfarin (a medicine to help your blood flow) as levels of this medicine may be increased. Your doctor may need to monitor how well your blood clots when taking medicines such as warfarin with OCALIVA.

These medicines may be affected by OCALIVA or may affect how well it works. You may need different amounts of your medicines, or you may need to take different medicines.

Your doctor and pharmacist have more information on medicines to be careful with or avoid while taking OCALIVA.

How to take OCALIVA

Follow all directions given to you by your doctor or pharmacist carefully. They may differ from the information contained in this leaflet.

If you do not understand the instructions on the bottle, ask your doctor or pharmacist for help.

How much to take

Your doctor will advise you of the dose to take and discuss any change of dose with you. Talk to your doctor or pharmacist if you are unsure.

The recommended dose is one 5 mg tablet once daily by mouth.

Depending on your body’s response after 6 months your doctor may increase your dose to 10 mg once daily.

How to take it

Swallow the tablet whole with a full glass of water.

When to take it

Take your medicine at about the same time each day. Taking it at the same time each day will have the best effect. It will also help you remember when to take it.

It does not matter if you take this medicine before or after food.

If you take bile acid binding resins, take this medicine at least 4-6 hours before or at least 4-6 hours after the bile acid binding resin (see section "Taking other medicines").

How long to take it

You should continue to take OCALIVA for as long as your doctor tells you to. Do not stop taking the medicine without talking to your doctor first.

If you forget to take it

Skip the missed dose and take your next dose when you would normally take it.

Do not take a double dose to make up for a forgotten tablet.

If you are not sure what to do, ask your doctor or pharmacist.

If you have trouble remembering to take your medicine, ask your pharmacist for some hints.

If you take too much (overdose)

If you accidentally take too many tablets, you may experience liver-related side effects such as yellowing of the skin.

Immediately telephone your doctor or the Poisons Information Centre (telephone 13 11 26) for advice, or go to Accident and Emergency at the nearest hospital, if you think that you or anyone else may have taken too much OCALIVA. Do this even if there are no signs of discomfort or poisoning.

While you are using OCALIVA

Things you must do

If you are about to be started on any new medicine, remind your doctor and pharmacist that you are taking OCALIVA.

Tell any other doctors, dentists, and pharmacists who treat you that you are taking this medicine.

If you are going to have surgery, tell the surgeon or anaesthetist that you are taking this medicine. It may affect other medicines used during surgery.

If you become pregnant while taking this medicine, tell your doctor immediately.

Your doctor will do blood tests to monitor the health of your liver when you start treatment and regularly from there on.

If you are going to have any blood tests, tell your doctor that you are taking this medicine. It may interfere with the results of some tests.

Keep all of your doctor appointments so that your progress can be checked. Your doctor may do some tests from time to time to make sure the medicine is working and to prevent unwanted side effects.

Things you must not do

Do not take OCALIVA to treat any other complaints unless your doctor tells you to.

Do not give your medicine to anyone else, even if they have the same condition as you.

Do not stop taking your medicine or lower the dosage without checking with your doctor. If you stop taking OCALIVA suddenly, your condition may worsen or you may have unwanted side effects.

Things to be careful of

This medicine is not expected to affect your ability to drive a car or operate machinery.

Side effects

Tell your doctor or pharmacist as soon as possible if you do not feel well while you are taking OCALIVA.

This medicine helps most people with primary biliary cholangitis, but it may have unwanted side effects in a few people.

All medicines can have side effects. Sometimes they are serious, most of the time they are not. You may need medical attention if you get some of the side effects.

Do not be alarmed by the following lists of side effects. You may not experience any of them.

Ask your doctor or pharmacist to answer any questions you may have.

Tell your doctor or pharmacist if you experience itching of the skin (pruritus) or an increase in the severity of itching while on this medicine. In general itching of the skin is a very common side effect that begins within the first month following the start of treatment with OCALIVA and decreases in severity over time. Your doctor may prescribe other medicines for treatment of itching or adjust your dose of OCALIVA or recommend other things you can do to relieve the itching.

Tell your doctor or pharmacist if you feel tired (fatigue) and it worries you. Fatigue is a very common side effect and your doctor may recommend things that might help you.

OCALIVA can lower high levels of HDL-C (“good” cholesterol). Your doctor will check your cholesterol levels during your treatment with OCALIVA.

Tell your doctor or pharmacist if you notice any of the following and they worry you:

  • stomach pain or discomfort
  • thyroid hormone irregularity
  • dizziness
  • fast or irregular heart beat (palpitations)
  • pain in the mouth and throat
  • constipation
  • dry skin, redness of the skin (eczema)
  • rash
  • pain in your joints
  • swelling in the hands and feet
  • fever.

The above list includes the more common side effects of your medicine.

The following side effects have been reported since the marketing of OCALIVA, but how often they occur is not known. If any of the following happen, tell your doctor immediately or go to Accident and Emergency at your nearest hospital:

  • bruising or bleeding easily, vomiting blood, swelling of your stomach-area from a build-up of fluid (liver failure)
  • increase in bilirubin (a substance produced by the liver) in the blood
  • yellowing of eyes or skin (jaundice)
  • weakness, tiredness, loss of appetite, weight loss, stomach pain, nausea, vomiting, ankle swelling (scarring of the liver known as cirrhosis).

Some of these side effects (for example, increase in bilirubin) can only be found when your doctor does liver function tests.

The above list includes very serious side effects. You may need urgent medical attention or hospitalisation.

Tell your doctor or pharmacist if you notice anything that is making you feel unwell.

Other side effects not listed above may also occur in some people.

After using OCALIVA

Storage

Keep your tablets in the bottle until it is time to take them. If you take the tablets out of the bottle they may not keep well.

Keep your tablets in a cool, dry place where the temperature stays below 25°C.

Do not store OCALIVA or any other medicine in the bathroom or near a sink. Do not leave it on a window sill or in the car. Heat and dampness can destroy some medicines.

Keep it where children cannot reach it. A locked cupboard at least one-and-a-half metres above the ground is a good place to store medicines.

Disposal

If your doctor tells you to stop taking this medicine or the expiry date has passed, ask your pharmacist what to do with any medicine that is left over.

Product description

What it looks like

OCALIVA 5 mg is a yellow, round film-coated tablet with ‘INT’ on one side and ‘5’ on the other side of the film-coated tablet.

OCALIVA 10 mg is a yellow, triangular film-coated tablet with ‘INT’ on one side and ‘10’ on the other side of the film-coated tablet.

Ingredients

The active substance is obeticholic acid.

OCALIVA 5 mg film-coated tablets contain 5 mg of obeticholic acid.

OCALIVA 10 mg film-coated tablets contain 10 mg of obeticholic acid.

The other ingredients are:

  • microcrystalline cellulose
  • sodium starch glycollate type A
  • magnesium stearate
  • Opadry II complete film coating system 85F32351 YELLOW.

Supplier

OCALIVA is supplied in Australia by:

Chiesi Australia Pty Ltd
Suite 3, 22 Gillman Street
Hawthorn East, VIC 3123
Email: [email protected]
Website: www.chiesi.com.au

Under licence from the Advanz Pharma group of companies.

® = Registered Trademark

This leaflet was prepared in November 2022

AUST R 293379 (5 mg)

AUST R 293378 (10 mg)

Published by MIMS February 2023

BRAND INFORMATION

Brand name

Ocaliva

Active ingredient

Obeticholic acid

Schedule

S4

 

1 Name of Medicine

Obeticholic acid.

2 Qualitative and Quantitative Composition

Each Ocaliva tablet contains the active ingredient obeticholic acid 5 mg or 10 mg.
For the full list of excipients, see Section 6.1 List of Excipients.

3 Pharmaceutical Form

Ocaliva 5 mg film-coated tablets.

Yellow, round tablet debossed with 'INT' on one side and '5' on the other side.

Ocaliva 10 mg film-coated tablets.

Yellow, triangular tablet debossed with 'INT' on one side and '10' on the other side.

4 Clinical Particulars

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 Dose and Method of Administration

Dosage.

Prior to the initiation of obeticholic acid, healthcare professionals should determine whether the patient has decompensated cirrhosis (including Child-Pugh Class B or C) or has had a prior decompensation event because obeticholic acid is contraindicated in these patients (see Section 4.3 Contraindications; Section 4.4 Special Warnings and Precautions for Use).
The starting dosage 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 dosage 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 of the following should be considered:
Reducing the dosage of obeticholic acid 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 interrupting obeticholic acid dosing for up to 2 weeks followed by restarting at a reduced dosage.
Increase the dosage to 10 mg once daily, as tolerated, to achieve optimal response.
Consider discontinuing treatment with obeticholic acid 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 4-6 hours before or 4-6 hours after taking a bile acid binding resin, or at as great an interval as possible (see Section 4.5 Interactions with Other Medicines and Other Forms of Interactions).

Special populations.

Elderly (≥ 65 years).

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

Renal impairment.

No dose adjustment is required for patients with renal impairment (see Section 5.2 Pharmacokinetic Properties).

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 Section 4.3 Contraindications; Section 4.4 Special Warnings and Precautions for Use). No dose adjustment is needed for mild hepatic impairment (Child-Pugh Class A) (see Section 4.4 Special Warnings and Precautions for Use; Section 5.2 Pharmacokinetic Properties).
Routinely monitor patients during obeticholic acid treatment for progression of PBC, including hepatic adverse reactions, with laboratory and clinical assessments to determine whether drug discontinuation is needed. Close monitoring is recommended for patients at increased risk of progression to cirrhosis and/or hepatic decompensation, including those with laboratory evidence of worsening liver function (e.g. elevated bilirubin levels), evidence of portal hypertension, concomitant hepatic disease (e.g. autoimmune hepatitis, alcoholic liver disease), and/or severe intercurrent illness to determine whether obeticholic acid treatment discontinuation is needed (see Section 4.4 Special Warnings and Precautions for Use). Permanently discontinue in patients with laboratory or clinical evidence of hepatic decompensation (see Section 4.3 Contraindications; Section 4.4 Special Warnings and Precautions for Use).
Discontinue in patients who develop complete biliary obstruction (see Section 4.3 Contraindications).

Paediatric population.

There is no relevant use of obeticholic acid in the paediatric population in the treatment of primary biliary cholangitis (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.
Patients with decompensated cirrhosis (e.g. Child-Pugh Class B or C) or a prior decompensation event (see Section 4.4 Special Warnings and Precautions for Use).
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 decompensated cirrhosis. Obeticholic acid has not been adequately studied in patients with hepatic decompensation.
Some of these cases occurred in patients with decompensated cirrhosis when they were treated with higher than recommended doses (e.g. started on Ocaliva 5 mg once daily); however, cases of hepatic decompensation and failure have continued to be reported in patients with decompensated cirrhosis even when they received lower doses (e.g. 5 mg once weekly). See Section 4.3 Contraindications.
In PBC patients with compensated cirrhosis, hepatic decompensation and failure have been reported. Some of these cases resulted in liver transplant.
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 Overdose).
After initiation of therapy, all patients should be routinely monitored for progression of PBC, including hepatic adverse reactions, with laboratory and clinical assessment to determine whether obeticholic acid treatment discontinuation is needed. Patients at increased risk of progression to cirrhosis and/or hepatic decompensation, including those with laboratory evidence of worsening liver function (e.g. elevated bilirubin levels), evidence of portal hypertension, 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 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 of the intercurrent illness or clinically significant hepatic adverse reactions, 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.
Treatment with obeticholic acid in patients with laboratory or clinical evidence of hepatic decompensation (e.g. ascites, jaundice, variceal bleeding, hepatic encephalopathy, Child-Pugh Class B or C) should be permanently discontinued (see Section 4.3 Contraindications).

Severe pruritus.

Severe pruritus was reported in 23% of patients treated with Ocaliva 10 mg arm, 19% of patients in the Ocaliva 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 Ocaliva 10 mg, Ocaliva 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 Section 4.2 Dose and Method of Administration; Section 4.8 Adverse Effects (Undesirable Effects)).
Consider clinical evaluation of patients with new onset or worsening severe pruritus.

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 the phase III clinical study, 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.

Use in the elderly.

Limited data exists in elderly patients. No dose adjustment is required for elderly patients (see Section 4.2 Dose and Method of Administration).

Paediatric use.

There is no relevant use of obeticholic acid in the paediatric population in the treatment of primary biliary cholangitis (PBC).

Effects on laboratory tests.

No data available.

4.5 Interactions with Other Medicines and Other Forms of Interactions

Overview.

Based on in vitro studies, obeticholic acid can inhibit CYP3A4. However, an in vivo study did not detect inhibition of CYP3A4 by obeticholic acid at the recommended dose of Ocaliva. Obeticholic acid is not expected to inhibit CYPs 2B6, 2C8, 2C9, 2C19, and 2D6, or induce CYPs 1A2, 2B6, 2C8, 2C9, 2C19, and 3A4 at the recommended dose of Ocaliva. Down-regulation of mRNA was observed in a concentration-dependent fashion for CYP1A2 and CYP3A4 by obeticholic acid and its glycine and taurine conjugates. In vitro studies suggest that there is potential for obeticholic acid and its glycine and taurine conjugates to inhibit OATP1B1 and OATP1B3 (the clinical significance of which is unknown), but not P-gp, BCRP, OAT1, OAT3, OCT2, and MATE transporters, at the recommended dose of Ocaliva.
In vitro data suggest that obeticholic acid is not metabolized to any significant extent by CYP450 enzymes.

Effect of obeticholic acid on other medicinal products.

Warfarin.

The 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.

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.

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 4-6 hours before or 4-6 hours after taking a bile acid binding resin, or at as great an interval as possible.

Inhibitors of bile salt efflux pump.

Avoid concomitant use of inhibitors of the bile salt efflux pump (BSEP) such as cyclosporine. Concomitant medications that inhibit canalicular membrane bile acid transporters such as the BSEP may exacerbate accumulation of conjugated bile salts including taurine conjugate of obeticholic acid in the liver and result in clinical symptoms. If concomitant use is deemed necessary, monitor serum transaminases and bilirubin.

4.6 Fertility, Pregnancy and Lactation

Effects on fertility.

No fertility data is available in humans. Obeticholic acid, administered at oral doses of 5, 25, and 50 mg/kg/day to male rats for 28 days before mating and throughout the mating period, and to female rats from 14 days before mating through mating and until gestation day 7, did not alter male or female fertility or early embryonic development at any dose (the 50 mg/kg/day dose is approximately 13 times the human exposure at the MRHD).
(Category B1)
The limited available human data on the use of obeticholic acid during pregnancy are not sufficient to inform a drug-associated risk. In animal reproduction studies, no developmental abnormalities or fetal harm was observed when pregnant rats or rabbits were administered obeticholic acid during the period of organogenesis at exposures approximately 13 times and 6 times human exposures, respectively, at the maximum recommended human dose (MRHD) of 10 mg.
 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. A decision should be made whether to discontinue breast-feeding or to discontinue/abstain from obeticholic acid therapy, taking into account the benefit of breast-feeding for the child and the benefit of therapy for the woman.

4.7 Effects on Ability to Drive and Use Machines

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

4.8 Adverse Effects (Undesirable Effects)

Summary of the safety profile.

The most commonly reported adverse reactions were pruritus (63%) and fatigue (22%). Adverse reactions leading to discontinuation were 1% in the Ocaliva titration arm and 11% in the Ocaliva 10 mg arm. 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 Ocaliva in the phase III clinical study are listed in Table 1 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).

Description of selected adverse reactions.

Hepatic adverse events.

Hepatic failure, sometimes fatal or resulting in liver transplant, has been reported in patients with obeticholic acid treatment in PBC patients with decompensated cirrhosis (e.g. Child-Pugh Class B or C) (see Section 4.3 Contraindications; Section 4.4 Special Warnings and Precautions for Use).

Pruritus.

Approximately 60% of patients had a history of pruritus upon enrolment 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 Ocaliva 10 mg arm, patients in the Ocaliva 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. dosage adjustments, treatment interruptions, or initiation of antihistamines or bile acid binding resins) were 41% in the Ocaliva 10 mg arm, 34% in the Ocaliva titration group, and 19% in the placebo group.

Post-marketing experience.

The following adverse reactions have been identified during post-approval use of Ocaliva. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure, particularly in PBC patients who have progressive liver disease.

Hepatobiliary disorders.

Hepatic failure, bilirubin increase, jaundice, cirrhosis.

Reporting suspected adverse effects.

Reporting suspected adverse reactions after registration 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 at www.tga.gov.au/reporting-problems.

4.9 Overdose

For information on the management of overdose, contact the Poisons Information Centre on 13 11 26 (Australia).
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 Ocaliva 25 mg once daily (2.5 times the highest recommended dosage) or 50 mg once daily (5 times the highest recommended dosage), experienced a dose-dependent increase in the incidence of hepatic adverse reactions (e.g. ascites, primary biliary cholangitis flares, 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.

5 Pharmacological Properties

5.1 Pharmacodynamic Properties

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.
In clinical trials with PBC patients, obeticholic acid decreased c-reactive protein (CRP), immunoglobin M (IGM) and cytokeratin 18 (CK 18) marker of inflammation and apoptosis.

Clinical trials.

A phase III, randomised, double-blind, placebo-controlled, parallel-group, 12-month study (POISE) evaluated the safety and efficacy of Ocaliva 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 x ULN but less 2 x ULN. Patients were randomised (1:1:1) to receive once daily placebo, Ocaliva 10 mg, or Ocaliva 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, Ocaliva (10 mg) or Ocaliva 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 micromol/L to 12 micromol/L across treatment arms, with 92% of patients within normal range.
Treatment with Ocaliva 10 mg or Ocaliva 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 (Ocaliva 5 mg compared with 10 mg at 6 months, p = 0.0358).

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 dosage throughout 12 months. For patients in the Ocaliva titration arm whose Ocaliva dosage 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 Ocaliva 10 mg arm, 138 (102, 174) U/L in the Ocaliva titration arm, and 8 (-48, 32) 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 Ocaliva as monotherapy (24 patients received Ocaliva 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%) Ocaliva-treated patients achieved a response to the composite endpoint, compared to 1 (4%) placebo-treated patient. The mean (95% CI) reduction in ALP in Ocaliva-treated patients was 246 (165, 327) U/L compared to an increase of 17 (-7, 42) U/L in the placebo-treated patients.

5.2 Pharmacokinetic Properties

Absorption.

Obeticholic acid is absorbed with peak plasma concentrations (Cmax) occurring at a median time (tmax) of approximately 2 hours. Peak plasma exposure of total obeticholic acid (sum of obeticholic acid and its two active conjugates, glyco- and tauro-obeticholic acid) occur after a meal similar to endogenous bile acids.
A study was conducted to assess the pharmacokinetics of obeticholic acid following a single 10 mg tablet under fed and fasted conditions. When Ocaliva 10 mg tablets were administered following consumption of a high fat, high calorie meal, there was an increase in AUC0-72 by approximately 20% while there was no significant effect on Cmax when compared to administration under fasting conditions.

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.

Metabolism.

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 medicine. 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.

Excretion.

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. The steady-state systemic exposure (AUC0-24h) achieved on Day 14 of total obeticholic acid was 4.2-, 6.6-, and 7.8-fold the systemic exposure (AUC0-24h) achieved on Day 1 after 5, 10, and 25 mg once daily dosing, respectively. There was high variability in the Cmax and AUC of obeticholic acid in a limited number of PBC patients.

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. There are insufficient data to make dosing recommendations for patients 75 years of age and older.

Paediatric population.

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

Body weight.

Based on population pharmacokinetic analysis, body weight was a significant predictor of obeticholic acid pharmacokinetics with lower obeticholic acid plasma exposure expected with higher body weight. Body weight is not expected to have a meaningful impact on efficacy.

Sex.

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 single-dose pharmacokinetic study using 25 mg of obeticholic acid, plasma exposures to obeticholic acid and its conjugates were increased by approximately 1.6 to 2.5-fold in subjects with mild (modification of diet in renal disease [MDRD] eGFR 60 - < 90 mL/min), moderate (MDRD eGFR 30 - < 60 mL/min) and severe (MDRD eGFR < 30 mL/min) 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 when compared to healthy controls.
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. There is no clinical data to guide the effects of a 4- to 17-fold increase in systemic exposure of obeticholic acid in patients with moderate or severe hepatic impairment.

5.3 Preclinical Safety Data

Genotoxicity.

Obeticholic acid was not genotoxic in the Ames test, a human peripheral blood lymphocyte chromosomal aberration test, and a mouse micronucleus test. The glycine conjugate of obeticholic acid was also not genotoxic in an Ames test and human peripheral blood lymphocyte chromosome aberration test. The taurine conjugate of obeticholic acid was not genotoxic in an Ames test, and was negative in a human peripheral blood lymphocyte chromosomal aberration test in the presence of metabolic activation; the findings of the chromosomal aberration assay in the absence of metabolic activation were inconclusive.

Carcinogenicity.

Carcinogenic potential of obeticholic acid was assessed in carcinogenicity studies of up to 2 years in duration in mice and rats. In mice, there were no drug-related neoplastic findings at doses up to 25 mg/kg/day obeticholic acid, a dose that produced systemic exposures approximately 12 times those in humans at the MRHD of 10 mg. In rats, obeticholic acid was administered at doses of 2, 7, and 20 mg/kg/day. At 20 mg/kg/day (approximately 12 times the human exposure at the MRHD), obeticholic acid caused an increase in the incidence of benign granulosa cell tumours in the ovaries and benign granular cell tumours in the cervix and vagina of female rats. There were no drug-related neoplastic findings in male rats.

6 Pharmaceutical Particulars

6.1 List of Excipients

Microcrystalline cellulose, sodium starch glycollate type A, magnesium stearate, Opadry II complete film coating system 85F32351 yellow.

6.2 Incompatibilities

Incompatibilities were either not assessed or not identified as part of the registration of this medicine.

6.3 Shelf Life

In Australia, information on the shelf life can be found on the public summary of the Australian Register of Therapeutic Goods (ARTG). The expiry date can be found on the packaging.

6.4 Special Precautions for Storage

Store below 25°C.

6.5 Nature and Contents of Container

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.

6.6 Special Precautions for Disposal

In Australia, any unused medicine or waste material should be disposed of by taking to your local pharmacy.

6.7 Physicochemical Properties

Obeticholic acid (OCA) is a 6-ethyl derivative of the human bile acid chenodeoxycholic acid. It is a poorly soluble and highly permeable white to off-white powder.

Chemical structure.

6α-ethylchenodeoxycholic acid:
Empirical formula: C26H44O4. MW: 420.63 g/mol.

CAS number.

459789-99-2.

7 Medicine Schedule (Poisons Standard)

Schedule 4 - Prescription Only Medicine.

Summary Table of Changes