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.

SUMMARY CMI

OCALIVA®

Consumer Medicine Information (CMI) summary

The full CMI on the next page has more details. If you are worried about using this medicine, speak to your doctor or pharmacist.

▼ This medicine is new or being used differently. Please report side effects. See the full CMI for further details.

WARNING: Important safety information is provided in a boxed warning in the full CMI. Read before using this medicine.

1. Why am I using OCALIVA?

OCALIVA contains the active ingredient obeticholic acid. OCALIVA is used to treat adults with a type of liver disease known as primary biliary cholangitis (PBC). It is used either by itself or with another medicine called ursodeoxycholic acid.

For more information, see Section 1. Why am I using OCALIVA? in the full CMI.

2. What should I know before I use OCALIVA?

Do not use if you have ever had an allergic reaction to obeticholic acid or any of the ingredients listed at the end of the CMI.

Do not use if you have or have had severe liver-related problems such as fluid in the belly, yellowing of the skin and/or eyes, or confusion (decompensated liver cirrhosis); you have bleeding in the digestive system, bleed or bruise more easily, or have been told you have low platelets in your blood (compensated cirrhosis with increased blood pressure in your abdomen); or you have a complete blockage in your liver or gallbladder.

Talk to your doctor if you have any other medical conditions, take any other medicines, or are pregnant or plan to become pregnant or are breastfeeding.

For more information, see Section 2. What should I know before I use OCALIVA? in the full CMI.

3. What if I am taking other medicines?

Some medicines may interfere with OCALIVA and affect how it works.

A list of these medicines is in Section 3. What if I am taking other medicines? in the full CMI.

4. How do I use OCALIVA?

  • Take one 5 mg tablet once daily for 6 months.
  • Depending on your response, your doctor may increase your dose to 10 mg once daily.

More instructions can be found in Section 4. How do I use OCALIVA? in the full CMI.

5. What should I know while using OCALIVA?

Things you should do
  • Remind any doctor, dentist or pharmacist you visit that you are using OCALIVA.
  • Keep all of your doctor appointments so that your progress can be checked. Your doctor will do some tests to make sure the medicine is working and to prevent unwanted side effects.
  • Call your doctor straight away if you have worsening liver problems or any other serious illness.
Things you should not do
  • Do not stop using this medicine suddenly or change the amount you take or take it for any other complaints without speaking to your doctor first.
Driving or using machines
  • Be careful before you drive or use any machines or tools until you know how OCALIVA affects you.
  • OCALIVA is not expected to affect your ability to drive a car or operate machinery.
Looking after your medicine
  • Store the bottle where the temperature stays below 25°C.

For more information, see Section 5. What should I know while using OCALIVA? in the full CMI.

6. Are there any side effects?

All medicines can have side effects. Most of them are minor and temporary, although some may need medical attention.

Very common side effects may include: feeling tired and itchy skin (particularly when first starting OCALIVA), and stomach pain and discomfort.

Serious side effects may include: allergic reactions and worsening of liver problems (such as yellowing of eyes or skin; bruising or bleeding easily; vomiting blood, swelling of your stomach-area; confusion; and loss of appetite or weight loss).

For more information, including what to do if you have any side effects, see Section 6. Are there any side effects? in the full CMI.

▼ This medicine is subject to additional monitoring in Australia. This will allow quick identification of new safety information. You can help by reporting any side effects you may get. You can report side effects to your doctor, or directly at www.tga.gov.au/reporting-problems.

WARNING

• Worsening of liver problems and liver failure in some cases leading to liver transplant or death has happened in some people with PBC with liver cirrhosis when taking OCALIVA
• Your doctor will check your liver before you take OCALIVA and while you are taking it. These liver tests will help your doctor decide if it is safe for you to start and continue taking OCALIVA.
• Do not use 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) or you have bleeding in the digestive system, bleed or bruise more easily, or have been told you have low platelets in your blood (compensated cirrhosis with increased blood pressure in your abdomen).
• You should stop taking OCALIVA and see your doctor immediately if you experience the above symptoms or have a complete blockage of the biliary tract (liver, gall bladder and bile ducts) or have worsening liver problems.



FULL CMI

OCALIVA®

Active ingredient: obeticholic acid

Consumer Medicine Information (CMI)

This leaflet provides important information about using OCALIVA. You should also speak to your doctor or pharmacist if you would like further information or if you have any concerns or questions about using OCALIVA.

Where to find information in this leaflet:

1. Why am I using OCALIVA?
2. What should I know before I use OCALIVA?
3. What if I am taking other medicines?
4. How do I use OCALIVA?
5. What should I know while using OCALIVA?
6. Are there any side effects?
7. Product details

1. Why am I using OCALIVA?

OCALIVA contains the active ingredient obeticholic acid.

OCALIVA is a “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 by reducing inflammation.

OCALIVA is used to treat adults with a type of liver disease known as primary biliary cholangitis (PBC). It is used either by itself or with another medicine called ursodeoxycholic acid.

2. What should I know before I use OCALIVA?

Warnings

Do not use OCALIVA if:

  • you are allergic to obeticholic acid, or any of the ingredients listed at the end of this leaflet. Always check the ingredients to make sure you can use this medicine.
  • 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)
  • you have bleeding in the digestive system, bleed or bruise more easily, or have been told you have low platelets in your blood (compensated cirrhosis with increased blood pressure in your abdomen)
  • you have a complete blockage of the biliary tract (liver, gall bladder and bile ducts).

Check with your doctor if you:

  • have any other medical conditions
  • take any medicines for any other condition.

Your doctor will do tests to check your liver before you start OCALIVA. These tests will help your doctor decide if it is safe for you to start taking OCALIVA. You will also have regular tests while you are taking OCALIVA to check your progress.

During treatment, you may be at risk of developing certain side effects. It is important you understand these risks and how to monitor for them. See additional information under Section 6. Are there any side effects?

Pregnancy and breastfeeding

Check with your doctor if you are pregnant or intend to become pregnant.

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.

Talk to your doctor if you are breastfeeding or intend to breastfeed.

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

Your doctor will decide whether you should stop breast-feeding or not take OCALIVA, by taking into account the benefit of breast feeding for the child and the benefit of therapy for you.

Children and adolescents

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

3. What if I am taking other medicines?

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

Some medicines may interfere with OCALIVA and affect how it works.

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.
  • cyclosporin (a medicine to prevent rejection of organ transplants and treat problems with the immune system). If it must be taken with OCALIVA then you may have extra tests to monitor your liver.

Check with your doctor or pharmacist if you are not sure about what medicines, vitamins or supplements you are taking and if these affect OCALIVA.

4. How do I use OCALIVA?

How much to take

  • Take one 5 mg tablet once daily for 6 months. Depending on your response, your doctor may increase your dose to 10 mg once daily.
  • Swallow the tablet whole with a full glass of water.
  • Follow the instructions provided and use OCALIVA until your doctor tells you to stop.
  • If you have worsening liver problems or a side effect such as severe itching, your doctor may decrease the dose, give you a break from taking it or tell you to stop taking it.

When to take OCALIVA

  • OCALIVA should be taken at the same time each day.
  • 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 after the bile acid binding resin (see Section 3. What if I am taking other medicines?).

If you forget to use OCALIVA

OCALIVA should be used regularly at the same time each day. If you miss your dose at the usual time, skip the dose you missed and take your next dose when you would normally take it.

Do not take a double dose to make up for the dose you missed.

If you use too much OCALIVA

If you think that you have used too much OCALIVA, you may need urgent medical attention.

You should immediately:

  • phone the Poisons Information Centre (by calling 13 11 26), or
  • contact your doctor, or
  • go to the Emergency Department at your nearest hospital.

You should do this even if there are no signs of discomfort or poisoning.

5. What should I know while using OCALIVA?

Things you should do

Keep all of your doctor appointments so that your progress can be checked.

Your doctor will do some tests from time to time to make sure the medicine is working and to prevent unwanted side effects.

Call your doctor straight away if you have any of the following signs of worsening liver problems:

  • 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, feeling sleepier than usual or harder to wake up, slurred speech, mood swings or changes in personality.

Worsening of liver problems and liver failure in some cases leading to liver transplant or death has happened in people with PBC with liver cirrhosis when taking OCALIVA (see also Section 6. Are there any side effects?).

Talk to your doctor or pharmacist if you experience itching of the skin (pruritus) or an increase in the severity of itching while taking OCALIVA.

Itching of the skin is a very common side effect that usually begins within the first month of treatment and decreases in severity over time. Your doctor may prescribe other medicines for treatment of itching, adjust your dose of OCALIVA or recommend other things you can do to relieve the itching.

Talk to 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.

Remind any doctor, dentist or pharmacist you visit that you are using OCALIVA.

Things you should not do

  • Do not stop taking your medicine or lower the dosage without checking with your doctor
  • 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.

Driving or using machines

Be careful before you drive or use any machines or tools until you know how OCALIVA affects you.

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

Looking after your medicine

  • Keep the tablets in the bottle until it is time to take them. If you take the tablets out of the bottle they may not keep as well.
  • Store the bottle where the temperature stays below 25°C.

Store it in a cool dry place away from moisture, heat or sunlight; for example, do not store it:

  • in the bathroom or near a sink, or
  • in the car or on window sills.

Keep it where young children cannot reach it.

Getting rid of any unwanted medicine

If you no longer need to use this medicine or it is out of date, take it to any pharmacy for safe disposal.

Do not use this medicine after the expiry date.

6. Are there any side effects?

All medicines can have side effects. If you do experience any side effects, most of them are minor and temporary. However, some side effects may need medical attention.

See the information below and, if you need to, ask your doctor or pharmacist if you have any further questions about side effects.

Less serious side effects

Less serious side effectsWhat to do
Digestive system:
  • stomach pain or discomfort
  • constipation
Ear, nose, throat and mouth:
  • sore mouth and throat
General body:
  • feeling tired
  • swelling in the hands and feet
  • fever
Heart:
  • fast or irregular heartbeat (palpitations)
Hormones:
  • changes in how your thyroid gland works
Muscles and bones:
  • joint pain
Nervous system:
  • feeling dizzy
Skin:
  • itchy skin
  • red, dry and inflamed skin (eczema)
  • rash
Tests requested by your doctor:
  • increase in bilirubin and liver enzymes
  • time taken for your blood to clot
  • lower levels of HDL-C (“good” cholesterol)
Speak to your doctor if you have any of these less serious side effects and they worry you.

Serious side effects

Serious side effectsWhat to do
Hypersensitivity (allergic) reaction:
  • may include rash, itching or hives on the skin; shortness of breath, wheezing or difficulty breathing; swelling of the face, lips, tongue or other parts of the body
Liver-related problems:
  • yellowing of eyes or skin (jaundice)
  • bruising or bleeding easily, vomiting blood, swelling of your stomach-area from a build-up of fluid (may be a sign of liver failure)
  • weakness, tiredness, loss of appetite, weight loss, stomach pain, nausea, vomiting, ankle swelling (may be sign of scarring of the liver known as cirrhosis)
Call your doctor straight away or go straight to the Emergency Department at your nearest hospital if you notice any of these serious side effects.

Tell your doctor or pharmacist if you notice anything else that may be making you feel unwell.

Other side effects not listed here may occur in some people.

Reporting side effects

After you have received medical advice for any side effects you experience, you can report side effects to the Therapeutic Goods Administration online at www.tga.gov.au/reporting-problems. By reporting side effects, you can help provide more information on the safety of this medicine.

Always make sure you speak to your doctor or pharmacist before you decide to stop taking any of your medicines.

7. Product details

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

What OCALIVA contains

Active ingredient
(main ingredient)
  • obeticholic acid
Other ingredients
(inactive ingredients)
  • microcrystalline cellulose
  • sodium starch glycollate type A
  • magnesium stearate
  • Opadry II complete film coating system 85F32351 YELLOW

Do not take this medicine if you are allergic to any of these ingredients.

What OCALIVA looks like

OCALIVA 5 mg is a yellow, round film-coated tablet with ‘INT’ on one side and ‘5’ on the other side (AUST R 293379).

OCALIVA 10 mg is a yellow, triangular film-coated tablet with ‘INT’ on one side and ‘10’ on the other side (AUST R 293378).

The tablets are packed in a plastic high-density polyethylene (HDPE) bottle with a child resistant polypropylene closure and an aluminium foil seal.

Bottles contain 30 tablets or 100* tablets.

*Pack size is not currently available.

Who supplies OCALIVA

Chiesi Australia Pty Ltd
Level 7, Suite 1, 500 Bourke Street,
Melbourne, VIC 3000

Email: [email protected]
Website: www.chiesi.com.au

This leaflet was prepared in July 2025.

Under licence from the Advanz Pharma group of companies.

Published by MIMS August 2025

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, or has compensated cirrhosis with evidence of portal hypertension (e.g. ascites, gastroesophageal varices, persistent thrombocytopenia) 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, or compensated cirrhosis with evidence of portal hypertension (e.g. ascites, gastroesophageal varices, persistent thrombocytopenia) (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 compensated cirrhosis who have evidence of portal hypertension (e.g. ascites, gastroesophageal varices, persistent thrombocytopenia) (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 either compensated or 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).
Liver tests should be obtained before initiating treatment with Ocaliva, within the first 6 months after initiation of treatment, and as clinically indicated thereafter.
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. Closely monitor patients at increased risk of compensated cirrhosis, concomitant hepatic disease (e.g. autoimmune hepatitis, alcohol-associated liver disease), and/or intercurrent illness (including hospitalisations) for new evidence of portal hypertension (e.g. ascites, gastroesophageal varices, persistent thrombocytopenia) or increases above the upper limit of normal in total bilirubin, direct bilirubin, or prothrombin time, to determine whether drug interruption or discontinuation is needed.
Treatment with obeticholic acid should be promptly interrupted in patients with suspected liver injury based on clinical signs or symptoms (e.g. anorexia, right upper abdominal discomfort, dark urine, jaundice, or new onset or worsening of fatigue), symptomatic cholelithiasis and/or cholecystitis (particularly with any suspicion of biliary obstruction) and clinically significant changes in laboratory results (e.g. rise in ALT, ALP, total bilirubin, or international normalised ratio (INR); decrease in albumin or platelets). After resolution of the suspected liver injury, obeticholic acid treatment can be resumed if an alternative probable cause has been found.
Treatment with obeticholic acid should be permanently discontinued in patients who develop laboratory or clinical evidence of hepatic decompensation (e.g. ascites, jaundice, variceal bleeding, hepatic encephalopathy), have compensated cirrhosis and develop evidence of portal hypertension (e.g. ascites, gastroesophageal varices, persistent thrombocytopenia), experience clinically significant liver injury, or develop complete biliary obstruction (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.

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 coadministering 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