Consumer medicine information

Revolade

Eltrombopag

BRAND INFORMATION

Brand name

Revolade

Active ingredient

Eltrombopag

Schedule

S4

 

Consumer medicine information (CMI) leaflet

Please read this leaflet carefully before you start using Revolade.

What is in this leaflet

This leaflet answers some common questions about REVOLADE.

It does not contain all the available information. It does not take the place of talking to your doctor or pharmacist.

The information in this leaflet was last updated on the date listed on the final page. More recent information on the medicine may be available.

You should ensure that you speak to your pharmacist or doctor to obtain the most up to date information on the medicine. You can also download the most up to date leaflet from www.novartis.com.au. Those updates may contain important information about the medicine and its use of which you should be aware.

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

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

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

What REVOLADE is used for

REVOLADE is a medicine that is used to treat a number of conditions.

Low platelet count
This is a bleeding disorder known as idiopathic thrombocytopenic purpura (ITP). Patients with ITP may suffer from an increased risk of bleeding. The symptoms of ITP may include:

  • Pinpoint sized flat round red spots under the skin (petechiae)
  • Bruising (purpura)
  • Nosebleeds
  • Bleeding gums
  • Not being able to control bleeding, if cuts or injuries occur.

REVOLADE helps to increase the number of platelets, a type of blood cell that helps to reduce or prevent bleeding.

Hepatitis C virus (HCV)
Many patients with HCV have low platelet counts (thrombocytopenia), not only as a result of the disease but also due to some of the medicines that are used to treat the disease.

The use of REVOLADE to increase and maintain the platelet count prior to and throughout antiviral treatment of HCV infection gives patients a better opportunity to maintain the optimal the dose and duration of their antiviral therapy.

Severe aplastic anaemia (SAA)
Severe aplastic anaemia, or SAA, is a blood disorder in which the bone marrow does not make enough blood cells, especially red and white blood cells and platelets. Red blood cells carry oxygen to tissues in the body. White blood cells fight infection and disease. Platelets help blood to clot.

The low number of blood cells puts a patient with this condition at risk of tiredness, infections, and bleeding. REVOLADE may be used to treat patients with these low blood counts:

  • In combination with immunosuppressive therapy in adults or children from 2 years of age or
  • In adult patients when other medicines to treat SAA have not worked well enough.

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.

It is not addictive.

REVOLADE may be used to treat children from 1 to 17 years with chronic immune thrombocytopaenia (ITP) who have failed other treatments and need an increased platelet concentration for a planned procedure or are at a high risk of bleeding.

REVOLADE may be used to treat children from 2 to 17 years with low blood counts caused by severe aplastic anaemia.

REVOLADE it is not recommended to treat children with hepatitis C virus (HCV) infections (to treat low platelet counts).

Before you take REVOLADE

Do not take REVOLADE if you are allergic (hypersensitive) to:

  • eltrombopag olamine, the active ingredient in REVOLADE
  • any other ingredients in REVOLADE tablets or powder for oral suspension 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 take this medicine after the expiry date printed on the pack or if the packaging is torn or shows signs of tampering.

If it 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 any of the following medical conditions:

  • Liver problems - your doctor will request blood tests to check your liver function before and during treatment with REVOLADE. You may need a lower dose of REVOLADE
  • Kidney problems
  • Risk factors for thrombosis (formation of a clot inside a blood vessel, obstructing the flow of blood), or you know that thrombosis occurs frequently in your family
  • A history of blood cancers
  • Another blood condition, such as myelodysplastic syndrome (MDS). Your doctor will carry out tests to check that you do not have this blood condition before you start REVOLADE. If you have MDS and take REVOLADE your MDS may get worse.
  • Had or developed sensitivity to the sun
  • A history of cataracts (problems with sight)
  • Are pregnant or plan to become pregnant (see PREGNANCY & BREAST-FEEDING)
  • Are breast feeding (see PREGNANCY & BREAST-FEEDING).

Taking other medicines

Tell your doctor or pharmacist if you:

  • Are taking any other medicines
  • Have taken any medicines recently, or
  • Start taking new medicines.

This includes herbal medicines and other medicines or complementary therapies you've bought without a prescription.

There are certain medicines, including some prescription, non-prescription medicines, and vitamins, that interact with REVOLADE.

You should not take these at the same time as REVOLADE or they may require dose adjustment while taking REVOLADE.

These medications include some products within the following groups:

  • Antacid medicines to treat stomach ulcers or heartburn
  • Certain medicines used to lower cholesterol (statins)
  • Certain drugs used to treat human immunodeficiency virus (HIV) (lopinavir / ritonavir)
  • A medicine used for transplantations or immune diseases (cyclosporin)
  • Minerals such as aluminium, calcium, iron, magnesium, selenium and zinc which may be found in mineral supplements and complementary medicines
  • Certain medicines used to treat low platelet count due to hepatitis C (interferon-based treatments).

Your doctor will review the medicines you are currently taking to make sure you are not taking something that cannot be taken with the REVOLADE.

If you require any of these medications and a suitable substitute is not available, please discuss this with your doctor.

Please tell your doctor or pharmacist if you are taking or have recently taken any other medicines, including medicines obtained without a prescription.

Taking REVOLADE with food and drink

Do not take Revolade with food rich in calcium.

REVOLADE is affected by calcium intake. REVOLADE may be taken with food low in calcium such as:

  • Pineapple, raisins and strawberries
  • Lean ham, chicken or beef
  • Unfortified fruit juice, soy milk and grain. (Unfortified means not containing any added calcium, magnesium or iron.)

Please discuss this matter with your doctor, pharmacist or healthcare provider. They will be able to advise on the most suitable meals to be eaten while you are taking REVOLADE.

Don't take REVOLADE during the 2 hours before or 4 hours after you take:

  • Antacid medication to treat indigestion
  • Mineral supplements, such as aluminium, calcium, iron, magnesium, selenium or zinc, or
  • Dairy products.

If you do, the medicine will not be properly absorbed into your body.

One way to avoid issues with these products would be to take them in the morning and REVOLADE in the evening.

Ask your doctor or pharmacist for advice if you are unsure.

Pregnancy & breast-feeding

You should avoid becoming pregnant while taking REVOLADE can harm an unborn baby.

If you are a woman who could become pregnant, you must use a reliable method of contraception (a way to prevent you from becoming pregnant) during treatment with REVOLADE and for at least 7 days after you stop taking REVOLADE.

Ask your doctor about options of effective birth control.

Breast feeding is not recommended while you are taking REVOLADE. It is not known whether REVOLADE passes into breast milk.

Ask your doctor or pharmacist for advice before taking any medicine if you are unsure.

How to take REVOLADE

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

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

When to take it

Take REVOLADE at least 2 hours before or at least 4 hours after antacids, dairy products or some mineral supplements such as iron, calcium, magnesium, aluminium, selenium and zinc.

One way to avoid issues with these products would be to take them in the morning and REVOLADE in the evening.

Taking REVOLADE at the same time each day will help you remember when to take it.

How much to take

Based on your response to REVOLADE or if you have kidney, liver or other problems or if you are elderly, your doctor may adapt the dose and may recommend that your daily dose of REVOLADE be increased or decreased.

Low platelet count
The usual starting dose for adult and paediatric ITP patients 6 to 17 years of age is one 50 mg REVOLADE tablet a day.

Patients of Asian origin (such as Chinese, Japanese, Taiwanese, Korean or Thai) need to start at a lower dose of one 25 mg tablet once a day.

The usual starting dose for paediatric ITP patients 1 to 5 years of age is one 25 mg sachet of REVOLADE powder for oral suspension or one 25 mg REVOLADE tablet a day.

Paediatric ITP patients 1 to 5 years of age of Asian origin need to start at a dose of one 25 mg sachet of REVOLADE powder for oral suspension or one 25 mg REVOLADE tablet every other day.

Hepatitis C virus
The usual starting dose for HCV patients is one 25 mg REVOLADE tablet a day.

Patients of Asian origin (such as Chinese, Japanese, Taiwanese, Korean or Thai) will start on the same 25 mg dose once daily.

Previously treated severe aplastic anaemia
The usual starting dose for these patients is one 50 mg REVOLADE tablet a day.

Patients of Asian origin (Chinese, Japanese, Taiwanese, Korean or Thai) need to start at a lower dose of one 25 mg tablet once a day.

Severe aplastic anaemia
The usual starting dose for patients with SAA, given with standard immunosuppressive therapy is:

  • Adults and children aged 12 to 17 years: 150 mg once a day for 6 months. Patients of Asian origin (such as Chinese, Japanese, Taiwanese, Korean, or Thai) should receive a reduced dose of 75 mg once a day for 6 months.
  • Children aged 6 to 11 years: 75 mg once a day for 6 months. Patients of Asian origin (such as Chinese, Japanese, Taiwanese, Korean, or Thai) should receive a reduced dose of 37.5 mg once a day for 6 months.
  • Children aged 2 to 5 years: 2.5 mg/kg once a day for 6 months. Patients of Asian origin (such as Chinese, Japanese, Taiwanese, Korean, or Thai) should receive a reduced dose of 1.25 mg/kg once a day for 6 months.

How to take it

TABLETS

Swallow REVOLADE tablets with a glass of water.

POWDER FOR ORAL SUSPENSION*

When administering REVOLADE powder for oral suspension to a child, follow all of the instructions given in the leaflet that is included in the carton.

How long to take it

Keep taking this medicine for as long as your doctor tells you. After you have stopped taking REVOLADE, your bleeding symptoms may come back.

Tell your doctor or pharmacist if you have any bleeding in the four (4) weeks after you stop taking REVOLADE.

If you forget to take REVOLADE

Do not take a double dose to make up for a missed dose. This may increase the chance of you getting an unwanted side effect.

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 more REVOLADE than you should (Overdose)

Immediately telephone your doctor or the Poisons Information Centre (on 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 REVOLADE.

Do this even if there are no signs of discomfort or poisoning.

Take the REVOLADE pack with you.

Medical treatment may be necessary.

While you are taking REVOLADE

Things you must do

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

Your doctor will do tests from time to time to make sure the medicine is working and to prevent unwanted side effects. Your doctor will also carry out blood tests to check your liver function before and during treatment with REVOLADE.

At the beginning of therapy, your platelet count and other routine blood parameters will need to be monitored frequently. Based on your response to REVOLADE, your doctor will adapt the dose and may recommend that your daily dose be increased or decreased.

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

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

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

If you have any further questions on the use of this product, ask your doctor or pharmacist.

Things to be careful of

  1. Be careful driving or operating machinery until you know how REVOLADE affects you.
  2. Liver problems
REVOLADE may damage your liver and cause serious, even life threatening, illness.
You must have blood tests to check your liver before you start taking REVOLADE and during treatment.
When you are given certain antiviral treatments together with REVOLADE for the treatment of thrombocytopenia due to hepatitis C virus (HCV) infections some liver problems can get worse.
Your doctor will order these blood tests and any other tests required. In some cases REVOLADE treatment may need to be stopped.
  1. Bleeding after you stop treatment
When you stop taking REVOLADE, your blood platelet count will drop back down to what it was before you started taking REVOLADE.
These effects are most likely to happen within 4 weeks after you stop taking REVOLADE.
The lower platelet counts may increase your risk of bleeding.
Your doctor will check your platelet counts for at least 4 weeks after you stop taking REVOLADE.
Tell your doctor or pharmacist if you have any bruising or bleeding in the 4 weeks after you stop taking REVOLADE.
  1. Problems with bone marrow
Patients taking this medication may have problems with their bone marrow. REVOLADE could make this problem worse.
Signs of bone marrow changes may show up as abnormal results in your blood tests. Your doctor may also carry out tests to check your bone marrow during treatment with REVOLADE.
  1. Higher chance for blood clots with higher platelet counts
You have a higher chance of getting a blood clot if your platelet count is too high during treatment with REVOLADE, but blood clots can occur with normal or even low platelet counts.
If you have cirrhosis of the liver, you are at risk of a blood clot in a blood vessel that feeds your liver (portal vein thrombosis). You may have severe complications from some forms of blood clots, such as clots that travel to the lungs or that cause heart attacks or strokes.
Your doctor will check your blood platelet counts, and change your dose or stop REVOLADE if your platelet counts get too high.
Tell your doctor right away if you have signs and symptoms of a blood clot in the leg, such as swelling or pain/tenderness of one leg.
  1. Phototoxicity
REVOLADE may cause you to sunburn more easily.
As a safety precaution, while taking REVOLADE, you should avoid exposure to high-intensity artificial UV light such as tanning beds and being unprotected when in direct sunlight. If you do need to be in the sun, use protective clothing, sun glasses and sunscreen.
  1. Cataracts
In animal studies, it was found that REVOLADE caused the development of cataracts (a clouding of the lens in the eye).
In HCV trials in humans, an increased risk in the incidence of cataracts has also been seen. Your doctor may recommend that you are checked for cataracts as part of any routine eye examination.

Things you must not do

Do not give this medicine to anyone else, even if their condition seems to be the same as yours.

Do not stop taking REVOLADE before talking to your doctor or pharmacist. After you have stopped taking REVOLADE, your bleeding symptoms may come back.

Possible side effects

Like all medicines, REVOLADE can cause side effects, although not everybody gets them.

Do not be alarmed by these lists of possible side effects. You may not experience any of them.

SERIOUS SIDE EFFECTS (All indications)

STOP taking REVOLADE and seek medical help immediately if you experience the following:

Serious side effects

  • Blood clots (thromboembolic events)
  • Loss of function of the liver due to side effects of this treatment (drug induced liver injury)
  • Liver failure
  • Damage occurring in the smallest blood vessels inside the kidney leading to loss of kidney function (thrombotic microangiopathy with acute renal failure).

ADULT PATIENTS WITH ITP

The following side effects have been associated with REVOLADE treatment in adult patients with ITP.

Very common side effects

These may affect more than 1 in 10 people treated with REVOLADE:

  • Diarrhoea
  • Nausea
  • Back pain

Very common side effect that may show up in blood tests:

  • Increase in a liver enzyme.

Common side effects

These may affect up to 1 in 10 people treated with REVOLADE:

  • Dry mouth
  • Rash
  • Vomiting
  • Cataract (clouding of the lens in the eye)
  • Sore throat or discomfort when swallowing
  • Muscle pain
  • Pain that affects muscles and tendons along with bones, including in your chest
  • Unusual hair loss or thinning
  • Urinary tract infections

Common side effects that may show up in blood tests

  • Increase level of a type of liver enzyme
  • Increased level of the pigment (bilirubin) in the blood, which may cause a yellow discolouration of your skin, the whites of your eyes, or body fluids (jaundice).

PAEDIATRIC PATIENTS (aged 1 to 17 years) with ITP

The following additional side effects have been reported to be associated with treatment with REVOLADE in paediatric patients (aged 1 to 17 years) with ITP.

Very common side effects

  • Infection in the nose, sinuses, throat and upper airways, common cold (upper respiratory tract)
  • Fever.
  • Abdominal pain
  • Sore throat, runny nose, nasal congestion and sneezing
  • Cough

Common side effects

  • Pain in the nose and throat
  • Toothache
  • Itchy, runny or blocked nose.

Other side effects

Other side effects have occurred during further studies with REVOLADE

Rare side effects (these may affect up to 1 in 1,000 people):

  • Clots in small blood vessels, which may harm organs such as the kidneys (Microangiopathy associated with renal impairment).

PATIENTS WITH HCV

The following side effects have been reported to be associated with treatment with REVOLADE in combination with pegylated interferon and ribavirin in patients with HCV.

Very common side effects

  • Fever
  • Feeling very tired (fatigue)
  • Headache
  • Nausea
  • Flu-like symptoms
  • Diarrhoea
  • Loss of appetite
  • Feeling tired, weak
  • Itching
  • Cough
  • Chills
  • Muscle pain
  • Unusual hair loss or thinning of the hair
  • Difficulty sleeping
  • Generalised swelling.

Very common side effects that may show up in blood tests:

  • Reduced number of red blood cells (anaemia)
  • Increase in bilirubin (a substance produced by the liver).

Common side effects

  • Liver failure (serious disturbance of liver function)
  • Loss of functions of the liver due to side effects of Revolade treatment
  • Blood clots
  • Rash
  • Cataract (clouding of the lens in the eye).

Tell your doctor immediately if you get any of these symptoms. These symptoms may persist after you stop taking REVOLADE.

Tell your doctor right away if you have any of these signs and symptoms of liver problems:

  • Jaundice (yellowing of the skin or the whites of the eyes)
  • Unusual darkening of the urine
  • Unusual tiredness
  • Right upper stomach area pain.

PATIENTS WITH SEVERE APLASTIC ANAEMIA (given with standard immunosuppressive therapy)

The following side effects have been reported to be associated with REVOLADE treatment in patients with SAA when it is given with standard immunosuppressive therapy.

Very common side effects

  • Yellowing of the skin or whites of the eyes (due to jaundice or increased level of the pigment bilirubin in the blood)

Very common side effects that may show up in blood tests:

  • Increase in some liver enzymes
  • Increase in bilirubin (a substance produced by the liver).

Common side effects

  • Rash
  • More intense colour of the skin (hyperpigmentation)
  • Nausea
  • Diarrhoea
  • Abdominal pain

PATIENTS WITH SEVERE APLASTIC ANAEMIA (where other medicines have not worked well)

The following side effects have been reported to be associated with REVOLADE treatment in patients with severe aplastic anaemia (SAA).

Very common side effects

  • Nausea
  • Feeling very tired (fatigue)
  • Cough
  • Headache
  • Diarrhoea
  • Shortness of breath
  • Pain in arms, legs, hands and feet (pain in extremities)
  • Pain in the mouth and throat
  • Dizziness
  • Fever
  • Abdominal pain
  • Joint pain
  • Muscle spasms
  • Muscle spasms
  • Runny nose
  • Bruising
  • Fever with very low number of neutrophils in the blood (white blood cells that are needed to fight infections) (febrile neutropenia).

Very common side effects that may show up in blood tests:

  • Increase in some liver enzymes.

Common side effects

  • Rash
  • Cataract (clouding of the lens in the eye).

Common side effects that may show up in blood tests

  • Increase in bilirubin (a substance produced by the liver).

Other side effects

  • Yellowing or darkening of skin (skin discolouration).

If you experience any of the side effects listed in this leaflet, or if you notice any side effects not listed in this leaflet, please tell your doctor or pharmacist.

After taking REVOLADE

Storage

  • Keep this medicine 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.
  • Store the tablets and powder for oral suspension in a cool, dark, dry place below 30°C.
  • Do not store REVOLADE or any other medicine in the car, in the bathroom, near a sink, or on a window sill.
    Heat and dampness can destroy some medicines.
  • Do not open the powder for oral suspension foil sachets until ready for use.

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.

Medicines should not be disposed of via wastewater or household waste.

Only discard the mixing bottle, lid with cap, and oral dosing syringe after you have used all of the powder for oral suspension* sachets in the pack. You will receive new items in another pack.

Product descriptions

What REVOLADE looks like

Tablets

REVOLADE is supplied in packs of 28 tablets. REVOLADE tablets are round, biconvex, film coated tablets, and available in different strengths.

  • 25 mg
    White, imprinted with 'GS NX3' and '25' on one side. The reverse face is plain. They contain 32 mg of eltrombopag olamine, equivalent to 25 mg of eltrombopag.
  • 50 mg
    Brown, imprinted with 'GS UFU' and '50' on one side. The reverse face is plain. They contain 64 mg of eltrombopag olamine, equivalent to 50 mg of eltrombopag.
  • 12.5 mg*
    White, imprinted with 'GS MZ1' and '12.5' on one side. The reverse face is plain. They contain 16 mg of eltrombopag olamine, equivalent to 12.5 mg of eltrombopag.

Powder for oral suspension*

The powder for oral suspension is supplied in packs containing:

  • 30 sachets
  • A re-usable plastic mixing bottle with lid and cap, and
  • A re-usable 20 mL dosing syringe.

Each sachet contains 32 mg of eltrombopag olamine, equivalent to 25 mg of eltrombopag, in a reddish-brown to yellow powder for oral suspension.

The powder must be reconstituted with water before oral administration.

You will also require the following items (not included in the pack) to prepare the powder for oral suspension:

  • A clean vessel containing more than 30 mL of drinking water, and
  • Clean scissors to cut the sachet(s).

Please see the leaflet in the pack for the reconstitution instructions.

The oral suspension contains about 40 times the amount of mannitol found in the 25 mg tablets.

Ingredients

REVOLADE tablets and powder for oral suspension contain the active ingredient eltrombopag olamine.

REVOLADE tablets contain the excipients:

  • Hypromellose (E464)
  • Macrogol 400 (E1521)
  • Magnesium stearate (E572)
  • Mannitol (E421)
  • Microcrystalline cellulose (E460(i))
  • Povidone (E1201)
  • Sodium starch glycollate
  • Titanium dioxide (E171).
  • Polysorbate 80 (E433) (12.5 mg tablet and 25 mg tablet only)
  • Iron oxide red CI77491 (E172) (50 mg tablet only)
  • Iron oxide yellow CI77492 (E172) (50 mg tablet only).

The powder for oral suspension* contains the excipients:

  • Mannitol (E421)
  • Sucralose (E955), and
  • Xanthan gum (E415).

REVOLADE tablets and powder for oral suspension* do not contain lactose, sucrose, tartrazine or any other azo dyes.

Supplier

REVOLADE is supplied in Australia by:

Novartis Pharmaceuticals Australia Pty Limited
ABN 18 004 244 160
54 Waterloo Road, Macquarie Park NSW 2113 AUSTRALIA.
Telephone 1 800 671 203
www.novartis.com.au

® = Registered Trademark

Australian Registration Numbers:

25 mg tablets AUST R 158419

50 mg tablets AUST R 158356

*12.5 mg tablets AUST R 236115

*25 mg powder for oral suspension AUST R 236116

*Not all strengths and pack sizes may be distributed in Australia.

This leaflet was prepared in September 2019.

Internal document code (rev050919allc based on PI rev050919i)

Published by MIMS November 2019

BRAND INFORMATION

Brand name

Revolade

Active ingredient

Eltrombopag

Schedule

S4

 

1 Name of Medicine

Australian Approved Name: eltrombopag olamine.

6.7 Physicochemical Properties

Chemical name: 3'-{(2Z)-2-[1-(3,4-dimethyl-phenyl)- 3-methyl-5-oxo-1,5-dihydro- 4H-pyrazol-4-ylidene]hydrazino}- 2'-hydroxy-3-biphenyl carboxylic acid-2-aminoethanol (1:2).

Chemical structure.


Molecular formula: C25H22N4O4.2(C2H7NO).
Molecular weight: 564.65.

CAS number.

496775-62-3.

2 Qualitative and Quantitative Composition

Revolade film-coated tablets and powder for oral suspension contain eltrombopag olamine. Eltrombopag olamine is practically insoluble in aqueous buffer across a pH range of 1 to 7.4, and is sparingly soluble in water.
Each film-coated tablet contains eltrombopag olamine equivalent to either 12.5 mg, 25 mg, 50 mg or 75 mg of eltrombopag as eltrombopag free acid.
Each Revolade 25 mg powder for oral suspension sachet delivers 32 mg of eltrombopag olamine equivalent to 25 mg of eltrombopag free acid. The powder for oral suspension also contains mannitol (see Section 4.4 Special Warnings and Precautions for Use).
For the full list of excipients, see Section 6.1 List of Excipients.

3 Pharmaceutical Form

Presentations.

12.5 mg film-coated tablet*.

Round, biconvex, white, and film-coated, debossed with 'GS MZ1' and '12.5' on one side.

25 mg film-coated tablets.

Round, biconvex, white, and film-coated, debossed with 'GS NX3' and '25' on one side. Blister packs containing 14*, 28, or 84* tablets.

50 mg film-coated tablets.

Round, biconvex, brown, and film-coated, debossed with 'GS UFU' and '50' on one side. Blister packs containing 14*, 28, or 84* tablets.

75 mg film-coated tablets*.

Round, biconvex, pink, and film-coated, debossed with 'GS FSS' and '75' on one side.

25 mg powder for oral suspension*.

Each eltrombopag 25 mg powder for oral suspension sachet contains a reddish-brown to yellow powder which produces a reddish-brown suspension when reconstituted with water.
Revolade Powder for Oral Suspension sachets are supplied in aluminium foil sachets. Packs of 30 sachets are co-packaged in a carton with a 40 mL reconstitution vessel, a 20 mL oral dosing syringe and a threaded closure with syringe-port capability.
*Not all strengths and pack sizes may be distributed in Australia.

5 Pharmacological Properties

5.1 Pharmacodynamic Properties

Eltrombopag differs from TPO with respect to the effects on platelet aggregation. Unlike TPO, eltrombopag treatment of normal human platelets does not enhance adenosine diphosphate (ADP) induced aggregation or induce P-selectin expression. Eltrombopag does not antagonise platelet aggregation induced by ADP or collagen.

Mechanism of action.

Eltrombopag olamine is an oral small molecule, and a thrombopoietin receptor (TPO-R) agonist. Thrombopoietin (TPO) is the main cytokine involved in the regulation of megakaryopoiesis and platelet production, and is the endogenous ligand for the thrombopoietin receptor (TPO-R). Eltrombopag interacts with the transmembrane domain of the human TPO-R, and initiates signaling cascades similar, but not identical, to that of endogenous thrombopoietin (TPO), inducing proliferation and differentiation of megakaryocytes and bone marrow progenitor cells.

Clinical trials.

Pharmacotherapeutic group: antihaemorrhagics; ATC code: B02BX 05.

Chronic immune thrombocytopaenia (ITP) studies.

Adults.

The safety and efficacy of Revolade have been demonstrated in two, randomised, double blind, placebo controlled studies (TRA102537 RAISE and TRA100773B) and one open label study (EXTEND TRA105325) in adult patients with previously treated chronic ITP.

Double blind placebo controlled studies. RAISE (TRA102537).

The primary efficacy endpoint was the odds of achieving a platelet count ≥ 50 x 109/L and ≤ 400 x 109/L, during the 6 month treatment period, for patients receiving Revolade relative to placebo. One hundred and ninety-seven patients were randomized 2:1, Revolade (n = 135) to placebo (n = 62), and were stratified based upon splenectomy status, use of ITP medication at baseline and baseline platelet count. Patients received study medication for up to 6 months, during which time the dose of Revolade could be adjusted based on individual platelet counts. In addition, patients could have tapered off concomitant ITP medications and received rescue treatments as dictated by local standard of care.
The odds of achieving a platelet count between 50 x 109/L and 400 x 109/L during the 6 month treatment period were 8 times higher for Revolade treated patients than for placebo treated patients (odds ratio: 8.2 [99% Cl: 3.59, 18.73] p = < 0.001). Median platelet counts were maintained above 50 x 109/L at all on therapy visits starting at day 15 in the Revolade group; in contrast, median platelet counts in the placebo group remained below 30 x 109/L throughout the study.
At baseline, 77% of patients in the placebo group and 73% of patients in the Revolade group reported any bleeding (WHO grades 1-4); clinically significant bleeding (WHO grades 2-4) at baseline was reported in 28% and 22% of patients in the placebo and Revolade groups, respectively. The proportion of patients with any bleeding (grades 1-4) and clinically significant bleeding (grades 2-4) was reduced from baseline by approximately 50% throughout the 6 month treatment period in Revolade treated patients. When compared to the placebo group, the odds of any bleeding (grades 1-4) and the odds of clinically significant bleeding (grades 2-4) were 76% and 65% lower in the Revolade treated patients compared to the placebo treated patients (p < 0.001).
Revolade therapy allowed significantly more patients to reduce or discontinue baseline ITP therapies compared to placebo (59% vs. 32%; p < 0.016).
Significantly fewer Revolade treated patients required rescue treatment compared to placebo treated patients [18% vs. 40%; p = 0.001].
Four placebo and 14 Revolade patients had at least 1 haemostatic challenge (defined as an invasive diagnostic or surgical procedure) during the study. Fewer Revolade treated patients (29%) required rescue treatment to manage their haemostatic challenge, compared to placebo treated patients (50%).
In terms of improvements in health related quality of life, statistically significant improvements from baseline were observed in the Revolade group in fatigue, including severity and impact on thrombocytopenia impacted daily activities and concerns [as measured by the vitality subscale of the SF36, the motivation and energy inventory, and the 6 item extract from the thrombocytopenia subscale of the FACIT-Th]. Comparing the Revolade group to the placebo group, statistically significant improvements were observed with thrombocytopenia impacted activities and concerns specifically regarding motivation, energy and fatigue, as well as physical and emotional role and overall mental health. The odds of meaningful improvement in health related quality of life while on therapy was significantly greater among patients treated with Revolade than placebo.

TRA100773B.

In TRA100773B, the primary efficacy endpoint was the proportion of responders, defined as patients who had an increase in platelet counts to ≥ 50 x 109/L at day 43 from a baseline < 30 x 109/L; patients who withdrew prematurely due to a platelet count > 200 x 109/L were considered responders, those discontinued for any other reason were considered nonresponders irrespective of platelet count. A total of 114 patients with previously treated chronic ITP were randomised 2:1, with 76 randomised to Revolade and 38 randomized to placebo.
Fifty-nine percent of patients on Revolade responded, compared to 16% of patients on placebo. The odds of responding were 9 times higher for Revolade treated patients compared to placebo (odds ratio: 9.6 [95% Cl: 3.31, 27.86], p < 0.001). At baseline, 61% of patients in the Revolade group and 66% of patients in the placebo group reported any bleeding (grade 1-4). At day 43, 39% of patients in the Revolade treatment group had bleeding compared with 60% in the placebo group. Analysis over the treatment period using a repeated measures model for binary data confirmed that a lower proportion of Revolade patients had bleeding (grade 1-4) at any point in time over the course of their treatment (day 8 up to day 43) compared to patients in the placebo group (OR = 0.49, 95% CI = [0.26, 0.89], p = 0.021). Two placebo and one Revolade patient had at least one haemostatic challenge during the study.
In both RAISE (TRA102537) and TRA100773B, the response to Revolade relative to placebo was similar irrespective of ITP medication use, splenectomy status and baseline platelet count (≤ 15 x 109/L, > 15 x 109/L) at randomization.

Open label studies. EXTEND (TRA105325).

EXTEND is an open label extension study which has evaluated the safety and efficacy of Revolade in patients with chronic ITP who were previously enrolled in a Revolade study. In this study, patients were permitted to modify their dose of study medication as well as decrease or eliminate concomitant ITP medications.
Revolade was administered to 207 ITP patients; 104 completed 3 months of treatment, 74 completed 6 months, and 27 completed 1 year of therapy. The median baseline platelet count was 18 x 109/L prior to Revolade administration. Revolade increased median platelet counts to ≥ 50 x 109/L at the majority of the postbaseline visits on the study. The median platelet count postbaseline increased to ≥ 50 x 109/L beginning at the second week on study and remained elevated until the end of the observation period presented (i.e. 55 weeks), with the exception of weeks 29, 33, and 45, where the median platelet count was 44 x 109/L, 43 x 109/L, and 42 x 109/L respectively. Just over half of the patients (51%) experienced ≥ 4 weeks of continuous elevation of platelets ≥ 50 x 109/L and 2 x baseline while receiving Revolade.
At baseline, 59% of patients had any bleeding (WHO bleeding grades 1-4) and 18% had clinically significant bleeding. By weeks 24, 36 and 48, 26%, 8% and 33% of patients, respectively, had any bleeding and 9%, 4% and 25% of patients, respectively, had clinically significant bleeding. The apparent increase in proportion of patients with clinically significant bleeding at week 48 in comparison to baseline may be due to few patients having assessments by week 48.
Seventy percent of patients who reduced a baseline medication permanently discontinued or had a sustained reduction of their baseline ITP medication and did not require any subsequent rescue treatment. Sixty-five percent of these patients maintained this discontinuation or reduction for at least 24 weeks. Sixty-one percent of patients completely discontinued at least one baseline ITP medication, and 55% of patients permanently discontinued all baseline ITP medications, without subsequent rescue treatment.
Twenty-four patients experienced at least one haemostatic challenge during the study. No patient experienced unexpected bleeding complications related to the procedure while on study.

Paediatric patients (aged 1 to 17 years).

The safety and efficacy of eltrombopag in paediatric patients with previously treated chronic ITP have been demonstrated in two studies.

Double blind placebo controlled studies. TRA115450 (PETIT 2).

The primary endpoint was a sustained response, defined as the proportion of patients receiving eltrombopag, compared to placebo, achieving platelet counts ≥ 50 x 109/L for at least 6 out of 8 weeks (in the absence of rescue therapy), between weeks 5 to 12 during the double blind randomised period. Patients were refractory or relapsed to at least one prior ITP therapy, or unable to continue other ITP treatments for a medical reason, and had platelet count < 30 x 109/L. Ninety-two patients were randomised by three age cohort strata (2:1) to eltrombopag (n = 63) or placebo (n = 29). The dose of eltrombopag could be adjusted based on individual platelet counts.
Overall, a significantly greater proportion of eltrombopag patients (40%) compared with placebo patients (3%) achieved the primary endpoint (odds ratio: 18.0 [95% CI: 2.3, 140.9], p < 0.001) which was similar across the three age cohorts (Table 14).
A significantly greater proportion of patients treated with eltrombopag (75%) compared with placebo (21%) had a platelet response (at least one platelet count > 50 x 109/L during the first 12 weeks of randomised treatment in absence of rescue therapy) (odds ratio: 11.7 [95% CI: 4.0, 34.5], p < 0.001).
Baseline platelet count was evaluated for effect on the primary endpoint. The majority of patients in the study population (57/91, 62.6%) had a baseline platelet count ≤ 15 x 109/L. In subgroups defined by baseline platelet count ≤ 15 x 109/L and > 15 x 109/L, response rates were 29% (11/38) and 54% (13/24) respectively in the eltrombopag treatment group.
The proportion of patients who responded to eltrombopag in the open label 24 week period (80%) was similar to that observed during the randomized portion of the study.
Statistically fewer eltrombopag patients required rescue treatment during the randomised period compared to placebo patients (19% [12/63] vs. 24% [7/29], p = 0.032).
At baseline, 71% of patients in the eltrombopag group and 69% in the placebo group reported any bleeding (WHO grades 1-4). At week 12, the proportion of eltrombopag patients reporting any bleeding was decreased to half of baseline (36%). In comparison, at week 12, 55% of placebo patients reported any bleeding.
Patients were permitted to reduce or discontinue baseline ITP therapy only during the open label phase of the study and 53% (8/15) of patients were able to reduce (n = 1) or discontinue (n = 7) baseline ITP therapy, mainly corticosteroids, without needing rescue therapy.

TRA108062 (PETIT).

The primary endpoint was the proportion of patients achieving platelet counts ≥ 50 x 109/L at least once between weeks 1 and 6 of the randomised period. Patients were refractory or relapsed to at least one prior ITP therapy with a platelet count < 30 x 109/L (n = 67). During the randomised period of the study, patients were randomised by 3 age cohort strata (2:1) to eltrombopag (n = 45) or placebo (n = 22). The dose of eltrombopag could be adjusted based on individual platelet counts.
Overall, a significantly greater proportion of eltrombopag patients (62%) compared with placebo patients (32%) met the primary endpoint (odds ratio: 4.3 [95% CI: 1.4, 13.3], p = 0.011). Table 15 shows platelet response across the three age cohorts.
A significantly greater proportion of patients treated with eltrombopag (36%) compared with placebo (0%) had a platelet response (platelet counts > 50 x 109/L for at least 60% of assessments between weeks 2 and 6) (odds ratio: 5.8 [95% CI: 1.2, 28.9], p = 0.002).
Statistically fewer eltrombopag treated patients required rescue treatment during the randomised period compared to placebo treated patients (13% [6/45] vs. 50% [11/22], p = 0.002).
At baseline, 82% of patients in the eltrombopag group and 78% in the placebo group reported any bleeding (WHO grades 1-4). The proportion of eltrombopag patients reporting any bleeding decreased to 22% at week 6. In comparison, 73% of placebo patients reported any bleeding at week 6.
Patients were permitted to reduce or discontinue baseline ITP therapy only during the open label phase of the study and 46% (6/13) of patients were able to reduce (n = 3) or discontinue (n = 3) baseline ITP therapy, mainly corticosteroids, without needing rescue therapy.
Long-term use (greater than nine months) of Revolade has not been studied in paediatric patients.

Chronic hepatitis C associated thrombocytopenia studies.

Double blind placebo controlled studies.

The efficacy and safety of Revolade for the treatment of thrombocytopenia in patients with HCV infection were evaluated in two randomized, double blind, placebo controlled, multicentre studies (TPL103922 ENABLE 1 and TPL108390 ENABLE 2).
ENABLE 1 utilised peginterferon alfa-2a plus ribavirin for antiviral treatment and ENABLE 2 utilised peginterferon alfa-2b plus ribavirin. In both studies, patients with a platelet count of < 75 x 109/L were enrolled and stratified by platelet count (< 50 x 109/L and ≥ 50 x 109/L to < 75 x 109/L), screening HCV RNA (< 8 x 105 IU/mL and ≥ 8 x 105 IU/mL), and HCV genotype (genotype 2/3, and genotype 1/4/6).
The studies consisted of two phases: a preantiviral treatment phase and an antiviral treatment phase. In the preantiviral treatment phase, patients received open label Revolade to increase the platelet count to ≥ 90 x 109/L for ENABLE 1 and ≥ 100 x 109/L for ENABLE 2. Revolade was administered at an initial dose of 25 mg once daily for 2 weeks and increased in 25 mg increments over 2 to 3 week periods to achieve the required platelet count for phase 2 of the study. The maximal time patients could receive open label Revolade was 9 weeks. If sufficient platelet counts were achieved, patients were randomized (2:1) to the same dose of Revolade at the end of the pretreatment phase or to placebo. Revolade was administered in combination with antiviral treatment per their respective product information for up to 48 weeks.
The primary efficacy endpoint for both studies was sustained virological response (SVR), defined as the percentage of patients with no detectable HCV-RNA at 24 weeks after completion of the planned treatment period. Approximately 70% of patients were genotype 1/4/6 and 30% were genotype 2/3. Approximately 30% of patients had been treated with prior HCV therapies, primarily pegylated interferon plus ribavirin. The median baseline platelet counts (approximately 60 x 109/L) were similar among all treatment groups. The median time to achieve the target platelet count ≥ 90 x 109/L was 2 weeks. The median time to achieve the target platelet count ≥ 90 x 109/L (ENABLE 1) or ≥ 100 x 109/L (ENABLE 2) was 2 weeks.
In both HCV studies, a significantly greater proportion of patients treated with Revolade achieved SVR compared to those treated with placebo (see Table 16). Significantly fewer patients treated with Revolade had any antiviral dose reductions compared to placebo. The proportion of patients with no antiviral dose reductions was 45% for Revolade compared to 27% for placebo. Significantly fewer patients treated with Revolade prematurely discontinued antiviral therapy compared to placebo (45% vs. 60%, p < 0.0001). The majority of patients treated with Revolade (76%) had minimum platelet counts that were ≥ 50 x 109/L compared to 19% for placebo. A greater proportion of patients in the placebo group (20%) had minimum platelet counts fall below 25 x 109/L during antiviral treatment compared to the Revolade group (3%). In the Revolade group, SVR rates in patients with high viral loads (> 8 x 105 IU/mL) were 18% as compared to 8% in the placebo group. Significantly more patients reached the antiviral milestones of early virologic response (EVR), complete early virologic response (cEVR), end of treatment response (ETR) and sustained virologic response at 12 week follow-up (SVR12) when treated with Revolade.

Definitive immunosuppressive therapy-naive severe aplastic anaemia study.

Revolade in combination with horse antithymocyte globulin (h-ATG) and cyclosporin was investigated in a single-arm, single-centre, open-label sequential cohort study in patients with severe aplastic anaemia who had not received prior definitive immunosuppressive therapy (i.e. ATG therapy, alemtuzumab, or high dose cyclophosphamide). The multiple cohorts differed by treatment start day and duration of Revolade and the initiation of low dose of cyclosporin (maintenance dose) for patients who achieved a hematologic response at 6 months. A total of 153 patients received Revolade in sequential cohorts: Revolade on Day 14 to Month 6 (D14-M6) plus h-ATG and cyclosporin (Cohort 1 regimen, n=30).
Revolade on Day 14 to Month 3 (D14-M3) plus h-ATG and cyclosporin (Cohort 2 regimen, n=31), with half of the patients eligible to receive low dose of cyclosporin (maintenance dose) if they achieved a hematologic response at 6 months.
Revolade on Day 1 to Month 6 (D1-M6) plus h-ATG and cyclosporin (Cohort 3 regimen, n=92), with all patients eligible to receive low dose of cyclosporin (maintenance dose) if they achieved a hematologic response at 6 months.
The starting dose of Revolade for adults and paediatric patients aged 12 to 17 years was 150 mg once daily (a reduced dose of 75 mg was administered for East and Southeast Asians), 75 mg once daily for patients aged 6 to 11 years (a reduced dose of 37.5 mg was administered for East and Southeast Asians), and 2.5 mg/kg once daily for patients aged 2 to 5 years (a reduced dose of 1.25 mg/kg was administered for East and Southeast Asians). The dose of Revolade was reduced if the platelet count exceeded 200 x 109/L and interrupted and reduced if it exceeded 400 x 109/L.
All patients received h-ATG 40 mg/kg/day on Days 1 to 4 of the 6-month treatment period and a total daily dose of 6 mg/kg/day of cyclosporin for 6 months in patients aged 12 years and older or a total daily dose of 12 mg/kg/day for 6 months in patients aged 2 to 11 years. A 2 mg/kg/day maintenance dose of cyclosporin was administered for an additional 18 months to 15 patients who achieved a hematologic response at 6 months in the Revolade D14-M3 cohort and all patients who achieved a hematologic response at 6 months in the Revolade D1-M6 cohort.
Data from the recommended schedule of Revolade on Day 1 to Month 6 (D1-M6) in combination with h-ATG and cyclosporin (Cohort 3 regimen) are presented in Table 17. This cohort had the highest complete response rates.
In the Revolade D1-M6 cohort, the median age was 28.0 years (range 5 to 82 years) with 16.3% and 28.3% of patients ≥ 65 years of age and < 18 years of age, respectively. 45.7% of patients were male and the majority of patients were White (62.0%).
The efficacy of Revolade in combination with h-ATG and cyclosporin was established on the basis of complete haematological response at 6 months. A complete response was defined as haematological parameters meeting all 3 of the following values on 2 consecutive serial blood count measurements at least one week apart: absolute neutrophil count (ANC) > 1 x 109/L, platelet count > 100 x 109/L and haemoglobin > 10 /L. A partial response was defined as blood counts no longer meeting the standard criteria for severe pancytopenia in severe aplastic anaemia equivalent to 2 of the following values on 2 consecutive serial blood count measurements at least one week apart: ANC > 0.5 x 109/L, platelet count > 20 x 109/L, or reticulocyte count > 60 x 109/L.
The overall and complete haematological response rates at Year 1 (n=78) are 56.4% and 38.5% and at Year 2 (n=62) are 38.7% and 30.6%, respectively.

Paediatric patients.

Thirty-seven patients aged 2 to 17 years were enrolled in the single-arm, sequential-cohort study. Of the 36 patients who reached the 6-month assessment point or withdrew earlier, the complete response rate at 6 months was 30.6% (0/2 in patients aged 2 to 5 years, 1/12 in patients aged 6 to 11 years, and 10/22 in patients aged 12 to 17 years) and the overall response rate at 6 months was 72.2% (2/2 in patients aged 2 to 5 years, 7/12 in patients aged 6 to 11 years, and 17/22 in patients aged 12 to 17 years). Out of 25 evaluable patients in the Revolade D1-M6 cohort, the complete response rate at 6 months was 28.0% (7/25) and the overall response rate at 6 months was 68.0% (17/25).

Refractory severe aplastic anaemia.

Revolade was studied in a single arm, single centre open label study (ELT112523) in 43 patients with severe aplastic anaemia who had an insufficient response to at least one prior immunosuppressive therapy, and had a platelet count ≤ 30 x 109/L (see Table 18). Revolade was administered at an initial dose of 50 mg once daily for 2 weeks and increased over 2 week periods up to a maximum dose of 150 mg once daily. The primary endpoint was haematological response assessed after 12 weeks of Revolade treatment.
Haematological response was defined as meeting one or more of the following criteria: 1) platelet count increases to 20 x 109/L above baseline or stable platelet counts with transfusion independence for a minimum of 8 weeks; 2) haemoglobin increase by > 15 g/L, or a reduction in ≥ 4 units of RBC transfusions for 8 consecutive weeks, compared to the number of transfusions in the 8 weeks pretreatment; 3) absolute neutrophil count (ANC) increase of 100% or an ANC increase > 0.5 x 109/L.
Revolade was discontinued after 16 weeks if no haematological response or transfusion independence was observed. Patients who responded continued therapy in an extension phase of the study.
The treated population had a median age of 45 years (range 17 to 77 years) and 56% of patients were male. At baseline the median platelet count was 20 x 109/L, haemoglobin was 84 g/L, and ANC was 0.58 x 109/L. The prior immunosuppressive history of these patients is given in Table 13 (see Section 5.1 Pharmacodynamic Properties, Clinical trials). The majority of patients (84%) had received at least 2 prior immunosuppressive therapies. Three patients had cytogenetic abnormalities at baseline (see Section 4.4 Special Warnings and Precautions for Use, Cytogenetic abnormalities).
At baseline, 91% (39/43) and 86% (37/43) of patients were platelet and RBC transfusion dependent respectively. Of these, 59% (23/39) became platelet transfusion independent (28 days without platelet transfusion) and 27% (10/37) became RBC transfusion independent (56 days without RBC transfusion) while being treated with Revolade.
The haematological response rate was 40% (17/43 patients; 95% CI 25, 56). In the 17 responders, the platelet transfusion free period ranged from 8 to 1,190 days with a median of 287 days, and the RBC transfusion free period ranged from 15 to 1,190 days with a median of 266 days. No major differences were observed in responses between cohorts regarding the number of prior ISTs received.
In the extension phase, 9 patients achieved a multilineage response; 5 of these patients subsequently tapered off of treatment with Revolade and maintained the response (median follow-up: 20.6 months, range: 5.7 to 22.5 months).

5.2 Pharmacokinetic Properties

The pharmacokinetic (PK) parameters of eltrombopag after administration of eltrombopag to adult patients with ITP are shown in Table 19. Plasma eltrombopag concentration time data collected in 590 patients with HCV enrolled in phase III studies TPL103922/ ENABLE 1 and TPL108390/ ENABLE 2 were combined with data from patients with HCV enrolled in the phase II study TPL102357 and healthy adult patients in a population PK analysis.
Plasma eltrombopag Cmax and AUC(0-T) estimates for patients with HCV enrolled in phase III studies TPL103922 (ENABLE 1) and TPL108390 (ENABLE 2) are presented for each dose studied in Table 20. A higher eltrombopag exposure was observed in patients with HCV at a given eltrombopag dose.
The pharmacokinetic parameters of eltrombopag after administration of Revolade 150 mg once daily 45 patients with definitive immunosuppressive therapy-naïve severe aplastic anaemia are shown in Table 21.

Special patient populations.

Renal impairment.

The PK of eltrombopag has been studied after administration of eltrombopag to adult patients with renal impairment. Following administration of a single 50 mg dose, the AUC0-∞ of eltrombopag was decreased by 32% (90% CI: 63% decrease, 26% increase) in patients with mild renal impairment, 36% (90% CI: 66% decrease, 19% increase) in patients with moderate renal impairment, and 60% (90% CI: 18% decrease, 80% decrease) in patients with severe renal impairment compared with healthy volunteers. There was a trend for reduced plasma eltrombopag exposure in patients with renal impairment, but there was substantial variability and significant overlap in exposures between patients with renal impairment and healthy volunteers. Patients with impaired renal function should use eltrombopag with caution and close monitoring (see Section 4.4 Special Warnings and Precautions for Use).

Hepatic impairment.

The PK of eltrombopag has been studied after administration of eltrombopag to adult patients with liver cirrhosis (hepatic impairment). Following the administration of a single 50 mg dose, the AUC0-∞ of eltrombopag was increased by 41% (90% CI: 13% decrease, 128% increase) in patients with mild hepatic impairment, 93% (90% CI: 19%, 213%) in patients with moderate hepatic impairment, and 80% (90% CI: 11%, 192%) in patients with severe hepatic impairment compared with healthy volunteers. There was substantial variability and significant overlap in exposures between patients with hepatic impairment and healthy volunteers.
ITP patients with liver cirrhosis (hepatic impairment) (Child-Pugh score ≥ 5), should use eltrombopag with caution and close monitoring (see Section 4.4 Special Warnings and Precautions for Use). For patients with chronic ITP and with mild, moderate and severe hepatic impairment, initiate eltrombopag at a reduced dose of 25 mg once daily (see Section 4.2 Dose and Method of Administration).
The influence of hepatic impairment on the PK of eltrombopag following repeat administration was evaluated using a population pharmacokinetic analysis in 28 healthy adults and 714 patients with hepatic impairment (673 patients with HCV and 41 patients with chronic liver disease of other aetiology). Of the 714 patients, 642 were with mild hepatic impairment, 67 with moderate hepatic impairment, and 2 with severe hepatic impairment. Compared to healthy volunteers, patients with mild hepatic impairment had approximately 111% (95% CI: 45% to 283%) higher plasma eltrombopag AUC(0-T) values and patients with moderate hepatic impairment had approximately 183% (95% CI: 90% to 459%) higher plasma eltrombopag AUC(0-T) values.
A similar analysis was also conducted in 28 healthy adults and 635 patients with HCV. A majority of patients had Child-Pugh score of 5-6. Based on estimates from the population pharmacokinetic analysis, patients with HCV had higher plasma eltrombopag AUC(0-T) values as compared to healthy patients, and AUC(0-T) increased with increasing Child-Pugh score, HCV patients with mild hepatic impairment had approximately 100-144% higher plasma eltrombopag AUC(0-T) compared with healthy patients. For patients with HCV initiate Revolade at a dose of 25 mg once daily (see Section 4.2 Dose and Method of Administration).

Race.

The influence of Asian ethnicity on the PK of eltrombopag was evaluated using a population pharmacokinetic analysis in 111 healthy adults (31 Asians) and 88 patients with ITP (18 Asians). Based on estimates from the population pharmacokinetic analysis, Asian (i.e. Japanese, Chinese, Taiwanese and Korean) ITP patients had approximately 87% higher plasma eltrombopag AUC(0-T) values as compared to non-Asian patients who were predominantly Caucasian, without adjustment for bodyweight differences (see Section 4.2 Dose and Method of Administration).
The influence of Asian ethnicity on the PK of eltrombopag was also evaluated using a population pharmacokinetic analysis in 635 patients with HCV (214 East Asians). On average, Asian patients had approximately 55% higher plasma eltrombopag AUC(0-T) values as compared to patients of other races who were predominantly Caucasian (see Section 4.2 Dose and Method of Administration).

Gender.

The influence of gender on the PK of eltrombopag was evaluated using a population pharmacokinetic analysis in 111 healthy adults (14 females) and 88 patients with ITP (57 females). Based on estimates from the population PK analysis, female ITP patients had approximately 50% higher plasma eltrombopag AUC(0-T) as compared to male patients, without adjustment for bodyweight differences.
The influence of gender on eltrombopag PK was evaluated also using population pharmacokinetics analysis in 635 patients with HCV (260 females). Based on model estimates, female HCV patients had approximately 41% higher plasma eltrombopag AUC(0-T) as compared to male patients.

Elderly population.

The age difference of eltrombopag PK was evaluated using population PK analysis in 28 healthy patients and 635 patients with HCV ranging from 19 to 74 years old. Based on model estimates, elderly (> 60 years) patients had approximately 36% higher plasma eltrombopag AUC(0-T) as compared to younger patients (see Section 4.2 Dose and Method of Administration).

Paediatric population (patients aged 1 to 17 years).

The PK of eltrombopag have been evaluated in 168 paediatric ITP patients dosed once daily in two studies, TRA108062/PETIT and TRA115450/PETIT-2. Patients aged 1 to 5 years received the eltrombopag powder for oral suspension. Patients aged 6 to 17 years received the eltrombopag tablet. The PK parameters of eltrombopag in paediatric patients with ITP are shown in Table 22. Plasma eltrombopag apparent clearance following oral administration (CL/F) increased with increasing bodyweight. Approximately 43% higher plasma eltrombopag AUC(0-T) was observed in patients of Asian descent and 25% higher AUC(0-T) was observed in female patients. The bioavailability of the powder for oral suspension in children was estimated as 29% lower than the tablet. Age and/or formulation may be confounding factors in the analysis.

Absorption.

Eltrombopag is absorbed with a peak concentration occurring 2 to 6 hours after oral administration.
The absolute oral bioavailability of eltrombopag after administration to humans has not been established. Based on urinary excretion and metabolites eliminated in faeces, the oral absorption of drug-related material following administration of a single 75 mg eltrombopag solution dose was estimated to be at least 52%.
In a relative bioavailability study in healthy adults, the eltrombopag powder for oral suspension delivered 22% higher plasma AUC(0-∞) than the tablet formulation. In a pooled analysis of data from paediatric ITP patients aged 1 to 17 years, the bioavailability of the powder for oral suspension in children was estimated as 29% lower than the tablet. Patients aged 1-5 years received the powder for oral suspension and patients aged 6-17 years received the tablets, so age may be a confounding factor in this analysis.

Food and chelation.

Administration of eltrombopag concomitantly with antacids and other products containing polyvalent cations such as dairy products and mineral supplements significantly reduces eltrombopag exposure (see Section 4.2 Dose and Method of Administration; Section 4.5 Interactions with Other Medicines and Other Forms of Interactions, Polyvalent cations (chelation)).
The effect of food on the pharmacokinetics of eltrombopag was studied in adults. Administration of a single 50 mg-dose of Revolade tablet with a standard high-calorie, high-fat breakfast that included dairy products reduced plasma eltrombopag AUC(0-∞) by 59% (90% CI: 54%, 64%) and Cmax by 65% (90% CI: 59%, 70%).
The administration of a single 25 mg dose of Revolade powder for oral suspension with a high-calcium, moderate fat and calorie meal reduced plasma eltrombopag AUC by 75% (90% CI: 71%, 88%) and Cmax by 79% (90% CI: 76%, 82%).
The administration of a single 25 mg dose of Revolade powder for oral suspension 2 hours after the high-calcium meal reduced plasma eltrombopag AUC by 47% (90% CI: 40%, 53%) and Cmax by 48% (90% CI: 40%, 54%).
The administration of a single 25 mg-dose of eltrombopag powder for oral suspension 2 hours before a high-calcium meal attenuated the effect, where plasma eltrombopag AUC(0-∞) was decreased by 20% (90% CI: 9%, 29%) and Cmax by 14% (90% CI: 2%, 25%).
Food low in calcium (< 50 mg calcium) including fruit, lean ham, beef and unfortified (no added calcium, magnesium, iron) fruit juice, unfortified soy milk, and unfortified grain did not significantly impact plasma eltrombopag exposure, regardless of calorie and fat content.
Revolade should be taken at a time away from food containing polyvalent cations, and preferably at the same time in relation to food (see Section 4.2 Dose and Method of Administration).

Distribution.

Eltrombopag is highly bound to human plasma proteins (> 99.9%). Eltrombopag is a substrate for BCRP, but is not a substrate for P-glycoprotein or OATP1B1.

Metabolism.

Eltrombopag is primarily metabolized through cleavage, oxidation and conjugation with glucuronic acid, glutathione, or cysteine. In a human radiolabel study, eltrombopag accounted for approximately 64% of plasma radiocarbon AUC0-∞. Minor metabolites, each accounting for < 10% of the plasma radioactivity, arising from glucuronidation and oxidation were also detected. Based on a human study with radiolabel eltrombopag, it is estimated that approximately 20% of a dose is metabolised by oxidation. In vitro studies identified CYP1A2 and CYP2C8 as the isoenzymes responsible for oxidative metabolism, uridine diphosphoglucuronyl transferase UGT1A1 and UGT1A3 as the isozymes responsible for glucuronidation, and that bacteria in the lower gastrointestinal tract may be responsible for the cleavage pathways.

Excretion.

Absorbed eltrombopag is extensively metabolised. The predominant route of eltrombopag excretion is via faeces (59%) with 31% of the dose found in the urine as metabolites. Unchanged parent compound (eltrombopag) is not detected in urine. Unchanged eltrombopag excreted in faeces accounts for approximately 20% of the dose. The plasma elimination half-life of eltrombopag is approximately 21-32 hours in healthy patients, and 26-35 hours in ITP patients.

5.3 Preclinical Safety Data

Genotoxicity.

Eltrombopag was not mutagenic in a bacterial mutation assay or clastogenic in two in vivo assays in rats (micronucleus and unscheduled DNA synthesis, 8 times the human clinical exposure based on Cmax in ITP patients at 75 mg/day and 5 times the human clinical exposure in HCV patients at 100 mg/day). In the in vitro mouse lymphoma assay, eltrombopag was marginally positive (< 3-fold increase in mutation frequency). The clinical significance of the in vitro finding remains unclear.

Carcinogenicity.

Eltrombopag was not carcinogenic in mice at doses up to 75 mg/kg/day or in rats at doses up to 40 mg/kg/day (exposures greater than 3 times the anticipated clinical exposure based on plasma AUC in ITP patients at 75 mg/day and 2 times the human clinical exposure based on AUC in HCV at 100 mg/day). Eltrombopag activates TPO receptors on the surface of haematopoietic cells and has been shown to stimulate the proliferation of megakaryocytic leukaemia cells in vitro. There is therefore a theoretical possibility that eltrombopag may increase the risk for haematologic malignancies.

4 Clinical Particulars

4.1 Therapeutic Indications

Revolade is indicated for the treatment of:
paediatric patients with chronic immune thrombocytopaenia (ITP) who have failed other treatments and either (a) need an increased platelet concentration for a planned procedure or (b) are at a high risk of bleeding;
adult patients with chronic ITP who have had an inadequate response or are intolerant to corticosteroids and immunoglobulins;
thrombocytopenia in adult patients with chronic hepatitis C to allow the initiation and maintenance of interferon based therapy;
severe aplastic anaemia (SAA) in combination with standard immunosuppressive therapy for the first-line treatment of adult and paediatric patients 2 years and older;
adult patients with SAA who have had an insufficient response to immunosuppressive therapy.

4.3 Contraindications

Revolade is contraindicated in patients with hypersensitivity to the active substance eltrombopag olamine or to any of the excipients (see Section 6.1 List of Excipients).

4.4 Special Warnings and Precautions for Use

The effectiveness and safety of Revolade have not been established for use in other thrombocytopenic conditions including chemotherapy induced thrombocytopenia and myelodysplastic syndromes (MDS).
Revolade should be used only in patients with chronic hepatitis C whose degree of thrombocytopenia prevents the initiation of interferon based therapy or limits the ability to maintain optimal interferon based therapy.
The safety and efficacy of Revolade have not been established in combination with direct acting antiviral agents approved for treatment of chronic hepatitis C genotype 1 infection.

Hepatotoxicity.

Revolade administration can cause hepatobiliary laboratory abnormalities, severe hepatotoxicity, and potentially fatal liver injury.

Clinical data.

In clinical studies of adult and paediatric patients (aged 1 to 17 years) with chronic ITP who received Revolade, increases in serum alanine aminotransferase (ALT), aspartate aminotransferase (AST) and indirect bilirubin were observed (see Section 4.8 Adverse Effects (Undesirable Effects)).
These findings were mostly mild (grade 1-2), reversible and not accompanied by clinically significant symptoms that would indicate impaired liver function. In two placebo controlled studies in adults with chronic ITP, adverse events of ALT increase were reported in 5.7% and 4.0% of eltrombopag and placebo treated patients respectively. In two placebo controlled studies in paediatric patients (aged 1 to 17 years) with chronic ITP, ALT ≥ 3 times the upper limit of normal (x ULN) was reported in 4.7% and 0% of the eltrombopag and placebo groups, respectively.
In two controlled clinical studies in thrombocytopenic patients with HCV, ALT or AST ≥ 3 x ULN were reported in 34% and 38% of the Revolade and placebo groups, respectively. Revolade administration in combination with peginterferon/ ribavirin therapy is associated with indirect hyperbilirubinaemia. Overall, total bilirubin ≥ 1.5 x ULN was reported in 76% and 50% of the Revolade and placebo groups, respectively.
In a single-arm open-label clinical study in definitive immunosuppressive therapy-naïve SAA patients who received Revolade concurrently with h-ATG and cyclosporin, ALT or AST > 3 x ULN with total bilirubin > 1.5 x ULN was reported in 43.5% (40/92) of patients. None of these elevations resulted in discontinuation.
In the single-arm phase II monotherapy study in patients with refractory SAA, concurrent ALT or AST > 3 x ULN with total (indirect) bilirubin > 1.5 x ULN were reported in 5% of patients. Total bilirubin > 1.5 x ULN occurred in 14% of patients.

Dosage adjustment.

In patients with ITP, HCV, and refractory SAA, serum ALT, AST and bilirubin should be monitored prior to initiation of Revolade, every 2 weeks during the dose adjustment phase and monthly following establishment of a stable dose. Eltrombopag inhibits UGT1A1 and OATP1B1, which may lead to indirect hyperbilirubinemia. If bilirubin is elevated, fractionation should be performed. Abnormal serum liver tests should be evaluated with repeat testing within 3 to 5 days. If the abnormalities are confirmed, serum liver tests should be monitored until the abnormalities resolve, stabilize, or return to baseline levels. Revolade should be discontinued if ALT levels increase to ≥ 3 x ULN in patients with normal liver function or ≥ 3 x baseline (or > 5 x ULN, whichever is the lower) in patients with elevations in transaminases before treatment and are:
progressive, or; persistent for ≥ 4 weeks, or; accompanied by increased direct bilirubin, or; accompanied by clinical symptoms of liver injury or evidence for hepatic decompensation.
In the first-line setting of severe aplastic anaemia, ALT, AST, and bilirubin should be measured prior to initiation of Revolade. During treatment, increases in ALT levels should be managed as recommended in Table 5.
Caution should be exercised when administering Revolade to patients with hepatic disease. In ITP and refractory SAA patients, a lower starting dose of Revolade should be used when administering to patients with hepatic impartment (see Section 4.2 Dose and Method of Administration).

Severe liver injury.

Isolated cases of severe liver injury were identified in clinical studies. The elevation of liver laboratory values improved or resolved following Revolade interruption or discontinuation. No cases of severe liver injury related to Revolade were identified in a clinical study in patients with definitive immunosuppressive therapy-naïve SAA or refractory SAA, however the number of exposed patients in these indications was limited. As the highest authorized dose is administered to patients in SAA indication (150 mg/day) and due to the nature of the reaction, drug induced liver injury might be expected in this patient’s population.
If the potential benefit for reinitiating Revolade treatment is considered to outweigh the risk for hepatotoxicity, then cautiously reintroduce Revolade and measure serum liver tests weekly during the dose adjusted phase. If liver test abnormalities persist, worsen or recur, then permanently discontinue Revolade.

Hepatic decompensation in patients with chronic HCV (concomitant use with interferons).

Chronic HCV patients with cirrhosis may be at risk for hepatic decompensation, some with fatal outcomes, when receiving Revolade and alpha interferon therapy. In two controlled clinical studies in thrombocytopenic patients with HCV, hepatic decompensation (ascites, hepatic encephalopathy, variceal haemorrhage, spontaneous bacterial peritonitis) occurred more frequently in the Revolade arm (13%) than in the placebo arm (7%). In patients with albumin levels ≤ 35 g/L or with a MELD score ≥ 10 at baseline, there was a threefold greater risk of hepatic decompensation and an increased risk of a fatal adverse event compared to those with less advanced liver disease. In addition, the benefits of treatment in terms of the proportion achieving SVR compared with placebo were modest in these patients (especially for those with baseline albumin ≤ 35 g/L) compared with the group overall. Revolade should only be administered to such patients after careful consideration of the expected benefits in comparison with the risks. Patients with these characteristics should be closely monitored for signs and symptoms of hepatic decompensation. The respective interferon product information for discontinuation criteria should be referred to. Revolade should be terminated if antiviral therapy is discontinued for hepatic decompensation.

Thrombotic/ thromboembolic complications.

Platelet counts above the normal range present a theoretical risk for thrombotic/ thromboembolic complications. In Revolade clinical studies in ITP thromboembolic events were observed at low and normal platelet counts.
Caution should be used when administering Revolade to patients with known risk factors for thromboembolism (e.g. advanced age, patients with prolonged periods of immobilisation, malignancies, contraceptives and hormone replacement therapy, surgery/ trauma, obesity, smoking, factor V Leiden, ATIII deficiency, and antiphospholipid syndrome). Platelet counts should be closely monitored and consideration given to reducing the dose or discontinuing Revolade treatment if the platelet count exceeds the target levels (see Section 4.2 Dose and Method of Administration).
In adult ITP studies, 21 thromboembolic/ thrombotic events (TEEs) were observed in 17 out of 446 patients (3.8%). The TEE events included: embolism including pulmonary embolism, deep vein thrombosis, transient ischaemic attack, myocardial infarction, ischaemic stroke, and suspected prolonged reversible ischemic neurologic deficiency. Patients who had a prior history of thrombosis and at least 2 additional proven risk factors for TEE were excluded from the pivotal studies and therefore the safety of the drug in such patients has not been established.
No cases of TEEs were identified in a clinical study in refractory SAA patients, however the number of exposed patients in this indication was limited. As the highest authorized dose is administered to patients in the SAA indication (150 mg/day) and due to the nature of the reaction, TEEs might be expected in this patient's population.
In two controlled studies in thrombocytopenic patients with HCV (n = 1439, safety population), 31 out of 955 patients (3%) treated with Revolade experienced a TEE and 5 out of 484 patients (1%) in the placebo group experienced TEEs. Portal vein thrombosis was the most common TEE in both treatment groups (1% in patients treated with Revolade versus < 1% for placebo). No specific temporal relationship between start of treatment and occurrence of TEE was observed. The majority of TEEs resolved and did not lead to the discontinuation of antiviral therapy.
In a controlled study in thrombocytopenic patients with chronic liver disease (n = 288, safety population) undergoing elective invasive procedures, the risk of portal vein thrombosis was increased in patients treated with 75 mg Revolade once daily for 14 days. Six of 143 (4%) adult patients with chronic liver disease receiving Revolade experienced TEEs (all of the portal venous system) and two out of 145 (1%) patients and one within the placebo group experienced TEEs (one in the portal venous system and one myocardial infarction). Five Revolade patients with a TEE experienced the event within 14 days of completing Revolade dosing and at a platelet count above 200 x 109/L.
Revolade is not indicated for the treatment of thrombocytopenia in patients with chronic liver disease undergoing invasive procedures.

QT/QTc prolongation.

A QTc study in healthy volunteers dosed 150 mg eltrombopag per day did not show a clinically significant effect on cardiac repolarisation. QTc interval prolongation has been reported in clinical studies of patients with ITP and thrombocytopenic patients with HCV. The clinical significance of these QTc prolongation events is unknown.

Loss of response to eltrombopag.

A loss of response or failure to maintain a platelet response with eltrombopag treatment within the recommended dosing range should prompt a search for causative factors, including an increased bone marrow reticulin.

Bleeding following discontinuation of Revolade.

Following discontinuation of Revolade in the ITP and HCV settings, platelet counts returned to baseline levels within 2 weeks in the majority of patients (see Section 5.1 Pharmacodynamic Properties, Clinical trials), which increases the bleeding risk and in some cases may lead to bleeding. Platelet counts must be monitored weekly for 4 weeks following discontinuation of Revolade.

Risk of bone marrow fibrosis.

Thrombopoietin receptor (TPO-R) agonists, including Revolade, may increase the risk for development or progression of reticulin fibres within the bone marrow. Analysis of the bone marrow biopsy data collected in the EXTEND (TRA105325) study (302 patients with chronic ITP who received eltrombopag treatment and were followed for up to 72 months or longer) did not suggest that Revolade is associated with clinically relevant increases in bone marrow reticulin or collagen fibres. Analysis of the bone marrow biopsy data collected from 159 patients in study TRA112940 (a longitudinal 2 year bone marrow study of eltrombopag in adults with chronic ITP) suggests that, for most chronic ITP patients, treatment with Revolade is not associated with clinically significant increases in bone marrow reticulin or collagen. Four patients in the TRA112940 study had bone marrow biopsies performed at > 14 days after the last dose of study medication to assess the reversibility in fibrosis after stopping Revolade. The bone marrow biopsies from half of them demonstrated a lower reticulin fibrosis grade when compared with prior biopsy results.
Prior to initiation of Revolade, examine the peripheral blood smear closely to establish a baseline level of cellular morphologic abnormalities. Following identification of a stable dose of Revolade, perform FBC with white blood cell count (WBC) differential monthly. If immature or dysplastic cells are observed, examine peripheral blood smears for new or worsening morphological abnormalities (e.g. teardrop and nucleated red blood cells, immature white blood cells) or cytopenia(s). If the patient develops new or worsening morphological abnormalities or cytopenia(s), discontinue treatment with Revolade and consider a bone marrow biopsy, including staining for fibrosis. Cytogenetic analysis of the bone marrow sample for clonal abnormality should also be considered.
Biennial bone marrow examinations are recommended while patients are receiving eltrombopag treatment until the clinical significance of such findings can be elucidated.
This risk has not been well characterised in children.

Cytogenetic abnormalities.

In study ELT112523, bone marrow aspirates were tested for cytogenetic abnormalities by the North American National Institute of Health (NIH). Consistent with the known occurrence of cytogenetic abnormalities in SAA, three out of forty-three patients had a cytogenetic abnormality present at baseline (7%).
At the primary response assessment, twelve to sixteen weeks after initiating Revolade treatment, eight patients (19%) had a new cytogenetic abnormality detected after treatment. Of these eight patients, five patients (all nonresponders) had cytogenetic abnormalities affecting the structure or number of chromosome 7. One patient subsequently developed fatal hypocellular MDS.

Malignancies and progression of malignancies.

There is a theoretical concern that TPO-R agonists may stimulate the progression of existing haematological malignancies such as MDS (see Section 5.3 Preclinical Safety Data, Carcinogenicity).
The effectiveness and safety of Revolade has not been established for the treatment of thrombocytopenia due to MDS. Revolade should not be used outside of clinical studies for the treatment of thrombocytopenia due to MDS.
There have been postmarketing cases describing appearance or progression of MDS in patients receiving Revolade. However, the information included in the postmarketing reports does not provide sufficient evidence to establish a causal relationship between treatment with Revolade and the appearance or worsening of MDS.

Cataracts.

Treatment related cataracts were detected in rodents; an effect that was both dose and time dependent. Cataract formation was observed after 6 weeks of treatment at systemic exposure ≥ 6 times and 3 times that anticipated in humans in ITP at 75 mg/day and HCV patients at 100 mg/day, respectively (based on plasma AUC). This effect was also evident during long-term (2 years) treatment at systemic exposure 2-5 times the anticipated clinical exposure, with the no effect dose level being similar to or below the anticipated clinical exposure level. Cataract formation progressed even after the cessation of treatment. Cataracts have not been observed in dogs after 52 weeks of dosing at 3 times the anticipated clinical exposure in ITP patients at 75 mg/day and equivalent to the human clinical exposure in HCV patients at 100 mg/day, based on plasma AUC.
In the 3 controlled ITP clinical studies, cataracts developed or worsened in 15 (7%) of patients who received 50 mg Revolade daily and 8 (7%) placebo group patients. Perform a baseline ocular examination prior to administration of Revolade and, during therapy with Revolade, regularly monitor patients for signs and symptoms of cataracts.
In controlled studies in thrombocytopenic patients with HCV receiving interferon based therapy (n = 1439), progression of pre-existing baseline cataract(s) or incident cataracts was reported in 8% of the Revolade group and 5% of the placebo group.
Routine monitoring of patients for cataracts is recommended.

Interference with serological testing.

Eltrombopag is highly coloured and so has the potential to interfere with some laboratory tests. Serum discoloration and interference with total bilirubin and creatinine testing have been reported in patients taking Revolade. If the laboratory results and clinical observations are inconsistent, evaluation of contemporaneous aminotransferase values may help in determining the validity of low total bilirubin levels in the presence of clinical jaundice and blood urea should be evaluated in the event of an unexpectedly high serum creatinine. Re-testing using another method may also help in determining the validity of the result.

Photosensitivity.

Eltrombopag is phototoxic and photoclastogenic in vitro. In vitro photoclastogenic effects were observed only at drug concentrations that were cytotoxic (≥ 15 microgram/mL) in the presence of high ultraviolet (UV) light exposures (700 mJ/cm2). There was no evidence of in vivo cutaneous phototoxicity in mice (10 times the human clinical exposure in ITP patients at 75 mg/day and 5 times the human clinical exposure in HCV patients at 100 mg/day based on AUC) or photo-ocular toxicity in mice or rats (up to 10 and 6 times the human clinical exposure in ITP patients at 75 mg/day and 5 and 3 times the human clinical exposure in HCV patients at 100 mg/day based on AUC). Furthermore, a clinical pharmacology study in 36 patients showed no evidence that photosensitivity was increased following administration of eltrombopag 75 mg once daily for six days. This was measured by delayed phototoxic index. Nevertheless, a potential risk of photoallergy cannot be ruled out since no specific preclinical study could be performed.

Mannitol.

Revolade powder for oral suspension contains mannitol. In clinical studies, paediatric patients aged 1-5 years experienced a higher frequency of diarrhoea than older children.

Use in hepatic impairment.

Revolade should not be used in patients with hepatic impairment (Child-Pugh score ≥ 5) unless the expected benefit outweighs the identified risk of portal venous thrombosis. When treatment is considered appropriate, caution should be exercised when administering Revolade to patients with hepatic impairment (see Section 4.2 Dose and Method of Administration; Section 4.8 Adverse Effects (Undesirable Effects)).

Use in renal impairment.

Patients with impaired renal function should use Revolade with caution and close monitoring, for example by testing serum creatinine and/or performing urine analysis (see Section 5.2 Pharmacokinetic Properties, Special patient populations).

Use in the elderly.

See Section 5.1 Pharmacodynamic Properties; Section 5.2 Pharmacokinetic Properties for information on elderly patients.

Paediatric use.

See Section 4.2 Dose and Method of Administration; Section 4.4 Special Warnings and Precautions for Use; Section 4.8 Adverse Effects (Undesirable Effects); Section 5.2 Pharmacokinetic Properties for information on paediatric patients.

Effects on laboratory tests.

See Section 4.2 Dose and Method of Administration; Section 4.4 Special Warnings and Precautions for Use for information on effects on laboratory tests.

4.5 Interactions with Other Medicines and Other Forms of Interactions

In vitro evaluation of drug interaction potential.

Based on a human study with radiolabelled eltrombopag, glucuronidation plays a minor role in the metabolism of eltrombopag. Human liver microsome studies identified UGT1A1 and UGT1A3 as the enzymes responsible for eltrombopag glucuronidation. In vitro studies demonstrate that eltrombopag is an inhibitor of UGT1A1, UGT1A3, UGT1A4, UGT1A6, UGT1A9, UGT2B7 and UGT2B15 (IC50 values 3-33 microM; 1.3-14.6 microgram/mL). Clinically significant drug interactions involving glucuronidation are not anticipated due to limited contribution of individual UGT enzymes in the glucuronidation of eltrombopag and potential comedications.
Based on a human study with radiolabelled eltrombopag, approximately 21% of an eltrombopag dose could undergo oxidative metabolism. Human liver microsome studies identified CYP1A2 and CYP2C8 as the enzymes responsible for eltrombopag oxidation. In vitro eltrombopag was an inhibitor of CYP2C8 and CYP2C9 (IC50 20-25 microM; 8.9-11 microgram/mL), but eltrombopag did not inhibit or induce the metabolism of the CYP2C9 probe substrate flurbiprofen in a clinical drug interaction study when eltrombopag was administered as 75 mg once daily for 7 days to 24 healthy adult patients. In the same study, eltrombopag also did not inhibit or induce the metabolism of probe substrates for CYP1A2 (caffeine), CYP2C19 (omeprazole) or CYP3A3 (midazolam). No clinically significant interactions are expected when eltrombopag and CYP450 substrates, inducers, or inhibitors are coadministered.
In vitro studies demonstrated that eltrombopag is not a substrate for the organic anion transporter polypeptide, OATP1B1, but is an inhibitor of this transporter with an IC50 value of 2.7 microM (1.2 microgram/mL). In vitro studies also demonstrated that eltrombopag is a breast cancer resistance protein (BCRP) substrate and inhibitor with an IC50 value of 2.7 microM (1.2 microgram/mL).

Effects of other drugs on Revolade and effects of Revolade on other drugs.

Rosuvastatin.

Administration of eltrombopag 75 mg once daily for 5 days with a single 10 mg dose of the OATP1B1 and BCRP substrate rosuvastatin to 39 healthy adult patients increased plasma rosuvastatin Cmax 103% (90% CI: 82%, 126%) and AUC0-∞ 55% (90% CI: 42%, 69%). When coadministered with eltrombopag, a reduced dose of rosuvastatin should be considered and careful monitoring should be undertaken. In clinical studies with eltrombopag, a dose reduction of rosuvastatin by 50% was recommended for coadministration of rosuvastatin and eltrombopag. Concomitant administration of eltrombopag and other OATP1B1 and BCRP substrates should be undertaken with caution.

Lopinavir/ ritonavir.

Coadministration of eltrombopag with lopinavir/ ritonavir (LPV/RTV) may cause a decrease in the concentration of eltrombopag. A study in 40 healthy volunteers, of which 23 (58%) were women and 30 (75%) were of White/ Caucasian/ European, 9 (23%) of African American/ African, and 1 (3%) of Central/ South Asian heritage, showed that the coadministration of a single dose of Revolade 100 mg with repeat dose LPV 400 mg/RTV 100 mg twice daily resulted in a reduction in eltrombopag plasma AUC(0-∞) by 17% (90% CI: 6.6%, 26.6%). Therefore, caution should be used when coadministration of eltrombopag with LPV/RTV takes place. Platelet count should be closely monitored at least weekly for 2 to 3 weeks in order to ensure appropriate medical management of the dose of eltrombopag when LPV/RTV therapy is initiated or discontinued.

Polyvalent cations (chelation).

Eltrombopag chelates with polyvalent cations such as aluminium, calcium, iron, magnesium, selenium and zinc. Administration of a single dose of eltrombopag 75 mg with a polyvalent cation containing antacid (1524 mg aluminium hydroxide and 1425 mg magnesium carbonate) decreased plasma eltrombopag AUC0-∞ by 70% (90% CI: 64%, 76%) and Cmax by 70% (90% CI: 62%, 76%). Revolade should be taken at least two hours before or four hours after any products such as antacids, dairy products and other products containing polyvalent cations to avoid significant reduction in eltrombopag absorption (see Section 4.2 Dose and Method of Administration).

Calcium interaction.

Administration of a single 50 mg dose of Revolade tablet with a standard high calorie, high fat breakfast that included dairy products, reduced plasma eltrombopag AUC0-∞ by 59% and Cmax by 65% (see Section 5.2 Pharmacokinetic Properties, Absorption; Section 4.2 Dose and Method of Administration).

Cyclosporin.

In vitro studies also demonstrated that eltrombopag is a breast cancer resistance protein (BCRP) substrate and inhibitor. A decrease in eltrombopag exposure was observed with coadministration of 200 mg and 600 mg cyclosporin (a BCRP inhibitor). Administration of a single dose of eltrombopag 50 mg with 200 mg cyclosporin (a BCRP inhibitor) decreased the Cmax and the AUC0-∞ of eltrombopag by 25% (90% CI: 15%, 35%) and 18% (90% CI: 8%, 28%), respectively. The coadministration of 600 mg cyclosporin decreased the Cmax and the AUC0-∞ of eltrombopag by 39% (90% CI: 30%, 47%) and 24% (90% CI: 14%, 32%), respectively. This decrease in exposure is not considered clinically meaningful. Eltrombopag dose adjustment is permitted during the course of the treatment based on the patient's platelet count (see Section 4.2 Dose and Method of Administration). Platelet count should be monitored at least weekly for 2 to 3 weeks when eltrombopag is coadministered with cyclosporin. Eltrombopag dose may need to be increased based on these platelet counts.

4.6 Fertility, Pregnancy and Lactation

Effects on fertility.

Eltrombopag did not affect female or male fertility in rats at doses 2-4 or 1-2 times the human clinical exposure (based on AUC) in ITP patients at 75 mg/day and in HCV patients at 100 mg/day, respectively. However, due to differences in TPO receptor specificity, data from nonclinical species do not fully model effects in humans.
(Category B3)
Eltrombopag was not teratogenic in rats or rabbits at doses up to 20 mg/kg/day and 150 mg/kg/day respectively. The doses resulted in exposures 2 and 0.5-fold the expected clinical AUC in ITP patients at 75 mg/day and subclinical exposures in HCV patients at 100 mg/day. At the maternally toxic dose of 60 mg/kg/day in rats, foetal weights were significantly reduced and there was an increase in foetal variation, cervical rib, when administered during the period of organogenesis. Eltrombopag treatment during early embryogenesis was associated with an increase in pre- and post-implantation loss (or embryonic death). Due to the fact that eltrombopag is not pharmacologically active in rats or rabbits, the potential teratogenicity of eltrombopag may not have been fully revealed in the studies with these animal species.
There are no adequate and well controlled studies of Revolade in pregnant woman. The effect of Revolade on human pregnancy is unknown. Revolade should not be used during pregnancy unless the expected benefit clearly outweighs the potential risk to the foetus.
It is not known whether Revolade is excreted in human milk. Eltrombopag was detected in the pups of lactating rats 10 days postpartum suggesting the potential for transfer during lactation. Revolade is not recommended for nursing mothers unless the expected benefit justifies the potential risk to the infant.

4.8 Adverse Effects (Undesirable Effects)

Summary of the safety profile.

Chronic ITP studies in adult and paediatric patients.

Adults.

The safety and efficacy of Revolade was assessed in adult patients using pooled, double blind, placebo controlled studies (TRA102537 RAISE and TRA100773A and B), and TRA113765 in which 403 patients were exposed to Revolade and 179 to placebo, in addition to data from completed open label studies TRA108057, TRA105325 (EXTEND), and TRA112940. Patients received study medication for up to 8 years (in EXTEND). Adverse drug reactions for the adult ITP study population are shown in Table 8.

Paediatrics.

The safety and efficacy of Revolade in paediatric patients (aged 1 to 17 years) with previously treated chronic ITP have been demonstrated in two studies. PETIT 2 (TRA115450) was a two-part, double blind and open label, randomised, placebo controlled study. Patients were randomised 2:1 and received Revolade (n = 63) or placebo (n = 29) for up to 13 weeks in the randomised period of the study. PETIT 1 (TRA108062) was a three-part, staggered cohort, open label and double blind, randomised, placebo controlled study. Patients were randomised 2:1 and received Revolade (n = 44) or placebo (n = 21), for up to 7 weeks.
Additional adverse drug reactions occurring in the paediatric adult ITP study population are shown in Table 9.

Thrombocytopenia in patients with HCV infection.

The safety of Revolade was assessed in adult patients, in two controlled studies, including data from patients who initially received Revolade in the pre-antiviral treatment phase and were later randomized to the placebo arm. ENABLE 1 (TPL103922, n = 716) and ENABLE 2 (TPL108390, n = 805) were randomized, double blind, placebo controlled, multicentre studies to assess the efficacy and safety of Revolade in thrombocytopenic subjects with HCV infection who were otherwise eligible to initiate antiviral therapy. In the HCV studies, the safety population consisted of all randomized subjects who received double blind study drug during part 2 of ENABLE 1 (Revolade treatment n = 449, placebo n = 232) and ENABLE 2 (Revolade treatment n = 506, placebo n = 252). Subjects are analysed according to the treatment received (total safety double blind population, Revolade n = 955 and placebo n = 484). The adverse reactions identified in the HCV study populations are presented in Table 10.

Definitive immunosuppressive therapy-naïve severe aplastic anaemia.

The safety of Revolade administered in combination with horse antithymocyte globulin (h-ATG) and cyclosporin to patients with severe aplastic anaemia who had not received prior definitive immunosuppressive therapy (i.e. ATG therapy, alemtuzumab, or high dose cyclophosphamide) was evaluated in a single-arm, sequential cohort study (see Section 5.1 Pharmacodynamic Properties, Clinical trials). A total of 154 patients were enrolled and 153 were dosed in this study, of which 92 patients were enrolled to the cohort where Revolade, h-ATG, and cyclosporin were initiated concurrently at the recommended dose and schedule (the trial's Cohort 3 regimen): Revolade up to 150 mg once daily on Day 1 to Month 6 (D1-M6) in combination with h-ATG on Days 1 to 4 and cyclosporin for 6 months, followed by low dose of cyclosporin (maintenance dose) for an additional 18 months for patients who achieved a hematologic response at 6 months. The median duration of exposure to Revolade in this cohort was 183 days with 83.7% of patients exposed for > 12 weeks. A summary of the safety profile is provided below (see section Definitive immunosuppressive therapy-naïve SAA population).

Refractory severe aplastic anaemia.

The safety of Revolade in refractory severe aplastic anaemia was assessed in a single-arm, open-label study (n = 43) in which 12 patients (28%) were treated for > 6 months and 9 patients (21%) were treated for > 1 year. The adverse reactions identified in the SAA study population are presented in Table 11 and Table 12.
The most undesirable reactions associated with Revolade were mild to moderate in severity, early in onset and rarely treatment limiting.

Tabulated summary of reactions from clinical studies.

Adverse reactions from clinical studies are listed below by MedDRA body system organ class and by frequency. Within each system organ class, the adverse drug reactions are ranked by frequency, with the most frequent reactions first. The corresponding frequency category for each adverse drug reaction is based on the following convention (CIOMS III):
very common (≥ 1 in 10); common (≥ 1 in 100 and < 1 in 10); uncommon (≥ 1 in 1,000 and < 1 in 100); rare (≥ 1 in 10,000 and < 1 in 1,000).

TRA102537 (RAISE).

In the RAISE study, 197 patients were randomised 2:1, Revolade (n=135) to placebo (n=62). Patients received study medication for up to 6 months. See Table 7.

TRA100773B.

In this study, 114 patients were randomised and treated for up to 42 days with either placebo (n = 38) or Revolade (n = 76).
In 3 controlled and 2 uncontrolled clinical studies, among adult chronic ITP patients receiving Revolade (n = 446), 17 subjects experienced a total of 19 TEEs, which included (in descending order of occurrence) deep vein thrombosis (n = 6), pulmonary embolism (n = 6), acute myocardial infarction (n = 2), cerebral infarction (n = 2), embolism (n = 1) (see Section 4.4 Special Warnings and Precautions for Use).
In the single arm, open label study in SAA, patients had bone marrow aspirates evaluated for cytogenetic abnormalities. Eight patients had a new cytogenetic abnormality reported, including 5 patients who had changes in chromosome 7 (see Section 4.4 Special Warnings and Precautions for Use).

Definitive immunosuppressive therapy-naïve SAA population.

The adverse drug reaction associated with Revolade reported in the definitive immunosuppressive therapy-naïve SAA patients are summarised in Table 12. In definitive immunosuppressive therapy-naïve SAA patients, blood bilirubin increase (very common) was reported more frequently than in the refractory SAA study population (common, see Table 11).
New or worsening liver function laboratory abnormalities (CTCAE Grade 3 and Grade 4) in the Revolade D1-M6 cohort were 15.2% and 2.2% for AST, 26.4% and 4.3% for ALT, and 12.1% and 1.1% for bilirubin, respectively.

Paediatric patients.

The safety assessment of Revolade in the definitive immunosuppressive therapy-naïve paediatric SAA patients 2 to 17 years old is based on 37 patients enrolled in the single-arm, sequential cohort study: 2 patients aged 2 to 5 years, 12 patients aged 6 to 11 years, and 23 patients aged 12 to 17 years. The safety profile in paediatric patients was consistent with the safety profile observed in the overall population.

Cytogenetic abnormalities.

In the single-arm study in patients with definitive immunosuppressive therapy-naïve SAA, patients had bone marrow aspirates evaluated for cytogenetic abnormalities. In the entire study across all cohorts, clonal cytogenetic evolution occurred in 15 out of 153 (10%) patients. Of the 15 patients who experienced a cytogenetic abnormality: 7 patients had the loss of chromosome 7, 6 of which occurred within 6.1 months, 4 patients had chromosomal aberrations which were of unclear significance, 3 patients had a deletion of chromosome 13, which is considered a good prognostic factor in aplastic anaemia; and 1 patient had a follow-up bone marrow assessment at 5 years with features of dysplasia with hypercellularity concerning for potential development of MDS. In the Revolade D1-M6 cohort, 7 out of 92 (7.6%) patients had a new cytogenetic abnormality reported of which 4 had the loss of chromosome 7, occurring within 6.1 months. It is unclear whether these findings occurred due to the underlying disease, the immunosuppressive therapy, and/or treatment with Revolade.

Adverse drug reactions from spontaneous reports and literature cases (frequency not known).

The following adverse drug reactions have been reported during post-approval use of Revolade (see Table 13). These include spontaneous case reports as well as serious adverse events from registries, investigator sponsored studies, clinical pharmacology studies and exploratory studies in unapproved indications. Because they are reported voluntarily from a population of uncertain size, it is not possible to reliably estimate their frequency, which is therefore categorized as not known. Adverse drug reactions are listed according to system organ classes in MedDRA.

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.

4.2 Dose and Method of Administration

Dosage.

Revolade dosing regimens must be individualised based on the patient's platelet counts. In most patients, measurable elevations in platelet counts take 1-2 weeks (see Section 5.1 Pharmacodynamic Properties, Clinical trials).
Switching is not recommended between the powder for oral suspension and the film coated tablet formulations. Whenever switching between these two formulations cannot be avoided, platelet count should be closely monitored during the 2 weeks following the switch, and the dose of eltrombopag adjusted accordingly.

Chronic ITP.

Use the lowest dose of Revolade to achieve and maintain a platelet count ≥ 50 x 109/L as necessary to reduce the risk for bleeding. Dose adjustments are based upon the platelet count response. Do not use Revolade in an attempt to normalise platelet counts. In clinical studies, platelet counts generally increased within 1 to 2 weeks after starting Revolade and decreased within 1 to 2 weeks after discontinuation.

Initial dose regimen.

Adults and paediatric patients aged 6 to 17 years.

The recommended starting dose of Revolade is 50 mg once daily.
For adult and paediatric patients aged 6-17 years of Asian ancestry (e.g. Chinese, Japanese, Taiwanese, Korean or Thai), Revolade should be initiated at a reduced dose of 25 mg once daily (see Section 5.2 Pharmacokinetic Properties, Special patient populations).

Paediatric patients aged 1 to 5 years.

The recommended starting dose of Revolade is 25 mg once daily. A lower starting dose (12.5 mg) followed by uptitration can be administered on a case per case basis after assessing the risk/ benefit.

Monitoring and dose adjustment.

Adults and paediatric patients aged 1 to 17 years.

After initiating Revolade, adjust the dose to achieve and maintain a platelet count ≥ 50 x 109/L as necessary to reduce the risk for bleeding (see Table 1). Do not exceed a dose of 75 mg daily. Monitor clinical haematology and liver function tests regularly throughout therapy with Revolade and the dose of Revolade modified based on platelet counts as outlined in Table 1. During therapy with Revolade, full blood counts (FBCs), including platelet count and peripheral blood smears, should be assessed weekly until a stable platelet count (≥ 50 x 109/L for at least 4 weeks) has been achieved. FBCs including platelet count and peripheral blood smears should be obtained monthly thereafter.
The lowest effective dosing regimen to maintain platelet counts should be used as clinically indicated.
The standard dose adjustment, either decrease or increase, would be 25 mg once daily. However, in a few patients a combination of different tablet strengths on different days or less frequent dosing may be required.
After any Revolade dose adjustment, platelet counts should be monitored at least weekly for 2 to 3 weeks. Wait for at least 2 weeks to see the effect of any dose adjustment on the patient's platelet response prior to considering another dose adjustment. In patients with any liver cirrhosis (i.e. hepatic impairment), wait 3 weeks before increasing the dose (see Section 4.2 Dose and Method of Administration, Special populations; Section 4.4 Special Warnings and Precautions for Use).
When switching between the tablet and powder for oral suspension formulations, platelet counts should be monitored weekly for 2 weeks.

Discontinuation.

Adults and paediatric patients aged 1 to 17 years.

Treatment with Revolade should be discontinued if the platelet count does not increase to a level sufficient to avoid clinically important bleeding after four weeks of Revolade therapy at 75 mg once daily.

Chronic hepatitis C associated thrombocytopenia.

When Revolade is given in combination with antiviral therapies reference should be made to the full product information of the respective coadministered medicinal products for comprehensive details of administration.
Use the lowest dose of Revolade to achieve and maintain a platelet count necessary to initiate and optimise antiviral therapy. Dose adjustments are based upon the platelet count response. Do not use Revolade in an attempt to normalize platelet counts. In clinical studies, platelet counts generally increased within 1 week of starting Revolade.

Initial dose regimen.

Adults.

Initiate Revolade at a dose of 25 mg once daily. No dose adjustment is required in chronic HCV patients of Asian ancestry (such as Chinese, Japanese, Taiwanese, Korean or Thai).

Monitoring and dose adjustment.

Adults.

Adjust the dose of Revolade in 25 mg increments every 2 weeks as necessary to achieve the target platelet count required to initiate antiviral therapy (see Table 2). Monitor platelet counts every week prior to starting antiviral therapy.
During antiviral therapy adjust the dose of Revolade as necessary to avoid dose reduction of peginterferon. Monitor platelet counts weekly during antiviral therapy until a stable platelet count is achieved. FBCs, including platelet counts and peripheral blood smears, should be obtained monthly thereafter.
Do not exceed a dose of 100 mg Revolade once daily.
For specific dosage instructions for peginterferon alfa or ribavirin, refer to their respective product information.

Discontinuation.

Adults.

In patients with HCV genotype 1/4/6, independent of the decision to continue interferon therapy, discontinuation of Revolade therapy should be considered in patients who do not achieve virological response at week 12. If HCV-RNA remains detectable after 24 weeks of therapy, Revolade therapy should be discontinued.
Revolade treatment should be terminated when antiviral therapy is discontinued. Excessive platelet count responses, as outlined in Table 2 or important liver test abnormalities may also necessitate discontinuation of Revolade (see Section 4.4 Special Warnings and Precautions for Use).

Children.

The safety and efficacy of Revolade in children with chronic HCV have not been established.

First-line severe aplastic anaemia.

Revolade should be initiated concurrently with standard immunosuppressive therapy (see Table 3). The initial dose of Revolade should not be exceeded.

Initial dose regimen.

Adult and adolescent patients aged 12 to 17 years.

The recommended initial dose of Revolade is 150 mg once daily for 6 months.
For adult and adolescent SAA patients of Asian ancestry (such as Chinese, Japanese, Taiwanese, Korean, or Thai), Revolade should be initiated at a dose of 75 mg once daily for 6 months.

Paediatric patients aged 6 to 11 years.

The recommended initial dose of Revolade is 75 mg once daily for 6 months.
For paediatric SAA patients of Asian ancestry (such as Chinese, Japanese, Taiwanese, Korean, or Thai) aged 6 to 11 years, Revolade should be initiated at a dose of 37.5 mg once daily for 6 months.

Paediatric patients aged 2 to 5 years.

The recommended initial dose of Revolade is 2.5 mg/kg once daily for 6 months.
For paediatric SAA patients of Asian ancestry (such as Chinese, Japanese, Taiwanese, Korean, or Thai) aged 2 to 5 years, Revolade should be initiated at a dose of 1.25 mg/kg once daily for 6 months.

Monitoring and dose adjustment for eltrombopag.

Clinical haematology and liver tests should be performed regularly throughout therapy with Revolade.
The dosage regimen of Revolade should be modified based on platelet counts as outlined in Table 4.
Table 5 summarizes the recommendations for dose interruption, reduction, or discontinuation of Revolade in the management of liver function abnormalities and thrombosis/embolism events.

Discontinuation.

The total duration of Revolade treatment is 6 months.
Excessive platelet count responses (as outlined in Table 4) or certain adverse events (as outlined in Table 5) also necessitate discontinuation of Revolade.

Refractory severe aplastic anaemia.

Initial dose regimen.

Adults.

Initiate Revolade at a dose of 50 mg once daily. For patients of East Asian ancestry (e.g. Chinese Japanese, Taiwanese, Korean or Thai), Revolade should be initiated at a dose of 25 mg once daily (see Section 5.2 Pharmacokinetic Properties; Section 4.2 Dose and Method of Administration, Special populations (all indications)).

Monitoring and dose adjustment.

Adults.

Haematological response requires dose titration, generally up to 150 mg, and may take up to 16 weeks after starting Revolade (see Section 5.1 Pharmacodynamic Properties, Clinical trials). Adjust the dose of Revolade in 50 mg increments every 2 weeks as necessary to achieve the target platelet count ≥ 50 x 109/L. Do not exceed a dose of 150 mg daily. Monitor clinical haematology and liver tests regularly throughout therapy with Revolade and modify the dosage regimen of Revolade based on platelet counts as outlined in Table 6.

Tapering for tri-lineage (white blood cells, red blood cells, and platelets) responders.

Once platelet count > 50 x 109/L, haemoglobin > 100 g/L in the absence of red blood cell (RBC) transfusion, and absolute neutrophil (ANC) > 1 x 109/L for more than 8 weeks, the dose of Revolade should be reduced by up to 50%. If counts stay stable after 8 weeks at the reduced dose, then discontinue Revolade and monitor blood counts. If platelet counts drop to < 30 x 109/L, haemoglobin to < 90 g/L or ANC < 0.5 x 109/L, Revolade may be reinitiated at the previous dose.

Discontinuation.

Adults.

If no haematological response has occurred after 16 weeks of therapy with Revolade, discontinue therapy. Consider Revolade discontinuation if new cytogenetic abnormalities are observed (see Section 4.8 Adverse Effects (Undesirable Effects)). Excessive platelet count responses (as outlined in Table 10) or important liver test abnormalities also necessitate discontinuation of Revolade (see Section 4.4 Special Warnings and Precautions for Use).

Children.

The safety and efficacy of Revolade in children with SAA have not been established.

Special populations (all indications).

Elderly.

There are limited data on the use of Revolade in patients aged 65 years and older. In the clinical studies of Revolade, overall no clinically significant differences in efficacy and safety of Revolade were observed between patients aged 65 years and older compared to younger patients. Other reported clinical experience has not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out (see Section 5.2 Pharmacokinetic Properties, Special patient populations).

Paediatric patients.

The safety and efficacy of Revolade have not been established in paediatric patients with ITP younger than 1 year of age, chronic HCV, refractory SAA, and definitive immunosuppressive therapy-naïve SAA younger than 2 years of age (see Section 4.8 Adverse Effects (Undesirable Effects); Section 5.1 Pharmacodynamic Properties, Clinical trials).

Hepatic impairment.

ITP patients with liver cirrhosis (hepatic impairment, Child-Pugh score ≥ 5) should use Revolade with caution and close monitoring (see Section 4.4 Special Warnings and Precautions for Use; Section 5.2 Pharmacokinetic Properties, Special patient populations). If the use of Revolade is deemed necessary for ITP patients with hepatic impairment the starting dose must be 25 mg once daily. After initiating the dose of Revolade in patients with hepatic impairment wait 3 weeks before increasing the dose.
Chronic HCV patients with hepatic impairment and severe aplastic anaemia patients with hepatic impairment should initiate Revolade at a dose of 25 mg once daily (see Section 5.2 Pharmacokinetic Properties, Special patient populations).
Revolade should not be used in patients with hepatic impairment (Child-Pugh score ≥ 5) unless the expected benefit outweighs the identified risk of portal venous thrombosis (see Section 4.4 Special Warnings and Precautions for Use).
The risk of thromboembolic events (TEEs) has been found to be increased in patients with chronic liver disease treated with 75 mg Revolade once daily for two weeks in preparation for invasive procedures (see Section 4.4 Special Warnings and Precautions for Use).
In a clinical study in definitive immunosuppressive therapy-naïve severe aplastic anaemia, patients with baseline AST/ALT > 5 x ULN were ineligible to participate. The initial dose of Revolade in patients with hepatic impairment in the first-line setting should be determined as necessary based on clinical judgement, tolerability, and close monitoring of liver function.

Renal impairment.

No dose adjustment is necessary in patients with renal impairment. Patients with impaired renal function should use Revolade with caution and close monitoring; for example, by testing serum creatinine and/or performing urine analysis (see Section 5.2 Pharmacokinetic Properties, Special patient populations).

Administration.

Swallow Revolade with a glass of water, at least two hours before or four hours after any products such as antacids, dairy products, or mineral supplements containing polyvalent cations (e.g. aluminium, calcium (see below paragraph), iron, magnesium, selenium, and/or zinc) (see Section 5.2 Pharmacokinetic Properties, Absorption; Section 4.5 Interactions with Other Medicines and Other Forms of Interactions).
Revolade may be taken with food containing little (< 50 mg) or preferably no calcium (see Section 4.5 Interactions with Other Medicines and Other Forms of Interactions; Section 5.2 Pharmacokinetic Properties).

Preparation of the powder for oral suspension.

Refer to the pack leaflet. Follow the handling procedures carefully. Avoid direct contact with the medicine. Wash any exposed area immediately with soap and water.
The contents of the prescribed number of sachets (depending on the recommended dose) should be added to the provided mixing bottle containing 20 mL of water.
Prepare the suspension with water at room temperature only. Do not use hot water to prepare the suspension.
The mixing bottle should be capped with threaded closure with syringe-port capability and gently shaken for 20 seconds. To prevent foaming, the bottle should not be shaken vigorously.
The entire contents of the bottle should be given to the patient using the accompanying oral syringe.
Some medication will remain in the mixing bottle so the bottle should be rinsed as follows to ensure the patient receives their full prescribed dose. An additional 10 mL of water should be added to the mixing bottle. After gently mixing, the entire contents of the bottle should be given to the patient using the accompanying oral syringe.
The oral suspension is intended for immediate use once reconstituted with water, but may be stored for a maximum period of 30 minutes.

4.7 Effects on Ability to Drive and Use Machines

There have been no studies to investigate the effect of Revolade on driving performance or the ability to operate machinery. A detrimental effect on such activities would not be anticipated from the pharmacology of Revolade. The clinical status of the patient and the adverse event profile of Revolade should be borne in mind when considering the patient's ability to perform tasks that require judgement, motor and cognitive skills. The effects of this medicine on a person's ability to drive and use machines were not assessed as part of its registration.

4.9 Overdose

Symptoms and signs.

In the clinical studies, there was one report of overdose where the patient ingested 5000 mg of Revolade. Reported adverse events included mild rash, transient bradycardia, fatigue and elevated transaminases. Liver enzymes measured between days 2 and 18 after ingestion peaked at 1.6 x ULN in AST, 3.9 x ULN in ALT, and 2.4 x ULN in total bilirubin. The platelet counts were 672 x 109/L on day 18 after ingestion and the maximum platelet count was 929 x 109/L. All events resolved without sequelae following treatment.

Treatment.

In the event of overdose, platelet counts may increase excessively and result in thrombotic/ thromboembolic complications. In case of an overdose, consider oral administration of a metal cation containing preparation, such as calcium, aluminium, or magnesium preparations to chelate eltrombopag and thus limit absorption. Closely monitor platelet counts. Reinitiate treatment with Revolade in accordance with dosing and administration recommendations (see Section 4.2 Dose and Method of Administration).
Because Revolade is not significantly renally excreted and is highly bound to plasma proteins, haemodialysis would not be expected to be an effective method to enhance the elimination of eltrombopag.
For information on the management of overdose, contact the Poisons Information Centre on 13 11 26 (Australia).

7 Medicine Schedule (Poisons Standard)

S4.

6 Pharmaceutical Particulars

6.1 List of Excipients

Each film-coated tablet also contains magnesium stearate, mannitol, microcrystalline cellulose, povidone, sodium starch glycollate, hypromellose, macrogol 400, titanium dioxide, polysorbate 80 (12.5 mg tablet and 25 mg tablet only), iron oxide red CI77491 (50 mg tablet and 75 mg tablets only), iron oxide yellow CI77492 (50 mg tablet only) and iron oxide black CI77499 (75 mg tablet only).
The powder for oral suspension also contains mannitol (see Section 4.4 Special Warnings and Precautions for Use), sucralose and xanthan gum. It contains no sugar.

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

Film-coated tablets.

Store below 30°C.

Powder for oral suspension.

Store below 30°C.
Following reconstitution, the suspension should be orally administered immediately but may be stored for a maximum period of 30 minutes when stored below 30°C.

6.5 Nature and Contents of Container

Revolade 25 mg and 50 mg film coated tablets are supplied in blister packs containing 28 tablets. Other packs sizes and tablet strengths are not supplied in Australia. Revolade 25 mg powder for oral suspension sachets are not supplied in Australia.

6.6 Special Precautions for Disposal

In Australia, any unused medicine or waste material should be disposed of in accordance with local requirements.

Summary Table of Changes