Active ingredients: Eltrombopag
Revolade 12.5 mg film-coated tablets
Revolade 25 mg film-coated tablets
Revolade 50 mg film-coated tablets
Revolade 75 mg film-coated tablets
Why is Revolade used? What is it for?
Revolade contains eltrombopag, which belongs to a group of medicines called thrombopoietin receptor agonists. It is used to help increase the number of platelets in the blood. Platelets are blood cells that serve to reduce or prevent bleeding.
- Revolade is used to treat a 'blood clotting disorder called autoimmune (idiopathic) thrombocytopenic purpura (ITP) in patients (over 1 year of age) who have already taken other medicines (corticosteroids or immunoglobulins) that have not been effective.
ITP is caused by a low number of platelets in the blood (thrombocytopenia). People with ITP have a higher risk of bleeding. Symptoms in patients with ITP can include petechiae (small flat red round spots on the skin), bruising, epistaxis (nosebleeds), bleeding gums, and not being able to control bleeding in case of cuts or wounds.
- Revolade can also be used to treat low platelet counts (thrombocytopenia) in hepatitis C virus (HCV) patients, if they have had problems with adverse reactions while using interferon. Many people with hepatitis C have low platelet counts. of platelets not only as a result of the disease itself but also due to some antiviral medicines that are used to treat it.
- Revolade can also be used to treat adult patients with low blood counts caused by severe aplastic anemia (SAA).
Contraindications When Revolade should not be used
Do not take Revolade
- if you are allergic to eltrombopag or any of the other ingredients of this medicine (What Revolade contains).
- Check with your doctor if you think this applies to you.
Precautions for use What you need to know before taking Revolade
Talk to your doctor before taking Revolade:
- if you have liver problems. People who have low platelet counts as well as chronic (long-lasting) advanced liver disease are more at risk of experiencing side effects, including liver damage and life-threatening blood clots. If your doctor believes that the benefits of taking Revolade outweigh the risks, you will be closely monitored during treatment.
- if you are at risk of forming blood clots in your veins or arteries, or if you are aware that blood clots are common in your family.
- You may be at increased risk of blood clot formation:
- if you are of advanced age
- if you have had to stay in bed for a long time
- if you have a tumor
- if you are taking the birth control pill or hormone replacement therapy
- if you have recently had surgery or have suffered physical trauma - if you are very overweight (obese)
- if you are a smoker
- if you have advanced chronic liver disease
- If any of these apply to you, please inform your doctor before starting treatment. You should not take Revolade unless your doctor considers that the expected benefits outweigh the risks of clot formation.
- if you suffer from cataracts (clouding of the lens of the eye)
- if you have another blood disorder such as myelodysplastic syndrome (MDS). Your doctor will carry out tests to check that you do not have this blood disorder before you start taking Revolade. If you have MDS and take Revolade, your MDS may get worse.
- Tell your doctor if any of these apply to you.
Eye examination
Your doctor will recommend that you check for cataracts. If you don't have routine eye exams, your doctor will schedule a regular exam. It may also be checked for any bleeding in or around the retina (the layer of light-sensitive cells at the back of the eye).
He will need regular exams
Before you start taking Revolade, your doctor will do blood tests to check your blood cells, including platelets. These tests will be repeated at intervals while you are taking the medicine.
Blood tests for liver function
Revolade can alter the results of blood tests which may indicate liver damage - an increase in some liver enzymes, especially bilirubin and alanine / aspartate transaminases. If you are being treated with interferon combined with Revolade to treat low platelet counts due to hepatitis C, some liver problems may get worse.
You will need to have blood tests to check your liver function before you start taking Revolade and during treatment. You may need to stop taking Revolade if the amount of these enzymes increases too much, or if physical signs of liver damage appear.
- Read the information "Liver problems" in section 4 of this leaflet
Blood tests for platelet counts
If you stop taking Revolade your platelet count will likely drop again within a few days. Your platelet count will be monitored and your doctor will tell you about appropriate precautions.
A very high platelet count can increase the risk of blood clots, however blood clots can also form with normal or even low platelet counts. Your doctor will adjust the dose of Revolade to ensure that the number of platelets does not increase too much.
Seek medical help right away if you have any of these signs of a blood clot:
- swelling, pain or tenderness in one leg
- sudden onset of shortness of breath especially together with sharp chest pain or rapid breathing
- abdominal (stomach) pain, swelling of the abdomen, blood in the stool.
Tests to check the bone marrow
In people who may have bone marrow problems, medicines like Revolade could make the problems worse. Signs of bone marrow changes may show up as abnormalities in blood test results. Your doctor may perform tests to check your bone marrow directly during treatment with Revolade.
Tests for digestive bleeding
If you are treated with interferon medicines combined with Revolade you will be checked for any signs of bleeding in your stomach or intestines after you stop taking Revolade.
Heart check
Your doctor may need to check your heart during Revolade treatment and have an electrocardiogram (ECG) done.
Children and adolescents
Revolade is not recommended for children younger than 1 year with ITP. It is also not recommended in people under the age of 18 with low platelet counts due to hepatitis C or severe aplastic anemia.
Interactions Which drugs or foods may change the effect of Revolade
Tell your doctor or pharmacist if you are taking, have recently taken or would take any other medicines.
Some of the common medicines interact with Revolade - including prescription and non-prescription medicines and minerals. These include:? antacid medicines to treat indigestion, heartburn or stomach ulcers When to take it)
- medicines called statins, to lower cholesterol
- some medicines to treat HIV infection, such as lopinavir and / or ritonavir
- cyclosporine used in transplants and immune diseases
- minerals such as iron, calcium, magnesium, aluminum, selenium and zinc which can be found in vitamin and mineral supplements (When to take it)
- medicines such as methotrexate and topotecan, to treat cancer
- Tell your doctor if you are taking any of these medicines. Some of them cannot be taken with Revolade, or the dose you take may need to be adjusted or the time you take it may need to be changed. Your doctor will review all medicines you are taking and if necessary suggest that you replace them as appropriate.
There is a higher risk of bleeding if you are also taking medicines to prevent blood clots. Your doctor will discuss this with you.
If you are taking corticosteroids, danazol and / or azathioprine, you may need to take a lower dose or stop taking them while you are taking Revolade.
Revolade with food and drink
Do not take Revolade with drinks or milk products and cheese, as the calcium in milk products affects the absorption of the medicine.
Warnings It is important to know that:
Pregnancy and breastfeeding
Do not use Revolade if you are pregnant unless your doctor specifically recommends it. The effect of Revolade during pregnancy is not known.
- Tell your doctor if you are pregnant, if you think you may be, or if you are planning to become pregnant.
- Use a reliable method of contraception while you are taking Revolade to prevent pregnancy
- If you become pregnant while taking Revolade, please tell your doctor.
Do not breastfeed while you are taking Revolade. It is not known if Revolade passes into breast milk.
- If you are breastfeeding or planning to breastfeed, please tell your doctor.
Driving and using machines
- Revolade can make you dizzy and have other side effects that lead to less attention.
- Do not drive vehicles or use machines unless you are sure you are not affected.
Dose, Method and Time of Administration How to use Revolade: Posology
Always take this medicine exactly as your doctor has told you. If in doubt, consult your doctor or pharmacist. Do not change your dose or your schedule of Revolade unless your doctor or pharmacist advises you to do so. While you are taking Revolade, you will be treated by a doctor with specialist experience in treating your condition.
How much to take
For ITP
Adults and children (6 to 17 years) - the recommended starting dose for ITP is one Revolade 50 mg tablet per day. If you are of East Asian origin (Chinese, Japanese, Taiwanese, Thai or Korean) you may need to start with a lower dose of 25 mg.
Children (1 to 5 years) - the recommended starting dose for ITP is one 25 mg tablet of Revolade per day.
For Hepatitis C
Adults - The recommended starting dose for hepatitis C is one 25 mg tablet of Revolade per day. If you are of East Asian origin (Chinese, Japanese, Taiwanese, Thai or Korean) you will start with the same 25 mg dose.
For SAA
Adults - the recommended starting dose for AAS is one Revolade 50 mg tablet per day. If you are of East Asian origin (Chinese, Japanese, Taiwanese, Thai or Korean) you may need to start with a lower dose of 25 mg.
Revolade can take 1 to 2 weeks to work. Based on your response to Revolade your doctor may recommend a daily dose modification.
How to take the tablets
Swallow the tablet whole with some water.
When to take it
Make sure that-
- in the 4 hours before taking Revolade
- and in the 2 hours after taking Revolade
You do not consume any of the following:
- foods such as cheese, butter, yogurt or ice cream
- milk or milk-based smoothies, drinks containing milk, yogurt or cream
- antacids, a type of medicine for indigestion and heartburn
- some vitamin and mineral supplements including iron, calcium, magnesium, aluminum, selenium and zinc.
If it does, the medicine will not be absorbed properly into the body.
For more advice on suitable food and drink, ask your doctor.
If you forget to take Revolade
Take the next dose at the usual time. Do not take more than one dose of Revolade in a day.
If you stop using Revolade
Do not stop taking Revolade without talking to your doctor. If your doctor advises you to stop treatment, your platelet count will be checked every week for four weeks.
If you have any further questions on the use of this medicine, ask your doctor or pharmacist.
Overdose What to do if you have taken too much Revolade
Contact your doctor or pharmacist immediately.If possible show them the box, or this leaflet. Any signs or symptoms of side effects will be checked for and will be treated appropriately immediately.
Side Effects What are the side effects of Revolade
Like all medicines, this medicine can cause side effects, although not everybody gets them.
Symptoms that need attention: See a doctor
People taking Revolade for ITP or low blood platelet counts due to hepatitis C could develop signs of potentially serious side effects. It is important to tell your doctor if you develop these symptoms.
Higher risk of blood clots
Some people may have a higher risk of blood clots, and medicines like Revolade could make this problem worse. Sudden blocking of a blood vessel by a blood clot is an uncommon side effect and may affect up to 1 in 100 people.
Get medical attention right away if you experience signs and symptoms of a blood clot, such as:
- swelling, pain, warmth, redness, or tenderness in one leg
- sudden onset of shortness of breath especially together with sharp chest pain or rapid breathing
- abdominal (stomach) pain, swelling of the abdomen, blood in the stool.
Liver problems
Revolade can cause changes that show up in blood tests and may be signs of liver damage. Liver problems (increases in enzymes found in blood tests) are common and may affect up to 1 in 10 people. Other liver problems (bile not flowing properly) are uncommon and may affect up to 1 in 10 people. 100.
If you have any of these signs of liver problems:
- yellowing of the skin or whites of the eyes (jaundice)
- unusually dark colored urine
- Tell your doctor immediately.
Bleeding or bruising after stopping treatment
Within two weeks after stopping Revolade, your platelet count will usually decrease to what it was before starting Revolade. A lower platelet count can increase the risk of bleeding or bruising. Your doctor will check your platelet count for at least 4 weeks after you stop taking Revolade.
- Tell your doctor if you have any bleeding or bruising after you stop Revolade.
Some people have bleeding in the digestive system after stopping taking peginterferon, ribavirin, and Revolade. Symptoms include:
- dark stools, stool color change is an uncommon side effect that may affect up to 1 in 100 people)
- blood in the stool
- throwing up blood or something like coffee grounds
- Tell your doctor immediately if you get any of these symptoms.
Other possible side effects in adults with ITP
Common side effects These may affect up to 1 in 10 people:
- nausea
- diarrhea
- cataract (clouding of the lens of the eye)
- dry eye
- unusual hair loss or thinning
- rash
- itch
- muscle pain, muscle spasms
- backache
- bone pain
- tingling and numbness in the hands or feet
- heavy menstrual cycle
- mouth ulcers.
Common side effects that may show up in a blood test:
- increased liver enzymes
- increased bilirubin (a substance produced by the liver)
- increased levels of some proteins.
Uncommon side effects
These may affect up to 1 in 100 people:
- interruption of blood supply to part of the heart
- sudden shortness of breath, especially when accompanied by sharp chest pain and / or rapid breathing which may be a sign of a blood clot in the lungs (see "Higher risk of blood clots" at the beginning of section 4
- loss of function of part of the lung caused by blockage of the pulmonary artery
- liver problems, including yellowing of the eyes and skin
- fast heart rate, irregular heartbeat, bluish discoloration of the skin
- heart rhythm disturbances (QT prolongation)
- inflammation of a vein
- bruises
- sore throat and discomfort when swallowing, inflammation of the lungs, sinuses, tonsils, nose and throat
- influence
- pneumonia
- loss of appetite
- painful swelling of the joints caused by uric acid (gout)
- trouble sleeping, depression, loss of interest, mood swings
- feeling sleepy, problems with balance, speech and nerve function, migraines, tremors
- eye problems, including blurred and less clear vision
- ear pain, dizziness
- problems with the nose, throat and sinuses, breathing problems during sleep
- digestive system problems including: vomiting, flatulence, frequent bowel movements, abdominal pain and tenderness, food poisoning
- rectal cancer
- mouth problems including dry or sore mouth, tenderness of the tongue, bleeding gums,
- skin changes including excessive sweating, blistered and itchy rash, red spots, changes in appearance
- sunburn
- redness or swelling around a wound
- bleeding around a catheter (if any)
- sensation of a foreign body at the injection site
- muscle weakness
- kidney problems including: inflammation of the kidneys, urinating excessively at night, kidney failure, urinary tract infection, white blood cells in the urine
- malaise, fever, feeling hot, chest pain
- cold sweat
- inflammation of the gums
- skin infection.
Uncommon side effects that may show up in a blood test:
- reduction in the number of red blood cells (anemia), white blood cells and platelets
- increased number of red blood cells
- changes in blood morphology
- changes in uric acid, calcium and potassium levels.
Other possible side effects in children with ITP
Very common side effects
These may affect more than 1 in 10 children:
- sore throat, runny nose, nasal congestion and sneezing
- infection of the nose, sinuses, throat and upper airways, common cold (upper respiratory infection)
- diarrhea.
Common side effects
These may affect up to 1 in 10 children:
- difficulty sleeping (insomnia)
- abdominal pain
- toothache
- cough
- pain in the nose and throat
- itchy nose, runny or stuffy nose
- high temperature.
Other possible side effects in people with hepatitis C.
Very common side effects
These may affect more than 1 in 10 people:
- headache
- decreased appetite
- insomnia
- cough
- nausea, diarrhea
- muscle pain, itching, lack of energy, high temperature, unusual hair loss, feeling of weakness, flu-like illness, swelling in the hands and feet, chills.
Very common side effects that may show up in a blood test:
- decrease in the number of red blood cells (anemia).
Common side effects
These may affect up to 1 in 10 people:
- urinary system infections
- inflammation of the nasal passages, throat and mouth, flu-like symptoms, dry mouth, sore or sore mouth, toothache
- weight loss
- sleep disturbances, abnormal sleepiness, confusion, depression, anxiety, agitation
- dizziness, problems with concentration and memory
- tingling or numbness in the hands or feet
- inflammation in the brain
- eye problems including cataracts (clouding of the lens of the eye) dry eye, small yellow deposits in the retina, yellowing of the whites of the eyes
- bleeding in or around the retina (present in the back of the eye)
- feeling of dizziness, palpitations, shortness of breath
- cough with phlegm
- digestive system problems, including: vomiting, stomach pain, indigestion, constipation, stomach swelling, taste disturbance, stomach inflammation, haemorrhoids, swollen blood vessels and bleeding in the esophagus (oesophagitis), irritation of the intestine
- liver problems, including: blood clot, yellowing of the whites of the eyes or skin (jaundice), liver cancer
- skin changes, including: rash, dry skin, eczema, redness of the skin, itching, excessive sweating, unusual skin growth? joint pain, back pain, bone pain, pain in the hands or feet, muscle spasms
- irritability, general feeling of being unwell, chest pains and discomfort
- reactions at the injection site
- heart rhythm disturbances (QT prolongation).
Common side effects that may show up in a blood test:
- increased blood sugar (hyperglycaemia)
- reduction in the number of white blood cells
- reduction of blood proteins
- breakdown of red blood cells (haemolytic anemia)
- increased bilirubin (a substance produced by the liver)
- changes in the enzymes that control blood clotting.
Uncommon side effects
These may affect up to 1 in 100 people:
- pain when passing urine.
Uncommon side effects
Frequency cannot be estimated from the available data
- discolouration of the skin
The following side effects have been reported in association with Revolade treatment in patients with severe aplastic anemia (SAA).
Very common side effects
These may affect up to 1 in 10 people:
- cough
- headache
- wheezing (dyspnoea)
- pain in the nose and throat
- a runny nose
- abdominal pain
- diarrhea
- nausea
- bruises
- joint pain
- muscle spasms
- pain in the arms, legs, hands and feet
- dizziness
- feeling very tired
- fever
- insomnia
Very common side effects that may show up in a blood test:
- increased liver enzymes (transaminases). Blood tests may show abnormal changes in the bone marrow cells.
Common side effects
These may affect up to 1 in 10 people:
- anxiety
- depression
- Feel cold
- general malaise
- eye problems which include: blurred and less clear vision, cataracts, vision of spots in the eye due to an imperfect transparency of the vitreous, dry eyes, itchy eyes, yellowing of the skin or whites of the eyes
- nosebleeds
- bleeding of the gums
- blisters in the mouth
- digestive system problems which include: vomiting, changes in appetite (increase or decrease), stomach pain / discomfort, bloated stomach, wind, change in stool color
- fainting
- skin problems which include: small red or purple spots caused by bleeding in the skin (petechiae), rash, itching, skin lesions
- back pain
- pain in the muscles
- bone pain
- weakness
- swelling of tissues, usually of the lower limbs, due to water retention
- abnormally discolored urine
- disruption of the blood supply to the spleen (splenic infarction).
Common side effects that may show up in a blood test:
- increase in enzymes due to muscle injury (creatine phosphokinase)
- accumulation of iron in the blood
- reduced number of white blood cells (neutropenia)
- decreased blood sugar (hypoglycaemia)
- increased bilirubin (a substance produced by the liver)
Uncommon side effects
Frequency cannot be estimated from the available data
- discolouration of the skin
Reporting of side effects
If you get any side effects, talk to your doctor, pharmacist or nurse. This includes any possible side effects not listed in this leaflet. You can also report side effects directly via the national reporting system. By reporting side effects you can help provide more information on the safety of this medicine.
Expiry and Retention
Keep this medicine out of the sight and reach of children.
Do not use this medicine after the expiry date which is stated on the carton and blister after EXP. The expiry date refers to the last day of that month.
This medicine does not require any special storage conditions.
Do not throw any medicines via wastewater or household waste. Ask your pharmacist how to throw away medicines you no longer use. This will help protect the environment.
Other Information
What Revolade contains
The active ingredient in Revolade is eltrombopag.
12.5 mg film-coated tablets
Each film-coated tablet contains eltrombopag olamine equivalent to 12.5 mg of eltrombopag.
25 mg film-coated tablets
Each film-coated tablet contains eltrombopag olamine equivalent to 25 mg of eltrombopag.
50 mg film-coated tablets
Each film-coated tablet contains eltrombopag olamine equivalent to 50 mg of eltrombopag.
75 mg film-coated tablets
Each film-coated tablet contains eltrombopag olamine equivalent to 75 mg of eltrombopag.
The other ingredients are: hypromellose, macrogol 400, magnesium stearate, mannitol (E421), microcrystalline cellulose, povidone, sodium starch glycolate, titanium dioxide (E171).
Revolade 50 mg film-coated tablets also contain red iron oxide (E172), yellow iron oxide (E172).
Revolade 75 mg film-coated tablets also contain red iron oxide (E172), yellow iron oxide (E172).
What Revolade looks like and contents of the pack
Revolade 12.5 mg film-coated tablets are round, biconvex, white, debossed with "GS MZ1" and "12.5" on one side.
Revolade 25 mg film-coated tablets are round, biconvex, white, with "GS NX3" and "25" debossed on one side.
Revolade 50 mg film-coated tablets are round, biconvex, brown, debossed with "GS UFU" and "50" on one side.
Revolade 75 mg film-coated tablets are round, biconvex, pink, debossed with "GS FFS" and "75" on one side.
They are supplied in aluminum blisters in a pack containing 14 or 28 film-coated tablets and a multipack containing 84 (3 packs of 28) film-coated tablets.
Not all pack sizes may be marketed in your country.
Source Package Leaflet: AIFA (Italian Medicines Agency). Content published in January 2016. The information present may not be up-to-date.
To have access to the most up-to-date version, it is advisable to access the AIFA (Italian Medicines Agency) website. Disclaimer and useful information.
01.0 NAME OF THE MEDICINAL PRODUCT
REVOLADE TABLETS COATED WITH FILM
02.0 QUALITATIVE AND QUANTITATIVE COMPOSITION
Revolade 12.5 mg film-coated tablets
Each film-coated tablet contains eltrombopag olamine equivalent to 12.5 mg of eltrombopag.
Revolade 25 mg film-coated tablets
Each film-coated tablet contains eltrombopag olamine equivalent to 25 mg of eltrombopag.
Revolade 50 mg film-coated tablets
Each film-coated tablet contains eltrombopag olamine equivalent to 50 mg of eltrombopag.
Revolade 75 mg film-coated tablets
Each film-coated tablet contains eltrombopag olamine equivalent to 75 mg of eltrombopag.
For the full list of excipients, see section 6.1.
03.0 PHARMACEUTICAL FORM
Film-coated tablet.
Revolade 12.5 mg film-coated tablets
Round, biconvex, white film-coated tablet (approximately 7.9 mm in diameter) debossed with "GS MZ1" and "12.5" on one side.
Revolade 25 mg film-coated tablets
Round, biconvex, white film-coated tablet (approximately 10.3 mm in diameter) debossed with "GS NX3" and "25" on one side.
Revolade 50 mg film-coated tablets
Round, biconvex, brown film-coated tablet (approximately 10.3 mm in diameter) debossed with "GS UFU" and "50" on one side.
Revolade 75 mg film-coated tablets
Round, biconvex, pink film-coated tablet (approximately 10.3 mm in diameter) debossed with "GS FFS" and "75" on one side.
04.0 CLINICAL INFORMATION
04.1 Therapeutic indications
Revolade is indicated in patients over 1 year of age with chronic autoimmune (idiopathic) thrombocytopenic purpura (ITP) who are refractory to other treatments (e.g. corticosteroids, immunoglobulins) (see sections 4.2 and 5.1).
Revolade is indicated in adult patients with chronic hepatitis C virus infection (Hepatitis C virus, HCV) for the treatment of thrombocytopenia, when the degree of thrombocytopenia is the major factor preventing initiation or limiting the ability to maintain optimal interferon-based therapy (see sections 4.4 and 5.1).
Revolade is indicated in adult patients with severe acquired aplastic anemia (SAA), refractory to prior immunosuppressive therapy or heavily pretreated and ineligible for haematopoietic stem cell transplantation (see section 5.1).
04.2 Posology and method of administration
Treatment with eltrombopag should be initiated and maintained under the supervision of a physician experienced in the treatment of haematological diseases or in the treatment of chronic hepatitis C and its complications.
Dosage
The required dosage of eltrombopag should be individualized based on the patient's platelet count. The goal of eltrombopag treatment should not be to normalize the platelet count.
The powder for oral suspension may lead to a higher exposure to eltrombopag than the tablet formulation (see section 5.2). When switching from the tablet formulation to the powder formulation for oral suspension, the platelet count should be monitored weekly for 2 weeks.
Chronic autoimmune (idiopathic) thrombocytopenia
The lowest dose of eltrombopag should be used to achieve and maintain a platelet count ≥ 50,000 / μl. Dose adjustments are based on platelet count response.
Eltrombopag should not be used to normalize platelet counts. In clinical studies, platelet counts generally increased within 1-2 weeks after starting eltrombopag and decreased within 1-2 weeks after stopping.
Adults and pediatric population aged 6-17 years
The recommended starting dose of eltrombopag is 50 mg once daily. For patients of East Asian origin (such as Chinese, Japanese, Taiwanese, Korean or Thai), eltrombopag treatment should be initiated at a reduced dose of 25 mg once daily (see section 5.2).
Pediatric population aged 1 to 5 years
The recommended starting dose of eltrombopag is 25 mg once daily.
Dose monitoring and modification
After initiation of eltrombopag treatment, the dose should be adjusted to achieve and maintain a platelet count ≥ 50,000 / μl necessary to reduce the risk of bleeding. The daily dose of 75 mg should not be exceeded.
Blood chemistry and liver function parameters should be monitored regularly during eltrombopag therapy and the eltrombopag dosing regimen should be adjusted based on the platelet count as reported in Table 1. During eltrombopag therapy, complete blood counts should be assessed weekly. , including platelet count and peripheral blood smear, until a stable platelet count is achieved (≥ 50,000 / μl for at least 4 weeks).
Subsequently, complete blood counts including platelet count and peripheral blood smear should be performed monthly.
Table 1 Eltrombopag dose modifications in ITP patients
* - For patients taking eltrombopag 25 mg once every two days, increase the dose to 25 mg once daily.
? - For patients taking eltrombopag 25 mg once daily, a dose of 12.5 mg once daily or alternatively a dose of 25 mg once every two days should be considered.
Eltrombopag can be given as an adjunct to other ITP medicines. The dosing regimen of concomitant medications for the treatment of ITP should be modified, as clinically appropriate, to avoid excessive increases in platelet counts during eltrombopag therapy.
It is necessary to wait at least 2 weeks to see the effect of any dose changes on the patient's platelet response before considering another dose adjustment.
The standard dose modification of eltrombopag, either downward or upward, should be 25 mg once daily.
Discontinuation of treatment
Treatment with eltrombopag should be discontinued if the platelet count does not increase to a level sufficient to avoid clinically important bleeding after four weeks of therapy with 75 mg eltrombopag once daily.
Patients should undergo periodic clinical evaluation and the continuation of treatment should be decided by the physician on an individual basis. In non-splenectomized patients, this should include a splenectomy evaluation. Recurrence of thrombocytopenia is possible upon discontinuation of treatment (see section 4.4).
Thrombocytopenia associated with chronic HCV hepatitis
When eltrombopag is administered in combination with antivirals, the summary of product characteristics of the respective concomitantly administered medicinal products should be referred to for full details of the relevant safety information and contraindications.
In clinical studies, platelet counts generally began to increase within 1 week of starting eltrombopag. The aim of eltrombopag treatment should be to achieve the minimum platelet count necessary to initiate antiviral therapy, in accordance with the recommendations in the clinical practice. During antiviral therapy, the aim of treatment should be to maintain platelet counts at a level that prevents the risk of bleeding complications, typically around 50,000 - 75,000 / μl. Platelet counts> 75,000 / μl should be avoided The lowest dose of eltrombopag necessary to achieve goals should be used Dose modifications are based on the response of the platelet count.
Initial dosage regimen
Eltrombopag should be started at a dose of 25 mg once daily. No dose modification is required for patients with chronic HCV hepatitis of East Asian origin or for patients with mild hepatic impairment (see section 5.2).
Dose monitoring and modification
The dose of eltrombopag should be changed in increments of 25 mg every 2 weeks in order to achieve the target platelet count required to initiate antiviral therapy. Platelet counts should be checked weekly before starting antiviral therapy. Platelet counts may fall upon initiation of antiviral therapy, therefore immediate changes in the dose of eltrombopag should be avoided (see Table 2).
During antiviral therapy, the dose of eltrombopag should be modified as necessary to avoid reductions in the dose of peginterferon due to reductions in platelet counts that could expose the patient to the risk of bleeding (see Table 2). Platelet counts should be monitored weekly during antiviral therapy until a stable platelet count is achieved, typically around 50,000-75,000 / μl. Complete blood counts, including platelet count and peripheral blood smear, should then be performed monthly. Dose reductions of 25 mg from the daily dose should be considered if platelet count exceeds the required target. It is advisable to wait 2 weeks to evaluate the effects of this and any subsequent dose adjustments.
A dose of 100 mg eltrombopag once daily should not be exceeded.
Table 2 Eltrombopag dose modifications in chronic HCV hepatitis patients during antiviral therapy
* - In patients taking 25 mg eltrombopag once daily, re-initiation of treatment at 25 mg every other day should be considered.
? - Platelet counts may decrease upon initiation of antiviral therapy, therefore immediate reductions in the dose of eltrombopag should be avoided.
Discontinuation of treatment
Treatment with eltrombopag should be discontinued if the platelet count required to initiate antiviral therapy has not been reached after 2 weeks of 100 mg therapy.
Unless otherwise justified, eltrombopag treatment should be terminated when antiviral therapy is discontinued. Excessive platelet count responses or major abnormalities in liver function tests also require discontinuation of treatment.
Severe Aplastic Anemia
Initial Dosage Regimen
Treatment with eltrombopag should start with a dose of 50 mg once daily. For patients of East Asian origin, eltrombopag treatment should be initiated at a reduced dose of 25 mg once daily (see section 5.2). Treatment should not be initiated when patients have pre-existing cytogenetic abnormalities of chromosome 7.
Dose monitoring and modification
Haematological response requires dose titration, typically up to 150 mg, and may take up to 16 weeks after initiation of eltrombopag treatment (see section 5.1). The eltrombopag dose should be changed in 50 mg increments. every 2 weeks in order to achieve target platelet count ≥ 50,000 / μl. For patients taking 25 mg once daily, the dose should be increased to 50 mg daily before subsequent 50 mg increments. It should not be exceeded. a dose of 150 mg per day Clinical haematological and hepatic tests should be monitored during therapy with eltrombopag and the modified eltrombopag dosing regimen based on platelet counts as indicated in Table 3.
Table 3 Eltrombopag dose modifications in patients with severe aplastic anemia
Reduction for patients with trilinear response (white blood cells, red blood cells and platelets)
For patients who achieve a trilinear response, including transfusion independence, lasting at least 8 weeks: the dose of eltrombopag can be reduced by 50%.
If blood counts remain stable after 8 weeks at the reduced dose, eltrombopag should be discontinued and blood counts monitored. If the platelet count were to drop from a hemoglobin level to a neutrophil level to a level
Interruption
If no haematological response has occurred after 16 weeks of eltrombopag therapy, therapy should be discontinued. Should new cytogenetic abnormalities be detected, it should be considered whether continued therapy with eltrombopag is appropriate (see sections 4.4 and 4.8). Excessive response in platelet counts (as indicated in Table 3) or major liver test abnormalities also require discontinuation of eltrombopag (see section 4.8).
Special populations
Kidney failure
No dose adjustment is required in patients with renal insufficiency. Patients with impaired renal function should use eltrombopag with caution and under careful supervision, for example by checking serum creatinine and / or urinalysis (see section 5.2).
Hepatic insufficiency
Eltrombopag should not be used in ITP patients with hepatic insufficiency (Child-Pugh score ≥ 5) unless the expected benefit outweighs the identified risk of portal vein thrombosis (see section 4.4).
If the use of eltrombopag is considered necessary for ITP patients with hepatic insufficiency, the starting dose should be 25 mg once daily. After starting the eltrombopag dose in patients with hepatic insufficiency, a dose should be observed. 3-week interval before increasing the dose.
No dose adjustment is required for thrombocytopenic patients with chronic HCV hepatitis and mild hepatic insufficiency (Child-Pugh score ≤ 6). Patients with chronic HCV hepatitis and severe aplastic anemia with hepatic insufficiency should start eltrombopag at a dose of 25 mg once daily (see section 5.2). After initiation of treatment with eltrombopag in patients with hepatic insufficiency an interval of 2 weeks should be observed before increasing the dose.
There is an increased risk of adverse events, including hepatic decompensation and thromboembolic events, in thrombocytopenic patients with advanced chronic liver disease treated with eltrombopag either in preparation for invasive procedures or in patients with chronic HCV hepatitis being treated with antiviral therapy (see sections 4.4 and 4.8).
Senior citizens
There are limited data on the use of eltrombopag in patients with ITP aged 65 years and older and no clinical experience in patients with ITP aged over 85. In clinical trials with eltrombopag, no overall differences were observed clinically. Significant in the safety of eltrombopag among subjects at least 65 years of age and younger subjects. Other reported clinical experiences have not identified differences in responses between elderly and younger patients, but greater sensitivity of some older subjects cannot be ruled out (see section 5.2). .
There are limited data on the use of eltrombopag in patients with chronic HCV-induced hepatitis and AAS over the age of 75. Caution should be exercised in these patients (see section 4.4).
East Asian Patients
In patients of East Asian origin (such as Chinese, Japanese, Taiwanese, Korean or Thai), including those with hepatic impairment, eltrombopag should be initiated at a dose of 25 mg once daily (see section 5.2).
The patient's platelet count should continue to be monitored and standard criteria for further dose modifications followed.
Pediatric population
Revolade is not recommended in children aged less than 1 year with chronic ITP due to insufficient data on safety and efficacy. The safety and efficacy of eltrombopag in children and adolescents (
Method of administration
Oral use.
The tablets should be taken at least two hours before or four hours after any product such as antacids, dairy products (or other food products containing calcium), or mineral supplements containing polyvalent cations (e.g. iron, calcium, magnesium, aluminum, selenium and zinc) (see sections 4.5 and 5.2).
04.3 Contraindications
Hypersensitivity to eltrombopag or to any of the excipients listed in section 6.1.
04.4 Special warnings and appropriate precautions for use
There is an increased risk of adverse reactions, including life-threatening hepatic decompensation and thromboembolic events, in thrombocytopenic HCV chronic hepatitis patients with advanced chronic liver disease, defined by low albumin ≤ 35 g / l or by a Model for score. End Stage Liver Disease (MELD) ≥ 10, when treated with eltrombopag in combination with interferon-based therapy. Furthermore, treatment benefits in terms of the proportion of patients achieving sustained virological response (SVR) compared to placebo were modest in these patients (especially those with baseline albumin ≤ 35g / l) compared to the overall group.Treatment with eltrombopag in these patients should only be initiated by physicians experienced in the treatment of advanced chronic HCV hepatitis, and only when the risks of thrombocytopenia or discontinuation of antiviral therapy require intervention. If treatment is considered clinically indicated, close monitoring of these patients is required.
Combination with direct acting antiviral agents
Safety and efficacy have not been established in combination with direct acting antiviral agents approved for the treatment of chronic HCV hepatitis.
Risk of hepatotoxicity
Administration of eltrombopag can cause abnormal liver function and severe hepatotoxicity, which can be life-threatening. In controlled clinical trials with eltrombopag in chronic ITP, elevations in serum alanine aminotransferase (ALT), aspartate aminotransferase (AST) and bilirubin were observed (see section 4.8).
These changes were mostly mild (Grade 1-2), reversible, and not accompanied by clinically significant symptoms that would have indicated "impaired liver function. In" the 3 placebo-controlled studies in adults with chronic ITP, 1 patient of the placebo group and 1 patient of the eltrombopag group had a Grade 4 abnormality in liver function parameters. In two placebo-controlled studies in pediatric patients (aged 1 to 17 years) with chronic ITP, an ALT ≥ 3 times the upper limit of normal (x ULN) was seen in 4.7% and 0% of the eltrombopag and placebo groups, respectively.
In 2 controlled clinical trials in patients with chronic HCV hepatitis, ALT or AST ≥ 3 times the upper limit of normal (ULN) were reported in 34% and 38% of the eltrombopag and placebo groups, respectively. Most patients who have received eltrombopag in combination with peginterferon / ribavirin therapy will experience indirect hyperbilirubinaemia. Overall, total bilirubin ≥ 1.5 times ULN was reported in 76% and 50% of the eltrombopag and placebo groups, respectively.
Serum ALT, AST, and serum bilirubin should be measured before starting eltrombopag, every 2 weeks during the dose adjustment phase, and monthly after reaching a stable dose.
Eltrombopag inhibits UDP glucorosyl transferase (UGT) 1A1 and organic anion transporter polypeptide (OATP) 1B1, which can lead to indirect hyperbilirubinemia. Fractionation should be performed if bilirubin is elevated. Abnormalities in serum liver function tests should be evaluated by retesting within 3-5 days.If abnormalities are confirmed, serum liver function tests should be monitored until abnormalities resolve, stabilize, or return to baseline.
Administration of eltrombopag should be discontinued if ALT levels increase (≥ 3 times ULN in patients with normal hepatic function, or ≥ 3 times baseline or> 5 times ULN, whichever is lower, in patients with pretreatment increases in transaminases) and are:
- progressive, or
- persist for ≥ 4 weeks, or
- are accompanied by an increase in direct bilirubin, or
- are accompanied by clinical symptoms of liver damage or evidence of hepatic decompensation.
Caution is required when administering eltrombopag to patients with hepatic disease. A lower starting dose of eltrombopag should be used in patients with ITP and SAA. Careful monitoring is required when administered to patients with hepatic insufficiency (see section 4.2).
Liver failure (use with interferon)
Hepatic decompensation in patients with chronic HCV hepatitis: Monitoring is required in patients with low albumin levels (≤ 35 g / L) or with baseline MELD score ≥ 10.
Patients with chronic HCV hepatitis and cirrhosis may be at risk for hepatic decompensation when receiving alpha interferon therapy. In 2 controlled clinical trials in thrombocytopenic patients with chronic HCV hepatitis, hepatic decompensation (ascites, hepatic encephalopathy, variceal haemorrhage, spontaneous bacterial peritonitis) was reported more frequently in the eltrombopag arm (11%) than in the placebo arm (6% ). In patients with low albumin levels (≤ 35 g / L) or MELD score ≥ 10 at baseline, there was a three-fold increased risk of hepatic decompensation and an increased risk of fatal adverse events compared to those with disease less advanced liver. Furthermore, the treatment benefits in terms of rate of achievement of SVR compared to placebo were modest in these patients (especially those with baseline albumin ≤ 35g / l) compared to the overall group. Eltrombopag should only be administered to these patients after careful consideration of the expected benefits versus the risks. Patients with these characteristics should be carefully monitored for signs and symptoms of hepatic decompensation. Reference should be made to the respective Interferon Summary of Product Characteristics for discontinuation criteria. Eltrombopag should be discontinued if antiviral therapy is discontinued due to hepatic decompensation.
Thrombotic / thromboembolic complications
In controlled clinical trials in thrombocytopenic patients with chronic HCV hepatitis receiving interferon-based therapy (n = 1439), 38 of 955 (4%) subjects treated with eltrombopag and 6 of 484 (1%) subjects in the placebo group had presented thromboembolic events (TEE). Reports of thrombotic / thromboembolic complications included both venous and arterial events. The majority of TEEs were non-serious and resolved by the end of the study. Portal vein thrombosis was the most common TEE in both treatment groups (2% in patients treated with eltrombopag compared with signs and symptoms of TEE.
The risk of TEE was increased in patients with chronic liver disease (chronic liver disease, CLD) treated with 75 mg eltrombopag once daily for two weeks in preparation for invasive procedures.
Six of 143 (4%) adult patients with CLD receiving eltrombopag experienced TEEs (all involving the portal venous system) and two of 145 subjects (1%) in the placebo group experienced TEEs (one involving the portal venous system and a myocardial infarction). Five of the 6 patients treated with eltrombopag experienced thrombotic complications with a platelet count> 200,000 / microliter and within 30 days of the last dose of eltrombopag. Eltrombopag is not indicated for the treatment of thrombocytopenia in patients with chronic liver disease in preparation for invasive procedures.
In clinical trials with eltrombopag in ITP, thromboembolic events were observed with low and normal platelet counts. Caution should be exercised when administering eltrombopag to patients with known risk factors for thromboembolism, including but not limited to inherited (e.g. Factor V Leiden) or acquired (e.g. ATIII deficiency, antiphospholipid syndrome) risk factors, older age , patients with prolonged periods of immobilization, malignancies, contraceptive or hormone replacement therapy, surgery / trauma, obesity and smoking. Platelet counts should be monitored closely and dose reduction or discontinuation of eltrombopag should be considered if the platelet count exceeds the required levels (see section 4.2). The benefit-risk ratio should be considered in the patients at risk for TEE events of any etiology.
Eltrombopag should not be used in ITP patients with hepatic insufficiency (Child-Pugh score ≥ 5) unless the expected benefit outweighs the identified risk of portal vein thrombosis. When treatment is considered appropriate, caution is required when administering eltrombopag to patients with hepatic insufficiency (see sections 4.2 and 4.8).
Bleeding following discontinuation of eltrombopag
Thrombocytopenia is likely to re-occur upon discontinuation of eltrombopag treatment. Following discontinuation of eltrombopag, platelet counts return to baseline within 2 weeks in the majority of patients, which increases the risk of bleeding and in some cases may lead to bleeding. This risk is increased if eltrombopag treatment is stopped in presence of anticoagulants and anti-platelet agents. It is recommended, if treatment with eltrombopag is discontinued, that ITP treatment is resumed according to current guidelines. In addition, medical management may include cessation of anticoagulant and / or anti-coagulation therapy. -platelet, anticoagulation reversal, or platelet support. Platelet counts should be monitored weekly for 4 weeks after stopping eltrombopag.
In clinical trials in chronic HCV hepatitis, a higher incidence of gastric bleeding, including severe and fatal cases, has been reported following discontinuation of peginterferon, ribavirin, and eltrombopag.
Following discontinuation of therapy, patients should be monitored for any signs or symptoms of gastric bleeding.
Bone marrow reticulin formation and risk of bone marrow fibrosis Eltrombopag may increase the risk of development or progression of reticulin fibers within the bone marrow. As with other thrombopoietin receptor agonists (TPO-R), the relevance of these alterations has not yet been established.
Before starting eltrombopag, the peripheral blood smear should be carefully examined to establish the baseline level of cellular morphological abnormalities. After identification of a stable dose of eltrombopag, a complete blood count with differential white blood cell count should be performed monthly. If immature or dysplastic cells are observed, peripheral blood smear should be examined for new morphological abnormalities ( for example, drip red blood cells (dacryocytes) and nucleated, immature white blood cells) or worsening or cytopenia. If the patient develops new or worsening morphological abnormalities or cytopenia, eltrombopag treatment should be stopped and taken Consider a bone marrow biopsy, including evaluation for fibrosis.
Progression of existing myelodysplastic syndrome (MDS)
TPO-R agonists are growth factors that induce proliferation and differentiation of thrombopoietic progenitor cells, and the production of platelets. TPO-R is predominantly expressed on the surface of myeloid lineage cells. For TPO-R agonists there is a risk that they may stimulate the progression of pre-existing neoplastic haemopathies such as myelodysplastic syndrome.
In clinical trials with a TPO-R agonist in patients with MDS, cases of transient increases in blast cell counts have been observed and cases of disease progression from MDS to acute myeloid leukemia (AML) have been reported.
The diagnosis of ITP or SAA in adult and elderly patients should be confirmed by excluding other pathologies presenting thrombocytopenia, in particular the diagnosis of MDS should be excluded. Bone marrow aspiration and biopsy should be considered during the course of disease and treatment, particularly in patients over 60 years of age with systemic symptoms or abnormal signs such as an increase in peripheral blast cells.
The efficacy and safety of eltrombopag have not been established for use in other thrombocytopenic conditions, including chemotherapy-induced thrombocytopenia or MDS.
Eltrombopag should not be used outside of clinical trials for the treatment of thrombocytopenia due to MDS or any other cause of thrombocytopenia other than the authorized indications.
Cytogenetic abnormalities and progression of MDS / AML in patients with AAS
Cytogenetic abnormalities are known to develop in patients with AAS. It is not known whether eltrombopag increases the risk of cytogenetic abnormalities in AAS patients. In the phase II clinical trial in which eltrombopag was used in AAS, the incidence of new cytogenetic abnormalities was observed in 19% of patients [8/43 (of which 5 had chromosome 7 abnormalities)]. The median time during the study for the appearance of a cytogenetic abnormality was 2.9 months.
In clinical trials with eltrombopag in ASA, 4% of patients (5/133) were diagnosed with MDS. The median time to diagnosis from initiation of eltrombopag treatment was three months.
For patients with refractory or heavily pretreated SAA and undergoing previous immunosuppressive therapy, bone marrow aspirate examination for cytogenetics is recommended before starting eltrombopag, at 3 months of treatment and every 6 months thereafter. In case of detection of new ones. cytogenetic abnormalities, it should be considered whether it is appropriate to continue eltrombopag.
Ocular alterations
Cataract has been observed in eltrombopag toxicology studies in rodents (see section 5.3). In controlled clinical trials in thrombocytopenic patients with chronic HCV hepatitis receiving interferon therapy (n = 1439), progression of a pre-existing baseline cataract or the appearance of a new cataract was reported in 8% of the group. eltrombopag and in 5% of the placebo group. Retinal haemorrhages, mainly Grade 1 or 2, were reported in patients with chronic HCV hepatitis receiving interferon, ribavirin and eltrombopag (2% in the eltrombopag group and 2% in the placebo group). Hemorrhages occurred on the surface of the retina (preretinal), under the retina (subretinal), or within the retinal tissue. Routine ophthalmological monitoring of patients is recommended.
QT / QTc extension
A QTc study in healthy volunteers at a dose of 150 mg eltrombopag per day did not show a clinically significant effect on cardiac repolarization. QTc interval prolongation has been reported in clinical trials with ITP patients and thrombocytopenic patients with chronic HCV hepatitis. The clinical significance of these QTc prolongation cases is unknown.
Loss of response to eltrombopag
Loss of response or failure to maintain platelet response to eltrombopag treatment within the recommended therapeutic range should trigger the search for causative factors, including an increase in bone marrow reticulin.
Pediatric population
The ITP warnings and precautions mentioned above are also applied to the pediatric population.
04.5 Interactions with other medicinal products and other forms of interaction
Effects of eltrombopag on other medicinal products
HMG CoA reductase inhibitors
Education in vitro demonstrated that eltrombopag is not a substrate of the organic anionic transporter polypeptide OATP1B1, but is an inhibitor of this transporter. Education in vitro have also shown that eltrombopag is a substrate and an inhibitor of breast cancer resistance protein (BCRP). Administration to 39 healthy adult subjects of eltrombopag 75 mg once daily for 5 days with a single 10 mg dose of rosuvastatin, a substrate of OATP1B1 and BCRP, increased the plasma C of rosuvastatin by 103% (90% confidence interval [CI]: 82%, 126%) and the AUC0-? 55% (90% CI: 42%, 69%). Interactions with other HMG-CoA reductase inhibitors are also expected, including atorvastatin, fluvastatin, lovastatin, pravastatin and simvastatin. When co-administered with eltrombopag, a reduction in the dose of statins should be considered and careful monitoring for statin adverse reactions undertaken (see section 5.2).
OATP1B1 and BCRP substrates
Concomitant administration of eltrombopag and substrates of OATP1B1 (e.g. methotrexate) and BCRP (e.g. topotecan and methotrexate) should be undertaken with caution (see section 5.2).
Cytochrome P450 substrates
In studies using human liver microsomes, eltrombopag (up to 100 mcM) showed no inhibition. in vitro of CYP450 enzymes 1A2, 2A6, 2C19, 2D6, 2E1, 3A4 / 5, and 4A9 / 11 and was an inhibitor of CYP2C8 and CYP2C9 measured using paclitaxel and diclofenac as probe substrates. Administration of eltrombopag 75 mg once daily for 7 days to 24 healthy male subjects did not inhibit or induce metabolism of probe substrates for 1A2 (caffeine), 2C19 (omeprazole), 2C9 (flurbiprofen), or 3A4 (midazolam) in the "human. No clinically significant interactions are expected when eltrombopag and CYP450 substrates are co-administered (see section 5.2).
HCV Protease Inhibitors
No dose modification is required when eltrombopag is co-administered with telaprevir or boceprevir.
Co-administration of a single dose of eltrombopag 200 mg with telaprevir 750 mg every 8 hours did not alter the plasma exposure of telaprevir.
Co-administration of a single dose of eltrombopag 200 mg with boceprevir 800 mg every 8 hours did not alter the plasma AUC (0-?) Of boceprevir, but increased C by 20% and decreased C by 32%. The clinical relevance of the decrease in Cmin has not been established: closer clinical and laboratory monitoring is recommended for suppression of HCV.
Effects of other medicinal products on eltrombopag
Cyclosporine
In vitro studies have shown that eltrombopag is a substrate and inhibitor of BCRP. A reduction in eltrombopag exposure was observed with the co-administration of 200 mg and 600 mg cyclosporine (BCRP inhibitor) (see section 5.2).Dose modification of eltrombopag during the course of treatment is allowed based on the patient's platelet count (see section 4.2). Platelet counts should be monitored at least weekly for 2 to 3 weeks when eltrombopag is co-administered with cyclosporine. The dose of eltrombopag may need to be increased based on platelet count results.
Polyvalent cations (chelation)
Eltrombopag chelates polyvalent cations such as iron, calcium, magnesium, aluminum, selenium and zinc. Administration of a single 75 mg dose of eltrombopag with an antacid containing a polyvalent cation (1524 mg of aluminum hydroxide and 1425 mg of magnesium carbonate) reduces AUC0-? plasma eltrombopag up to 70% (90% CI: 64%, 76%) and Cmax up to 70% (90% CI: 62%, 76%).
Eltrombopag should be taken at least 2 hours before or 4 hours after any antacid type product, dairy product or mineral supplement containing polyvalent cations to avoid a significant reduction in eltrombopag absorption due to chelation (see sections 4.2 and 5.2).
Interaction with food
Administration of eltrombopag tablets or powder for oral suspension with a high-calcium meal (e.g. a meal that included dairy products) significantly reduced AUC0-? and plasma Cmax of eltrombopag. Conversely, administration of eltrombopag 2 hours before or 4 hours after a high-calcium meal or low-calcium food [
Lopinavir / ritonavir
Concomitant administration of eltrombopag with lopinavir / ritonavir may cause a decrease in eltrombopag concentration. A study in 40 healthy volunteers demonstrated that concomitant administration of a single 100 mg dose of eltrombopag with a repeat dose of 400/100 mg lopinavir / ritonavir twice daily resulted in a reduction in AUC (0-?) Of eltrombopag of 17% (90% CI: 6.6%; 26.6%). Therefore, caution should be used when administering eltrombopag concomitantly with lopinavir / ritonavir. Platelet counts should be closely monitored to ensure appropriate clinical dose management of eltrombopag when lopinavir / ritonavir therapy is initiated or discontinued.
CYP1A2 and CYP2C8 inhibitors and inducers
Eltrombopag is metabolised via multiple pathways including CYP1A2, CYP2C8, UGT1A1, and UGT1A3 (see section 5.2). Medicinal products that inhibit or induce a single enzyme are unlikely to significantly affect the plasma concentrations of eltrombopag; while medicinal products that inhibit or induce multiple enzymes have the potential to increase (eg fluvoxamine) or decrease (eg rifampicin) concentrations of eltrombopag.
HCV Protease Inhibitors
The results of a drug-drug interaction pharmacokinetic study show that co-administration of repeated doses of boceprevir 800 mg every 8 hours or telaprevir 750 mg every 8 hours with a single dose of eltrombopag 200 mg did not alter the plasma exposure of eltrombopag. at clinically significant levels.
Medicines for the treatment of ITP
Medicines used in clinical trials in the treatment of ITP in combination with eltrombopag included corticosteroids, danazol, and / or azathioprine, intravenous immunoglobulin (IVIG), and anti-D immunoglobulin. Platelet counts should be monitored when eltrombopag is administered in combination with other medicinal products for the treatment of ITP, to avoid that the platelet count is outside the recommended range (see section 4.2).
04.6 Pregnancy and breastfeeding
Pregnancy
There are no, or limited amount of data from the use of eltrombopag in pregnant women. Animal studies have shown reproductive toxicity (see section 5.3). The potential risk for humans is unknown.
Revolade is not recommended during pregnancy.
Women of childbearing age / Contraception in men and women
Revolade is not recommended for women of childbearing potential who are not using contraceptives.
Feeding time
It is unknown whether eltrombopag / its metabolites are excreted in human milk. Animal studies have shown that eltrombopag is probably excreted in milk (see section 5.3); therefore a risk to the nursing infant cannot be excluded. A decision must be made whether to discontinue breastfeeding or to continue / abstain from therapy with Revolade, evaluating the benefit of breastfeeding for the baby and the benefit of therapy for the woman.
Fertility
Fertility was not affected in male and female rats at exposures that were comparable to those in humans. However, a risk to humans cannot be excluded (see section 5.3).
04.7 Effects on ability to drive and use machines
Eltrombopag has negligible influence on the ability to drive or use machines. The clinical status of the patient and the adverse reaction profile of eltrombopag, including dizziness and lack of alertness, should be borne in mind when considering the patient's ability to perform tasks that require judgment, motor and cognitive skills.
04.8 Undesirable effects
Summary of the safety profile
In 4 controlled and 2 uncontrolled clinical trials, 530 adult patients with chronic ITP were treated with eltrombopag%. The mean duration of exposure to eltrombopag was 260 days. The most important serious adverse reactions were hepatotoxicity and thrombotic / thromboembolic events. The most common adverse reactions that occurred in at least 10% of patients included: headache, anemia, decreased appetite, insomnia, cough, nausea, diarrhea, alopecia, pruritus, myalgia, fever, fatigue, flu-like illness, asthenia , chills and peripheral edema.
In 2 controlled clinical trials, 171 pediatric patients with chronic ITP were treated with eltrombopag. The median duration of exposure was 171 days. The adverse reaction profile was comparable to that seen in adults with some additional adverse reactions, marked? In the following table.
The most common adverse reactions in pediatric patients aged 1 year and over with ITP (≥ 3% and greater than placebo) were major respiratory tract infections, nasopharyngitis, cough, diarrhea, pyrexia, rhinitis, abdominal pain, oropharyngeal pain, sore of teeth, skin rash, increased AST and rhinorrhea.
In 2 controlled clinical trials, 955 thrombocytopenic patients with HCV infection were treated with eltrombopag. The median duration of exposure was 183 days. The most important serious adverse reactions identified were hepatotoxicity and thrombotic / thromboembolic events. The most common adverse reactions that occurred in at least 10% of patients included: headache, anemia, decreased appetite, insomnia, cough, nausea, diarrhea, alopecia, itching, myalgia, fever, fatigue, flu-like illness, asthenia, chills and peripheral edema.
The safety of eltrombopag in severe aplastic anemia was evaluated in an open-label, single-arm clinical study (N = 43) in which 12 patients (28%) were treated for> 6 months and 9 patients (21%) were been treated for> 1 year. The most important serious adverse reactions were febrile neutropenia and sepsis / infections. The most common adverse reactions that occurred (in at least 10% of patients) included: headache, dizziness, insomnia, cough, breathlessness, oropharyngeal pain, rhinorrhea, nausea, diarrhea, abdominal pain, increased transaminases, bruising, arthralgia, muscle spasms, pain in limbs, fatigue, febrile neutropenia, and pyrexia.
List of adverse reactions
Adverse reactions in adult ITP studies (N = 550), pediatric ITP studies (N = 107) and HCV infected studies (N = 955), AAS studies (N = 43) and postmarketing reports are listed below by MedDRA system organ class and frequency.
Very common (≥ 1/10)
Common (≥ 1/100 to
Uncommon (≥ 1 / 1,000 to
Rare (≥ 1 / 10,000 to
Very rare (
Not known (cannot be estimated from the available data)
Population of the clinical trial in ITP
Infections and infestations
Very common
Nasopharyngitis?, upper respiratory tract infections?
common
Rhinitis?
Uncommon
Pharyngitis, urinary tract infections, flu, oral herpes, pneumonia, sinusitis, tonsillitis, respiratory tract infections, gingivitis, skin infection
Neoplasms benign, malignant and unspecified (including cysts and polyps)
Uncommon
Tumor of the rectosigmoid tract
Disorders of the blood and lymphatic system
Uncommon
Anemia, anisocytosis, eosinophilia, haemolytic anemia, leukocytosis, myelocytosis, thrombocytopenia, increased hemoglobin, increased band neutrophil count, decreased hemoglobin, presence of myelocytes, increased platelet count, decreased white blood cell count.
Disorders of the immune system
Uncommon
Hypersensitivity
Metabolism and nutrition disorders
Uncommon
Anorexia, hypokalaemia, decreased appetite, gout, hypocalcemia, increased blood uric acid
Psychiatric disorders
Uncommon
Sleep disturbances, depression, apathy, mood swings, easy crying
Nervous system disorders
common
Paresthesias
Uncommon
Hypoesthesia, somnolence, migraine, tremors, balance disturbances, dysesthesia, hemiparesis, migraine with aura, peripheral neuropathy, peripheral sensory neuropathy, speech disorders, toxic neuropathy, vascular headache
Eye disorders
common
Dry eye
Uncommon
Blurred vision, lenticular opacity, astigmatism, cortical cataract, eye pain, lacrimation increased, retinal haemorrhage, retinal pigment epitheliopathy, visual acuity decreased, visual impairment, visual acuity test abnormalities, blepharitis and keratoconjunctivitis sicca
Ear and labyrinth disorders
Uncommon
Ear pain, dizziness
Cardiac pathologies
Uncommon
Tachycardia, acute myocardial infarction, cardiovascular disorders, cyanosis, sinus tachycardia, QT prolongation of the electrocardiogram
Vascular pathologies
Uncommon
Deep vein thrombosis, embolism, flushing, superficial thrombophlebitis, redness, hematoma
Respiratory, thoracic and mediastinal disorders
common
Cough ?, oropharyngeal pain ?, rhinorrhea?
Uncommon
Pulmonary embolism, pulmonary infarction, nose discomfort, oropharynx blistering, oropharynx pain, sinus disorder, sleep apnea syndrome
Gastrointestinal disorders
common
Nausea, diarrhea *, mouth ulcerations, toothache?
* Very common in pediatric ITP patients
Uncommon
Dry mouth, vomiting, abdominal pain, glossodynia, bleeding in the mouth, abdominal tension, discolored stools, flatulence, food poisoning, frequent abdominal movements, haematemesis, mouth discomfort
Hepatobiliary disorders
common
Alanine aminotransferase * increased, aspartate aminotransferase * increased, hyperbilirubinaemia, liver function abnormalities
Uncommon
Cholestasis, liver injury, hepatitis, drug induced liver injury
* Elevation of alanine aminotransferase and aspartate aminotransferase may occur simultaneously, albeit at a lower frequency.
Skin and subcutaneous tissue disorders
common
Rash, alopecia
Uncommon Hyperhidrosis, generalized itching, urticaria, dermatosis, petechiae, cold sweats, erythema, melanosis, pigmentation disorders, skin discolouration, skin peeling
Musculoskeletal and connective tissue disorders
common
Myalgia, muscle spasms, musculoskeletal pain, bone pain, back pain
Uncommon
Muscle weakness
Renal and urinary disorders
Uncommon
Renal failure, leukocyturia, lupoid nephritis, nocturia, proteinuria, blood urea increased, blood creatinine increased, protein / creatinine ratio increased
Diseases of the reproductive system and breast
common
Menorrhagia
General disorders and administration site conditions
common
Pyrexia?
Uncommon
Chest pain, feeling hot, bleeding at the parenteral injection site, asthenia, feeling jittery, wound inflammation, malaise, pyrexia, foreign body sensation
Diagnostic tests
Uncommon
Increased blood albumin, increased blood alkaline phosphatase, increased total protein, decreased blood albumin, increased urinary pH
Injury, poisoning and procedural complications
Uncommon
Sunburn
? Additional adverse reactions observed in pediatric population studies (1 to 17 years)
HCV infected clinical trial population (in combination with interferon and ribavirin antiviral therapy)
Infections and infestations
common
Urinary tract infections, upper respiratory tract infections, bronchitis, nasopharyngitis, flu, oral herpes, gastroenteritis, pharyngitis.
Neoplasms benign, malignant and unspecified (including cysts and polyps)
common
Malignant liver tumor
Disorders of the blood and lymphatic system
Very common
Anemia
common lymphocytopenia, haemolytic anemia
Metabolism and nutrition disorders
Very common
Decreased appetite
common
Hyperglycemia, abnormal weight loss
Psychiatric disorders
Very common
Insomnia
common
Depression, anxiety, sleep disturbances, confusion, agitation
Nervous system disorders
Very common
Headache
common
Dizziness, attention disturbance, dysgeusia, hepatic encephalopathy, lethargy, memory disturbances, paraesthesia
Eye disorders
common
Cataract, retinal exudates, dry eye, scleral jaundice, retinal haemorrhage
Ear and labyrinth disorders
common
Dizziness
Cardiac pathologies
common
Palpitations
Respiratory, thoracic and mediastinal disorders
Very common
Cough
common
Dyspnoea, oropharyngeal pain, dyspnea on exertion, productive cough
Gastrointestinal disorders
Very common
Nausea, diarrhea
common
Vomiting, ascites, abdominal pain, upper abdominal pain, dyspepsia, dry mouth, constipation, abdominal distension, toothache, stomatitis, oesophageal reflux disease, haemorrhoids, abdominal discomfort, gastritis, esophageal varices, aphthous stomatitis, esophageal varices
Hepatobiliary disorders
common
Hyperbilirubinaemia, jaundice, portal vein thrombosis, liver failure, drug-induced liver injury
Skin and subcutaneous tissue disorders
Very common
Itching, alopecia
common
Rash, dry skin, eczema, pruritic rash, erythema, hyperhidrosis, generalized itching, night sweats, skin lesions
Uncommon
Skin discolouration, skin hyperpigmentation
Musculoskeletal and connective tissue disorders
Very common
Myalgia
common
Arthralgia, muscle spasms, back pain, pain in extremity, musculoskeletal pain, bone pain
Renal and urinary disorders
Uncommon
Dysuria
General disorders and administration site conditions
Very common
Pyrexia, fatigue, flu-like illness, asthenia, chills, peripheral edema
common
Irritability, pain, malaise, injection site reactions, non-cardiac chest pain, edema, injection site rash, chest discomfort, injection site pruritus
Diagnostic tests
common
Blood bilirubin increased, weight decreased, white blood cell count decreased, hemoglobin decreased, neutrophil count decreased, International normalized ratio (INR) increased, activated partial thromboplastin time prolonged, increased blood glucose, blood albumin reduction, QT prolongation in the electrocardiogram
Population of the clinical study in AAS
Disorders of the blood and lymphatic system
common
Neutropenia, splenic infarction
Metabolism and nutrition disorders
common
Iron overload, loss of appetite, hypoglycemia, increased appetite
Psychiatric disorders
Very common
Insomnia
common
Anxiety, depression
Nervous system disorders
Very common
Headache, dizziness
common
Syncope
Eye disorders
common
Dry eye, eye itching, cataract, ocular jaundice, blurred vision, visual impairment, floaters
Respiratory, thoracic and mediastinal disorders
Very common
Cough, dyspnoea, oropharynx pain, rhinorrhea
common
Epistaxis
Gastrointestinal disorders
Very common
Abdominal pain, diarrhea, nausea
common
Gingival bleeding, oral mucosal blisters, oral pain, vomiting, abdominal discomfort, abdominal pain, constipation, abdominal distension, dysphagia, discolored stools, swollen tongue, intestinal motility disturbances, flatulence
Hepatobiliary disorders
Very common
Increased transaminases
common
Increased blood bilirubin (hyperbilirubinemia), jaundice
Not known
Drug-induced liver injury *
* Cases of drug-induced liver injury have been reported in ITP and HCV patients
Skin and subcutaneous tissue disorders
Very common
Bruising
common
Petechiae, rash, itching, hives, skin lesions, macular rash
Uncommon
Skin discolouration, skin hyperpigmentation
Musculoskeletal and connective tissue disorders
Very common
Arthralgia, muscle spasms, pain in extremities
common
Back pain, myalgia, bone pain
Renal and urinary disorders
common
Chromaturia
General disorders and administration site conditions
Very common
Fatigue, febrile neutropenia, pyrexia
common
Asthenia, peripheral edema, chills, malaise
Diagnostic tests
common
Blood creatinine phosphokinase increased
Description of selected adverse reactions
Thrombotic / thromboembolic events (TEE)
In 3 controlled and 2 uncontrolled clinical trials, among adult patients with chronic ITP receiving eltrombopag (n = 446), 17 subjects experienced a total of 19 thromboembolic events, which included (in order of decreasing frequency) 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).
In a placebo-controlled study (n = 288, safety population), after 2 weeks of treatment in preparation for invasive procedures, 6 of 143 (4%) adult patients with chronic liver disease receiving eltrombopag experienced 7 TEEs. portal venous system and 2 of 145 subjects (1%) in the placebo group had 3 TEEs. Five of the 6 patients treated with eltrombopag had TEEs with a platelet count> 200,000 / μl.
No specific risk factors were identified in those subjects who experienced a TEE, except for a platelet count ≥ 200,000 / microliter (see section 4.4).
In controlled studies in thrombocytopenic HCV-infected patients (n = 1439), 38 of 955 (4%) subjects treated with eltrombopag had TEEs and 6 of 484 subjects (1%) in the placebo group had TEEs. Portal vein thrombosis was the most common TEE in both treatment groups (2% in patients treated with eltrombopag versus
Liver failure (use with interferon)
Chronic HCV hepatitis patients with cirrhosis may be at risk for hepatic decompensation when receiving alpha interferon therapy. In 2 controlled clinical trials in thrombocytopenic patients with HCV infection, hepatic decompensation (ascites, hepatic encephalopathy, variceal haemorrhage, spontaneous bacterial peritonitis) was reported more frequently in the eltrombopag arm (11%) than in the placebo arm ( 6%). In patients with low albumin levels (≤ 35 g / L) or MELD score ≥ 10 at baseline, there was a three times higher risk of hepatic decompensation and an increased risk of fatal adverse event compared to those with less liver disease. advanced. Eltrombopag should only be administered to such patients after careful consideration of the expected benefits versus the risks. Patients with these characteristics should be carefully monitored for signs and symptoms of hepatic decompensation (see section 4.4).
Thrombocytopenia after discontinuation of treatment
In the 3 ITP-controlled clinical trials, transient decreases in platelet counts to below baseline levels following discontinuation of treatment were observed in 8% of the eltrombopag group and 8% of the placebo group, respectively (see section 4.4 ).
Increased reticulin in the bone marrow
In the program, no patients had evidence of clinically relevant bone marrow abnormalities or clinical signs indicating bone marrow dysfunction. In a small number of ITP patients, eltrombopag treatment was discontinued due to marrow reticulin. bone (see section 4.4).
Cytogenetic anomalies
In the single-arm, open-label clinical study in AAS, patients underwent bone marrow aspirates for evaluation of cytogenetic abnormalities. A new cytogenetic abnormality was reported in eight (19%) patients, including 5 patients in whom a chromosome 7 alteration was found. In the two ongoing studies (ELT116826 and ELT116643), cytogenetic abnormalities were found in 4/28 (14%) and 4/62 (6%) subjects respectively.
Hematological neoplasms
In three (7%) patients in the single-arm, open-label AAS clinical study, MDS was diagnosed after treatment with eltrombopag, in the two ongoing studies (ELT116826 and ELT116643), MDS or AML was diagnosed in 1 / 28 (4%) and 1/62 (2%) subjects in each study.
Reporting of suspected adverse reactions
The reporting of suspected adverse reactions that occur after the authorization of the medicinal product is important, as it allows continuous monitoring of the benefit / risk ratio of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the Italian Medicines Agency. , website: www.agenziafarmaco.gov.it/it/responsabili.
04.9 Overdose
In the event of an overdose, the platelet count may rise excessively and lead to thrombotic / thromboembolic complications. In the event of an overdose, consideration should be given to oral administration of a preparation containing a metal cation, such as calcium, aluminum or magnesium preparations, to chelate eltrombopag and thus limit its absorption. Platelet counts should be monitored closely. Treatment with eltrombopag should be restarted according to the dosage and administration recommendations (see section 4.2).
In clinical trials there was a report of overdose in which the subject ingested 5000 mg of eltrombopag. Adverse reactions reported included mild rash, transient bradycardia, ALT and AST elevation, and fatigue. Liver enzymes measured between Day 2 and 18 after ingestion had a peak in AST at 1.6 times l "ULN, and ALT at 3.9 times l" ULN, and total bilirubin at 2.4 times l. "ULN. The platelet count was 672,000 / μl on day 18 after ingestion and the maximum platelet count was 929,000 / μl. All events resolved without sequelae after treatment.
Since eltrombopag is not significantly renally excreted and is highly bound to plasma proteins, hemodialysis is not expected to be an effective method of increasing eltrombopag elimination.
05.0 PHARMACOLOGICAL PROPERTIES
05.1 Pharmacodynamic properties
Pharmacotherapeutic group: antihaemorrhagics, other systemic haemostats.
ATC code: B02BX 05.
Mechanism of action
Thrombopoietin (TPO) is the major cytokine involved in the regulation of megakarypoiesis and the production of platelets, and is the endogenous ligant for the TPO receptor (TPO-R). Eltrombopag interacts with the transmembrane domain of human TPO-R and initiates the signal cascade similar but not identical to that of endogenous TPO, inducing proliferation and differentiation from bone marrow progenitor cells.
Clinical efficacy and safety
Studies in chronic autoimmune (idiopathic) thrombocytopenia (ITP)
Two Phase III, randomized, double-blind, placebo-controlled studies, RAISE (TRA102537) and TRA100773B and two open-label studies, REPEAT (TRA108057) and EXTEND (TRA105325) evaluated the safety and efficacy of eltrombopag in adult patients with previously treated chronic ITP.
Overall, eltrombopag was administered to 277 patients with ITP for at least 6 months and to 202 patients for at least 1 year.
Double-blind placebo-controlled studies
RAISE: 197 patients with ITP were randomized in a 2: 1 ratio to eltrombopag (n = 135) and placebo (n = 62), and randomization was stratified by splenectomy, baseline use for TPI and baseline platelet count. The dose of eltrombopag was adjusted during the 6 month treatment period based on the individual platelet count. All patients started on eltrombopag 50 mg. Day 29 to end of treatment, from Day 15 28% of eltrombopag-treated patients were maintained at ≤ 25 mg and 29 to 53% received 75 mg.
In addition, patients could progressively taper off concomitant ITP medications and receive rescue treatments as directed by local treatment guidelines. More than half of all patients in each treatment group had ≥ 3 prior ITP therapies and 36% had prior splenectomy.
The median baseline platelet count was 16,000 / μl for both treatment groups and in the eltrombopag group it remained above 50,000 / μl at all visits during therapy, starting on Day 15; however, the median platelet count in the placebo group remained
Platelet count response between 50,000-400,000 / μl in the absence of salvage treatment was achieved by significantly higher numbers of patients in the eltrombopag group during the 6-month treatment period, p
Table 4: Secondary efficacy results from the RAISE study
a Logistic regression model adjusted for randomized stratification variables
b 21 out of 63 (33%) patients treated with eltrombopag who were taking a basic ITP medicine permanently discontinued all basic ITP medicines.
At baseline, more than 70% of ITP patients in each treatment group reported bleeding of any type (WHO Grade 1-4) and more than 20% reported clinically significant bleeding (WHO Grade 2-4) , respectively. The proportion of eltrombopag-treated patients with bleeding of any type (Grades 1-4) and clinically significant bleeding (Grades 2-4) decreased from baseline by approximately 50% from Day 15 to the end of treatment throughout the period of 6 months treatment.
TRA100773B: L "endpoint primary efficacy was the proportion of responders, defined as patients with ITP who had an increase in platelet count to ≥ 50,000 / μl on Day 43 from a baseline value of 200,000 / μl were considered responders, those who discontinued for any other reason were considered non-responders regardless of the platelet count. A total of 114 patients with previously treated chronic ITP were randomized 2: 1 to eltrombopag (n = 76) and placebo (n = 38).
Table 5: Efficacy results from TRA100773B study
a - Logistic regression model adjusted for randomized stratification variables
In both RAISE and TRA100773B, the response to eltrombopag compared to placebo was similar regardless of the ITP drug in use, splenectomy and baseline platelet count (≤ 15,000 / μl,> 15,000 / μl) at randomization.
In studies RAISE and TRA100773B in the subgroup of ITP patients with baseline platelet count ≤ 15,000 / μl the required level (> 50,000 / μl) of the median platelet count was not achieved, although in both studies 43% of these patients treated with eltrombopag they responded at the end of the 6-week treatment period. In addition, in the RAISE study, 42% of patients with baseline platelet counts ≤ 15,000 / μl treated with eltrombopag responded at the end of the 6 month treatment period. Forty-two to 60% of eltrombopag-treated patients in the RAISE study received 75 mg from Day 29 to the end of treatment.
An open label, repeated dose study (3 courses of 6 weeks of treatment, interspersed with 4 weeks without treatment) showed that episodic use with multiple courses of eltrombopag did not result in a reduction in response.
Eltrombopag was administered to 302 patients with ITP in the open-label continuation study EXTEND (TRA105325), 218 completed 1 year, 180 completed 2 years, 107 completed 3 years, 75 completed 4 years, 34 completed 5 years and 18 completed 6 years. Median platelet count at baseline was 19,000 / μl prior to eltrombopag administration. The median platelet counts at 1, 2, 3, 4, 5, 6, and 7 years of the study were 85,000 / microliter, 85,000 / microliter, 105,000 / microliter, 64,000 / microliter, 75,000 / microliter, 119,000 / microliter, and 76,000 / microliter microliter, respectively.
No clinical studies have been conducted comparing eltrombopag to other therapeutic options (e.g. splenectomy). The long-term safety of eltrombopag should be considered prior to initiation of treatment.
Pediatric population (aged 1-17 years)
The safety and efficacy of eltrombopag in pediatric subjects was evaluated in two studies. TRA115450 (PETIT2): The primary endpoint was sustained response, defined as the proportion of subjects treated with eltrombopag, compared to placebo, who achieved platelet counts ≥50,000 / mcl for at least 6 of 8 weeks (in the absence of salvage therapy), among the weeks 5 and 12 during the randomized double-blind period. Subjects who had been diagnosed with chronic ITP for at least 1 year and who were refractory or relapsed to at least one prior ITP therapy or unable to continue other ITP treatments for a reason and had a platelet count
Overall, a significantly higher percentage of subjects in the eltrombopag group (40%) achieved the primary endpoint (Odds Ratio: 18.0 [95% CI: 2.3, 140.9] p
Table 6: Sustained Platelet Response Rates by Cohort Age in Pediatric Subjects with Chronic ITP
Statistically fewer eltrombopag-treated subjects required rescue treatment during the randomized period than placebo-treated subjects (19% [12/63] vs 24% [7/29], p = 0.032).
At baseline, 71% of subjects in the eltrombopag group and 69% in the placebo group reported bleeding (WHO Grades 1-4). At week 12, the proportion of eltrombopag-treated subjects who reported bleeding was halved from baseline (36%). In comparison, at week 12, 55% of placebo-treated subjects reported no bleeding.
Subjects were allowed to reduce or discontinue background therapy for ITP only during the open-label phase of the study, and 53% (8/15) of subjects were able to reduce (n = 1) or discontinue (n = 7) basic therapy for ITP, mainly corticosteroids, without the need for rescue therapy.
TRA108062 (PETIT): The primary endpoint was the percentage of subjects who achieved platelet counts ≥50,000 / mcl at least once between weeks 1 and 6 of the randomized period. Subjects were refractory or relapsed to at least one prior ITP therapy and with a platelet
Overall, a significantly higher percentage of subjects in the eltrombopag group (62%) achieved the primary endpoint (Odds Ratio: 4.3 [95% CI: 1.4, 13.3] p = 0.011).
Sustained response was observed in 50% of initial respondents at 20 of 24 weeks in the PETIT 2 study and 15 of 24 weeks in the PETIT study.
Studies in thrombocytopenia associated with chronic HCV hepatitis
The efficacy and safety of eltrombopag for the treatment of thrombocytopenia in HCV-infected patients were evaluated in two randomized, double-blind, placebo-controlled studies. ENABLE 1 used peginterferon alfa-2a plus ribavirin for antiviral treatment and ENABLE 2 used peginterferon alfa-2b plus ribavirin. Patients did not receive direct-acting antiviral agents. In both studies, patients with screened platelet counts were enrolled (
Disease characteristics at baseline were similar in both studies and were consistent with the HCV-infected patient population with compensated cirrhosis. Most patients had HCV genotype 1 (64%) and had bridging fibrosis / cirrhosis. Thirty-one percent of patients had previously been treated with therapies for HCV infection, mainly pegylated interferon plus ribavirin. Median platelet count at baseline was 59,500 / μl in both treatment groups: 0.8%, 28 % and 72% of the recruited patients had platelet counts
The studies consisted of two phases - an antiviral pre-treatment phase and an antiviral treatment phase. In the antiviral pre-treatment phase, subjects received open-label eltrombopag to increase platelet counts to ≥ 90,000 / mcl for ENABLE 1 and ≥ 100,000 / mcl for ENABLE 2. Median time to reach platelet count goal ≥ 90,000 / mcl (ENABLE 1) or ≥ 100,000 / mcl (ENABLE 2) was 2 weeks.
L"endpoint primary efficacy for both studies was sustained virologic response (sustained virologic response, SVR), defined as the percentage of patients with HCV infection with undetectable HCV RNA at 24 weeks after completion of the planned treatment period.
In both HCV-infected studies, a significantly higher proportion of eltrombopag-treated patients (n = 201, 21%) achieved SVR compared to those treated with placebo (n = 65, 13%) (see Table 7). . The improvement in the proportion of patients achieving SVR was consistent across all subgroups across the randomization strata (baseline platelet count (vs.> 50,000), viral load (vs. ≥ 800,000 IU / mL), and genotype (2 / 3 vs. 1/4/6).
Table 7: Virological response of patients with HCV infection in ENABLE 1 and ENABLE 2
a Eltrombopag given in combination with peginterferon alfa-2a (180 μg once weekly for 48 weeks for genotypes 1/4/6; for 24 weeks for genotypes 2/3) plus ribavirin (from 800
at 1200 mg per day in 2 divided doses orally)
b Eltrombopag administered in combination with peginterferon alfa-2b (1.5 mcg / kg once weekly for 48 weeks for genotype 1/4/6; for 24 weeks for genotype 2/3) plus ribavirin (800 to 1400 mg orally in 2 divided doses)
c Target platelet count was ≥ 90,000 / mcl for ENABLE 1 and ≥ 100,000 / mcl for ENABLE 2. For ENABLE 1, 682 patients were randomized to the antiviral treatment phase; however 2 subjects then withdrew their consent before receiving antiviral therapy.
d value p versus placebo
and 64% of the subjects participating in the ENABLE 1 and ENABLE 2 study had genotype 1
f Post-hoc analyses
Other secondary observations from the studies included the following: Significantly fewer patients treated with eltrombopag had prematurely discontinued antiviral therapy compared to those treated with placebo (45% vs. 60%, p = versus 27%). Treatment with eltrombopag delayed and decreased the number of peginterferon dose reductions.
Severe Aplastic Anemia
Eltrombopag was studied in a single-arm, single-center, open-label clinical study in 43 patients with severe aplastic anemia with refractory thrombocytopenia after at least one prior immunosuppressive therapy (STI) and with a platelet count ≤ 30,000 / μl.
Most of the subjects, 33 (77%), were considered to have a "primary refractory disease", defined as the "absence of an adequate first response to immunosuppressive therapy in any line. The remaining 10 subjects had a platelet response. insufficient on previous therapies. All 10 received had undergone at least 2 previous immunosuppressive therapy regimens, and 50% had received at least 3 previous immunosuppressive therapy regimens. Patients diagnosed with anemia
Fanconi, infection unresponsive to appropriate therapy, a PNH clone in neutrophils of size ≥ 50%, were excluded from the study.
At baseline the median platelet count was 20,000 / μl, the hemoglobin was 8.4 g / dL, the absolute neutrophil count was 0.58 x 109 / l and the absolute reticulocyte count was 24.3 x109 / 1. Eighty-six percent of patients were dependent on erythrocyte transfusions, and 91% were dependent on platelet transfusions. Most patients (84%) had received at least 2 prior immunosuppressive therapies. Three patients had cytogenetic abnormalities at baseline.
The primary endpoint was haematological response assessed after 12 weeks of treatment with eltrombopag. Haematological response was defined as achievement of one or more of the following criteria: 1) increase in platelet count to 20,000 / μl above baseline or platelet count stable with transfusion independence for a minimum of 8 weeks; 2) an increase in hemoglobin of> 1.5 g / dl, or a reduction in transfusions of ≥ 4 units of red blood cells (RBC) for 8 consecutive weeks; 3) increase in absolute neutrophil count (ANC) by 100% or increase in ANC> 0.5 x 109 / L.
The haematological response rate was 40% (17/43 patients; 95% CI 25, 56), and the majority of responses were limited to a single line (13 / 17.76%) while 3 responses were recorded. bi-linear and 1 tri-linear response at week 12. Eltrombopag was discontinued after 16 weeks if no haematologic response or transfusion independence was observed. Responders continued therapy in an extension phase of the study. A total of 14 patients took part in the extension phase of the study. Nine of these patients achieved a multi-linear response, 4 of 9 continued treatment and 5 declined gradually with eltrombopag treatment and maintaining response (follow up). median: 20.6 months, range: 5.7 to 22.5 months) The remaining 5 patients discontinued treatment, three due to a relapse observed at the third month visit of the extension phase.
During treatment with eltrombopag 59% (23/39) became independent of platelet transfusion (28 days without a platelet transfusion) and 27% (10/37) became independent of RBC transfusion (56 days without transfusion of RBC). The longest platelet transfusion-free period for non-responders was 27 days (median). The longest platelet transfusion-free period for responders was 29 days (median). The longest erythrocyte transfusion-free period for responders was 266 days (median).
Over 50% of responders who were transfusion dependent at baseline had a> 80% reduction in need for both platelet and RBC transfusions from baseline.
Preliminary results from a supportive study (Study ELT116826), an ongoing non-randomized, phase II, single-arm, open-label study in refractory subjects with AAS, showed consistent results. Data are limited to 21 of the 60 predicted patients, and a haematological response was seen in 52% of patients at 6 months. Multi-linear responses were reported in 45% of patients.
05.2 Pharmacokinetic properties
Pharmacokinetics
Eltrombopag plasma concentration data - time collected in 88 ITP patients in TRA100773A and TRA100773B were combined with data from 111 healthy adult subjects in a population pharmacokinetic analysis. Estimates of the plasma AUC (0-?) And Cmax values of eltrombopag in patients with ITP are presented (Table 8).
Table 8: Geometric mean (95% confidence interval) of eltrombopag plasma pharmacokinetic parameters at steady state in adults with ITP
a - Estimates of AUC (0-?) and Cmax based on post-hoc population pharmacokinetic values.
Data on plasma concentrations over time of eltrombopag collected in 590 HCV infected subjects enrolled in the phase III studies TPL103922 / ENABLE 1 and TPL108390 / ENABLE 2 were combined with data from HCV infected patients enrolled in the phase II study TPL102357 and healthy adult subjects in a population pharmacokinetic analysis. Estimates of eltrombopag plasma Cmax and AUC (0-?) In HCV-infected patients enrolled in phase 3 studies are listed for each dose in Table 9.
Table 9 Geometric mean (95% CI) allo steady-state eltrombopag plasma pharmacokinetic parameters in patients with chronic HCV infection
Data presented as geometric mean (95% CI).
AUC (0-?) And Cmax based on estimates post-hoc population pharmacokinetics at the highest dose in each patient data.
Absorption and bioavailability
Eltrombopag is absorbed with a peak concentration occurring 2 to 6 hours after oral administration. 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).. In a relative bioavailability study in adults, eltrombopag powder for oral suspension achieved a 22% higher plasma AUC (0-?) Compared to the tablet formulation. The absolute oral bioavailability of eltrombopag following human administration has not been established. Based on urinary excretion and metabolites excreted in faeces, oral absorption of drug-related substances following administration of a single dose of a solution from 75 mg of eltrombopag was estimated to be at least 52%.
Distribution
Eltrombopag is highly bound to human plasma proteins (> 99.9%), predominantly albumin. Eltrombopag is a BCRP substrate, but is not a P-glycoprotein or OATP1B1 substrate.
Biotransformation
Eltrombopag is primarily metabolised by cleavage, oxidation and conjugation with glucuronic acid, glutathione or cysteine. In a radio-labeled human study, eltrombopag accounts for approximately 64% of the AUC0-? plasma concentration of radiolabeled coal. Minor metabolites due to glucuronidation and oxidation were also found. Education in vitro suggest that CYP1A2 and CYP2C8 are responsible for the oxidative metabolism of eltrombopag. The uridine diphosphoglucuronyl transferases UGT1A1 and UGT1A3 are responsible for glucuronidation, and bacteria from the lower gastrointestinal tract may be responsible for cleavage.
Elimination
Once absorbed, eltrombopag is extensively metabolised. The predominant route of eltrombopag excretion is via the faeces (59%) with 31% of the dose found in the urine as metabolites. The unchanged compound (eltrombopag) is not detected in the urine. Unchanged eltrombopag excreted in the faeces represents approximately 20% of the dose. The plasma elimination half-life of eltrombopag is approximately 21-32 hours.
Pharmacokinetic interactions
Based on a study in humans with radiolabelled eltrombopag, glucuronidation plays a minor role in the metabolism of eltrombopag. Studies in human liver microsome have identified UGT1A1 and UGT1A3 as the enzymes responsible for the glucuronidation of eltrombopag. Eltrombopag is an inhibitor of several UGT enzymes. in vitro. Clinically significant drug interactions involving glucuronidation are not anticipated due to the limited contribution of individual UGT enzymes in eltrombopag glucuronidation and potential co-administered drugs.
Approximately 21% of an eltrombopag dose could undergo oxidative metabolism. Studies in human liver microsome have identified CYP1A2 and CYP2C8 as the enzymes responsible for the oxidation of eltrombopag. Eltrombopag does not inhibit or induce CYP enzymes based on data in vitro and in vivo (see section 4.5)
Education in vitro demonstrated that eltrombopag is an inhibitor of the transporter OATP1B1 and is an inhibitor of the transporter BCRP and eltrombopag in a clinical interaction study increases the exposure of OATP1B1 and BCRP of the rosuvastatin substrate (see section 4.5). In clinical studies with eltrombopag, it has been a 50% dose reduction of statins recommended. Co-administration of 200 mg cyclosporine (BCRP inhibitor) reduced eltrombopag Cmax and AUCinf by 25% and 18%, respectively. Co-administration of 600 mg cyclosporine reduced eltrombopag Cmax and AUCinf by 39% and 24%, respectively.
Eltrombopag chelates polyvalent cations such as iron, calcium, magnesium, aluminum, selenium and zinc (see sections 4.2 and 4.5).
Administration of a single 50 mg dose of eltrombopag in tablets with a standard high-calorie meal, a high-fat breakfast that included dairy products, reduced the mean plasma AUC of eltrombopag by 59% and Cmax. average of 65%.
Administration of a single 25 mg dose of eltrombopag powder for oral suspension with a meal high in calcium, moderate fat and calories reduced the mean plasma AUC0-? Of eltrombopag by 75% and mean Cmax by 79%. This decrease in exposure was attenuated when a single 25 mg dose of eltrombopag powder for oral suspension was administered 2 hours before a high-calcium meal (mean AUC0-? Decreased by 20% and Mean Cmax of 14%).
Low-calcium foods (fruit, lean ham, beef and fruit juice without added calcium, magnesium or iron), soy milk without added and wheat has no significant impact on plasma exposure of eltrombopag, regardless of the calorie and fat content (see sections 4.2 and 4.5).
Special patient populations
Kidney failure
The pharmacokinetics of eltrombopag were studied following administration of eltrombopag to adult subjects with renal insufficiency. Following administration of a single 50 mg dose, the AUC0-? Of eltrombopag was 32% to 36% lower in subjects with mild to moderate renal impairment, and 60% lower in subjects with severe renal impairment. compared to healthy volunteers. There was substantial variability and significant overlap in exposures between patients with renal insufficiency and healthy volunteers. Free (active) eltrombopag concentrations for this highly protein bound medicinal product were not measured. patients with impaired renal function should use eltrombopag with caution and under careful monitoring, for example by performing serum creatinine and / or urinalysis (see section 4.2). The efficacy and safety of eltrombopag have not been established. in subjects with both moderate to severe renal insufficiency and hepatic insufficiency.
Hepatic insufficiency
The pharmacokinetics of eltrombopag were studied following administration of eltrombopag to adult subjects with hepatic insufficiency. Following administration of a single 50 mg dose, the AUC0-? Of eltrombopag was 41% higher in subjects with mild hepatic impairment, and 80% to 93% higher in subjects with moderate to moderate hepatic impairment. severe, compared to healthy volunteers. There was substantial variability and significant overlap in exposures between patients with hepatic insufficiency and healthy volunteers. Free (active) eltrombopag concentrations for this highly protein bound medicinal product have not been measured.
The influence of hepatic insufficiency on eltrombopag pharmacokinetics following repeated administration was evaluated using a population pharmacokinetic analysis in 28 healthy adults and 714 patients with hepatic insufficiency (673 patients with HCV infection and 41 patients with liver disease chronic of other etiology). Of these 714 patients, 642 had mild hepatic insufficiency, 67 had moderate hepatic insufficiency and 2 had severe hepatic insufficiency. Compared to healthy volunteers, patients with mild hepatic impairment had plasma eltrombopag AUC (0-?) Values greater than approximately 111% (95% CI: 45% to 283%) and patients with moderate hepatic impairment had plasma values eltrombopag AUC (0-?) greater than approximately 183% (95% CI: 90% to 459%).
Therefore, eltrombopag should not be used in ITP patients with moderate to severe hepatic impairment (Child-Pugh score ≥ 5) unless the expected benefit outweighs the identified risk of portal vein thrombosis (see sections 4.2 and 4.4). For HCV infected patients start eltrombopag at a dose of 25 mg once daily (see section 4.2).
Race
The influence of East Asian ethnicity in eltrombopag pharmacokinetics was evaluated using population pharmacokinetic analysis in 111 healthy adults (31 East Asians) and 88 patients with ITP (18 East Asians). Based on the estimates. From population pharmacokinetic analyzes, East Asian ITP patients (such as Japanese, Chinese, Taiwanese and Koreans) had approximately 49% higher plasma eltrombopag AUC (0-?) values compared to non-East Asian patients, who were predominantly Caucasian (see section 4.2).
The influence of East Asian ethnicity (such as Chinese, Japanese, Taiwanese, Korean and Thai) on eltrombopag pharmacokinetics was evaluated using a population pharmacokinetic analysis in 635 HCV infected patients (145 East Asians and 69 South East Asians) Based on estimates from the population pharmacokinetic analysis, patients of East Asian ethnicity had approximately 55% higher plasma eltrombopag AUC (0-?) values compared to patients of other races, which they were predominantly Caucasian (see section 4.2).
Sex
The influence of gender on eltrombopag pharmacokinetics was evaluated using population pharmacokinetic analysis in 111 healthy adults (14 female) in 88 ITP patients (57 female).Based on estimates from population pharmacokinetic analyzes, female ITP patients had approximately 23% greater plasma eltrombopag AUC (0-?) Values compared to male patients, with no adjustments for weight differences. bodily.
The influence of gender on eltrombopag pharmacokinetics was evaluated using population pharmacokinetic analysis in 635 HCV-infected patients (260 females). Based on model estimates, female patients with HCV infection had approximately 41% higher plasma eltrombopag AUC (0-?) Values compared to male patients.
Age
The influence of age on eltrombopag pharmacokinetics was evaluated using population pharmacokinetic analysis in 28 healthy subjects, 673 patients with HCV infection and 41 patients with chronic liver disease of other etiology with an age range of 19. age 74. No pharmacokinetic data are available on the use of eltrombopag in patients ≥ 75 years of age. Based on model estimates, elderly patients (≥ 65 years) had approximately 41% higher plasma eltrombopag AUC (0-?) Values compared to younger patients (see section 4.2).
Pediatric population (aged 1-17 years)
The pharmacokinetics of eltrombopag were evaluated in 168 pediatric subjects with ITP in two once daily studies, TRA108062 / PETIT and TRA115450 / PETIT-2. The apparent plasma clearance of eltrombopag following oral administration (CL / F) increased with increasing body weight.
The effects of race and gender on plasma eltrombopag CL / F estimates were consistent between pediatric and adult patients. East Asian pediatric ITP patients had approximately 43% higher plasma eltrombopag AUC (0-?) Compared to non-East Asian patients. Female pediatric ITP patients had an approximately 25% increase in plasma AUC. "Plasma AUC (0-?) Of eltrombopag compared to male patients.
The pharmacokinetic parameters of eltrombopag in pediatric subjects with ITP are shown in Table 10.
Table 10. Geometric mean (95% CI) of steady-state pharmacokinetic parameters of eltrombopag plasma concentration in pediatric subjects with ITP (50 mg once daily dosing regimen)
Data presented as geometric mean (95% CI). AUC (0-?) And Cmax are based on post-hoc population pharmacokinetic estimates.
05.3 Preclinical safety data
Eltrombopag does not stimulate platelet production in mice, rats or dogs due to the specificity of the unique TPO receptor. Therefore, data derived from these animals do not represent a complete model for evaluating the potential pharmacology-related adverse effects of eltrombopag in humans. including reproductive and carcinogenic studies.
Treatment-related cataracts were detected in rodents and were dose- and time-dependent. At exposures greater than 6 times the human clinical exposure in adult ITP patients at a dose of 75 mg / day and at exposures 3 times the human clinical exposure in HCV-infected adult patients at 100 mg / day, exposures based on AUC, cataracts were observed in mice after 6 weeks and in rats after 28 weeks of treatment. At exposures greater than or equal to 4 times the human clinical exposure in ITP patients at 75 mg / day and Exposures 2 times the human clinical exposure in HCV infected patients at a dose of 100 mg / day, exposures based on AUC, cataracts were observed in mice after 13 weeks and in rats after 39 weeks of treatment. At non-tolerated doses in juvenile pre-weaning rats administered from day 4 to 32 (approximately 2 human years at the end of the dosing period), ocular opacities (histology not performed) were observed at equal doses of 75 mg / day. to 9 times the maximum human clinical exposure in pediatric ITP patients, based on AUC. However, no cataract was observed in juvenile rats given tolerated doses of 5 times the human clinical exposure in pediatric ITP patients, based on AUC. No cataract was observed in adult dogs after 52 weeks. treatment (2 times the clinical exposure in humans in adult or pediatric patients with ITP at a dose of 75 mg / day and equivalent to the clinical exposure in humans in patients with HCV infection at a dose of 100 mg / day, based on the AUC).
In studies in mice and rats up to 14 days in duration, renal tubular toxicity was observed at exposures that were generally associated with morbidity and mortality. Tubular toxicity was also observed in a 2-year oral carcinogenicity study in mice at doses of 25, 75 and 150 mg / kg / day. Effects were less severe at lower doses and were characterized by a range of regenerative modifications. The exposure at the lowest dose was 1.2 or 0.8 times the human clinical exposure based on AUC in adult or pediatric ITP patients at 75 mg / day and 0.6 times L. human clinical exposure in HCV patients at a dose of 100 mg / day, exposures based on AUC. Renal effects were not observed in the rat after 28 weeks or in the dog after 52 weeks at exposures 4 and 2 times the clinical exposure. in humans in adult ITP patients and 3 and 2 times the human clinical exposure in pediatric patients with ITP at a dose of 75 mg / day and at exposures 2 times and equivalent to human clinical exposure in patients with HCV at a dose of 100 mg / day, exposures based on AUC.
Hepatocyte degeneration and / or necrosis, often accompanied by elevated serum liver enzymes, was observed in mice, rats and dogs at doses that were associated with morbidity and mortality or were poorly tolerated. No hepatic effects were observed after chronic treatment in rats (28 weeks) and dogs (52 weeks) at exposures 4 or 2 times the human clinical exposure in adult patients with ITP and exposures 3 or 2 times the clinical exposure. human in pediatric ITP patients at a dose of 75 mg / day and 2 times or equivalent to human clinical exposure in HCV infected patients at a dose of 100 mg / day, exposures based on AUC.
In short-term studies, at poorly tolerated doses in rats and dogs (exposure greater than 10 or 7 times the human clinical exposure in adult or pediatric ITP patients at a dose of 75 mg / day and exposure greater than 4 times l " human clinical exposure in HCV infected patients at a dose of 100 mg / day, exposures based on AUC), decreased reticulocyte counts and regenerative erythroid hyperplasia of the bone marrow (rat only) were observed. Notable effects on red blood cell or reticulocyte mass counts after treatment for up to 28 weeks in rats, 52 weeks in dogs and 2 years in mice or rats at maximally tolerated doses, which corresponded to 2 to 4-fold exposures human clinical exposure in adult or pediatric ITP patients at a dose of 75 mg / day and at exposures less than 2 times the human clinical exposure in HCV-infected patients at a dose of 100 mg / day, exposure ions based on AUC.
Endosteal hyperostosis was observed in a 28-week toxicity study in rats at an intolerable dose of 60 mg / kg / day (6 times or 4 times the human clinical exposure in adult or pediatric patients with ITP at a dose of 75 mg / day and 3 times the human clinical exposure in HCV infected patients at a dose of 100 mg / day, exposures based on AUC). No bone changes were observed in mice or rats after exposure to lifetime (2 years) at 4 or 2 times the human clinical exposure in adult or pediatric ITP patients at a dose of 75 mg / day and at 2 times the human clinical exposure in patients with HCV at a dose of 100 mg / day, exposures based on AUC.
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 up to 4 or 2 times the human clinical exposure in adult or pediatric patients with ITP at a dose of 75 mg / day and 2 times the human clinical exposure in patients with HCV infection at a dose of 100 mg / day, exposures based on AUC). Eltrombopag was not mutagenic or clastogenic in a test mutation on bacteria or in two tests in vivo in the rat (micronucleus and unscheduled DNA synthesis, 10 times or 8 times the human clinical exposure in adult or pediatric ITP patients at a dose of 75 mg / day and 7 times the human clinical exposure in patients with HCV infection at a dose of 100 mg / day, exposures based on Cmax). In the test in vitro on mouse lymphoma, eltrombopag was marginally positive (increased mutations). These observations in vitro And in vivo suggest that eltrombopag does not pose a genotoxic risk to humans.
Eltrombopag does not affect female fertility, early embryo development or embryo-fetal development in rats at doses up to 20 mg / kg / day (2 times the human clinical exposure in adult or adolescent patients (12 to 17 years) with ITP at a dose of 75 mg / day and equivalent to human clinical exposure in patients with HCV infection at a dose of 100 mg / day, exposures based on AUC). In addition, there was no effect on embryofoetal development in rabbits at doses up to 150 mg / kg / day, the highest dose tested (0.3 to 0.5 times the human clinical exposure in ITP patients at the dose of 75 mg / day and in HCV-infected patients at a dose of 100 mg / day, exposures based on AUC). human clinical exposure in patients with ITP at a dose of 75 mg / day and 3 times the human clinical exposure in patients with HCV infection at a dose of 100 mg / day, exposures based on AUC), treatment with eltrombopag was associated with embryonic lethality (increased pre- and post-implantation loss), decreased fetal body weight and weight of the pregnant uterus in the female fertility study and a low incidence of cervical ribs and decreased fetal body weight in the female fertility study. embryo-fetal development study Eltrombopag should only be used during pregnancy if the expected benefit justifies the potential risk to the fetus (see section 4.6). Eltrombopag did not affect fertility in male rats at doses up to 40 mg / kg / day, the highest dose tested (3 times the human clinical exposure in ITP patients at 75 mg / day and 2 times l " human clinical exposure in HCV infected patients at a dose of 100 mg / day, exposures based on AUC). In the rat pre- and postnatal development study, there were no adverse effects on pregnancy, parturition or lactation of female F0 rats at maternally non-toxic doses (10 and 20 mg / kg / day) and no effect on the growth, development, neurological behavior or reproductive function of the offspring (F1).
Eltrombopag was detected in the plasma of all F1 rat offspring during the entire 22 hour sampling period following drug administration to F0 mothers, suggesting that exposure of neonatal rats to eltrombopag was likely through lactation. .
Education in vitro with eltrombopag suggest a potential risk of phototoxicity; however, in rodents there was no evidence of cutaneous phototoxicity (10 or 7 times the human clinical exposure in adult or pediatric ITP patients at 75 mg / day and 5 times the human clinical exposure in patients with HCV infection at a dose of 100 mg / day, exposures based on AUC) or ocular phototoxicity (exposures greater than 4 times the human clinical exposure in adult or pediatric ITP patients at 75 mg / day and 3 times human clinical exposure in HCV infected patients at a dose of 100 mg / day, exposures based on AUC). Furthermore, a clinical pharmacology study in 36 subjects showed no evidence that photosensitivity was increased following administration of 75 mg of eltrombopag. This was measured by the delayed phototoxic index. However a potential risk of photoallergy cannot be excluded as specific preclinical studies cannot be performed.
There are no findings in juvenile rats suggesting a greater risk of toxicity with eltrombopag treatment in pediatric patients than in adults with ITP.
06.0 PHARMACEUTICAL INFORMATION
06.1 Excipients
Revolade 12.5 mg film-coated tablets
Core of the tablet
Magnesium stearate
Mannitol (E421)
Microcrystalline cellulose
Povidone (K30)
Sodium starch glycolate
Tablet coating
Hypromellose
Macrogol 400
Polysorbate 80
Titanium dioxide (E171)
Revolade 25 mg film-coated tablets
Core of the tablet
Magnesium stearate
Mannitol (E421)
Microcrystalline cellulose
Povidone
Sodium starch glycolate
Tablet coating
Hypromellose
Macrogol 400
Polysorbate 80
Titanium dioxide (E171)
Revolade 50 mg film-coated tablets
Core of the tablet
Magnesium stearate
Mannitol (E421)
Microcrystalline cellulose
Povidone
Sodium starch glycolate
Tablet coating
Hypromellose
Red iron oxide (E172)
Yellow iron oxide (E172)
Macrogol 400
Titanium dioxide (E171)
Revolade 75 mg film-coated tablets
Core of the tablet
Magnesium stearate
Mannitol (E421)
Microcrystalline cellulose
Povidone
Sodium starch glycolate
Tablet coating
Hypromellose
Red iron oxide (E172)
Black iron oxide (E172)
Macrogol 400
Titanium dioxide (E171)
06.2 Incompatibility
Not relevant.
06.3 Period of validity
4 years.
06.4 Special precautions for storage
This medicine does not require any special storage conditions.
06.5 Nature of the immediate packaging and contents of the package
Film-coated tablets
Aluminum blisters (PA / Alu / PVC / Alu) in a pack containing 14 or 28 film-coated tablets and in a multipack containing 84 (3 packs of 28) film-coated tablets.
Not all pack sizes may be marketed.
06.6 Instructions for use and handling
Unused medicine and wastes derived from this medicine must be disposed of in accordance with local regulations.
07.0 MARKETING AUTHORIZATION HOLDER
Novartis Europharm Limited
Frimley Business Park
Camberley GU16 7SR
UK
08.0 MARKETING AUTHORIZATION NUMBER
Revolade 12.5 mg film-coated tablets
EU / 1/10/612/010
039827100
EU / 1/10/612/011
039827112
EU / 1/10/612/012
039827124
Revolade 25 mg film-coated tablets
EU / 1/10/612/001
039827011
EU / 1/10/612/002
039827023
EU / 1/10/612/003
039827035
Revolade 50 mg film-coated tablets
EU / 1/10/612/004
039827047
EU / 1/10/612/005
039827050
EU / 1/10/612/006
039827062
Revolade 75 mg film-coated tablets
EU / 1/10/612/007
039827074
EU / 1/10/612/008
039827086
EU / 1/10/612/009
039827098
09.0 DATE OF FIRST AUTHORIZATION OR RENEWAL OF THE AUTHORIZATION
Date of first authorization: 11 March 2010
Date of most recent renewal: January 15, 2015
10.0 DATE OF REVISION OF THE TEXT
November 2016
