Bosutinib Zentiva

Patient Information Leaflet

Bosutinib Zentiva 100 mg film-coated tablets, 400 mg film-coated tablets, 500 mg film-coated tablets

Generic Medicine
Please read all of this leaflet carefully before you start taking this medicine because it contains important information for you.

• Keep this leaflet. You may need to read it again.
• If you have any questions, ask your doctor or pharmacist.
• This medicine has been prescribed for you only. Do not give it to other people, even if they have the same symptoms as yours, as it may be harmful.
• If you experience any side effects, including those not listed in this leaflet, tell your doctor. See section 4.

Contents of this leaflet

1. What Bosutinib Zentiva is and what it is used for
2. What you need to know before taking Bosutinib Zentiva
3. How to take Bosutinib Zentiva
4. Possible side effects
5. How to store Bosutinib Zentiva
6. Contents of the pack and other information

1. What Bosutinib Zentiva is and what it is used for

Bosutinib Zentiva contains the active substance bosutinib. It is used to treat adult patients with a type of leukaemia called Philadelphia chromosome-positive chronic myeloid leukaemia (Ph+ CML), either at the time of diagnosis or in patients for whom previous treatments for chronic myeloid leukaemia have failed or were inadequate. Philadelphia chromosome-positive chronic myeloid leukaemia is a form of blood cancer that causes the overproduction of a specific type of white blood cells called granulocytes.
If you have any questions about how Bosutinib Zentiva works or why this medicine has been prescribed for you, please consult your doctor.

2. What you need to know before taking Bosutinib Zentiva

Do not take Bosutinib Zentiva

• if you are allergic to bosutinib or to any of the other ingredients of this medicine (listed in section 6).
• if your doctor has told you that you have liver damage and that your liver is not functioning normally.

Warnings and precautions
Talk to your doctor, pharmacist, or nurse before taking Bosutinib Zentiva:

• if you have or have previously had liver problems. Inform your doctor if you have previously had liver problems, including hepatitis (liver infection or inflammation) of any type, or if you have previously experienced any of the following signs and symptoms of liver problems: itching, yellowing of the skin or eyes, dark urine, or pain or discomfort in the upper right part of the abdomen. Your doctor must perform blood tests to monitor liver function before starting treatment with Bosutinib Zentiva, during the first 3 months of treatment with Bosutinib Zentiva, and whenever clinically indicated.
• if you have diarrhoea and vomiting. Inform your doctor if you develop any of the following signs and symptoms: an increased number of daily bowel movements (stools), increased episodes of vomiting, blood in vomit, stools (bowel movements), or urine, or black stools (tarry bowel movements). Ask your doctor whether treatment for vomiting may increase the risk of developing cardiac arrhythmias. In particular, consult your doctor if you wish to use a medicine containing domperidone to treat nausea and/or vomiting, as taking such medicines together with Bosutinib Zentiva may increase the risk of dangerous cardiac arrhythmias.
• if you have bleeding problems. Inform your doctor if you develop any of the following signs and symptoms, such as bleeding or abnormal bruising, without any injury.
• if you have an infection. Inform your doctor if you develop any of the following signs and symptoms, such as fever, urinary problems (for example, a burning sensation when urinating), new onset of cough, or new onset of sore throat.
• if you have fluid retention. Inform your doctor if you develop any of the following signs and symptoms of fluid retention during treatment with Bosutinib Zentiva, such as swelling of the ankles, feet, or legs, difficulty breathing, chest pain, or cough (these may be signs of fluid retention in the lungs or chest).
• if you have heart problems. Inform your doctor if you have a heart condition, such as heart failure or reduced blood flow to the heart, which may lead to a heart attack. Seek immediate medical help if you experience shortness of breath, weight gain, chest pain, or swelling in your hands, ankles, or feet.
• if you have been told you have an abnormal heart rhythm. Inform your doctor if you have arrhythmias or an abnormal electrical signal known as “QT interval prolongation.” This is always important, but particularly if you experience frequent or prolonged diarrhoea, as described above. If you faint (lose consciousness) or have an irregular heartbeat while taking Bosutinib Zentiva, inform your doctor immediately, as this may be a sign of a serious heart condition.
• if you have been told you have kidney problems. Inform your doctor if you urinate more frequently and produce larger amounts of light-coloured urine, or if you urinate less frequently and produce smaller amounts of dark-coloured urine. Also inform your doctor if you are losing weight or have developed swelling in your feet, ankles, legs, hands, or face.
• if you have ever had or may currently have hepatitis B infection. This is because Bosutinib Zentiva may cause reactivation of hepatitis B, which in some cases can be fatal. Your doctor will carefully monitor you for signs of this infection before starting treatment.
• if you have or have previously had pancreas problems. Inform your doctor if you develop abdominal pain or discomfort.
• if you develop any of these symptoms: severe skin rash. Inform your doctor if you develop any of the following signs or symptoms of a painful, red or purplish skin rash that spreads progressively, and blisters and/or other lesions beginning to appear on mucous membranes (e.g., mouth and lips).
• if you experience any of these symptoms: flank pain, blood in the urine, or reduced urine output. If your condition is very severe, your body may not be able to eliminate waste products from dead tumour cells. This condition is known as tumour lysis syndrome and may lead to kidney failure and heart problems within 48 hours of the first dose of Bosutinib Zentiva. Your doctor is aware of this risk and may ensure you receive adequate hydration and possibly other medicines to prevent this condition.

Sun protection / UV radiation
While taking bosutinib, you may become more sensitive to sunlight or UV radiation. It is important to cover areas of skin exposed to sunlight and to use sunscreen creams with a high sun protection factor (SPF).

Children and adolescents
Bosutinib Zentiva is not recommended for people under 18 years of age. This medicine has not been studied in children and adolescents.

Other medicines and Bosutinib Zentiva
Inform your doctor or pharmacist if you are taking, have recently taken, or might take any other medicines, including those without a prescription, vitamins, and herbal supplements.
Some medicines may affect the levels of Bosutinib Zentiva in your body. You must inform your doctor if you are taking medicines containing any of the following active substances:

The following active substances may increase the risk of Bosutinib Zentiva side effects:

• ketoconazole, itraconazole, voriconazole, posaconazole, and fluconazole, used to treat fungal infections.
• clarithromycin, telithromycin, erythromycin, and ciprofloxacin, used to treat bacterial infections.
• nefazodone, used to treat depression.
• mibefradil, diltiazem, and verapamil, used to lower blood pressure in people with high blood pressure.
• ritonavir, lopinavir/ritonavir, indinavir, nelfinavir, saquinavir, atazanavir, amprenavir, fosamprenavir, and darunavir, used to treat HIV/AIDS infections.
• boceprevir and telaprevir, used to treat hepatitis C.
• aprepitant, used to prevent and control nausea and vomiting.
• imatinib, used to treat a type of leukaemia.
• crizotinib, used to treat a type of lung cancer called non-small cell lung cancer.

The following active substances may reduce the effectiveness of Bosutinib Zentiva:

• rifampicin, used to treat tuberculosis.
• phenytoin and carbamazepine, used to treat epilepsy.
• bosentan, used to lower high blood pressure in the lungs (pulmonary arterial hypertension).
• nafcillin, an antibiotic used to treat bacterial infections.
• St. John’s wort (Hypericum perforatum, an herbal preparation sold without prescription), used to treat depression.
• efavirenz and etravirine, used to treat human immunodeficiency virus (HIV)/AIDS infections.
• modafinil, used to treat certain types of sleep disorders.

These medicines should be avoided during treatment with Bosutinib Zentiva. If you are taking any of these medicines, inform your doctor. Your doctor may adjust the dose of these medicines, change the dose of Bosutinib Zentiva, or prescribe a different medicine.

The following active substances may alter heart rhythm:

• amiodarone, disopyramide, procainamide, quinidine, and sotalol, used to treat heart diseases.
• chloroquine, halofantrine, used to treat malaria.
• clarithromycin and moxifloxacin, antibiotics used to treat bacterial infections.
• haloperidol, used to treat psychotic disorders such as schizophrenia.
• domperidone, used to treat nausea and vomiting or to stimulate breast milk production.
• methadone, used to treat pain.

These medicines should be taken with caution during treatment with Bosutinib Zentiva. If you are taking any of these medicines, inform your doctor.
The medicines listed here may not be the only ones that interact with Bosutinib Zentiva.

Bosutinib Zentiva with food and drink
Do not take Bosutinib Zentiva with grapefruit or grapefruit juice, as the risk of side effects may increase.

Pregnancy, breastfeeding, and fertility
Bosutinib Zentiva must not be used during pregnancy unless considered clinically necessary, as it may harm the unborn baby. Consult your doctor before taking Bosutinib Zentiva if you are pregnant or could become pregnant.
Women taking Bosutinib Zentiva will be advised to use an effective method of contraception during treatment and for at least 1 month after the last dose. Vomiting or diarrhoea may reduce the effectiveness of oral contraceptives.
Treatment with Bosutinib Zentiva may potentially reduce male fertility; therefore, you may wish to discuss sperm preservation before starting therapy.
If you are breastfeeding, inform your doctor. Do not breastfeed during treatment with Bosutinib Zentiva, as it may harm the baby.

Driving and using machines
If you experience dizziness, blurred vision, or feel unusually tired, do not drive or operate machinery until these side effects have resolved.

Bosutinib Zentiva contains sodium
This medicine contains less than 1 mmol (23 mg) of sodium per tablet, i.e., essentially “sodium-free”.

3. How to take Bosutinib Zentiva

Take this medicine exactly as your doctor has told you. If you are not sure, consult your doctor or pharmacist.
Bosutinib Zentiva will only be prescribed by a doctor experienced in the use of medicines for the treatment of leukaemia.

Dosage and method of administration
The recommended dose is 400 mg once daily for patients with newly diagnosed chronic myeloid leukaemia. The recommended dose is 500 mg once daily for patients for whom previous medicines for the treatment of chronic myeloid leukaemia have not worked or are unsuitable. If you have moderate or severe kidney problems, your doctor will reduce the dose by 100 mg once daily for moderate kidney problems and by a further 100 mg once daily for severe kidney problems. Depending on your medical condition, your response to treatment and/or any side effects you may experience, your doctor may adjust the dose using the 100 mg tablets. Take the tablet(s) once daily with food. Swallow the tablet(s) whole with some water.

If you take more Bosutinib Zentiva than you should
If you accidentally take too many Bosutinib Zentiva tablets or a higher dose than required, contact a doctor immediately for advice. If possible, show the doctor the pack or this leaflet. You may require medical treatment.

If you forget to take Bosutinib Zentiva
If less than 12 hours have passed since the scheduled dose time, take the recommended dose. If more than 12 hours have passed, take the next dose at the usual time the following day. Do not take a double dose to make up for forgotten tablets.

If you stop taking Bosutinib Zentiva
Do not stop taking Bosutinib Zentiva unless your doctor tells you to. If you are unable to take the medicine as prescribed by your doctor or if you feel you no longer need it, contact your doctor immediately.

If you have any questions about how to use this medicine, consult your doctor or pharmacist.

4. Possible side effects

Like all medicines, this medicine can cause side effects, although not all people may experience them.
You must contact your doctor immediately if you experience any of the serious side effects listed below (see also section 2 “What you should know before taking Bosutinib Zentiva”):

Blood disorders. Immediately inform your doctor if you have any of the following symptoms:
bleeding, fever, or easy bruising (you may have a blood or lymphatic system disorder).

Liver disorders. Immediately inform your doctor if you have any of the following symptoms:
itching, yellowing of the skin or eyes, dark urine, pain or discomfort in the upper right part of the stomach, or fever.

Stomach/intestinal disorders. Inform your doctor if you develop stomach pain, heartburn, diarrhoea, constipation, nausea, or vomiting.

Heart problems. Inform your doctor if you have a heart condition, such as heart failure, reduced blood flow to the heart, an abnormal electrical signal known as “QT interval prolongation”, or if you faint (lose consciousness) or have an irregular heartbeat while taking Bosutinib Zentiva.

Reactivation of hepatitis B. Recurrence (reactivation) of hepatitis B infection if you have previously had hepatitis B (a liver infection).

Severe skin reactions. Seek immediate medical attention if you experience any of the following symptoms: painful, red or purplish rash that spreads progressively, and blisters and/or other lesions starting to appear on mucous membranes (e.g. mouth and lips).

Side effects of Bosutinib Zentiva may include:

Very common side effects (may affect more than 1 in 10 people):

• decrease in the number of platelets, red blood cells, and/or neutrophils (a type of white blood cell).
• diarrhoea, vomiting, stomach pain, nausea.
• fever, swelling of the hands, feet or face, fatigue, weakness.
• respiratory tract infection.
• nasopharyngitis.
• changes in blood tests indicating that Bosutinib Zentiva is affecting the liver and/or pancreas, kidneys.
• loss of appetite.
• joint pain, back pain.
• headache.
• skin rash, which may be itchy and/or widespread.
• cough.
• shortness of breath.
• feeling of instability (dizziness).
• fluid in the lungs (pleural effusion).
• itching.

Common side effects (may affect up to 1 in 10 people):

• low white blood cell count (leucopenia).
• stomach irritation (gastritis), bleeding from the stomach or intestine.
• chest pain, pain.
• toxic liver damage, abnormal liver function, including liver disorders.
• lung infection (pneumonia), influenza, bronchitis.
• when the heart does not pump blood properly (heart failure).
• a heart rhythm disorder that may lead to fainting, dizziness, and palpitations.
• increased blood pressure.
• high potassium levels in the blood, low phosphorus levels in the blood, excessive loss of body fluids (dehydration).
• muscle pain.
• altered sense of taste (dysgeusia).
• acute kidney failure, kidney failure, kidney impairment.
• fluid around the heart (pericardial effusion).
• ringing in the ears (tinnitus).
• urticaria, acne.
• photosensitivity reaction (sensitivity to UV rays from sunlight and other light sources).
• allergic reaction.
• abnormally high blood pressure in the arteries of the lungs (pulmonary hypertension).
• acute inflammation of the pancreas (acute pancreatitis).
• respiratory failure.

Uncommon side effects (may affect up to 1 in 100 people):

• fever associated with low white blood cell count (febrile neutropenia).
• liver damage.
• potentially life-threatening allergic reaction (anaphylactic shock).
• abnormal accumulation of fluid in the lungs (acute pulmonary edema).
• skin rash.
• inflammation of the membrane surrounding the heart (pericarditis).
• marked decrease in the number of granulocytes (a type of white blood cell).
• severe skin disorder (erythema multiforme).
• nausea, shortness of breath, irregular heartbeat, muscle cramps, seizures, cloudy urine, and fatigue associated with abnormal laboratory test results (elevated levels of potassium, uric acid, and phosphorus, and low calcium levels in the blood) which may lead to changes in kidney function and acute kidney failure – (tumour lysis syndrome (TLS)).
• inflammation of blood vessels in the skin that may cause skin rash or bruising (cutaneous vasculitis).

Not known (frequency cannot be estimated from the available data):

• severe skin disorder (Stevens-Johnson syndrome, toxic epidermal necrolysis) due to an allergic reaction, exfoliative rash (scaly skin, exfoliation).
• interstitial lung disease (a condition causing scarring in the lungs): signs include cough, difficulty breathing, painful breathing.

Reporting of side effects
If you experience any side effect, including those not listed in this leaflet, talk to your doctor, pharmacist, or nurse. You can also report side effects directly via the national reporting system at https://www.aifa.gov.it/content/segnalazioni-reazioni-avverse.
Reporting side effects can help provide more information on the safety of this medicine.

5. How to store Bosutinib Zentiva

Keep this medicine out of the sight and reach of children.
Do not use this medicine after the expiry date stated on the blister and carton after "Exp.". The expiry date refers to the last day of that month.
This medicine does not require any special storage conditions.
Do not use this medicine if you notice that the packaging is damaged or shows signs of tampering.
Do not dispose of medicines via wastewater or household waste. Ask your pharmacist how to dispose of medicines you no longer use. This will help protect the environment.

6. Package contents and other information

What Bosutinib Zentiva contains

• The active substance is bosutinib. Bosutinib Zentiva film-coated tablets are available in different strengths.
  Bosutinib Zentiva 100 mg: each film-coated tablet contains 100 mg of bosutinib.
  Bosutinib Zentiva 400 mg: each film-coated tablet contains 400 mg of bosutinib.
  Bosutinib Zentiva 500 mg: each film-coated tablet contains 500 mg of bosutinib.
• The other ingredients are: microcrystalline cellulose (E460), sodium croscarmellose (E468), anhydrous colloidal silica, magnesium stearate. The film coating contains polyvinyl alcohol (E1203), macrogol, talc (E553b), titanium dioxide (E171), yellow iron oxide (E172, for Bosutinib Zentiva 100 mg and 400 mg), red iron oxide (E172, for Bosutinib Zentiva 400 mg and 500 mg).

Description of the appearance of Bosutinib Zentiva and package contents
The 100 mg film-coated tablets of Bosutinib Zentiva are yellow, oval (6 mm x 11 mm), biconvex, with "C18" engraved on one side.
Bosutinib Zentiva 100 mg is available in blisters containing 28 or 112 film-coated tablets.
Bosutinib Zentiva 100 mg is also available in unit-dose divisible blisters containing 28x1 or 112x1 film-coated tablets.
The 400 mg film-coated tablets of Bosutinib Zentiva are orange, oval (9 mm x 17 mm), biconvex, with "C19" engraved on one side.
Bosutinib Zentiva 400 mg is available in blisters containing 28 film-coated tablets.
Bosutinib Zentiva 400 mg is also available in unit-dose divisible blisters containing 28x1 film-coated tablets.
The 500 mg film-coated tablets of Bosutinib Zentiva are pink, oval (10 mm x 18 mm), biconvex, with "C20" engraved on one side.
Bosutinib Zentiva 500 mg is available in blisters containing 28 film-coated tablets.
Bosutinib Zentiva 500 mg is also available in unit-dose divisible blisters containing 28x1 film-coated tablets.
Not all pack sizes may be marketed.

Marketing Authorisation Holder and Manufacturer
Marketing Authorisation Holder
Zentiva Italia S.r.l.
Via P. Paleocapa, 7
20121 Milano
Italy

Manufacturer
Coripharma ehf
Reykjavíkurvegur 78
220 Hafnarfjörður
Iceland

This medicinal product is authorised in the Member States of the European Economic Area under the following names: