Bosutinib zentiva

Package leaflet: Information for the user

Bosutinib Zentiva, 100 mg, film-coated tablets
Bosutinib Zentiva, 400 mg, film-coated tablets
Bosutinib Zentiva, 500 mg, film-coated tablets
Bosutinib
Please read all of this leaflet carefully before taking this medicine, because it contains
important information for you.

• Keep this leaflet, as you may need to read it again.
• If you have any further questions, please ask your doctor or pharmacist.
• This medicine has been prescribed for you personally. Do not pass it on to others. It may harm someone else, even if their symptoms are the same as yours.
• If you experience any side effects, including any not listed in this leaflet, tell your doctor. See section 4.

Contents of the 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. This medicine is used to treat
adult patients with a type of leukaemia called Philadelphia chromosome-positive chronic myeloid
leukaemia (Ph+ CML), either when the disease has just been diagnosed, or when previous treatments
for chronic myeloid leukaemia have not worked or were unsuitable. Philadelphia chromosome-positive
chronic myeloid leukaemia is a blood cancer that causes the body to produce too many specific 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. Important information before taking Bosutinib Zentiva

When not to take Bosutinib Zentiva

• if the patient is allergic to bosutinib or any of the other ingredients of this medicine (listed in section 6)
• if the patient has been informed by their doctor that they have liver damage and the liver is not functioning properly.

Warnings and precautions

Before starting treatment with Bosutinib Zentiva, discuss the following with your doctor, pharmacist, or nurse:

• if the patient has or has previously had liver disease. Inform the doctor about any prior liver conditions, including hepatitis (infection or inflammation of the liver) regardless of type, as well as any previous occurrence of the following signs and symptoms related to the liver: itching, yellowing of the whites of the eyes or skin, dark urine, and pain or discomfort in the upper right part of the abdomen. Before starting treatment with Bosutinib Zentiva and during the first 3 months of treatment, and whenever clinically indicated, the doctor should perform blood tests to monitor liver function.

• if the patient has diarrhoea and vomiting. Inform the doctor if any of the following signs or symptoms occur: an increase in the number of daily bowel movements beyond normal, increased frequency of vomiting episodes, presence of blood in vomit, stools, or urine, or black stools (tarry-black stools). Ask the doctor whether antiemetic treatment could increase the risk of heart arrhythmias. Consult the doctor especially if treatment for nausea and/or vomiting includes a medicine containing domperidone. Treating nausea or vomiting with such medicines together with Bosutinib Zentiva may increase the risk of serious heart arrhythmias.

• if the patient has bleeding. Inform the doctor if any signs or symptoms of unusual bleeding or bruising occur, especially without injury.

• if the patient has an infection. Inform the doctor if any of the following signs or symptoms occur: fever, problems with urination (e.g. burning sensation), new cough, or sore throat.

• if the patient has fluid retention. Inform the doctor if any of the following signs or symptoms of fluid retention occur during treatment with Bosutinib Zentiva: swelling of the ankles, feet, or legs, difficulty breathing, chest pain, or cough (which may indicate fluid accumulation in the lungs or chest cavity).

• if the patient has heart disease. Inform the doctor about any heart conditions, such as heart failure or reduced blood flow to the heart, which may lead to heart attack. If shortness of breath, weight gain, chest pain, or swelling of the hands, ankles, or feet occurs, seek immediate medical help.

• if the patient has been diagnosed with irregular heart rhythm. Inform the doctor if arrhythmias occur or if an electrocardiogram (ECG) shows abnormal findings referred to as "QT interval prolongation." These conditions are always important but are particularly significant in cases of frequent or prolonged diarrhoea, as described above. If fainting (loss of consciousness) or irregular heartbeat occurs while taking Bosutinib Zentiva, contact the doctor immediately, as this may be a sign of a serious heart condition.

• if the patient has previously been diagnosed with kidney disease. Inform the doctor about increased frequency of urination and production of large volumes of pale-coloured urine, or reduced frequency of urination and production of small volumes of dark-coloured urine. Also inform the doctor about weight loss and swelling of the feet, ankles, legs, hands, or face.

• if the patient has ever had or may currently have hepatitis B virus infection; this is because Bosutinib Zentiva may cause reactivation of hepatitis B virus infection, which in some cases may lead to death; patients will be closely monitored by the doctor for signs of this infection before starting treatment.

• if the patient has or has previously had pancreas disorders. Inform the doctor if abdominal pain or discomfort occurs.

• if the patient develops any of the following symptoms: severe skin rash.

Inform the doctor if any of the following symptoms occur: painful, red, or purplish spreading rash, blisters, and/or other changes starting in the mucous membranes (e.g. inside the mouth or lips).

• if the patient notices any of the following symptoms: flank pain, blood in the urine, or reduced urine output. In very severe disease, the body may be unable to eliminate all components from dying tumour cells. This complication is known as tumour lysis syndrome and may lead to kidney failure and heart problems within 48 hours after the first dose of Bosutinib Zentiva. The doctor is aware of the possibility of this complication and may recommend adequate hydration and other medicines to prevent its occurrence.

Protection from sunlight/UV radiation
While taking bosutinib, the patient may be more sensitive to sunlight or UV radiation. It is important to cover skin areas exposed to sunlight and to use sunscreen with a high sun protection factor (SPF).

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

Bosutinib Zentiva and other medicines
Inform the doctor or pharmacist about all medicines the patient is currently taking, has recently taken, or plans to take, including over-the-counter medicines, vitamins, and herbal supplements. Some medicines may affect bosutinib levels in the patient's body. Inform the doctor about taking medicines containing any of the following active substances:

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

• 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 human immunodeficiency virus (HIV)/AIDS;
• boceprevir and telaprevir used to treat hepatitis C;
• aprepitant used to prevent and control nausea and vomiting;
• imatinib used to treat one 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 treat high blood pressure in the lungs (pulmonary arterial hypertension);
• nafcillin – an antibiotic used to treat bacterial infections;
• St. John’s wort (a herbal remedy available without prescription) used to treat depression;
• efavirenz and etravirine used to treat HIV/AIDS infections;
• modafinil used to treat certain types of sleep disorders.

Avoid using these medicines during treatment with Bosutinib Zentiva. Inform the doctor if any of these medicines are being taken. The doctor may adjust the doses of these medicines, adjust the dose of Bosutinib Zentiva, or switch to another medicine.

The following active substances may affect heart rhythm:

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

Exercise caution when taking these medicines during treatment with Bosutinib Zentiva. Inform the doctor if any of these medicines are being taken.

Other medicines not listed above may also interact with Bosutinib Zentiva.

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

Pregnancy, breastfeeding, and fertility
Bosutinib Zentiva may harm an unborn child; therefore, it should not be taken during pregnancy unless considered essential. If the patient is pregnant or if there is a possibility of becoming pregnant, consult the doctor before taking Bosutinib Zentiva.
Women taking Bosutinib Zentiva should use an effective method of contraception during treatment and for at least one month after the last dose. Vomiting and diarrhoea may reduce the effectiveness of oral contraceptives.
Due to the risk of reduced fertility in men, sperm preservation should be considered before starting treatment with Bosutinib Zentiva.
If the patient is breastfeeding, inform the doctor. Breastfeeding should not be continued during treatment with Bosutinib Zentiva, as it may harm the baby.

Driving and using machines
If the patient experiences dizziness, blurred vision, or unusual tiredness, they should 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 100 mg, 400 mg, or 500 mg tablet, meaning the medicine is considered "sodium-free".

3. How to take Bosutinib Zentiva

This medicine should always be taken as directed by your doctor. If you have any doubts, 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 for patients with newly diagnosed chronic myeloid leukaemia is 400 mg once daily. The recommended dose for patients who have previously failed treatment for chronic myeloid leukaemia or for whom prior treatment was inappropriate is 500 mg once daily. For patients with moderate or severe renal impairment, the doctor will reduce the dose by 100 mg daily for moderate renal impairment and by an additional 100 mg daily for severe renal impairment.

The doctor may adjust the dose using 100 mg tablets, depending on the patient's condition, response to treatment, and/or occurrence of possible adverse reactions. The tablets should be taken once daily with food. Bosutinib Zentiva tablets should be swallowed whole with water.

Accidental overdose of Bosutinib Zentiva
If you accidentally take more tablets or a higher dose than recommended, seek medical advice immediately. If possible, show the doctor the medicine packaging or this leaflet. You may require medical attention.

Missed dose of Bosutinib Zentiva
If less than 12 hours have passed since the missed dose, take the recommended dose. If more than 12 hours have passed since the missed dose, take the next dose at the usual time on the following day.
Do not take a double dose to make up for a missed tablet.

Stopping treatment with Bosutinib Zentiva
Do not stop taking Bosutinib Zentiva unless your doctor advises you to do so. If you are unable to take the medicine as directed by your doctor or if you think you no longer need the medicine, contact your doctor immediately.

If you have any further questions about the use of this medicine, consult your doctor or pharmacist.

4. Possible adverse reactions

Like all medicines, this medicine can cause adverse reactions, although not everybody will get them.
If any of the serious adverse reactions listed below occur,
contact your doctor immediately (see also section 2 "Important information before taking
Bosutinib Zentiva"):

Blood disorders. Immediately inform your doctor if any of the following symptoms occur: bleeding, fever or easy bruising (this may indicate a disease of the blood or lymphatic system).

Liver function disorders. Immediately inform your doctor if any of the following symptoms occur: itching, yellowing of the whites of the eyes or skin, dark-coloured urine, pain or discomfort in the upper right part of the abdomen, or fever.

Stomach and (or) intestinal disorders. Inform your doctor if you experience stomach pain, heartburn, diarrhoea, constipation, nausea or vomiting.

Heart problems. Inform your doctor about heart function disorders such as heart failure, reduced blood flow to the heart, abnormal electrical signals called "QT prolongation", fainting (loss of consciousness), or irregular heartbeat while taking Bosutinib Zentiva.

Reactivation of hepatitis B virus infection. Recurrence (reactivation) of hepatitis B virus infection (liver infection) in patients who have previously had this disease.

Severe skin reactions. Immediately inform your doctor if any of the following symptoms occur: painful, red or purple spreading rash, blisters and (or) other changes starting in the mucous membranes (e.g. inside the mouth and lips).

Adverse reactions associated with the use of Bosutinib Zentiva may include:

Very common adverse reactions (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 cells),
• diarrhoea, vomiting, abdominal pain, nausea,
• fever, swelling of hands, feet or face, fatigue, weakness,
• respiratory tract infection,
• inflammation of the nose and throat,
• changes in blood test results used to determine whether Bosutinib Zentiva affects 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 imbalance (dizziness),
• presence of fluid in the lungs (pleural effusion),
• itching.

Common adverse reactions (may affect up to 1 in 10 people):

• low white blood cell count (leukopenia),
• gastritis (inflammation of the stomach), bleeding from the stomach or intestines,
• chest pain, pain,
• toxic liver damage, abnormal liver function, including liver dysfunction,
• lung infection (pneumonia), influenza, bronchitis,
• heart does not pump blood as well as it should (heart failure),
• heart rhythm disorders predisposing to fainting, dizziness and palpitations,
• increased blood pressure,
• high potassium levels in the blood, low phosphate levels in the blood, excessive loss of body fluids (dehydration),
• muscle pain,
• altered sense (disturbance) of taste,
• acute kidney failure, kidney failure, kidney function disorders,
• presence of fluid around the heart (pericardial effusion),
• ringing in the ears,
• urticaria, acne,
• hypersensitivity reaction to light (sensitivity to UV rays from sunlight and other light sources),
• allergic reaction,
• abnormally high blood pressure in the pulmonary arteries (pulmonary hypertension),
• acute pancreatitis,
• respiratory failure.

Uncommon adverse reactions (may affect up to 1 in 100 people):

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

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

• severe skin disorders (Stevens-Johnson syndrome, toxic epidermal necrolysis) due to allergic reaction, scaly rash,
• interstitial lung disease (disorders causing lung scarring): symptoms include cough, difficulty breathing, painful breathing.

Reporting of adverse reactions
If any adverse symptoms occur, including any adverse symptoms not listed
in this leaflet, inform your doctor or pharmacist. Adverse reactions can be reported
directly to the Department of Monitoring Adverse Drug Reactions of the Office for Registration of Medicinal Products, Medical Devices and Biocidal Products,
Al. Jerozolimskie 181C, 02-222 Warsaw,
tel.: + 48 22 49 21 301, fax: + 48 22 49 21 309,
website: https://smz.ezdrowie.gov.pl
Adverse reactions can also be reported to the marketing authorisation holder or its local representative. Reporting adverse reactions helps to provide more information on the safety of this medicine.

5. How to store Bosutinib Zentiva

Keep this medicine out of 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 the stated month.
No special storage conditions are required for this medicine.
Do not use this medicine if you notice damage to the packaging or signs of tampering.
Medicines must not be disposed of via wastewater or household waste. Ask your pharmacist how to dispose of medicines no longer required. Such measures will help protect the environment.

6. Contents of the pack and other information

What Bosutinib Zentiva contains

• The active substance is bosutinib. Bosutinib Zentiva coated tablets are available in different strengths.
  Bosutinib Zentiva 100 mg: each coated tablet contains 100 mg of bosutinib.
  Bosutinib Zentiva 400 mg: each coated tablet contains 400 mg of bosutinib.
  Bosutinib Zentiva 500 mg: each coated tablet contains 500 mg of bosutinib.
• The other ingredients are: microcrystalline cellulose (E 460), sodium croscarmellose (E 468),
  colloidal anhydrous silica, magnesium stearate.
  The tablet coating contains polyvinyl alcohol (E 1203), macrogol, talc (E 553b), titanium dioxide (E 171),
  iron oxide yellow (E 172) for Bosutinib Zentiva 100 mg and 400 mg, iron oxide red (E 172) for Bosutinib Zentiva 400 mg and 500 mg.

What Bosutinib Zentiva looks like and contents of the pack
Bosutinib Zentiva 100 mg, coated tablets: yellow, oval (measuring 6 mm x 11 mm), biconvex, with an engraved mark “C18” on one side.
Bosutinib Zentiva 100 mg is available in blisters containing 28 or 112 coated tablets, in a cardboard carton.
Bosutinib Zentiva 100 mg is also available in single-dose perforated blister packs containing 28 x 1 or 112 x 1 coated tablets, in a cardboard carton.

Bosutinib Zentiva 400 mg, coated tablets: orange, oval (measuring 9 mm x 17 mm), biconvex, with an engraved mark “C19” on one side.
Bosutinib Zentiva 400 mg is available in blisters containing 28 coated tablets, in a cardboard carton.
Bosutinib Zentiva 400 mg is also available in single-dose perforated blister packs containing 28 x 1 coated tablets, in a cardboard carton.

Bosutinib Zentiva 500 mg, coated tablets: pink, oval (measuring 10 mm x 18 mm), biconvex, with an engraved mark “C20” on one side.
Bosutinib Zentiva 500 mg is available in blisters containing 28 coated tablets, in a cardboard carton.
Bosutinib Zentiva 500 mg is also available in single-dose perforated blister packs containing 28 x 1 coated tablets, in a cardboard carton.

Not all pack sizes may be marketed.

Marketing Authorisation Holder
Zentiva, k.s.
U kabelovny 130
Dolní Měcholupy
102 37 Prague 10
Czech Republic

Manufacturer
Coripharma ehf
Reykjavíkurvegur 78
220 Hafnarfjörður
Iceland

This medicinal product is authorised for marketing in the European Economic Area under the following names:

For further information, contact the local representative of the marketing authorization holder:
Zentiva Polska Sp. z.o.o.,
ul. Bonifraterska 17
00-203 Warsaw, Poland
tel.: +48 22 375 92 00