Package leaflet: Information for the user

Bosulif 100 mg film-coated tablets, 400 mg film-coated tablets, 500 mg film-coated tablets

bosutinib
Please read this leaflet carefully before taking this medicine because it contains
important information for you and the person caring 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 their symptoms are the same as yours, as it may be harmful.
If you experience any side effects, including those not listed in this leaflet, consult your doctor. See section 4.

Contents of this leaflet

What Bosulif is and what it is used for
What you need to know before taking Bosulif
How to take Bosulif
Possible side effects
How to store Bosulif
Contents of the pack and other information

1. What Bosulif is and what it is used for

Bosulif contains the active substance bosutinib. Bosulif is used to treat adult and pediatric patients aged 6 years and older who have a type of leukaemia called Philadelphia chromosome-positive (Ph+) chronic myeloid leukaemia (CML) in the chronic phase (CP), either at the time of diagnosis or when previous treatments for chronic myeloid leukaemia have not worked or were not suitable. It is also used to treat adult patients with Ph+ chronic myeloid leukaemia in the accelerated phase (AP) and blast phase (BP) when previous treatments for chronic myeloid leukaemia have not worked or were not suitable.

In patients with Ph+ chronic myeloid leukaemia, a genetic abnormality in the DNA (genetic material) activates a signal that instructs the body to produce excessive numbers of a specific type of white blood cells called granulocytes. Bosulif blocks this signal and thereby stops the production of these cells.

If you have any questions about how Bosulif works or why this medicine has been prescribed for you, please consult your doctor.

2. What you should know before taking Bosulif

Do not take Bosulif

if you are allergic to bosutinib or any of the other ingredients of this medicine (listed in section 6).
if your doctor has told you that you have impaired liver function.

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

if you have or have previously had liver problems. Inform your doctor if you have previously experienced liver problems, including hepatitis (liver infection or inflammation) of any kind, or if you have previously had any signs or symptoms of liver problems (see section 4, “Possible side effects”), as Bosulif may affect your liver function. Your doctor should perform blood tests to monitor your liver function before starting treatment with Bosulif, during the first 3 months of treatment, and whenever clinically indicated.
if you have diarrhoea or vomiting. Inform your doctor if you develop any signs or symptoms of stomach or intestinal problems (see section 4, “Possible side effects”). To reduce symptoms, your doctor may prescribe an anti-diarrhoeal or antiemetic medication and/or fluids. Your doctor may also temporarily suspend, reduce the dose of, or permanently discontinue treatment with Bosulif (see section 3, “How to take Bosulif”). Ask your doctor whether taking anti-nausea or anti-vomiting medication together with Bosulif may increase your risk of developing cardiac arrhythmias.
if you have bleeding problems. Inform your doctor if you develop signs or symptoms of blood-related problems (see section 4, “Possible side effects”), as Bosulif reduces your body’s ability to stop bleeding. During the first month of treatment, your doctor should perform a complete blood count weekly, then monthly thereafter. Your doctor may also temporarily suspend, reduce the dose of, or permanently discontinue treatment with Bosulif (see section 3, “How to take Bosulif”).
if you have an infection. Inform your doctor if you develop any of the following signs or symptoms, such as fever, urinary problems (e.g. burning sensation when urinating), new onset of cough, or new onset of sore throat, as Bosulif reduces your body’s ability to fight infections.
if you have fluid retention. Inform your doctor if you develop any of the following signs or symptoms of fluid retention during treatment with Bosulif, such as swelling of the ankles, feet, or legs, difficulty breathing, chest pain, or cough (these may be signs of fluid accumulation in the lungs or chest). Your doctor will monitor for fluid retention and manage any symptoms accordingly.
if you have heart problems. Inform your doctor if you have heart disease, such as heart failure or reduced blood flow to the heart, which may lead to a heart attack. Seek immediate medical attention if you experience shortness of breath, rapid weight gain, chest pain, or swelling in your hands, ankles, or feet.
if you have been diagnosed with an abnormal heart rhythm. Inform your doctor if you have arrhythmias or an abnormal electrical signal known as “QT interval prolongation.” This is particularly important if you experience frequent or prolonged diarrhoea, as described above. If you faint (lose consciousness) or experience an irregular heartbeat while taking Bosulif, inform your doctor immediately, as this may be a sign of a serious heart condition (see section 2, “What you should know before taking Bosulif”). Before starting treatment, your doctor will perform an electrocardiogram (ECG). Your doctor will perform blood tests before and during treatment; if you have low levels of potassium or magnesium, your doctor will prescribe treatment to correct these deficiencies.
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 swelling in your feet, ankles, legs, hands, or face. Your doctor will assess kidney function before treatment and monitor it closely during bosutinib therapy.
if you have ever had or may currently have hepatitis B infection. This is because Bosulif may cause reactivation of hepatitis B, which in some cases can be fatal. Before starting treatment, your doctor will test you for this infection. If you have this infection, your doctor will closely monitor you for signs and symptoms during and for several months after treatment.
if you have or have had pancreas problems. Inform your doctor if you develop abdominal pain or discomfort. If you experience abdominal pain and blood tests show elevated levels of lipase—an enzyme that helps your body break down fats in food—your doctor may discontinue treatment and perform tests to rule out pancreas problems.
if you develop any of the following symptoms: severe skin rash. Inform your doctor if you develop any of the following signs or symptoms of a painful, red or purplish rash that spreads progressively, along with blisters and/or other lesions starting on mucous membranes (e.g. mouth and lips). If a severe skin reaction occurs during treatment, your doctor will permanently discontinue treatment.
if you experience any of the following symptoms: flank pain, blood in the urine, or reduced urine output. If your condition is very severe, your body may be unable 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 Bosulif. Your doctor is aware of this risk and may ensure you receive adequate hydration and possibly other medications to prevent this condition. Before starting treatment, your doctor will perform a blood test to check for high levels of uric acid and prescribe treatment to correct these levels if necessary.

Sun protection / UV exposure
While taking bosutinib, you may become 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).

Patients of Asian origin
If you are of Asian origin, you may have a higher risk of experiencing side effects during treatment with Bosulif. Your doctor will closely monitor you for any serious side effects, especially when the dose is increased.

Children and adolescents
Bosulif is not recommended for individuals under 6 years of age. This medicine has not been studied in children under 1 year of age.

Other medicines and Bosulif
Inform your doctor or pharmacist if you are taking, have recently taken, or might take any other medicines, including those without a prescription, vitamins, or herbal supplements. Some medicines may affect bosutinib levels 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 Bosulif 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 Bosulif:

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 (Hypericum perforatum, a 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 Bosulif. If you are taking any of these
medicines, inform your doctor. Your doctor may adjust the dose of these medicines, change the dose of
Bosulif, or prescribe an alternative medicine.

The following active substances may alter heart rhythm:

amiodarone, disopyramide, procainamide, quinidine, and sotalol, used to treat heart conditions.
chloroquine and 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 used with caution during treatment with Bosulif. If you are taking any
of these medicines, inform your doctor.

Agents that reduce acidity
Proton pump inhibitors (PPIs) should be used with caution during treatment with Bosulif, as they may reduce its effectiveness. Your doctor may consider short-acting antacids as an alternative to PPIs, and if possible, the administration times of Bosulif and antacids should be separated (e.g., take Bosulif in the morning and antacids in the evening).

The medicines listed above may not be the only ones that interact with Bosulif. If you are unsure whether the information above applies to you or your child, consult your doctor.

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

Pregnancy, breastfeeding, and fertility
Bosulif may harm the unborn baby and therefore should not be used during pregnancy unless considered essential. Consult your doctor before taking Bosulif if you are pregnant or may become pregnant.
Women of childbearing potential should 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 Bosulif may reduce fertility; therefore, you may wish to discuss sperm preservation before starting treatment.
If you are breastfeeding, inform your doctor. Do not breastfeed during treatment with Bosulif, as it may harm the baby.

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

Bosulif contains sodium
This medicine contains less than 1 mmol (23 mg) of sodium per 100 mg, 400 mg, or 500 mg film-coated tablet, i.e., it is essentially “sodium-free”.

3. How to take Bosulif

Take this medicine exactly as prescribed by your doctor. If you have any doubts, consult your doctor or pharmacist.
Bosulif will only be prescribed by a doctor experienced in the use of medicines for the treatment of leukaemia.

Dosage and method of administration
Adults
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 treatments for chronic myeloid leukaemia have failed or are unsuitable. If you are unable to tolerate the recommended dose or do not respond adequately to Bosulif, your doctor may further adjust the dose.

Children and adolescents (from 6 years of age)
The recommended dose is 300 mg/m² body surface area once daily in paediatric patients with newly diagnosed disease. The recommended dose is 400 mg/m² body surface area once daily in paediatric patients who are resistant or intolerant.

Dosage recommendations are provided in the table below. Depending on the case, the recommended dose may be achieved by combining different strengths of bosutinib film-coated tablets and/or hard capsules (see the Package Leaflet for hard capsules).

Bosutinib dosing for paediatric patients with newly diagnosed disease (ND) and for paediatric patients resistant or intolerant (R/I)

| Body surface area | ND recommended dose | R/I recommended dose |
|------------------------|---------------------------|---------------------------|
| 0.55–<0.63 m² | 200 mg | 250 mg |
| 0.63–<0.75 m² | 200 mg | 300 mg |
| 0.75–<0.9 m² | 250 mg | 350 mg |
| 0.9–<1.1 m² | 300 mg | 400 mg |
| ≥1.1 m² | 400 mg | 500 mg |

If you are unable to tolerate the recommended dose or do not respond adequately to Bosulif, your doctor may further adjust the dose.

Take the capsule(s) once daily with food. The hard capsule must be swallowed whole.
For patients unable to swallow a tablet, a capsule formulation is available.

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

If you forget to take Bosulif
If less than 12 hours have passed since the scheduled dose, 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 a missed dose.

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

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

4. Possible side effects

Like all medicines, this medicine can cause side effects, although not everybody will experience them.
Serious side effects
Contact your doctor immediately if you experience any of the following serious side effects
(see also section 2, “What you need to know before taking Bosulif”):
Very common (may affect more than 1 in 10 people):

reduction in the number of platelets (thrombocytopenia), red blood cells (anaemia) and/or neutrophils (a type of white blood cells) (neutropenia), which may cause abnormal bleeding, fever or bruising without injury (you may have a disorder of the blood or lymphatic system) (see section 2, “What you need to know before taking Bosulif”).
fluid around the lungs (pleural effusion).

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

low number of white blood cells (leucopenia).
bleeding from the stomach or intestine (gastrointestinal haemorrhage), which may include blood in vomit, faeces (bowel movements) or urine, or black stools (black, tarry bowel movements) (see section 2, “What you need to know before taking Bosulif”).
chest pain.
toxic liver damage (hepatotoxicity), abnormal liver function, including liver disorders (abnormal liver function), which may be accompanied by itching, yellowing of the eyes or skin, dark urine, pain or discomfort in the upper right part of the stomach, or fever (see section 2, “What you need to know before taking Bosulif”).
when the heart does not pump blood properly (heart failure).
when there is reduced blood flow to the heart (cardiac ischemia).
lung infection (pneumonia).
disturbance in heart rhythm (prolonged QT on electrocardiogram), which may lead to fainting, dizziness, and palpitations.
increased blood pressure (hypertension).
high levels of potassium in the blood (hyperkalemia).
acute kidney failure, kidney failure, impaired kidney function.
fluid around the heart (pericardial effusion).
allergic reaction (drug hypersensitivity).
abnormally high blood pressure in the arteries of the lungs (pulmonary hypertension).
acute inflammation of the pancreas (acute pancreatitis).

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

fever associated with low red blood cell count (febrile neutropenia).
liver damage (liver injury).
potentially life-threatening allergic reaction (anaphylactic shock).
abnormal accumulation of fluid in the lungs (acute pulmonary edema).
skin rash (drug rash).
scaly and exfoliative skin rash (exfoliative rash).
inflammation of the membrane lining the heart (pericarditis).
marked reduction in the number of granulocytes (a type of white blood cells, granulocytopenia).
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 levels of calcium in the blood), which may lead to changes in kidney function and acute kidney failure (tumour lysis syndrome (TLS)).
respiratory failure.

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

severe skin disease (Stevens-Johnson syndrome, toxic epidermal necrolysis), which may include painful red or purple rash spreading and blistering and/or other lesions starting to appear on mucous membranes (e.g., mouth and lips) due to an allergic reaction.
interstitial lung disease (a condition causing scarring in the lungs): signs include cough, difficulty breathing, painful breathing.
recurrence (reactivation) of hepatitis B infection if you have previously had hepatitis B (a liver infection).

Other side effects of Bosulif may include:
Very common (may affect more than 1 in 10 people):

diarrhoea, vomiting, stomach ache (abdominal pain), nausea.
fever (pyrexia), swelling of the hands, feet or face (oedema), fatigue, weakness.
respiratory tract infection.
nasopharyngitis.
changes in blood tests indicating that Bosulif is affecting the liver (increased alanine aminotransferase (ALT), increased aspartate aminotransferase (AST)) and/or the pancreas (increased lipase), and the kidneys (increased blood creatinine).
decreased appetite.
joint pain (arthralgia), back pain.
headache.
skin rash, which may be itchy and/or widespread (rash).
cough.
shortness of breath (dyspnoea).
feeling unsteady (dizziness).

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

stomach irritation (gastritis).
pain.
influenza, bronchitis.
changes in blood tests indicating that Bosulif is affecting the heart (increased blood creatine phosphokinase), the liver (increased blood bilirubin, increased gamma-glutamyl transferase (GGT)) and/or the pancreas (increased amylase).
low level of phosphorus in the blood (hypophosphataemia), excessive loss of body fluids (dehydration).
muscle pain (myalgia).
altered sense of taste (dysgeusia).
ringing in the ears (tinnitus).
urticaria, acne.
sensitivity to UV rays from sunlight and other light sources (photosensitivity reaction).
itching.

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 listed in Annex V.
By reporting side effects, you can help provide more information on the safety of this medicine.

5. How to store Bosulif

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 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 any medicine 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 Bosulif contains

The active substance is bosutinib. Bosulif film-coated tablets are available in different strengths. Bosulif 100 mg: each film-coated tablet contains 100 mg of bosutinib (monohydrate). Bosulif 400 mg: each film-coated tablet contains 400 mg of bosutinib (monohydrate). Bosulif 500 mg: each film-coated tablet contains 500 mg of bosutinib (monohydrate).
The other components are: microcrystalline cellulose (E460), sodium croscarmellose (E468), poloxamers 188, povidone (E1201), and magnesium stearate (E470b). The tablet film coating contains polyvinyl alcohol, titanium dioxide (E171), macrogol 3350, talc (E553b), and yellow iron oxide (E172, for Bosulif 100 mg and 400 mg) or red iron oxide (E172, for Bosulif 400 mg and 500 mg) (see section 2, “Bosulif contains sodium”).

Description of the appearance of Bosulif and package contents
Bosulif 100 mg film-coated tablets are yellow, oval, biconvex, and marked with “Pfizer” on one side and “100” on the other.
Bosulif 100 mg is available in blisters containing 14 or 15 film-coated tablets. Each pack contains 28, 30, or 112 film-coated tablets.
Bosulif 400 mg film-coated tablets are orange, oval, biconvex, and marked with “Pfizer” on one side and “400” on the other.
Bosulif 400 mg is available in blisters containing 14 or 15 film-coated tablets. Each pack contains 28 or 30 film-coated tablets.
Bosulif 500 mg film-coated tablets are red, oval, biconvex, and marked with “Pfizer” on one side and “500” on the other.
Bosulif 500 mg is available in blisters containing 14 or 15 film-coated tablets. Each pack contains 28 or 30 film-coated tablets.
Not all pack sizes may be marketed.

Marketing Authorisation Holder
Pfizer Europe MA EEIG
Boulevard de la Plaine 17
1050 Brussels
Belgium

Manufacturer
Pfizer Manufacturing Deutschland GmbH
Betriebsstätte Freiburg
Mooswaldallee 1
79090 Freiburg
Germany

For further information on this medicinal product, please contact the local representative of the Marketing Authorisation Holder:

België / Belgique / Belgien
Pfizer NV/SA
Tél/Tel: +32 (0)2 554 62 11

България
Пфайзер Люксембург САРЛ, Клон България
Тел.: +359 2 970 4333

Česká republika
Pfizer, spol. s r.o.
Tel.: +420 283 004 111

Danmark
Pfizer ApS
Tlf.: +45 44 20 11 00

Deutschland
PFIZER PHARMA GmbH
Tel: +49 (0)30 550055 51000

Eesti
Pfizer Luxembourg SARL Eesti filiaal
Tel.: +372 666 7500

Ελλάδα
Pfizer Ελλάς A.E.
Τηλ: +30 210 6785 800

España
Pfizer, S.L.
Tél: +34 91 490 99 00

France
Pfizer Laboratoires
Tél: +33 (0)1 58 07 34 40

Hrvatska
Pfizer Croatia d.o.o.
Tel: +385 1 3908 777

Ireland
Pfizer Healthcare Ireland
Tel: 1800 633 363 (toll free)
+44 (0)1304 616161

Ísland
Icepharma hf.
Sími: +354 540 8000

Italia
Pfizer S.r.l.
Tel: +39 06 33 18 21

Kύπρος
Pfizer Ελλάς Α.Ε. (Cyprus Branch)
Τηλ: +357 22 817690

Latvija
Pfizer Luxembourg SARL filiāle Latvijā
Tel.: +371 670 35 775

Lietuva
Pfizer Luxembourg SARL filialas Lietuvoje
Tel. +370 52 51 4000

Luxembourg/Luxemburg
Pfizer Luxembourg SARL
Tél/Tel: +32 (0)2 554 62 11

Magyarország
Pfizer Kft.
Tel.: +36-1-488-37-00

Malta
Vivian Corporation Ltd.
Tel: +356 21344610

Nederland
Pfizer BV
Tel: +31 (0)10 406 43 01

Norge
Pfizer AS
Tlf: +47 67 52 61 00

Österreich
Pfizer Corporation Austria Ges.m.b.H.
Tel: +43 (0)1 521 15-0

Polska
Pfizer Polska Sp.z.o.o.
Tel: +48 22 335 61 00

Portugal
Pfizer, Lda.
Tel: +351 21 423 5500

România
Pfizer Romania S.R.L.
Tel: +40 (0) 21 207 28 00

Slovenija
Pfizer, podružnica za svetovanje s področja farmacevtske dejavnosti, Ljubljana
Tel.: +386 (0)1 52 11 400

Slovenská republika
Pfizer Luxembourg SARL, organizačná zložka
Tel.: +421 2 3355 5500

Suomi/Finland
Pfizer Oy
Puh./Tel: +358 (0)9 43 00 40

Sverige
Pfizer AB
Tel: +46 (0)8 550 52000

United Kingdom (Northern Ireland)
Pfizer Limited
Tel: +44 (0) 1304 616161

More detailed information on this medicinal product is available on the European Medicines Agency website: https://www.ema.europa.eu.

Package leaflet: information for the user

Bosulif 50 mg hard capsules, 100 mg hard capsules

bosutinib
Please read this entire leaflet carefully before taking this medicine, as it contains important information for you and the person caring for you.

Keep this leaflet. You may need to read it again.
If you have any questions, consult your doctor or pharmacist.
This medicine has been prescribed for you only. Do not give it to others, even if their symptoms are the same as yours, as it could be harmful.
If you experience any side effect, including those not listed in this leaflet, contact your doctor. See section 4.

Contents of this leaflet

What Bosulif is and what it is used for
What you need to know before taking Bosulif
How to take Bosulif
Possible side effects
How to store Bosulif
Contents of the pack and other information

1. What Bosulif is and what it is used for

Bosulif contains the active substance bosutinib. Bosulif is used to treat adult and pediatric patients aged 6 years and older who have a type of leukemia called Philadelphia chromosome-positive (Ph+) chronic myeloid leukemia (CML) in the chronic phase (CP), either at the time of diagnosis or when previous treatments for chronic myeloid leukemia have failed or were inadequate. It is also used to treat adult patients with Ph+ chronic myeloid leukemia in the accelerated phase (AP) and blast phase (BP) when previous treatments for chronic myeloid leukemia have failed or were inadequate.
In patients with Ph+ chronic myeloid leukemia, a genetic alteration in the DNA (genetic material) activates a signal that causes the body to produce an excessive number of a specific type of white blood cells called granulocytes. Bosulif blocks this signal and thereby stops the production of these cells.
If you have any questions about how Bosulif works or why this medicine has been prescribed for you, please consult your doctor.

2. What you should know before taking Bosulif

Do not take Bosulif

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 Bosulif:

if you have or have previously had liver problems. Inform your doctor if you have previously experienced liver problems, including hepatitis (liver infection or inflammation) of any kind, or
if you have previously had any signs or symptoms of liver problems (see
section 4, "Possible side effects"), because Bosulif may affect your liver function. Your doctor should perform blood tests to monitor liver function before starting treatment with Bosulif, during the first 3 months of treatment with Bosulif, and whenever clinically indicated.
if you have diarrhoea or vomiting. Inform your doctor if you develop any signs or symptoms of stomach or intestinal problems (see section 4, "Possible side effects"). To reduce symptoms, your doctor may prescribe an antidiarrhoeal or antiemetic medication and/or fluids. Your doctor may also temporarily suspend, reduce the dose, or permanently discontinue treatment with Bosulif (see section 3, "How to take Bosulif"). Ask your doctor whether anti-nausea or anti-vomiting medications taken together with Bosulif may increase the risk of developing cardiac arrhythmias.
if you have bleeding problems. Inform your doctor if you develop signs or symptoms of blood problems (see section 4, "Possible side effects"), as Bosulif reduces the body's ability to stop bleeding. Your doctor should perform a complete blood count weekly during the first month, then monthly. Your doctor may also temporarily suspend, reduce the dose, or permanently discontinue treatment with Bosulif (see section 3, "How to take Bosulif").
if you have an infection. Inform your doctor if you develop any of the following signs or symptoms, such as fever, urinary problems (e.g. burning sensation when urinating), new onset of cough or new onset of sore throat, because Bosulif reduces the body's ability to defend against infections.
if you have fluid retention. Inform your doctor if you develop any of the following signs or symptoms of fluid retention during treatment with Bosulif, 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). Your doctor will monitor for fluid retention and manage any symptoms.
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 diagnosed with 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 Bosulif, inform your doctor immediately, as this may be a sign of a serious heart condition (see section 2, "What you should know before taking Bosulif"). Before starting treatment, your doctor will perform an electrocardiogram (ECG). Your doctor will perform blood tests before and during treatment, and if you have low levels of potassium or magnesium, will prescribe treatment to correct these low levels.
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 swelling in your feet, ankles, legs, hands, or face. Your doctor will assess kidney function before treatment and monitor it closely during treatment with bosutinib.
if you have ever had or may currently have hepatitis B infection. This is because Bosulif may cause reactivation of hepatitis B, which in some cases can be fatal. Before starting treatment, your doctor will test you for this infection. If you have this infection,
your doctor will monitor you closely for signs and symptoms of infection
during therapy and for several months after stopping treatment.
if you have or have previously had pancreas problems. Inform your doctor if you develop abdominal pain or discomfort. If you experience abdominal pain and blood tests show elevated levels of lipase, an enzyme that helps the body break down fats in food, your doctor may discontinue treatment and perform tests to rule out pancreas problems.
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 rash that spreads progressively, and blisters and/or other lesions starting in the mucosa (e.g. mouth and lips). If a severe skin reaction occurs during treatment, your doctor will permanently discontinue treatment.
if you experience any of these symptoms: flank pain, blood in the urine, or reduced urine output. If your disease is very advanced, your body may be unable to eliminate waste products from dead tumor cells. This condition is called tumor lysis syndrome and may cause kidney failure and heart problems within 48 hours of the first dose of Bosulif. Your doctor is aware of this risk and may ensure you receive adequate hydration and possibly other medications to prevent this condition. Before starting treatment, your doctor will perform a blood test to check for high levels of uric acid and prescribe treatment to correct these values.

Sun protection / UV exposure
While taking bosutinib, you may become more sensitive to sunlight or UV rays. It is important
to cover skin areas exposed to sunlight and to use sunscreen creams with a high sun protection factor (SPF).
Patients of Asian origin
If you are of Asian origin, you may have a higher risk of experiencing side effects during
treatment with Bosulif. Your doctor will monitor you closely for any serious side effects, especially when the dose is increased.
Children and adolescents
Bosulif is not recommended for people under 6 years of age.
This medicine has not been studied in children under 1 year of age.
Other medicines and Bosulif
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 bosutinib levels in your body. You must inform your doctor if you
are taking medicines containing the following active substances:
The following active substances may increase the risk of Bosulif 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 human immunodeficiency virus (HIV/AIDS) infections.
boceprevir and telaprevir, used to treat hepatitis C.
aprepitant, used to prevent and control nausea (feeling unwell)
and vomiting.
imatinib, used to treat a type of leukemia.
crizotinib, used to treat a type of lung cancer called non-small cell lung cancer.

The following active substances may reduce the effectiveness of Bosulif:

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, a 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 Bosulif. If you are taking any of these
medicines, inform your doctor. Your doctor may adjust the dose of these medicines, adjust the dose of
Bosulif, or prescribe an alternative medicine.
The following active substances may alter heart rhythm:

amiodarone, disopyramide, procainamide, quinidine, and sotalol, used to treat heart conditions.
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 used with caution during treatment with Bosulif. If you are taking any
of these medicines, inform your doctor.
Agents that reduce stomach acidity
Proton pump inhibitors (PPIs) should be used with caution during treatment with
Bosulif, as they may reduce its effectiveness. Your doctor may consider short-acting antacids as an alternative to PPIs, and, if possible, the administration times of Bosulif and antacids should be separated (e.g., take Bosulif in the morning and antacids in the evening).
The medicines listed here may not be the only ones that interact with Bosulif; if you are unsure whether
the above applies to you or your child, consult your doctor.
Bosulif with food and drink
Do not take Bosulif with grapefruit or grapefruit juice, as the risk of side effects may
increase.
Pregnancy, breastfeeding, and fertility
Bosulif may harm the unborn baby and therefore should not be used during pregnancy unless considered necessary. Ask your doctor for advice before taking Bosulif if you are pregnant or think you might be pregnant.
Women taking Bosulif 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 Bosulif may reduce fertility; therefore, you may wish to seek advice about sperm preservation before starting treatment.
If you are breastfeeding, inform your doctor. Do not breastfeed during treatment with Bosulif, as it may harm the baby.
Driving and using machines
If you experience dizziness, blurred vision, or unusual tiredness, do not drive or operate machinery
until these side effects have resolved.
Bosulif contains sodium
This medicine contains less than 1 mmol (23 mg) of sodium per 50 mg or 100 mg hard capsule,
i.e., it is essentially “sodium-free”.

3. How to take Bosulif

Take this medicine exactly as instructed by your doctor. If you have any doubts, consult your
doctor or pharmacist.
Bosulif will be prescribed to you only by a physician experienced in medications for the treatment of
leukemia.
Dosage and method of administration
Adults
The recommended dose is 400 mg once daily for patients with newly diagnosed chronic myeloid leukemia. The recommended dose is 500 mg once daily for patients for whom previous treatments for chronic myeloid leukemia have failed or are unsuitable. If you are unable to tolerate the recommended dose or do not respond adequately to Bosulif, your doctor may further adjust the dose.
Children and adolescents (from 6 years of age and older)
The recommended dose is 300 mg/m² body surface area once daily for pediatric patients with newly diagnosed disease. The recommended dose is 400 mg/m² body surface area once daily for pediatric patients who are resistant or intolerant.
Dosage recommendations are provided in the table below. Depending on the case, the recommended dose may be achieved by combining different strengths of bosutinib film-coated tablets and/or hard capsules (see the Package Leaflet for film-coated tablets).
Bosutinib dosing for pediatric patients with newly diagnosed (ND) disease and for pediatric patients
resistant or intolerant (R/I)
Body surface area ND recommended dose R/I recommended dose
0.55–<0.63 m² 200 mg 250 mg
0.63–<0.75 m² 200 mg 300 mg
0.75–<0.9 m² 250 mg 350 mg
0.9–<1.1 m² 300 mg 400 mg
≥1.1 m² 400 mg 500 mg
If you are unable to tolerate the recommended dose or do not respond adequately to Bosulif, your doctor may further adjust the dose.
Take the capsule(s) once daily with food. The hard capsule must be swallowed whole.
Instructions for preparing the dose in patients unable to swallow
For patients unable to swallow intact hard capsules, each capsule may be opened and its contents mixed with apple puree or yogurt. Mixing the contents of the hard capsule with apple puree or yogurt should not be considered a substitute for a complete meal; the dose must be taken with food to improve the medicine's digestibility.
Remove the required number of hard capsules from the container to prepare the dose as indicated, and pour the specified amount of room-temperature apple puree or yogurt into a clean container, as shown in the table below. Carefully open each hard capsule, add all the contents of each capsule to the apple puree or yogurt, and then mix the entire dose thoroughly with the apple puree or yogurt. Patients must consume the entire mixture immediately, without chewing. Do not store the mixture for later use. If the entire preparation cannot be ingested, do not take an additional dose. Wait until the next day to resume administration. To facilitate administration, the recommended volume of apple puree or yogurt is provided in the table below.
Bosutinib dose using hard capsules and volumes of soft food

Dose	Volume of apple puree or yogurt
200 mg	20 ml (4 teaspoons)
250 mg	25 ml (5 teaspoons)
300 mg	30 ml (6 teaspoons)
350 mg	30 ml (6 teaspoons)
400 mg	35 ml (7 teaspoons)
500 mg	45 ml (9 teaspoons)

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

If you forget to take Bosulif
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 a missed dose.

If you stop taking Bosulif
Do not stop taking Bosulif 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 the use of this medicine, consult your doctor or pharmacist.

4. Possible side effects

Like all medicines, this medicine can cause side effects, although not everybody gets them.
Serious side effects
You must contact your doctor immediately if you experience any of the following serious side effects
(see also section 2, “What you should know before taking Bosulif”):
Very common (may affect more than 1 in 10 people):

reduction in the number of platelets (thrombocytopenia), red blood cells (anemia) and/or neutrophils (a type of white blood cells) (neutropenia), which may cause abnormal bleeding, fever or bruising without injury (you may have a disorder of the blood or lymphatic system) (see section 2, “What you should know before taking Bosulif”).
fluid around the lungs (pleural effusion).

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

low number of white blood cells (leukopenia).
bleeding from the stomach or intestine (gastrointestinal haemorrhage), which may include blood in vomit, faeces (bowel movements) or urine, or black stools (black, tarry bowel movements) (see section 2, “What you should know before taking Bosulif”).
chest pain.
liver toxicity (hepatotoxicity), abnormal liver function, including liver disorders (abnormal liver function), which may be accompanied by itching, yellowing of the eyes or skin, dark urine, pain or discomfort in the upper right part of the stomach or fever (see section 2, “What you should know before taking Bosulif”).
when the heart does not pump blood properly (heart failure).
when there is reduced blood flow to the heart (cardiac ischemia).
lung infection (pneumonia).
disturbance in heart rhythm (prolonged QT on electrocardiogram) which may lead to fainting, dizziness and palpitations.
increased blood pressure (hypertension).
high levels of potassium in the blood (hyperkalemia).
acute kidney failure, kidney failure, kidney impairment.
fluid around the heart (pericardial effusion).
allergic reaction (drug hypersensitivity).
abnormally high blood pressure in the arteries of the lungs (pulmonary hypertension).
acute inflammation of the pancreas (acute pancreatitis).

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

fever associated with low number of red blood cells (febrile neutropenia).
liver damage (liver injury).
potentially life-threatening allergic reaction (anaphylactic shock).
abnormal accumulation of fluid in the lungs (acute pulmonary edema).
skin rash (drug rash).
scaly and exfoliative skin rash (exfoliative rash).
inflammation of the membrane lining the heart (pericarditis).
marked reduction in the number of granulocytes (a type of white blood cells, granulocytopenia).
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 levels of calcium in the blood), which may lead to changes in kidney function and acute kidney failure (tumour lysis syndrome (TLS)).
respiratory failure.

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

severe skin disease (Stevens-Johnson syndrome, toxic epidermal necrolysis), which may include painful red or purplish rash that spreads and forms blisters and/or other lesions starting to appear on mucous membranes (e.g., mouth and lips) due to an allergic reaction.
interstitial lung disease (a disease causing scarring in the lungs): signs include cough, difficulty breathing, painful breathing.
reactivation of hepatitis B infection if you have previously had hepatitis B (a liver infection).

Other side effects of Bosulif may include:
Very common (may affect more than 1 in 10 people):

diarrhoea, vomiting, stomach ache (abdominal pain), nausea.
fever (pyrexia), swelling of the hands, feet or face (oedema), fatigue, weakness.
respiratory tract infection.
nasopharyngitis.
changes in blood tests indicating that Bosulif is affecting the liver (increased alanine aminotransferase (ALT), increased aspartate aminotransferase (AST)) and/or the pancreas (increased lipase), the kidneys (increased blood creatinine).
decreased appetite.
joint pain (arthralgia), back pain.
headache.
Skin rash, which may be itchy and/or generalized (rash).
cough.
shortness of breath (dyspnoea).
feeling unsteady (dizziness).

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

stomach irritation (gastritis).
pain.
influenza, bronchitis.
changes in blood tests indicating that Bosulif is affecting the heart (increased blood creatine phosphokinase), the liver (increased blood bilirubin, increased gamma-glutamyl transferase (GGT)) and/or the pancreas (increased amylase).
low level of phosphorus in the blood (hypophosphatemia), excessive loss of body fluids (dehydration).
muscle pain (myalgia).
altered sense of taste (dysgeusia).
ringing in the ears (tinnitus).
urticaria, acne.
sensitivity to UV light from the sun and other light sources (photosensitivity reaction).
itching.

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 listed in Annex V. By reporting side effects, you can help provide more information on the safety of this medicine.

5. How to store Bosulif

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 bottle and carton after "Exp.". The expiry date refers to the last day of that month.
Do not store above 30 °C. Store in the original packaging to protect the medicine from light.
Do not use this medicine if you notice that the packaging is damaged or shows any signs of tampering.
Do not dispose of any medicine 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 Bosulif contains

The active substance is bosutinib. Bosulif hard capsules are available in different strengths. Bosulif 50 mg: each hard capsule contains 50 mg of bosutinib (monohydrate). Bosulif 100 mg: each hard capsule contains 100 mg of bosutinib (monohydrate).

The other components are: mannitol (E421), microcrystalline cellulose (E460), sodium croscarmellose (E468), poloxamers 188, povidone (E1201) and magnesium stearate (E470b). The capsule shell contains gelatin, titanium dioxide (E171), yellow iron oxide (E172) and red iron oxide (E172). The printing ink contains shellac (E904), propylene glycol (E1520), concentrated ammonia solution (E527), black iron oxide (E172), potassium hydroxide (E525) (see section 2, “Bosulif contains sodium”).

Description of Bosulif and contents of the pack

Bosulif 50 mg hard capsules have a white body/orange cap with “BOS 50” printed on the body and “Pfizer” printed on the cap, both in black ink. Bosulif 50 mg hard capsules are available in bottles containing 30 hard capsules.

Bosulif 100 mg hard capsules have a white body/reddish-brown cap with “BOS 100” printed on the body and “Pfizer” printed on the cap, both in black ink. Bosulif 100 mg hard capsules are available in bottles containing 150 hard capsules.

Not all pack sizes may be marketed.

Marketing Authorisation Holder

Pfizer Europe MA EEIG
Boulevard de la Plaine 17
1050 Brussels
Belgium

Manufacturer

Pfizer Manufacturing Deutschland GmbH
Mooswaldallee 1
79108 Freiburg im Breisgau
Germany

For further information on this medicinal product, please contact the local representative of the Marketing Authorisation Holder:

België / Belgique / Belgien Lietuva
Luxembourg/Luxemburg Pfizer Luxembourg SARL filialas Lietuvoje
Pfizer NV/SA Tel. + 370 52 51 4000
Tél/Tel: +32 (0)2 554 62 11

България
Пфайзер Люксембург САРЛ, Клон България
Тел.: +359 2 970 4333

Česká republika Magyarország
Pfizer, spol. s r.o. Pfizer Kft.
Tel.: +420 283 004 111 Tel.: +36-1-488-37-00

Danmark Malta
Pfizer ApS Vivian Corporation Ltd.
Tlf.: +45 44 20 11 00 Tel: +356 21344610

Deutschland Nederland
PFIZER PHARMA GmbH Pfizer BV
Tel: +49 (0)30 550055 51000 Tel: +31 (0)10 406 43 01

Eesti Norge
Pfizer Luxembourg SARL Eesti filiaal Pfizer AS
Tel.: +372 666 7500 Tlf: +47 67 52 61 00

Ελλάδα Österreich
Pfizer Ελλάς A.E. Pfizer Corporation Austria Ges.m.b.H.
Τηλ: +30 210 6785 800 Tel: +43 (0)1 521 15-0

España Polska
Pfizer, S.L. Pfizer Polska Sp.z.o.o.
Tél: +34 91 490 99 00 Tel:+48 22 335 61 00

France Portugal
Pfizer Laboratoires Pfizer, Lda.
Tél: +33 (0)1 58 07 34 40 Tel: +351 21 423 5500

Hrvatska România
Pfizer Croatia d.o.o. Pfizer Romania S.R.L.
Tel: + 385 1 3908 777 Tel: +40 (0) 21 207 28 00

Ireland Slovenija
Pfizer Healthcare Ireland Pfizer Luxembourg SARL
Tel: 1800 633 363 (toll free) Pfizer, podružnica za svetovanje s področja
+44 (0)1304 616161 farmacevtske dejavnosti, Ljubljana
Tel.: + 386 (0)1 52 11 400

Ísland Slovenská republika
Icepharma hf. Pfizer Luxembourg SARL, organizačná zložka
Sími: +354 540 8000 Tel.: + 421 2 3355 5500

Italia Suomi/Finland
Pfizer S.r.l. Pfizer Oy
Tel: +39 06 33 18 21 Puh./Tel: +358 (0)9 43 00 40

Kύπρος Sverige
Pfizer Ελλάς Α.Ε. (Cyprus Branch) Pfizer AB
Tηλ: +357 22 817690 Tel: +46 (0)8 550 52000

Latvija United Kingdom (Northern Ireland)
Pfizer Luxembourg SARL filiāle Latvijā Pfizer Limited
Tel.: + 371 670 35 775 Tel: +44 (0) 1304 616161

More detailed information on this medicinal product is available on the website of the European Medicines Agency, https://www.ema.europa.eu.