Package leaflet: Information for the user

Bosutinib MSN, 100 mg, coated tablets
Bosutinib MSN, 400 mg, coated tablets
Bosutinib MSN, 500 mg, coated tablets
Bosutinibum
Please read this leaflet carefully before taking this medicine, because it contains
important information for the patient.

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

Contents of the leaflet

What Bosutinib MSN is and what it is used for
Important information before taking Bosutinib MSN
How to take Bosutinib MSN
Possible side effects
How to store Bosutinib MSN
Contents of the pack and other information

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

Bosutinib MSN contains the active substance bosutinib. This medicine is used to treat
adult patients, as well as children and adolescents aged 6 years and older, who have a type of
leukaemia called Philadelphia chromosome-positive chronic myeloid leukaemia (Ph-positive CML),
either when the disease has just been diagnosed, or when previous treatments for chronic myeloid
leukaemia have not worked or were unsuitable. This medicine is also used to treat adult patients
with Ph-positive chronic myeloid leukaemia in the accelerated phase or blast phase, when
previous treatments for chronic myeloid leukaemia have been ineffective or inappropriate.
In patients with Ph-positive chronic myeloid leukaemia, a change in DNA (genetic material)
triggers a signal that causes the body to produce too many specific white blood cells called
granulocytes. Bosutinib MSN blocks this signal, thereby inhibiting the production of these cells.
If you have any questions about how Bosutinib MSN works or why this medicine has been
prescribed, please consult your doctor.

2. Important information before taking Bosutinib MSN

When not to take Bosutinib MSN

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 the doctor that they have impaired liver function.

Warnings and precautions
Before starting treatment with Bosutinib MSN, discuss this with your doctor, pharmacist, or
nurse:

if the patient has or has had liver disease. Inform the doctor about any previous liver conditions, including hepatitis (infection or inflammation of the liver) regardless of type, as well as any prior signs or symptoms of liver disease (see section 4 “Possible side effects”), because Bosutinib MSN may affect liver function. Before starting treatment with Bosutinib MSN and during the first 3 months of treatment, and as clinically indicated thereafter, the doctor should perform blood tests to monitor liver function.
if the patient has diarrhoea and vomiting. Inform the doctor about any signs or symptoms of gastrointestinal disturbances (see section 4 “Possible side effects”). The doctor may prescribe anti-diarrhoeal or anti-emetic medication and/or fluids to relieve symptoms. The doctor may also temporarily interrupt treatment with Bosutinib MSN, reduce the dose, or permanently discontinue treatment (see section 3 “How to take Bosutinib MSN”). Ask the doctor whether using anti-nausea or anti-vomiting medicines with Bosutinib MSN could increase the risk of heart arrhythmias.
if the patient has bleeding. Inform the doctor about any signs or symptoms of bleeding problems (see section 4 “Possible side effects”), as Bosutinib MSN reduces the body’s ability to stop bleeding. During the first month, the doctor will order a complete blood count once a week, and thereafter once a month. The doctor may also temporarily interrupt treatment with Bosutinib MSN, reduce the dose, or permanently discontinue treatment (see section 3 “How to take Bosutinib MSN”).
if the patient has an infection. Inform the doctor about any of the following signs or symptoms, such as fever, problems with urination (e.g. burning sensation), new cough or sore throat, because Bosutinib MSN reduces the body’s ability to fight infections.
if the patient develops fluid retention. Inform the doctor if, during treatment with Bosutinib MSN, any of the following signs or symptoms of fluid retention occur: swelling of the ankles, feet or legs, difficulty breathing, chest pain or cough (which may indicate fluid accumulation in the lungs or chest cavity). The doctor will monitor the patient for fluid retention and take appropriate steps to relieve symptoms.
if the patient has heart conditions. Inform the doctor about heart diseases 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 an abnormal heart rhythm. Inform the doctor about any history of arrhythmias or an abnormal ECG finding known as “QT prolongation”. These conditions are always important, but particularly significant in cases of frequent or prolonged diarrhoea, as described above. If the patient experiences fainting (loss of consciousness) or irregular heartbeat while taking Bosutinib MSN, contact the doctor immediately, as this may be a sign of a serious heart condition (see section 2 “Important information before taking Bosutinib MSN”). Before starting treatment, the doctor will order an electrocardiogram (ECG). The doctor will also order blood tests before and during therapy, and if low levels of potassium or magnesium are detected, appropriate treatment will be initiated to correct these blood parameters.
if the patient has been told they have kidney disease. Inform the doctor about more frequent urination and producing larger amounts of pale-coloured urine, as well as less frequent urination and producing smaller amounts of dark-coloured urine. Also inform the doctor about weight loss and swelling of the feet, ankles, legs, hands or face. Before starting treatment, the doctor will assess kidney function and closely monitor kidney function during bosutinib therapy.
if the patient has ever had or may currently have hepatitis B virus infection. This is because Bosutinib MSN may cause reactivation of hepatitis B virus, which in some cases may lead to death. Before starting treatment, the doctor will perform tests to detect this infection. If the patient has this infection, the doctor will closely monitor for signs and symptoms of hepatitis B throughout treatment and for several months after treatment ends.
if the patient has or has had pancreas disorders. Inform the doctor about the onset of abdominal pain or discomfort in this area. If the patient experiences abdominal pain and blood tests show elevated levels of lipase, an enzyme that helps the body break down dietary fats, the doctor may discontinue treatment and order appropriate tests to rule out pancreas problems.
if the patient experiences any of the following symptoms: severe skin rashes. Inform the doctor if any of the following occur: painful, red or purplish spreading rash, blisters and/or other changes starting on mucous membranes (e.g. inside the mouth or lips). If the patient develops a severe skin reaction during treatment, the doctor will recommend permanent discontinuation of therapy.
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 of the first dose of Bosutinib MSN. The doctor is aware of this potential complication and may recommend adequate hydration and other medications to prevent it. The doctor will order blood tests to check for elevated uric acid levels and initiate appropriate treatment before starting therapy to correct this parameter.

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 high sun protection factor (SPF) sunscreen.
Patients of Asian origin
Patients of Asian origin may have an increased risk of adverse reactions associated with Bosutinib MSN. The doctor will closely monitor the patient for severe adverse reactions, especially during dose escalation.
Children and adolescents
Bosutinib MSN is not recommended for use in children under 6 years of age. The use of this medicine has not been studied in children under 1 year of age.
Bosutinib MSN and other medicines
Inform the doctor or pharmacist about all medicines currently or recently taken, as well as any medicines planned for future use, including over-the-counter medicines, vitamins, and herbal remedies. 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 MSN:

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 patients 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 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 MSN:

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 virus infections.
modafinil used to treat certain types of sleep disorders.

Avoid using these medicines during treatment with Bosutinib MSN. 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 MSN, 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 MSN. Inform the doctor if any of these medicines are being taken.
Medicines that neutralise gastric acid
Proton pump inhibitors (PPIs) should be used cautiously during treatment with Bosutinib MSN, as they may reduce its effectiveness. The doctor may consider using short-acting acid-neutralising medicines as an alternative to PPIs. If possible, maintain a time interval between taking Bosutinib MSN and acid-neutralising medicines (i.e. take Bosutinib MSN in the morning and acid-neutralising medicines in the evening).
Other medicines not listed above may also interact with Bosutinib MSN. If the patient is unsure whether the above information applies to them, they should consult their doctor.
Bosutinib MSN with food and drink
Do not take Bosutinib MSN with grapefruit or grapefruit juice, as this may increase the risk of adverse effects.
Pregnancy, breastfeeding and effects on fertility
Bosutinib MSN may harm the unborn child; therefore, it should not be taken during pregnancy unless considered necessary. If the patient is pregnant or may become pregnant, consult the doctor before taking Bosutinib MSN.
Women taking Bosutinib MSN are advised to 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 MSN.
If the patient is breastfeeding, inform the doctor. Breastfeeding should not be continued during treatment with Bosutinib MSN, as it may harm the infant.
Driving and operating machinery
If the patient experiences dizziness, blurred vision, or unusual fatigue, they should not drive or operate machinery until these side effects resolve.

3. How to take Bosutinib MSN

This medicine should always be taken exactly as directed by the doctor. If in doubt,
consult the doctor or pharmacist.
Bosutinib MSN will only be prescribed by a physician experienced in the use of drugs for the treatment of leukemia.
Dosage and method of administration
Adult patients
The recommended dose for patients with newly diagnosed chronic myeloid leukemia is 400 mg once daily. The recommended dose for patients who have previously failed treatment or were intolerant to prior therapy for chronic myeloid leukemia is 500 mg once daily. If the patient does not tolerate the recommended dose or does not respond adequately to Bosutinib MSN, the doctor may adjust the dose accordingly.
Children and adolescents (aged 6 years and older)
The recommended dose for children and adolescents with newly diagnosed disease is 300 mg/m^2 of body surface area administered once daily. The recommended dose for children and adolescents with resistance to or intolerance of prior treatment is 400 mg/m^2 of body surface area administered once daily.
Dosing recommendations are provided in the table below.
Dosing of bosutinib in children and adolescents with newly diagnosed disease and with resistance to or intolerance of treatment

Body surface area	Recommended dose – newly diagnosed disease	Recommended dose – treatment-resistant or treatment-intolerant disease
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*

* Maximum initial dose (corresponding to the maximum initial dose in the indication for adults)
If the patient does not tolerate the recommended dose or does not respond appropriately to Bosutinib MSN, the doctor may adjust the dose accordingly.
The tablets should be taken once daily with food. The tablets should be swallowed whole with water.
Taking more Bosutinib MSN than prescribed
If too many tablets of Bosutinib MSN or a larger than recommended dose has been taken by accident, consult a doctor immediately. If possible, show the doctor the packaging of the medicine or this leaflet. The patient may require medical attention.
Missing a dose of Bosutinib MSN
If less than 12 hours have passed since the missed dose, the patient should take the recommended dose.
If more than 12 hours have passed since the missed dose, the next dose should be taken 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 MSN
Do not stop taking Bosutinib MSN unless instructed by the doctor. If the patient is unable to take the medicine as directed by the doctor or thinks they no longer need the medicine, they should contact their doctor immediately.
If there are any further questions about the use of this medicine, consult the doctor or pharmacist.

4. Possible adverse reactions

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

Very common (may occur in more than 1 in 10 people):

Decreased 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 tendency to develop bruises without injury (patients may have blood or lymphatic system disorders) (see section 2 "Important information before taking Bosutinib MSN").
Presence of fluid around the lungs (pleural effusion).

Common (may occur in no more than 1 in 10 people):

Decreased number of white blood cells (leukopenia).
Bleeding from the stomach or intestines (gastrointestinal hemorrhage), which may present as blood in vomit, stool (bowel movements), or urine, or manifest as black stools (tarry, black bowel movements) (see section 2 "Important information before taking Bosutinib MSN").
Chest pain.
Toxic liver damage (hepatotoxicity), abnormal liver function, including liver function disorders (abnormal liver function), which may be accompanied by itching, yellowing of the whites of the eyes or skin, dark-colored urine, pain or discomfort in the upper right part of the abdomen, or fever (see section 2 "Important information before taking Bosutinib MSN").
Heart unable to pump blood as effectively as it should (heart failure).
Reduced blood flow to the heart (cardiac ischemia).
Lung infection (pneumonia).
Heart rhythm disorders (prolongation of QT interval on ECG) predisposing to fainting, dizziness, and palpitations.
Increased blood pressure (hypertension).
Increased potassium levels in the blood (hyperkalemia).
Acute kidney injury, kidney failure, kidney function disorders.
Fluid around the heart (pericardial effusion).
Allergic reaction (hypersensitivity to the medicine).
Abnormally high blood pressure in the pulmonary arteries (pulmonary hypertension).
Acute pancreatitis.

Uncommon (may occur in no more than 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 edema).
Skin rashes.
Peeling rash (exfoliative rash).
Inflammation of the sac surrounding the heart (pericarditis).
Marked decrease in granulocytes (a type of white blood cells, granulocytopenia).
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 (tumor lysis syndrome).
Respiratory failure.

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

Severe skin disorders (Stevens-Johnson syndrome, toxic epidermal necrolysis), which may include painful, red or purple rash spreading and forming blisters and/or other changes, beginning to appear on mucous membranes (e.g., in the mouth and on the lips) due to an allergic reaction.
Interstitial lung disease (disorders causing scarring in the lungs): symptoms include cough, difficulty breathing, painful breathing.
Reactivation (recurrence) of hepatitis B virus infection in patients who have previously had this disease.

Other adverse reactions associated with the use of Bosutinib MSN may include:
Very common (may occur in more than 1 in 10 people):

Diarrhea, vomiting, abdominal pain, nausea.
Fever, swelling of hands, feet, or face (edema), fatigue, weakness.
Respiratory tract infection.
Inflammation of the nose and throat.
Changes in blood test results aimed at determining whether Bosutinib MSN affects the liver (increased alanine aminotransferase and aspartate aminotransferase activity) and/or pancreas (increased lipase activity), kidney (increased blood creatinine levels).
Decreased appetite.
Joint pain (arthralgia), back pain.
Headache.
Skin rash, which may be itchy and/or generalized (rash).
Cough.
Shortness of breath (dyspnea).
Feeling of imbalance (dizziness).

Common (may occur in no more than 1 in 10 people):

Gastritis (inflammation of the stomach).
Pain.
Influenza, bronchitis.
Changes in blood test results aimed at determining whether Bosutinib MSN affects the heart (increased blood creatine phosphokinase activity), liver (increased blood bilirubin levels, increased gamma-glutamyltransferase activity), and/or pancreas (increased amylase activity).
Low phosphate levels in the blood (hypophosphatemia), excessive loss of body fluids (dehydration).
Muscle pain.
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 (pruritus).

Reporting of adverse reactions
If any adverse reactions occur, including any not listed in this leaflet, inform your doctor, pharmacist, or nurse. Adverse reactions can be reported directly to the Department of Monitoring Adverse Drug Reactions, 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 authorization holder.
Reporting adverse reactions helps provide more information on the safety of this medicine.

5. How to store Bosutinib MSN

Keep this medicine out of the sight and reach of children.
Do not use this medicine after the expiry date stated on the blister pack and the cardboard box after: EXP. The expiry date refers to the last day of the stated month.
There are no special storage instructions for this medicine.
Do not use this medicine if you notice damage to the packaging or any 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. These measures help protect the environment.

6. Contents of the pack and other information

What Bosutinib MSN contains
The active substance is bosutinib.
Bosutinib MSN 100 mg: each film-coated tablet contains 106.79 mg of bosutinib dihydrate,
equivalent to 100 mg of bosutinib.
Bosutinib MSN 400 mg: each film-coated tablet contains 427.16 mg of bosutinib dihydrate,
equivalent to 400 mg of bosutinib.
Bosutinib MSN 500 mg: each film-coated tablet contains 533.95 mg of bosutinib dihydrate,
equivalent to 500 mg of bosutinib.
The other ingredients are:
Tablet core: microcrystalline cellulose, crospovidone, poloxamer 188, povidone, and magnesium stearate.
Tablet coating:
[100 mg]: Hypromellose 2910 (E 464), titanium dioxide (E 171), macrogol 3350 (E 1521), iron oxide yellow (E 172).
[400 mg]: Hypromellose 2910 (E 464), titanium dioxide (E 171), macrogol 6000 (E 1521), iron oxide yellow (E 172), iron oxide red (E 172).
[500 mg]: Hypromellose 2910 (E 464), titanium dioxide (E 171), macrogol 400 (E 1521), talc (E 553b), iron oxide red (E 172).

What Bosutinib MSN looks like and contents of the pack
Bosutinib MSN 100 mg film-coated tablets are yellow, oval-shaped, biconvex film-coated tablets, approximately 11 mm in length and 5 mm in width, with the imprint “100” on one side and “B” on the other side.
Bosutinib MSN 100 mg is available in blister packs containing 28, 30 or 112 film-coated tablets, and in perforated unit dose blisters containing 28 x 1, 30 x 1 or 112 x 1 film-coated tablet.

Bosutinib MSN 400 mg film-coated tablets are orange, oval-shaped, biconvex film-coated tablets, approximately 16 mm in length and 9 mm in width, with the imprint “400” on one side and “B” on the other side.
Bosutinib MSN 400 mg is available in blister packs containing 28 or 30 film-coated tablets, and in perforated unit dose blisters containing 28 x 1 or 30 x 1 film-coated tablet.

Bosutinib MSN 500 mg film-coated tablets are red, oval-shaped, biconvex film-coated tablets, approximately 18 mm in length and 9 mm in width, with the imprint “500” on one side and “B” on the other side.
Bosutinib MSN 500 mg is available in blister packs containing 28 or 30 film-coated tablets, and in perforated unit dose blisters containing 28 x 1 or 30 x 1 film-coated tablet.

Not all pack sizes may be marketed.

Marketing Authorisation Holder and Manufacturer/Importer
Marketing Authorisation Holder:
MSN Labs Europe Limited
KW20A Corradino Park
Paola, PLA 3000
Malta
tel.: (+48) 699 711 147
{logo of the marketing authorisation holder}

Manufacturer/Importer:
Pharmadox Healthcare Limited
KW20A Kordin Industrial Park
Paola, PLA 3000
Malta
MSN Labs Europe Limited
KW20A Corradino Park
Paola, PLA 3000
Malta

This medicinal product is authorised in the Member States of the European Economic Area under the following names:
Bulgaria: босутиниб MSN 100 mg филмирани таблетки
босутиниб MSN 400 mg филмирани таблетки
босутиниб MSN 500 mg филмирани таблетки
Croatia: Bosutinib MSN 100 mg filmom obložene tablete
Bosutinib MSN 400 mg filmom obložene tablete
Bosutinib MSN 500 mg filmom obložene tablete
Czech Republic: Bosutinib MSN
Estonia: Bosutinib MSN
Spain: Bosutinib Vivanta 100 mg comprimidos recubiertos con película EFG
Bosutinib Vivanta 400 mg comprimidos recubiertos con película EFG
Bosutinib Vivanta 500 mg comprimidos recubiertos con película EFG
Lithuania: Bosutinib MSN 100 mg plėvele dengtos tabletės
Bosutinib MSN 400 mg plėvele dengtos tabletės
Bosutinib MSN 500 mg plėvele dengtos tabletės
Latvia: Bosutinib MSN 100 mg apvalkotās tabletes
Bosutinib MSN 400 mg apvalkotās tabletes
Bosutinib MSN 500 mg apvalkotās tabletes
Poland: Bosutinib MSN
Slovenia: Bosutinib MSN 100 mg filmsko obložene tablete
Bosutinib MSN 400 mg filmsko obložene tablete
Bosutinib MSN 500 mg filmsko obložene tablete
Hungary: Bosutinib MSN 100 mg filmtabletta
Bosutinib MSN 400 mg filmtabletta
Bosutinib MSN 500 mg filmtabletta

Bosutinib msn