BOSULIF 50 mg HARD CAPSULES

Introduction

Package Leaflet: Information for the User

Bosulif 50mg hard capsules

Bosulif 100mg hard capsules

bosutinib

Read all of this leaflet carefully before you start taking this medicine because it contains important information for you and your caregiver.

• Keep this leaflet, as you may need to read it again.
• If you have any further questions, ask your doctor or pharmacist.
• This medicine has been prescribed for you only. Do not pass it on to others. It may harm them, even if their signs of illness are the same as yours.
• If you experience any side effects, talk to your doctor or pharmacist. This includes any possible side effects not listed in this leaflet. See section 4.

Contents of the pack

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

1. What is Bosulif and what is it used for

Bosulif contains the active substance bosutinib. Bosulif is used to treat adult and pediatric patients from 6 years of age who suffer from a type of leukemia called chronic myeloid leukemia (CML) with positive Philadelphia chromosome (Ph-positive) in the chronic phase (CP) newly diagnosed or for whom previous medications for CML have not been effective or are not suitable. It is also used to treat adult patients with Ph+ CML in the accelerated phase (AP) or blast phase (BP) for whom previous medications for CML have not been effective or are not suitable.

In patients with Ph-positive CML, a change in DNA (genetic material) triggers a signal that causes the body to produce an excessive amount of a specific type of white blood cell called granulocytes. Bosulif blocks this signal and thus stops the production of these cells.

If you have any questions about how Bosulif works or why you have been prescribed this medicine, ask your doctor.

2. What you need to know before you take 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 liver damage and that it does not function normally.

Warnings and precautions

Talk to your doctor, pharmacist, or nurse before starting Bosulif:

• Tell your doctor if you have a history of liver problems, including any type of hepatitis (infection or inflammation of the liver), or a history of any signs and symptoms of liver problems (see section 4 "Possible side effects"), as Bosulif may affect liver function. Your doctor should perform blood tests to check your liver function before starting treatment with Bosulif and during the first 3 months of treatment with Bosulif, or as clinically indicated.

• Tell your doctor if you experience any signs and symptoms of stomach or intestinal problems (see section 4 "Possible side effects"). Your doctor may provide you with an anti-diarrheal or anti-emetic and/or fluids to reduce symptoms. Your doctor may also temporarily interrupt, reduce the dose, or permanently discontinue treatment with Bosulif (see section 3 "How to take Bosulif"). Ask your doctor if the use of treatment for nausea or vomiting along with Bosulif may increase the risk of cardiac arrhythmias.

• Tell your doctor if you experience any signs and symptoms of blood problems (see section 4 "Possible side effects"), as Bosulif reduces the ability of the blood to stop bleeding. During the first month, your doctor should perform complete blood counts weekly and then monthly. Your doctor may also temporarily interrupt, reduce the dose, or permanently discontinue treatment with Bosulif (see section 3 "How to take Bosulif").

• Tell your doctor if you experience any of the following signs and symptoms, such as fever, problems with urination such as burning sensation while urinating, new onset cough, or new onset sore throat, as Bosulif reduces the ability of the blood to fight infections.

• Tell your doctor if you experience any of the following signs and symptoms of fluid retention during treatment with Bosulif, such as swelling of the ankles, feet, or legs; difficulty breathing, chest pain, or cough (all of which may be signs of fluid retention in the lungs or chest). Your doctor will monitor fluid retention and treat your symptoms.

• Tell your doctor if you have any heart condition, such as heart failure and decreased blood flow to the heart that can cause a heart attack. Seek medical help immediately if you experience difficulty breathing, weight gain, chest pain, or swelling of the hands, ankles, or feet.

• . Tell your doctor if you have arrhythmias or an abnormal electrical signal called "prolonged QT interval". These problems are always important, but even more so if you experience frequent or prolonged diarrhea as indicated above. If you faint (lose consciousness) or experience irregular heartbeats during treatment with Bosulif, tell your doctor immediately, as they may be signs of a serious heart condition (see section 2 "What you need to know before you take Bosulif"). Your doctor will perform an electrocardiogram (ECG) before starting treatment. Your doctor will also perform blood tests before and during treatment, and if you have low levels of potassium or magnesium, your doctor will provide treatment to correct low blood levels.

• Tell your doctor if you urinate more frequently and produce larger amounts of urine with a light color, or if you urinate less frequently and produce smaller amounts of dark-colored urine. Also, tell your doctor if you lose weight or experience swelling of the feet, ankles, legs, hands, or face. Your doctor will check how well your kidneys are working before treatment and will closely monitor their function during treatment with bosutinib.

• if you have ever had or may currently have a hepatitis B virus infection. This is because Bosulif could cause hepatitis B to become active again, which can be fatal in some cases. Before starting treatment, your doctor will perform hepatitis B tests. If you have this infection, your doctor will closely monitor you for signs or symptoms of infection during treatment and for several months after stopping treatment.

• Tell your doctor if you experience abdominal pain or discomfort. If you have abdominal pain and your blood tests show high levels of lipase, an enzyme that helps the body break down fat from food, your doctor may stop treatment and perform tests to rule out pancreas problems.

• Tell your doctor if you experience any of the following signs and symptoms of a painful red or purple rash that spreads and if blisters and/or other lesions appear on the mucous membranes (e.g., mouth and lips). If you develop a severe skin reaction during treatment, your doctor will permanently discontinue treatment.

• If your disease is very severe, your body may not be able to eliminate all the waste products from dying cancer cells. This is known as tumor lysis syndrome and can cause kidney failure and heart problems within 48 hours of the first dose of Bosulif. Your doctor will ensure that you are adequately hydrated and will provide you with other medications to help prevent it. Your doctor will perform a blood test to check if you have high levels of uric acid and will provide treatment to correct high levels before starting treatment.

Sun/UV protection

During treatment with bosutinib, you may be more sensitive to the sun or UV rays. It is essential that you cover exposed skin areas and 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 side effects with Bosulif. Your doctor will closely monitor you for the possible occurrence of severe side effects, especially when the dose is increased.

Children and adolescents

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

Other medicines and Bosulif

Tell your doctor or pharmacist if you are taking, have recently taken, or might take any other medicines, including those obtained without a prescription, vitamins, and herbal medicines. Some medicines may affect the levels of Bosulif in your body. You should tell your doctor if you are using medicines that contain the following active substances:

The following active substances may increase the risk of side effects with Bosulif:

• 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.
• boceprevir and telaprevir, used to treat hepatitis C.
• aprepitant, used to prevent and control nausea 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 hypertension).
• nafcillin, an antibiotic used to treat bacterial infections.
• St. John's Wort (a herbal medicine obtained without a prescription), used to treat depression.
• efavirenz and etravirine, used to treat HIV/AIDS.
• modafinil, used to treat certain types of sleep disorders.

You should avoid using these medicines during treatment with Bosulif. If you are using any of them, tell your doctor. It may be possible for your doctor to change the doses of these medicines, change the dose of Bosulif, or have you use a different medicine.

The following active substances may affect heart rate:

• amiodarone, disopyramide, procainamide, quinidine, and sotalol, used to treat heart disorders.
• chloroquine and halofantrine, used to treat malaria.
• clarithromycin and moxifloxacin, which are 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 milk production.
• methadone, used to treat pain.

These medicines should be used with caution during treatment with Bosulif. If you are taking any of them, tell your doctor.

Acid-reducing medicines

Proton pump inhibitors (PPIs) should be used with caution during treatment with Bosulif, as they may reduce the effectiveness of Bosulif. Your doctor may consider using short-acting antacids as an alternative to PPIs and administer Bosulif and antacids at different times (i.e., take Bosulif in the morning and antacids at night), whenever possible.

It is possible that the medicines mentioned in this leaflet are not the only ones that may interact with Bosulif; if you are unsure whether the above applies to you or your child, ask your doctor.

Taking Bosulif with food and drinks

Do not take Bosulif with grapefruit or grapefruit juice, as it may increase the risk of side effects.

Pregnancy, breastfeeding, and fertility

Bosulif should not be used during pregnancy unless clearly necessary, as Bosulif may harm the fetus. If you are pregnant or think you may be pregnant, consult your doctor before taking Bosulif.

Women taking Bosulif should be advised to use effective contraceptive methods during treatment and for at least 1 month after the last dose. Vomiting and diarrhea may reduce the effectiveness of oral contraceptives.

Ask for information about sperm preservation before starting treatment, if desired, due to the risk that treatment with Bosulif may reduce fertility.

If you are breastfeeding, tell your doctor. Do not breastfeed during treatment with Bosulif, as it may harm the baby.

Driving and using machines

If you experience dizziness, have blurred vision, or feel unusual fatigue, do not drive or use machines until these side effects have disappeared.

Bosulif contains sodium

This medicine contains less than 1 mmol of sodium (23 mg) per 50 mg or 100 mg hard capsule; this is essentially "sodium-free".

3. How to take Bosulif

Follow exactly the administration instructions of this medicine indicated by your doctor. In case of doubt, consult your doctor or pharmacist again.

Bosulif will only be prescribed by a doctor who has experience with the medicines used to treat leukemia.

Dose and method of administration

Adults

The recommended dose is 400 mg once a day for patients with newly diagnosed CML. The recommended dose is 500 mg once a day for patients whose previous medications for CML were not effective or are not suitable. If you are unable to tolerate the recommended dose or are not responding correctly to treatment with Bosulif, your doctor may adjust the dose further.

Children and adolescents (from 6 years of age)

The recommended dose is 300 mg/m2 according to body surface area once a day for newly diagnosed pediatric patients. The recommended dose is 400 mg/m2 according to body surface area once a day for pediatric patients who are resistant or intolerant.

The following table provides dose recommendations. As appropriate, the recommended dose can be obtained by combining different film-coated tablet presentations and/or hard capsules (see the summary of product characteristics of the film-coated tablets).

Dose of bosutinib for newly diagnosed pediatric patients (ND) and for resistant or intolerant patients (R/I)

• maximum initial dose (corresponding to the maximum initial dose in the indication for adults)

If you are unable to tolerate the recommended dose or are not responding correctly to treatment with Bosulif, your doctor may adjust the dose further.

Take the capsule(s) once a day with food. The hard capsule should be swallowed whole.

Instructions for preparing the dose for patients who cannot swallow

In the case of patients who cannot swallow whole capsules, they can be opened and mixed with apple sauce or yogurt. The mixture of the hard capsule contents with apple sauce or yogurt cannot be considered a substitute for a proper meal; the dose should be taken with food to increase gastrointestinal tolerability.

Remove from the packaging the number of hard capsules necessary to prepare the dose according to the instructions and pour the amount of apple sauce or yogurt indicated in the following table at room temperature into a clean container. Carefully open each hard capsule, add the complete contents of the hard capsule to the apple sauce or yogurt, and then mix the complete dose in the apple sauce or yogurt. You should consume the mixture immediately in its entirety, without chewing. Do not conserve the mixture for later use. If you do not ingest the entire preparation, do not take an additional dose. Wait until the next day to resume administration. To facilitate administration, the recommended volume of apple sauce or yogurt is provided in the following table.

Dose of Bosulif using hard capsules and soft food volumes

If you take more Bosulifthan you should

If you accidentally take too many Bosulif capsules or a higher dose than you need, go immediately to a doctor. If possible, show the doctor the packaging or this leaflet. You may need medical attention.

If you forget to take Bosulif

If it has been less than 12 hours, take the recommended dose. If it has been more than 12 hours, take your next dose at the usual time the next day.

Do not take a double dose to make up for forgotten doses.

If you interrupt treatment with Bosulif

Do not stop taking Bosulif unless your doctor tells you to. If you cannot take the medicine as indicated by your doctor or think you no longer need it, consult your doctor immediately.

If you have any other questions about the use of this medicine, ask 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 should consult your doctor immediately if you suffer any serious side effect (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 (anemia), or neutrophils (a type of white blood cell) (neutropenia), which can cause abnormal bleeding, fever, or frequent bruising without having had any injury (you may have a blood or lymphatic system disorder) (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):

• decrease in white blood cell count (leucopenia).
• bleeding in the stomach or intestine (gastrointestinal hemorrhage) that may include blood in vomit, stools, or urine, or black stools (“tarry” stools) (see section 2 “What you need to know before taking Bosulif”).
• chest pain.
• toxic liver damage (hepatotoxicity), abnormal liver function, including liver disorder (abnormal liver function) that may be accompanied by itching, yellow eyes and skin, dark urine, and pain or discomfort in the upper right part of the stomach or fever (see section 2 “What you need to know before taking Bosulif”).
• the heart does not pump blood as it should (heart failure).
• decreased blood flow to the heart (cardiac ischemia).
• lung infection (pneumonia).
• abnormal heart rhythm (prolongation of the QT interval on the electrocardiogram) that predisposes to fainting, dizziness, and palpitations.
• high blood pressure (hypertension).
• high potassium levels in the blood (hyperkalemia).
• acute kidney failure, kidney failure, kidney deterioration.
• fluid around the heart (pericardial effusion).
• allergic reaction (drug hypersensitivity).
• abnormally high blood pressure in the lungs (pulmonary hypertension).
• acute pancreas inflammation (acute pancreatitis).

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

• fever associated with a low white blood cell count (febrile neutropenia).
• liver damage (liver injury).
• life-threatening allergic reaction (anaphylactic shock).
• abnormal fluid accumulation in the lungs (acute pulmonary edema).
• skin rash (drug rash).
• scaling, scaly rash (exfoliative rash).
• inflammation of the heart lining or pericardium (pericarditis).
• significant decrease in the number of granulocytes (a type of white blood cell, granulocytopenia).
• severe skin disorder (erythema multiforme).
• nausea, difficulty breathing, irregular heartbeats, muscle cramps, seizures, cloudy urine, and fatigue related to abnormal test results (elevated potassium, uric acid, and phosphorus in the blood and decreased calcium in the blood) that can cause changes in kidney function and acute kidney failure (tumor lysis syndrome [TLS]).
• respiratory failure.

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

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

Other side effects that may occur with Bosulif are:

Very common(may affect more than 1 in 10 patients):

• diarrhea, vomiting, stomach pain (abdominal pain), nausea.
• fever (pyrexia), swelling of the hands, feet, or face (edema), fatigue, weakness.
• respiratory tract infection.
• nasopharyngitis.
• alteration of blood tests for liver function (elevated alanine aminotransferase [ALT], elevated aspartate aminotransferase [AST]) and/or pancreas (elevated lipase), kidney (elevated creatinine in blood) function.
• decreased appetite.
• joint pain (arthralgia), back pain.
• headache.
• skin rash, with itching of the skin and/or generalized (rash).
• cough.
• difficulty breathing (dyspnea).
• feeling of instability (dizziness).

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

• stomach irritation (gastritis).
• pain.
• flu, bronchitis.
• alterations in blood tests to determine if Bosulif is affecting the heart (elevated creatine phosphokinase in blood), liver (elevated bilirubin in blood, elevated gamma-glutamyltransferase [GGT]), and/or pancreas (elevated amylase).
• decreased phosphorus in the blood (hypophosphatemia), excessive loss of body fluids (dehydration).
• muscle pain (myalgia).
• alteration of taste (dysgeusia).
• ringing in the ears (tinnitus).
• hives (urticaria), acne.
• sensitivity to UV rays from the sun and other light sources (photosensitivity reaction).
• itching (pruritus).

Reporting of side effects

If you experience any side effect, consult your doctor, pharmacist, or nurse, even if it is a possible side effect not listed in this leaflet. You can also report them directly through the national reporting system included in Appendix V. By reporting side effects, you can help provide more information on the safety of this medicine.

5. Storage of Bosulif

• Keep this medicine out of the sight and reach of children.
• Do not use this medicine after the expiration date stated on the bottle and packaging after “EXP”. The expiration date is the last day of the month indicated.
• Do not store above 30°C. Store in the original packaging to protect from light.
• Do not use this medicine if you notice that the packaging is damaged or shows signs of tampering.
• Medicines should not be disposed of via wastewater or household waste. Ask your pharmacist how to dispose of the packaging and medicines you no longer need. This will help protect the environment.

6. Package contents and additional information

Composition of Bosulif

Hard capsules:

• The active substance is bosutinib. Bosulif hard capsules are available in various doses.

Bosulif 50 mg: each hard capsule contains 50 mg of bosutinib (as monohydrate).

Bosulif 100 mg: each hard capsule contains 100 mg of bosutinib (as monohydrate).

• The other ingredients are: mannitol (E421), microcrystalline cellulose (E460), sodium croscarmellose (E468), poloxamers 188, povidone (E1201), and magnesium stearate (E470b). The hard 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), and potassium hydroxide (E525) (see section 2 “Bosulif contains sodium”).

Appearance of the product and package contents

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

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

Not all pack sizes may be marketed.

Marketing authorization 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

You can request more information about this medicine by contacting the local representative of the marketing authorization holder:

Date of last revision of this leaflet:

Detailed information on this medicine is available on the European Medicines Agency website: https://www.ema.europa.eu.