Bosulif

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ANNEX I 

 

SUMMARY OF PRODUCT CHARACTERISTICS 

 



 

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This medicinal product is subject to additional monitoring. This will allow quick identification of 

new safety information. Healthcare professionals are asked to report any suspected adverse 

reactions. See section 4.8 for how to report adverse reactions. 

 

 

1. NAME OF THE MEDICINAL PRODUCT 

 

Bosulif 100 mg film-coated tablets  

Bosulif 400 mg film-coated tablets  

Bosulif 500 mg film-coated tablets 

 

 

2. QUALITATIVE AND QUANTITATIVE COMPOSITION 

 

Bosulif 100 mg film-coated tablets 

Each film-coated tablet contains 100 mg bosutinib (as monohydrate). 

 

Bosulif 400 mg film-coated tablets 

Each film-coated tablet contains 400 mg bosutinib (as monohydrate). 

 

Bosulif 500 mg film-coated tablets 

Each film-coated tablet contains 500 mg bosutinib (as monohydrate). 

 

For the full list of excipients, see section 6.1. 

 

 

3. PHARMACEUTICAL FORM 

 

Film-coated tablet.  

 

Bosulif 100 mg film-coated tablets 

Yellow oval (width: 5.6 mm; length: 10.7 mm) biconvex, film-coated tablet debossed with “Pfizer” 

on one side and “100” on the other side. 

 

Bosulif 400 mg film-coated tablets 

Orange oval (width: 8.8 mm; length: 16.9 mm) biconvex, film-coated tablet debossed with “Pfizer” 

on one side and “400” on the other side. 

 

Bosulif 500 mg film-coated tablets 

Red oval (width: 9.5 mm; length: 18.3 mm) biconvex, film-coated tablet debossed with “Pfizer” on 

one side and “500”on the other side. 

 

 

4. CLINICAL PARTICULARS 

 

4.1 Therapeutic indications 

 

Bosulif is indicated for the treatment of adult patients with: 

• newly-diagnosed chronic phase (CP) Philadelphia chromosome-positive chronic 
myelogenous leukaemia (Ph+ CML). 

• CP, accelerated phase (AP), and blast phase (BP) Ph+ CML previously treated with one or 
more tyrosine kinase inhibitor(s) [TKI(s)] and for whom imatinib, nilotinib and dasatinib are 

not considered appropriate treatment options. 



 

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4.2 Posology and method of administration 

 

Therapy should be initiated by a physician experienced in the diagnosis and the treatment of patients  

with CML. 

 

Posology 

 

Newly-diagnosed CP Ph+ CML 

The recommended dose is 400 mg bosutinib once daily. 

 

CP, AP, or BP Ph+ CML with resistance or intolerance to prior therapy 

The recommended dose is 500 mg bosutinib once daily. 

 

In clinical trials for both indications, treatment with bosutinib continued until disease progression or 

intolerance to therapy. 

 

Dose adjustments 

 

In the Phase 1/2 clinical study in patients with CML who were resistant or intolerant to prior 

therapy, dose escalations from 500 mg to 600 mg once daily with food were allowed in patients 

who failed to demonstrate complete haematological response (CHR) by Week 8 or complete 

cytogenetic response (CCyR) by Week 12 and did not have Grade 3 or higher adverse events 

possibly-related to the investigational product. Whereas, in the Phase 3 study in patients with 

newly-diagnosed CP CML treated with bosutinib 400 mg, dose escalations by 100 mg increments to 

a maximum of 600 mg once daily with food were permitted if the patient failed to demonstrate 

breakpoint cluster region-Abelson (BCR-ABL) transcripts ≤ 10% at Month 3, did not have a 

Grade 3 or 4 adverse reaction at the time of escalation, and all Grade 2 non-haematological toxicities 

were resolved to at least Grade 1.  

 

In the Phase 1/2 clinical study in patients with CML who were resistant or intolerant to prior 

therapy who started treatment at ≤ 500 mg, 93 (93/558; 16.7%) patients had dose escalations to 

600 mg daily.  

 

In the Phase 3 study in patients with newly-diagnosed CP CML who started bosutinib treatment at 

400 mg, a total of 46 patients (17.2%) received dose escalations to 500 mg. In addition, 5.6% of 

patients in the bosutinib treatment group had further dose escalations to 600 mg. 

 

Doses greater than 600 mg/day have not been studied and, therefore, should not be given. 

 

Dose adjustments for adverse reactions 

 

Non-haematological adverse reactions 

If clinically significant moderate or severe non-haematological toxicity develops, bosutinib should be 

interrupted, and may be resumed at a dose reduced by 100 mg taken once daily after the toxicity 

has resolved. If clinically appropriate, re-escalation to the dose prior to the dose reduction taken 

once daily should be considered (see section 4.4). Doses less than 300 mg/day have been used in 

patients; however, efficacy has not been established. 

 

Elevated liver transaminases: If elevations in liver transaminases > 5 × institutional upper limit of 

normal (ULN) occur, bosutinib should be interrupted until recovery to ≤ 2.5 × ULN and may be 

resumed at 400 mg once daily thereafter. If recovery takes longer than 4 weeks, discontinuation of 

bosutinib should be considered. If transaminase elevations ≥ 3 × ULN occur concurrently with 



 

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bilirubin elevations > 2 × ULN and alkaline phosphatase < 2 × ULN, bosutinib should be 

discontinued (see section 4.4).  

 

Diarrhoea: For NCI Common Terminology Criteria for Adverse Events (CTCAE) Grade 3-4 

diarrhoea, bosutinib should be interrupted and may be resumed at 400 mg once daily upon recovery 

to grade ≤ 1 (see section 4.4). 

 

Haematological adverse reactions 

Dose reductions are recommended for severe or persistent neutropenia and thrombocytopenia as 

described in Table 1: 

 

Table 1 – Dose adjustments for neutropenia and thrombocytopenia 

 

ANCa < 1.0 × 109/L  

 

and/or 

 

Platelets < 50 × 109/L 

Hold bosutinib until ANC  1.0 × 109/L and platelets 

 50 × 109/L. 

 

Resume treatment with bosutinib at the same dose if recovery 

occurs within 2 weeks. If blood counts remain low for 

> 2 weeks, upon recovery reduce dose by 100 mg and resume 

treatment. 

 

If cytopoenia recurs, reduce dose by an additional 100 mg 

upon recovery and resume treatment.  

 

Doses less than 300 mg/day have been used; however, 

efficacy has not been established. 
a ANC = absolute neutrophil count 

 

Special populations 

 

Elderly patients (≥ 65 years) 

No specific dose recommendation is necessary in the elderly. Since there is limited information in 

the elderly, caution should be exercised in these patients.  

 

Renal impairment  

Patients with serum creatinine > 1.5×ULN were excluded from CML studies. Increasing exposure 

(area under curve [AUC]) in patients with moderate and severe renal impairment during studies was 

observed.  

 

Newly-diagnosed CP Ph+ CML 

In patients with moderate renal impairment (creatinine clearance [CLCr] 30 to 50 mL/min, estimated 

by the Cockcroft-Gault formula), the recommended dose of bosutinib is 300 mg daily with food 

(see sections 4.4 and 5.2).  

 

In patients with severe renal impairment (CLCr < 30 mL/min, estimated by the Cockcroft-Gault 

formula), the recommended dose of bosutinib is 200 mg daily with food (see sections 4.4 and 5.2). 

 

Dose escalation to 400 mg once daily with food for patients with moderate renal impairment or to 

300 mg once daily for patients with severe renal impairment may be considered if they do not 

experience severe or persistent moderate adverse reactions and if they do not achieve an adequate 

haematological, cytogenetic, or molecular response. 

 



 

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CP, AP, or BP Ph+ CML with resistance or intolerance to prior therapy 

In patients with moderate renal impairment (CLCr 30 to 50 mL/min, calculated by the 

Cockcroft-Gault formula), the recommended dose of bosutinib is 400 mg daily (see sections 4.4 

and 5.2). 

 

In patients with severe renal impairment (CLCr < 30 mL/min, calculated by the Cockcroft-Gault 

formula), the recommended dose of bosutinib is 300 mg daily (see sections 4.4 and 5.2). 

 

Dose escalation to 500 mg once daily for patients with moderate renal impairment or to 400 mg 

once daily in patients with severe renal impairment may be considered in those who did not 

experience severe or persistent moderate adverse reactions, and if they do not achieve an adequate 

haematological, cytogenetic, or molecular response. 

 

Cardiac disorders  

In clinical studies, patients with uncontrolled or significant cardiac disease (e.g., recent myocardial 

infarction, congestive heart failure or unstable angina) were excluded. Caution should be exercised 

in patients with relevant cardiac disorders (see section 4.4). 

 

Recent or ongoing clinically significant gastrointestinal disorder 

In clinical studies, patients with recent or ongoing clinically significant gastrointestinal disorder 

(e.g., severe vomiting and/or diarrhoea) were excluded. Caution should be exercised in patients with 

recent or ongoing clinically significant gastrointestinal disorder (see section 4.4).  

 

Paediatric population  

The safety and efficacy of bosutinib in children and adolescents less than 18 years of age have not 

been established. No data are available. 

 

Method of administration 

Bosulif should be taken orally once daily with food (see section 5.2). If a dose is missed by more 

than 12 hours, the patient should not be given an additional dose. The patient should take the usual 

prescribed dose on the following day. 

 

4.3 Contraindications 

 

Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.  

 

Hepatic impairment (see sections 5.1 and 5.2). 

 

4.4 Special warnings and precautions for use 

 

Liver function abnormalities 

Treatment with bosutinib is associated with elevations in serum transaminases (alanine 

aminotransferase [ALT], aspartate aminotransferase [AST]). 

 

Transaminase elevations generally occurred early in the course of treatment (of the patients who 

experienced transaminase elevations of any grade, > 80% experienced their first event within the 

first 3 months). Patients receiving bosutinib should have liver function tests prior to treatment 

initiation and monthly for the first 3 months of treatment, and as clinically indicated.  

 

Patients with transaminase elevations should be managed by withholding bosutinib temporarily (with 

consideration given to dose reduction after recovery to Grade 1 or baseline), and/or discontinuation 

of bosutinib. Elevations of transaminases, particularly in the setting of concomitant increases in 

bilirubin, may be an early indication of drug-induced liver injury and these patients should be 

managed appropriately (see sections 4.2 and 4.8). 



 

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Diarrhoea and vomiting 

Treatment with bosutinib is associated with diarrhoea and vomiting; therefore, patients with recent 

or ongoing clinically significant gastrointestinal disorder should use this medicinal product with 

caution and only after a careful benefit-risk assessment as respective patients were excluded from 

the clinical studies. Patients with diarrhoea and vomiting should be managed using standard-of-care 

treatment, including an antidiarrhoeal or antiemetic medicinal product and/or fluid replacement. In 

addition, diarrhoea and vomiting can also be managed by withholding bosutinib temporarily, dose 

reduction, and/or discontinuation of bosutinib (see sections 4.2 and 4.8). The antiemetic agent, 

domperidone, has the potential to increase QT interval (QTc) prolongation and to induce “torsade de 

pointes”- arrhythmias; therefore, co-administration with domperidone should be avoided. It should 

only be used, if other medicinal products are not efficacious. In these situations an individual 

benefit-risk assessment is mandatory and patients should be monitored for occurrence of QTc 

prolongation. 

 

Myelosuppression 

Treatment with bosutinib is associated with myelosuppression, defined as anaemia, neutropenia, and 

thrombocytopenia. Complete blood counts should be performed weekly for the first month and then 

monthly thereafter, or as clinically indicated. Myelosuppression should/can be managed by 

withholding bosutinib temporarily, dose reduction, and/or discontinuation of bosutinib (see 

sections 4.2 and 4.8). 

 

Fluid retention 

Treatment with bosutinib may be associated with fluid retention including pericardial effusion, 

pleural effusion, pulmonary oedema and/or peripheral oedema. Patients should be monitored and 

managed using standard-of-care treatment. In addition, fluid retention can also be managed by 

withholding bosutinib temporarily, dose reduction, and/or discontinuation of bosutinib (see 

sections 4.2 and 4.8). 

 

Serum lipase  

Elevation in serum lipase has been observed. Caution is recommended in patients with previous 

history of pancreatitis. In case lipase elevations are accompanied by abdominal symptoms, bosutinib 

should be interrupted and appropriate diagnostic measures considered to exclude pancreatitis  (see 

section 4.2). 

 

Infections  

Bosutinib may predispose patients to bacterial, fungal, viral, or protozoan infections. 

 

Proarrhythmic potential 

Automated machine-read QTc prolongation without accompanying arrhythmia has been observed. 

Bosutinib should be administered with caution to patients who have a history of or predisposition 

for QTc prolongation, who have uncontrolled or significant cardiac disease including recent 

myocardial infarction, congestive heart failure, unstable angina or clinically significant bradycardia, 

or who are taking medicinal products that are known to prolong the QTc (e.g., anti-arrhythmic 

medicinal products and other substances that may prolong QTc [see section 4.5]). The presence of 

hypokalaemia and hypomagnesaemia may further enhance this effect. 

 

Monitoring for an effect on the QTc is advisable and a baseline electrocardiogram (ECG) is 

recommended prior to initiating therapy with bosutinib and as clinically indicated. Hypokalaemia or 

hypomagnesaemia must be corrected prior to bosutinib administration and should be monitored 

periodically during therapy. 

 

Renal impairment 

Treatment with bosutinib may result in a clinically significant decline in renal function in CML 

patients. A decline over time in estimated glomerular filtration rate (eGFR) has been observed in 

patients treated with bosutinib in clinical studies. In patients with newly-diagnosed CP CML treated 



 

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with 400 mg, the median decline from baseline in eGFR was 4.9 ml/min/1.73 m2 at 3 months, 

9.2 ml/min/1.73 m2 at 6 months and 11.1 ml/min/1.73 m2 at 12 months. Treatment-naïve CML 

patients treated with 500 mg showed a median eGFR decline of 5.1 ml/min/1.73 m2 at 3 months, of 

9.2 ml/min/1.73 m2 at 12 months and of up to 16.3 ml/min/1.73 m2 until 5 years follow-up for 

patients on treatment. Pretreated and advanced stage CML patients on 500 mg showed a median 

eGFR decline of 5.3 ml/min/1.73 m2 at 3 months, of 7.6 ml/min/1.73 m2 at 12 months and of up to 

10.9 ml/min/1.73 m2 in up to 4 years on treatment. It is important that renal function is assessed 

prior to treatment initiation and closely monitored during therapy with bosutinib, with particular 

attention in those patients who have pre-existing renal compromise or in those patients exhibiting 

risk factors for renal dysfunction, including concomitant use of medicinal products with potential 

for nephrotoxicity, such as diuretics, angiotensin-converting enzyme (ACE) inhibitors, angiotensin 

receptor blockers, and nonsteroidal anti-inflammatory drugs (NSAIDs).  

 

In a renal impairment study, bosutinib exposures were increased in subjects with moderately and 

severely impaired renal function. Dose reduction is recommended for patients with moderate or 

severe renal impairment (see sections 4.2 and 5.2). 

 

Patients with serum creatinine > 1.5 × ULN were excluded from the CML studies. Based on a 

population pharmacokinetic analysis increasing exposure (AUC) in patients with moderate and 

severe renal impairment at initiation of treatment during studies was observed (see sections  4.2 and 

5.2). 

 

Clinical data are very limited (n = 3) for CML patients with moderate renal impairment receiving an 

escalated dose of 600 mg bosutinib. 

 

Severe skin reactions 

Bosutinib can induce severe skin reactions such as Stevens-Johnson Syndrome and Toxic 

Epidermal Necrolysis. Bosutinib should be permanently discontinued in patients who experience a 

severe skin reaction during treatment. 

 

Tumour lysis syndrome  

Due to the possible occurrence of tumour lysis syndrome (TLS), correction of clinically significant 

dehydration and treatment of high uric acid levels are recommended prior to initiation of bosutinib 

(see section 4.8). 

 

Hepatitis B reactivation 

Reactivation of hepatitis B (HBV) in patients who are chronic carriers of this virus has occurred 

after these patients received BCR-ABL TKIs. Some cases resulted in acute hepatic failure or 

fulminant hepatitis leading to liver transplantation or a fatal outcome.  

 

Patients should be tested for HBV infection before initiating treatment with bosutinib. Experts in 

liver disease and in the treatment of HBV should be consulted before treatment is initiated in patients 

with positive HBV serology (including those with active disease) and for patients who test positive 

for HBV infection during treatment. Carriers of HBV who require treatment with bosutinib should be 

closely monitored for signs and symptoms of active HBV infection throughout therapy and for 

several months following termination of therapy (see section 4.8). 

 

Cytochrome P-450 (CYP)3A inhibitors 

The concomitant use of bosutinib with strong or moderate CYP3A inhibitors should be avoided, as 

an increase in bosutinib plasma concentration will occur (see section 4.5).  

 

Selection of an alternate concomitant medicinal product with no or minimal CYP3A inhibition 

potential, if possible, is recommended. 

 

If a strong or moderate CYP3A inhibitor must be administered during bosutinib treatment, an 

interruption of bosutinib therapy or a dose reduction in bosutinib should be considered. 



 

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CYP3A inducers 

The concomitant use of bosutinib with strong or moderate CYP3A inducers should be avoided as a 

decrease in bosutinib plasma concentration will occur (see section 4.5). 

 

Food effect 

Grapefruit products, including grapefruit juice and other foods that are known to inhibit CYP3A 

should be avoided (see section 4.5). 

 

4.5 Interaction with other medicinal products and other forms of interaction 

 

Effects of other medicinal products on bosutinib 

 

CYP3A inhibitors 

The concomitant use of bosutinib with strong CYP3A inhibitors (including, but not limited to 

itraconazole, ketoconazole, posaconazole, voriconazole, clarithromycin, telithromycin, nefazodone, 

mibefradil, indinavir, lopinavir/ritonavir, nelfinavir, ritonavir, saquinavir, boceprevir, telaprevir, 

grapefruit products including grapefruit juice) or moderate CYP3A inhibitors (including, but not 

limited to fluconazole, ciprofloxacin, erythromycin, diltiazem, verapamil, amprenavir, atazanavir, 

darunavir/ritonavir, fosamprenavir, aprepitant, crizotinib, imatinib) should be avoided, as an increase 

in bosutinib plasma concentration will occur.  

 

Caution should be exercised if mild CYP3A inhibitors are used concomitantly with bosutinib. 

 

Selection of an alternate concomitant medicinal product with no or minimal CYP3A enzyme 

inhibition potential, if possible, is recommended. 

 

If a strong or moderate CYP3A inhibitor must be administered during bosutinib treatment, an 

interruption of bosutinib therapy or a dose reduction in bosutinib should be considered. 

 

In a study of 24 healthy subjects in whom 5 daily doses of 400 mg ketoconazole (a strong CYP3A 

inhibitor) were co-administered with a single dose of 100 mg bosutinib under fasting conditions, 

ketoconazole increased bosutinib Cmax by 5.2-fold, and bosutinib AUC in plasma by 8.6-fold, as 

compared with administration of bosutinib alone. 

 

In a study of 20 healthy subjects, in whom a single dose of 125 mg aprepitant (a moderate CYP3A 

inhibitor) was co-administered with a single dose of 500 mg bosutinib under fed conditions, 

aprepitant increased bosutinib Cmax by 1.5-fold, and bosutinib AUC in plasma by 2.0-fold, as 

compared with administration of bosutinib alone. 

 

CYP3A inducers  

The concomitant use of bosutinib with strong CYP3A inducers (including, but not limited to 

carbamazepine, phenytoin, rifampicin, St. John’s Wort), or moderate CYP3A inducers (including, 

but not limited to bosentan, efavirenz, etravirine, modafinil, nafcillin) should be avoided, as a 

decrease in bosutinib plasma concentration will occur.  

 

Based on the large reduction in bosutinib exposure that occurred when bosutinib was 

co-administered with rifampicin, increasing the dose of bosutinib when co-administering with 

strong or moderate CYP3A inducers is unlikely to sufficiently compensate for the loss of exposure.  

 

Caution is warranted if mild CYP3A inducers are used concomitantly with bosutinib.  

 

Following concomitant administration of a single dose bosutinib with 6 daily doses of 600 mg 

rifampicin, in 24 healthy subjects in fed state bosutinib exposure (Cmax and AUC in plasma) 

decreased to 14% and 6%, respectively, of the values when bosutinib 500 mg was administered 

alone. 



 

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Proton pump inhibitors (PPIs) 

Caution should be exercised when administering bosutinib concomitantly with PPIs. Short-acting 

antacids should be considered as an alternative to PPIs and administration times of bosutinib and 

antacids should be separated (i.e. take bosutinib in the morning and antacids in the evening) 

whenever possible. Bosutinib displays pH-dependent aqueous solubility in vitro. When a single oral 

dose of bosutinib (400 mg) was co-administered with multiple-oral doses of lansoprazole (60 mg) in 

a study of 24 healthy fasting subjects, bosutinib Cmax and AUC decreased to 54% and 74%, 

respectively, of the values seen when bosutinib (400 mg) was given alone. 
 

Effects of bosutinib on other medicinal products 

In a study of 27 healthy subjects, in whom a single dose of 500 mg bosutinib was co-administered 

with a single dose of 150 mg dabigatran etexilate mesylate (a P-glycoprotein [P-gp] substrate) under 

fed conditions, bosutinib did not increase Cmax or AUC of dabigatran in plasma, as compared with 

administration of dabigatran etexilate mesylate alone. The study results indicate that bosutinib does 

not exhibit clinically relevant P-gp inhibitory effects.  

 

An in vitro study indicates that drug-drug interactions are unlikely to occur at therapeutic doses as a 

result of induction by bosutinib on the metabolism of medicinal products that are substrates for 

CYP1A2, CYP2B6, CYP2C9, CYP2C19, and CYP3A4. 

 

In vitro studies indicate that clinical drug-drug interactions are unlikely to occur at therapeutic doses 

as a result of inhibition by bosutinib on the metabolism of medicinal products that are substrates for 

CYP1A2, CYP2A6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, or CYP3A4/5.  

 

In vitro studies indicate that bosutinib has a low potential to inhibit breast cancer resistance protein 

(BCRP, systemically), organic anion transporting polypeptide (OATP)1B1, OATP1B3, organic anion 

transporter (OAT)1, OAT3, organic cation transporter (OCT)2 at clinically relevant concentrations, 

but may have the potential to inhibit BCRP in the gastrointestinal tract and OCT1. 

 

Anti-arrhythmic medicinal products and other substances that may prolong QT  

Bosutinib should be used with caution in patients who have or may develop prolongation of QT, 

including those patients taking anti-arrhythmic medicinal products such as amiodarone, 

disopyramide, procainamide, quinidine and sotalol or other medicinal products that may lead to QT 

prolongation such as chloroquine, halofantrine, clarithromycin, domperidone, haloperidol, 

methadone, and moxifloxacin (see section 4.4). 

 

4.6 Fertility, pregnancy and lactation 

 

Women of childbearing potential/Contraception 

Women of childbearing potential should be advised to use effective contraception during treatment 

with bosutinib and for at least 1 month after the last dose and to avoid becoming pregnant while 

receiving bosutinib. In addition, the patient should be advised that vomiting or diarrhoea may reduce 

the efficacy of oral contraceptives by preventing full absorption.  

 

Pregnancy 

There are limited amount of data in pregnant women from the use of bosutinib. Studies in animals 

have shown reproductive toxicity (see section 5.3). Bosutinib is not recommended for use during 

pregnancy, or in women of childbearing potential not using contraception. If bosutinib is used 

during pregnancy, or the patient becomes pregnant while taking bosutinib, she should be apprised of 

the potential hazard to the foetus. 

 

Breast-feeding 

It is unknown whether bosutinib and its metabolites are excreted in human milk. A study of [14C] 

radiolabelled bosutinib in rats demonstrated excretion of bosutinib-derived radioactivity in breast 

milk (see section 5.3). A potential risk to the breast-feeding infant cannot be excluded. 



 

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Breast-feeding should be discontinued during treatment with bosutinib. 

 

Fertility 

Based on non-clinical findings, bosutinib has the potential to impair reproductive function and 

fertility in humans (see section 5.3). Men being treated with bosutinib are advised to seek advice on 

conservation of sperm prior to treatment because of the possibility of decreased fertility due to 

therapy with bosutinib. 

 

4.7 Effects on ability to drive and use machines  

 

Bosutinib has no or negligible influence on the ability to drive and use machines.  However, if a 

patient taking bosutinib experiences dizziness, fatigue, visual impairment or other undesirable effects 

with a potential impact on the ability to drive or use machines safely, the patient should refrain from 

these activities for as long as the undesirable effects persist.  

 

4.8 Undesirable effects 

 

Summary of safety profile 

A total of 1,272 leukaemia patients received at least 1 dose of single-agent bosutinib. The median 

duration of therapy was 13.8 months (range: 0.03 to 123.3 months). These patients were either 

newly diagnosed, with CP CML or were resistant or intolerant to prior therapy with chronic, 

accelerated, or blast phase CML or Ph+ acute lymphoblastic leukaemia (ALL). Of these patients, 

268 (400 mg starting dose) and 248 (500 mg starting dose) are from the 2 Phase 3 studies in 

previously untreated CML patients, 570 and 63 are from 2 Phase 1/2 studies in previously treated 

Ph+ leukaemias, and 123 patients from a Phase 4 study in previously treated CML. The median 

duration of therapy was 14.1 months (range: 0.3 to 24.7 months), 61.6 months (0.03 to 

99.6 months), 11.1 months (range: 0.03 to 123.3 months), 30.2 months (range: 0.3 to 

85.6 months), and 5.7 months (range: 0.07 to 17.8 months), respectively. The safety analyses 

included data from an ongoing extension study.   

 

At least 1 adverse reaction of any toxicity grade was reported for 1,240 (97.5%) patients. The most 

frequent adverse reactions reported for  20% of patients were diarrhoea (78.1%), nausea (40.8%), 

thrombocytopenia (34.9%), abdominal pain (34.0%), vomiting (33.0%), rash (31.5%), anaemia 

(25.6%), pyrexia (21.8%), fatigue (21.4%), and ALT increased (25.0%). At least 1 Grade 3 or 

Grade 4 adverse reaction was reported for 814 (63.9%) patients. The Grade 3 or Grade 4 adverse 

reactions reported for  5% of patients were thrombocytopenia (20.3%), anaemia (10.2%), 

neutropenia (10.5%), ALT increased (12.7%), diarrhoea (9.6%), rash (5.0%), lipase increased 

(8.2%), and AST increased (5.8%). 

 

Tabulated list of adverse reactions 

The following adverse reactions were reported in patients in bosutinib clinical studies (Table 2). 

These represent an evaluation of the adverse reaction data from 1,272 patients with either 

newly-diagnosed CP CML or with chronic, accelerated, or blast phase CML resistant or intolerant 

to prior therapy or Ph+ ALL who have received at least 1 dose of single-agent bosutinib. These 

adverse reactions are presented by system organ class and frequency. Frequency categories are 

defined as: very common ( 1/10), common ( 1/100 to < 1/10), uncommon ( 1/1,000 to 

< 1/100), rare ( 1/10,000 to < 1/1,000), very rare (< 1/10,000), not known (cannot be estimated 

from the available data). Within each frequency grouping, adverse reactions are presented in order 

of decreasing seriousness. 

 



 

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Table 2 - Adverse reactions for bosutinib 

 

Infections and infestations 

Very common Respiratory tract infection (including Lower respiratory tract infection, 

Respiratory tract infection viral, Upper respiratory tract infection, Viral 

upper respiratory tract infection), Nasopharyngitis 

Common Pneumonia (including Atypical pneumonia), Influenza, Bronchitis 

Neoplasms benign, malignant and unspecified (incl cysts and polyps)  

Uncommon Tumour lysis syndrome** 

Blood and lymphatic system disorders 

Very common Thrombocytopenia (including Platelet count decreased), Neutropenia 

(including Neutrophil count decreased), Anaemia (including haemoglobin 

decreased) 

Common Leukopenia (including White blood cell count decreased) 

Uncommon Febrile neutropenia, Granulocytopenia 

Immune system disorders 

Uncommon Anaphylactic shock, Hypersensitivity 

Metabolism and nutrition disorders 

Very common Decreased appetite 

Common Dehydration, Hyperkalaemia, Hypophosphataemia 

Nervous system disorders 

Very common Headache 

Common Dizziness, Dysgeusia 

Ear and labyrinth disorders 

Common Tinnitus 

Cardiac disorders 

Common Pericardial effusion, Electrocardiogram QTc prolonged (including Long 

QTc syndrome) 

Uncommon Pericarditis 

Vascular disorders 

Common Hypertension (including Blood pressure increased, Blood pressure systolic 

increased, Essential hypertension, Hypertensive crisis) 

Respiratory, thoracic and mediastinal disorders 

Very common Dyspnoea, Cough 

Common Pleural effusion 

Uncommon Pulmonary hypertension, Respiratory failure, Acute pulmonary oedema 

Gastrointestinal disorders 

Very common Diarrhoea, Vomiting, Nausea, Abdominal pain (including Abdominal 

discomfort, Abdominal pain lower, Abdominal pain upper, Abdominal 

tenderness, Gastrointestinal pain) 

Common Gastritis, Gastrointestinal haemorrhage (including Anal haemorrhage, 

Gastric haemorrhage, Intestinal haemorrhage, Lower gastrointestinal 

haemorrhage, Rectal haemorrhage) 

Uncommon Pancreatitis (including Pancreatitis acute) 

Hepatobiliary disorders 

Very common Alanine aminotransferase increased, Aspartate aminotransferase increased 

Common Hepatotoxicity (including Hepatitis, Hepatitis toxic, Liver disorder), Hepatic 

function abnormal (including Liver function test abnormal, Liver function 

test increased, Transaminases increased), Blood bilirubin increased 

(including Hyperbilirubinaemia), Gamma-glutamyltransferase increased 

Uncommon Liver injury (including Drug-induced liver injury) 

Skin and subcutaneous tissue disorders 

Very common Rash (including Rash generalised, Rash macular, Rash maculo-papular, 

Rash papular, Rash pruritic) 



 

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Common Urticaria, Acne, Pruritus 

Uncommon Exfoliative rash, Drug eruption 

Rare Erythema multiforme 

Unknown Stevens-Johnson Syndrome**, Toxic epidermal necrolysis** 

Musculoskeletal and connective tissue disorders 

Very common Arthralgia, Back pain 

Common Myalgia 

Renal and urinary disorders 

Common Acute kidney injury, Renal failure, Renal impairment 

General disorders and administration site conditions 

Very common Pyrexia, Asthenia, Oedema (including Face oedema, Localised oedema, 

Oedema peripheral), Fatigue (including Malaise) 

Common Chest pain (including Chest discomfort), Pain  

Investigations 

Very common Lipase increased (including Hyperlipasaemia) 

Common Blood creatinine increased, Amylase increased, Blood creatine 

phosphokinase increased 
** Adverse reaction identified post marketing. 

 

Description of selected adverse reactions 

The descriptions included below are based on the safety population of 1,272 patients who received 

at least 1 dose of bosutinib for either newly-diagnosed CP CML or were resistant or intolerant to 

prior therapy with CP, AP, or BP CML, or Ph+ ALL. 

 

Blood and lymphatic system disorders 

Of the 297 (23%) patients with reports of adverse reactions of anaemia, 3 patients discontinued 

bosutinib due to anaemia. In these patients, the maximum toxicity of Grade 1 or 2 was experienced 

in 174 (58%) patients, Grade 3 in 96 patients (32%), and Grade 4 in 27 (9%) patients. Among these 

patients, the median time to first event was 28 days (range: 1 to 2,633 days) and the median 

duration per event was 15 days (range: 1 to 1,529 days).  

 

Of the 197 (15%) patients with reports of adverse reactions of neutropenia, 15 patients 

discontinued bosutinib due to neutropenia. Maximum Grade 1 or 2 events were experienced by 

63 (32%) patients. The maximum toxicity of Grade 3 neutropenia was experienced in 

90 (46%) patients and of Grade 4 in 44 (22%) patients. The median time to first event was 59 days 

(range: 27 to 505 days), and the median duration per event was 15 days (range: 1 to 913 days).  

 

Of the 445 (35%) patients with reports of adverse reactions of thrombocytopenia, 41 (9%) patients 

discontinued treatment with bosutinib due to thrombocytopenia. Maximum Grade 1 or 2 events 

were experienced by 186 (42%) patients. The maximum toxicity of thrombocytopenia of Grade 3 

was experienced in 161 (36%) patients and Grade 4 in 98 (22%) patients. Among patients with 

thrombocytopenia reactions, the median time to first event was 28 days (range: 1 to 1,688 days), 

and median duration per event was 15 days (range: 1 to 1,762 days). 

 

Hepatobiliary disorders 

Among patients with reports of adverse reactions of elevations in either ALT or AST (all grades), 

the median time of onset observed was 29 days with a range of onset 1 to 2,465 days for ALT and 

AST. The median duration of an event was 18 days (range: 1 to 775 days), and 15 days (range: 1 to 

803 days) for ALT and AST, respectively. 

 

In the entire development program, concurrent elevation in transaminases ≥ 3 × ULN and bilirubin 

> 2 × ULN with alkaline phosphatase < 2 × ULN occurred without alternative causes in 

1/1,611 (< 0.1%) subjects treated with bosutinib. This finding was in a study of bosutinib in 

combination with letrozole in a patient with metastatic breast cancer. 



 

13 

 

Hepatitis B reactivation 

Hepatitis B reactivation has been reported in association with BCR-ABL TKIs. Some cases resulted 

in acute hepatic failure or fulminant hepatitis leading to liver transplantation or a fatal outcome (see 

section 4.4). 

 

Gastrointestinal disorders 

Of the 994 (78%) patients that experienced diarrhoea, 10 patients discontinued bosutinib due to this 

event. Concomitant medicinal products were given to treat diarrhoea in 662 (66%) patients. The 

maximum toxicity of diarrhoea was Grade 1 or 2 in 88% of patients, Grade 3 in 12% of patients; 

1 patient (< 1%) experienced a Grade 4 event. Among patients with diarrhoea, the median time to 

first event was 2 days (range: 1 to 2,415 days) and the median duration of any grade of diarrhoea 

was 2 days (range: 1 to 2,511 days). 

  

Among the 994 patients with diarrhoea, 180 patients (18%) were managed with treatment 

interruption and of these 170 (94%) were rechallenged with bosutinib. Of those who were 

rechallenged, 167 (98%) did not have a subsequent event or did not discontinue bosutinib due to a 

subsequent event of diarrhoea. 

 

Cardiac disorders 

Four patients (0.3%) experienced QTcF interval prolongation (greater than 500 ms). Nine (0.8%) 

patients experienced QTcF increase from baseline exceeding 60 ms. Patients with uncontrolled or 

significant cardiovascular disease including QTc prolongation, at baseline, were not included in 

clinical studies (see sections 5.1 and 5.3).  

 

Reporting of suspected adverse reactions  

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It 

allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare 

professionals are asked to report any suspected adverse reactions via the national reporting system 

listed in Appendix V. 

 

4.9 Overdose 

 

Experience with bosutinib overdose in clinical studies was limited to isolated cases. Patients who 

take an overdose of bosutinib should be observed and given appropriate supportive treatment. 

 

 

5. PHARMACOLOGICAL PROPERTIES 

 

5.1  Pharmacodynamic properties 

 

Pharmacotherapeutic group: Antineoplastic agents, protein kinase inhibitors, ATC code: L01XE14. 

 

Mechanism of action 

Bosutinib belongs to a pharmacological class of medicinal products known as kinase inhibitors. 

Bosutinib inhibits the abnormal BCR-ABL kinase that promotes CML. Modeling studies indicate that 

bosutinib binds the kinase domain of BCR-ABL. Bosutinib is also an inhibitor of Src family kinases 

including Src, Lyn and Hck. Bosutinib minimally inhibits platelet-derived growth factor (PDGF) 

receptor and c-Kit. 

 

In in vitro studies, bosutinib inhibits proliferation and survival of established CML cell lines, 

Ph+ ALL cell lines, and patient-derived primary primitive CML cells. Bosutinib inhibited 16 of 

18 imatinib-resistant forms of BCR-ABL expressed in murine myeloid cell lines. Bosutinib treatment 

reduced the size of CML tumours growing in nude mice and inhibited growth of murine myeloid 

tumours expressing imatinib-resistant forms of BCR-ABL. Bosutinib also inhibits receptor tyrosine 



 

14 

kinases c-Fms, EphA and B receptors, Trk family kinases, Axl family kinases, Tec family kinases, 

some members of the ErbB family, the non-receptor tyrosine kinase Csk, serine/threonine kinases 

of the Ste20 family, and 2 calmodulin-dependent protein kinases. 

 

Pharmacodynamic effects 

The effect of bosutinib 500 mg administration on corrected QTc was evaluated in a randomised, 

single-dose, double-blind (with respect to bosutinib), crossover, placebo- and open-label 

moxifloxacin-controlled study in healthy subjects. 

 

The data from this study indicate that bosutinib does not prolong the QTc in healthy subjects at the 

dose of 500 mg daily with food, and under conditions that give rise to supratherapeutic plasma 

concentrations. Following administration of a single oral dose of bosutinib 500 mg (therapeutic 

dose) and bosutinib 500 mg with ketoconazole 400 mg (to achieve supratherapeutic concentrations 

of bosutinib) in healthy subjects, the upper bound of the 1-sided 95% confidence interval (CI) 

around the mean change in QTc was less than 10 ms at all post-dose time points, and no adverse 

events suggestive of QTc prolongation were observed. 

 

In a study in liver impaired subjects, an increasing frequency of QTc prolongation > 450 ms with 

declining hepatic function was observed. In the Phase 1/2 clinical study in patients with previously 

treated Ph+ leukaemias, QTcF interval changes > 60 ms from baseline were observed in 6 (1.1%) 

of 562 patients. In the Phase 3 clinical study in patients with newly-diagnosed CP CML treated with 

bosutinib 400 mg, there were no patients in the bosutinib treatment group with an increase of 

> 60 ms from baseline when the QT interval was corrected using Fridericia’s formula (QTcF). In 

the Phase 3 clinical study in patients with newly diagnosed Ph+ CP CML treated with bosutinib 

500 mg, QTcF interval changes > 60 ms from baseline were observed in 2 (0.8%) of 248 patients 

receiving bosutinib. A proarrhythmic potential of bosutinib cannot be ruled out. 

 

Clinical efficacy 

 

Clinical study in CP previously untreated CML 

 

Bosutinib 400 mg study 

A 2-arm, Phase 3, open-label, multicentre superiority trial was conducted to investigate the efficacy 

and safety of bosutinib 400 mg once daily alone compared with imatinib 400 mg once daily alone in 

adult patients with newly-diagnosed Ph+ CP CML. The trial randomised 536 patients (268 in each 

treatment group) with Ph+ or Ph- newly-diagnosed CP CML (intent-to-treat population [ITT]) 

including 487 patients with Ph+ CML harbouring b2a2 and/or b3a2 transcripts and baseline 

BCR-ABL copies > 0 (modified intent-to-treat [mITT] population). 

 

The primary efficacy endpoint was the proportion demonstrating a major molecular response 

(MMR) at 12 months (48 weeks) in the bosutinib treatment group compared with that in the 

imatinib treatment group in the mITT population. MMR was defined as ≤ 0.1% BCR-ABL/ABL ratio 

by international scale (corresponding to ≥ 3 log reduction from standardised baseline) with a 

minimum of 3,000 ABL transcripts as assessed by the central laboratory. The secondary efficacy 

endpoints included MMR by 18 months, duration of MMR, CCyR by 12 months, duration of CCyR, 

event-free survival (EFS), and overall survival (OS). Complete cytogenetic response by Month 12, a 

secondary endpoint, was defined as the absence of Ph+ metaphases in chromosome banding 

analysis of ≥ 20 metaphases derived from bone marrow aspirate or MMR if an adequate cytogenetic 

assessment was unavailable. The p-values for endpoints other than MMR at 12 months and CCyR 

by 12 months have not been adjusted for multiple comparisons.  

 

Baseline characteristics for the mITT population were well balanced between the 2 treatment 

groups with respect to age (median age was 52 years for the bosutinib group and 53 years for the 

imatinib group with 19.5% and 17.4% of patients 65 years of age or older, respectively); gender 

(women 42.3% and 44.0%, respectively); and race (Caucasian 77.6% and 77.2%, Asian 12.2% and 



 

15 

12.4%, Black or African American 4.1% and 4.1%, and Other 5.7% and 5.8%, respectively, and 

1 unknown in each group).  

 

After a minimum of 12 months of follow-up in the mITT population, 77.6% of patients treated with 

bosutinib (N=241) and 72.4% of patients treated with imatinib (N=239) were still receiving first-line 

treatment.  

 

After a minimum of 12 months of follow-up in the mITT population, discontinuations due to 

disease progression to AP or BP CML for bosutinib-treated patients were 0.4% compared to 1.7% 

for imatinib-treated patients. Five bosutinib patients and 7 imatinib patients transformed to AP CML 

or BP CML. Discontinuations due to suboptimal response or treatment failure as assessed by the 

investigator occurred for 2.0% of patients in the bosutinib-treated group compared to 6.3% of 

patients in the imatinib-treated group. One patient on bosutinib and 7 patients on imatinib died while 

on study. 

 

The efficacy results are summarised in Table 3.  

 

Table 3 - Summary of MMR at Months 12 and 18 and CCyR by Month 12, by treatment 

group in the mITT population 

 

 

Response 

Bosutinib 

(N=246) 

Imatinib 

(N=241) 

1-sided 

p-value 

Major molecular response (n, 

%) 

MMR at Month 12 

(95% CI) 

 

MMR at Month 18 

(95% CI) 

 

116 (47.2)a 

(40.9,53.4) 

 

140 (56.9) 

(50.7,63.1) 

 

89 (36.9) 

(30.8,43.0) 

 

115 (47.7) 

(41.4,54.0) 

 

0.0100a 

 

 

0.0208b 

Complete cytogenetic response 

by Month 12 (n, %) 

CCyR 

(95% CI) 

 

 

190 (77.2)a 

(72.0,82.5) 

 

 

160 (66.4) 

(60.4,72.4) 

 

 

0.0037a 

Note: MMR was defined as ≤ 0.1% BCR-ABL/ABL ratio by international scale (corresponding to 

≥ 3 log reduction from standardised baseline) with a minimum of 3,000 ABL transcripts assessed by 

the central laboratory. Complete cytogenetic response was defined as the absence of Ph+ 

metaphases in chromosome banding analysis of ≥ 20 metaphases derived from bone marrow aspirate 

or MMR if an adequate cytogenetic assessment was unavailable. 

Abbreviations: BCR-ABL=breakpoint cluster region-Abelson; CI=confidence interval; 

CMH=Cochran-Mantel-Haenszel; CCyR=complete cytogenetic response;  mITT=modified 

intent-to-treat; MMR=major molecular response; N/n=number of patients; Ph+=Philadelphia 

chromosome-positive.  
a Statistically significant comparison at the pre-specified significance level; based on CMH test 

stratified by geographical region and Sokal score at randomisation. 
b Based on CMH test stratified by geographical region and Sokal score at randomisation. 

 

At Month 12, the MR4 rate (defined as ≤ 0.01% BCR-ABL [corresponding to ≥ 4 log reduction 

from standardised baseline] with a minimum of 9,800 ABL transcripts) was higher in the bosutinib 

treatment group compared to the imatinib treatment group in the mITT population (20.7% [95% CI: 

15.7%, 25.8%] versus 12.0% [95% CI: 7.9%, 16.1%], respectively, 1-sided p-value=0.0052). 

 

At Months 3, 6, and 9, the proportion of patients with MMR was higher in the bosutinib treatment 

group compared to the imatinib treatment group (Table 4). 

 



 

16 

Table 4 - Comparison of MMR at Months 3, 6, and 9 by treatment in the mITT population 

 

 

 

Time  

Number (%) of subjects with MMR  

1-sided 

p-valuea 

Bosutinib 

(N=246) 

Imatinib 

(N=241) 

Month 3 

(95% CI) 

 

Month 6 

(95% CI) 

 

Month 9 

(95% CI) 

10 (4.1) 

(1.6,6.5) 

 

86 (35.0) 

(29.0,40.9) 

 

104 (42.3) 

(36.1,48.4) 

4 (1.7) 

(0.0,3.3) 

 

44 (18.3) 

(13.4,23.1) 

 

71 (29.5) 

(23.7,35.2) 

0.0578 

 

 

< 0.0001 

 

 

0.0015 

Note: Percentages were based on number of patients in each treatment group. MMR was defined as 

≤ 0.1% BCR-ABL/ABL ratio on international scale (corresponding to ≥ 3 log reduction from 

standardised baseline) with a minimum of 3,000 ABL transcripts assessed by the central laboratory. 

Abbreviations: BCR-ABL=breakpoint cluster region-Abelson; CI=confidence interval; 

CMH=Cochran-Mantel-Haenszel; CML=chronic myelogenous leukaemia; mITT=modified 

intent-to-treat; MMR=major molecular response; Ph+=Philadelphia chromosome-positive. 
a  p-value based on CMH test stratified by geographical region and Sokal score at randomisation. 

 

The cumulative incidence of MMR adjusting for competing risk of treatment discontinuation 

without MMR was higher in the bosutinib treatment group compared to the imatinib treatment 

group in the mITT population (45.1% [95% CI: 38.8%, 51.2%] versus 33.7% [95% CI: 27.8%, 

39.6%] at Week 48; hazard ratio [HR] from a stratified proportional subdistributional hazards model: 

1.35 [95% CI: 1.07, 1.70], 1-sided p-value = 0.0086). The median time to MMR for responders 

was 24.7 weeks versus 36.3 weeks for the bosutinib treatment and imatinib treatment groups, 

respectively, in the mITT population.  

 

The cumulative incidence of CCyR adjusted for the competing risk of treatment discontinuation 

without CCyR was higher in the bosutinib treatment group compared to the imatinib treatment 

group in the mITT population (79.1% [95% CI: 73.4%, 83.7%] versus 67.3% [95% CI: 60.9%, 

72.8%] at Week 48; HR: 1.38, [95% CI: 1.13, 1.68]; 1-sided p-value=0.0003). The median time to 

CCyR (responders only) was 23.9 weeks in the bosutinib group compared to the 24.3 weeks 

imatinib group.  

 

The Kaplan-Meier estimates of OS at 48 weeks for bosutinib and imatinib patients in the 

mITT population were 99.6% (95% CI: 97.1%, 99.9%) and 97.9% (95% CI: 95.0%, 99.1%), 

respectively.  

 

No additional deaths or transformations occurred in the ITT population.  

 

Clinical study in imatinib-resistant or intolerant CML in CP, AP, and BP 

A single-arm, Phase 1/2 open-label, multicentre trial was conducted to evaluate the efficacy and 

safety of bosutinib 500 mg once daily in patients with imatinib-resistant or -intolerant CML with 

separate cohorts for chronic, accelerated, and blast phase disease previously treated with 1 prior 

TKI (imatinib) or more than 1 TKI (imatinib followed by dasatinib and/or nilotinib). 

 

There were 570 patients treated with bosutinib in this trial including CP CML patients previously 

treated with only 1 prior TKI (imatinib), CP CML patients previously treated with imatinib and at 

least 1 additional TKI (dasatinib and/or nilotinib), CML patients in accelerated or blast phase 

previously treated with at least 1 TKI (imatinib) and patients with Ph+ ALL previously treated with 

at least 1 TKI (imatinib). 

 



 

17 

The primary efficacy endpoint of the study was the major cytogenetic response (MCyR) rate at 

Week 24 in patients with imatinib-resistant CP CML previously treated with only 1 prior TKI 

(imatinib). Other efficacy endpoints include the cumulative MCyR rate, time to and duration of 

MCyR, and time to and duration of CHR, in patients with CP CML previously treated with only 

1 prior TKI (imatinib). For patients previously treated with both imatinib and at least 1 additional 

TKI, the endpoints include the cumulative MCyR rate, time to and duration of MCyR, and time to 

and duration of CHR. For patients with AP and BP CML previously treated with at least 1 prior TKI 

(imatinib), the endpoints were cumulative overall haematological response (OHR) and time to and 

duration of OHR. Other efficacy endpoints include transformation to AP/BP, progression free 

survival and OS for all cohorts. 

 

CP 

The efficacy results for Ph+ CP CML patients previously treated with imatinib and at least 

1 additional TKI (minimum follow-up 48 months, median treatment duration of 9 months and 

24.4% still on-treatment at 48 months) and the results for Ph+ CP CML patients previously treated 

with only imatinib (minimum follow-up 60 months, median treatment duration of 26 months and 

40.5% still on-treatment at 60 months) are presented in Table 5.   

 

AP and BP CML patients 

The efficacy results for AP (minimum follow-up 48 months, median treatment duration of 

10 months and 17.7% still on-treatment at 48 months) and BP (minimum follow-up 48 months, 

median treatment duration of 2.8 months and 3.1% still on-treatment at 48 months) Ph+ CML 

patients are present in Table 5. 

 

Table 5 - Efficacy results in previously treated patients with chronic and advanced phase 

CML* 

 

 Ph+ CP CML 

with prior 

imatinib 

treatment only 

Ph+ CP CML 

with prior 

treatment with 

imatinib and 

dasatinib or 

nilotinib 

Accelerated 

phase with prior 

treatment of at 

least imatinib 

Blast phase 

with prior 

treatment of at 

least imatinib 

Cumulative cytogenetic 

responsea 

  MCyR, %  (95%  CI) 

  CCyR, %  (95%  CI) 

N=262 

59.5 (53.3,65.5) 

49.6 (43.4,55.8) 

N=112 

40.2(31.0,49.9) 

32.1(23.6,41.6) 

N=72 

40.3 (28.9,52.5) 

30.6 (20.2,42.5) 

N=54 

37.0 (24.3,51.3) 

27.8 (16.5,41.6) 

Time to MCyR for responders 

onlyb, weeks (95%  CI) 

12.3 (12.1,12.7) 12.3 (12.0,14.1) 12.0 (11.9,12.1) 8.2 (4.3,12.0) 

Duration of MCyRb 

  K-M at year 1/2, %  (95%  CI)c 

  K-M at year 4/5, %  (95%  CI)c 

  Median, weeks (95%  CI) 

N=156 

76.4 (68.5,82.5) 

71.1 (62.6,78.0) 

N/R 

N=45 

72.0 (55.1,83.4) 

69.3 (52.3,81.3) 

N/R 

N=29 

62.2 (41.1,77.6) 

46.7 (27.1,64.1) 

84.0 (24.0,N/E) 

N=20 

21.2 (5.2,44.2) 

21.2 (5.2,44.2) 

29.1 (11.9,38.3) 

Cumulative haematological 

responsed 

  Overall, %  (95%  CI) 

  Major, %  (95%  CI) 

  Complete, %  (95%  CI) 

N=283 

 

N/A 

N/A 

86.6 (82.0,90.3) 

N=117 

 

N/A 

N/A 

73.5 (64.5,81.2) 

N=72 

 

56. 9 (44.7,68.6) 

47.2 (35.3,59.3) 

33.3 (22.7,45.4) 

N=60 

 

28.3 (17.5,41.4) 

18.3 (9.5,30.4) 

16.7 (8.3,28.5) 

Time to OHR for responders 

only, weeks (95%  CI) 

N/A N/A 12.0 (11.1,12.1) 8.9 (4.1,12.0) 

Duration of CHR/OHRe 

  K-M at year 1/2, %  (95%  CI)c 

  K-M at year 4/5, %  (95%  CI)c 

  Median, weeks (95%  CI) 

N=245 

71.9 (65.1,77.6) 

66.0 (58.8,72.3) 

N/R 

N=86 

73.4 (61.7,82.1) 

62.9 (50.1,73.3) 

N/R 

N=41 

78.2 (59.4,89.0) 

52.0 (32.3,68.5) 

207.0 (63.1,N/E) 

N=17 

28.4 (7.8,53.9)  

19.0 (3.3,44.5) 

32.0 (29.0,54.6) 



 

18 

Transformation to AP/BPf 

  On--treatment transformation, 

n 

N=284 

15 

N=119 

5 

N=79 

3 

N/A 

Progression-free survivalf 

  K-M at year 1/2, %  (95%  CI)c 

  K-M at year 4/5, %  (95%  CI)c 

  Median, months (95%  CI) 

N=284 

80.0 (73.9,84.8) 

72.5 (65.6,78.2) 

N/R 

N=119 

75.1 (64.6,82.9)  

65.1 (53.1,74.8)  

N/R 

N=79 

66.8 (53.4,77.1)  

40.8 (26.6,54.5) 

22.1 (14.6,N/E)  

N=64 

16.1 (6.6,29.3) 

8.0 (1.7,21.2) 

4.4 (3.2,8.5)  

Overall survivalf 

  K-M at year 1/2, %  (95%  CI)c 

  K-M at year 4/5, %  (95%  CI)c 

  Median, months (95%  CI) 

N=284 

91.2 (87.1,94.0) 

83.1 (77.5,87.4) 

N/R 

N=119 

91.3 (84.5,95.2) 

77.0 (66.9,84.4) 

N/R 

N=79 

78.1 (67.1,85.8) 

58.4 (45.6,69.1) 

N/R 

N=64 

42.1 (29.7,53.9) 

20.1 (6.2,39.8) 

10.9 (8.7,19.7) 

* For efficacy results in the subgroup of patients corresponding to the approved indication, see text above.  

Snapshot date: 02Oct2015 

Cytogenetic Response criteria: Major Cytogenetic Response included Complete [0% Ph+ metaphases from 

bone marrow or < 1% positive cells from fluorescent in situ hybridisation (FISH)] or partial (1%-35%) 

cytogenetic responses. Cytogenetic responses were based on the percentage of Ph+ metaphases among 

≥ 20 metaphase cells in each bone marrow sample. FISH analysis (≥ 200 cells) could be used for post-baseline 

cytogenetic assessments if ≥ 20 metaphases were not available. 

Overall haematological response (OHR)=major haematological response (complete haematological 

response + no evidence of leukaemia) or return to chronic phase (RCP). All responses were confirmed after 

4 weeks. Complete haematological response (CHR for AP and BP CML: WBC less than or equal to institutional 

upper limit of normal (ULN), platelets greater than or equal to 100,000/mm3 and less than 450,000/mm3, absolute 

neutrophil count (ANC) greater than or equal to 1.0×109/L, no blasts or promyelocytes in peripheral blood, less 

than 5% myelocytes + metamyelocytes in bone marrow, less than 20% basophils in peripheral b lood, and no 

extramedullary involvement. No evidence of leukaemia (NEL): Meets all other criteria for CHR except may have 

thrombocytopenia (platelets greater than or equal to 20,000/mm3 and less than 100,000/mm3) and/or 

neutropenia (ANC greater than or equal to 0.5×109/L and less than 1.0×109/L). Return to chronic phase 

(RCP)=disappearance of features defining accelerated or blast phases but still in chronic phase.  

Abbreviations: AP=accelerated phase; BP=blast phase; Ph+=Philadelphia chromosome-positive; CP=chronic 

phase; CML=chronic myelogenous leukaemia; K-M=Kaplan-Meier; N/n=number of patients; N/A=not 

applicable; N/R=not reached as of minimum follow-up; N/E=not estimable; CI=confidence interval; 

MCyR=major cytogenetic response; CCyR=complete cytogenetic response; OHR=overall haematological 

response; CHR=complete haematological response.   
a  Includes patients (N) with a valid baseline assessment. The analyses allow baseline responders who 

maintained response post-baseline to be responders. Minimum follow-up time (time from last patient first 

dose to data snapshot date) of 60 months for CP treated with imatinib only and, 48 months for CP treated 

with imatinib and at least 1 other TKI, AP and BP. 
b  Includes  patients (N) who attained or maintained MCyR. 
c  Years 2 (Month 24) and 5 (60 months) for CP treated with imatinib only and Years  1 (Month 12) and 

4 (48 months) for CP treated with imatinib and at least 1 other TKI, AP, and BP. 
d  Sample size (N) includes patients with a valid baseline haematological ass essment. These analyses allow 

baseline responders who maintained response post-baseline to be responders. 
e  Includes patients (N) who attained or maintained CHR for CP patients and OHR for AP and BP patients.  
f  Including patients (N) who received at least 1 dose of bosutinib. 

 

Based on the limited clinical information from the Phase 1/2 study, some evidence of clinical activity 

was observed in patients with BCR-ABL mutations (see Table 6). 

 



 

19 

Table 6 - Response by baseline BCR-ABL mutation status in CP CML evaluable population:  

prior imatinib and dasatinib and/or nilotinib (third-line) 

 

BCR-ABL mutation status at 

baseline 

Incidence at 

baseline 

n (%)a 

MCyR attained or maintained  

Resp/Evalb (%)  

N=112 

Mutation assessed 96 (100.0) 34/92 (37.0) 

No mutation 57 (59.4) 21/55 (38.2) 

At least 1 mutation 39 (40.6) 13/37 (35.1) 

Dasatinib resistant mutations 10 (10.4) 1/9 (11.1) 

     E255K/V 2 (2.0) 0/2 

     F317L 8 (8.3) 1/7 (14.3) 

Nilotinib resistant mutationsc 13 (13.5) 8/13 (61.5) 

     Y253H 6 (6.3) 5/6 (83.3) 

     E255K/V 2 (2.0) 0/2 

     F359C/I/V 7 (7.3) 5/7 (71.4) 

Snapshot date: 02Oct2015 

Note: Baseline mutations were identified before the patient's first dose of study drug. 

Abbreviations: BCR-ABL=breakpoint cluster region-Abelson; CP=chronic phase; CML=chronic 

myelogenous leukaemia; MCyR=major cytogenetic response; N/n=number of patients; 

Resp=responders; Eval=evaluable. 
a The percentage is based on number of patients with baseline mutation assessment. 
b The evaluable population includes patients who had a valid baseline disease assessment. 
c 2 patients had more than 1 mutation in this category. 

 

One patient with the E255V mutation previously treated with nilotinib achieved CHR as best 

response. 

 

In vitro testing indicated that bosutinib had limited activity against the T315I or the V299L mutation. 

Therefore, clinical activity in patients with these mutations is not expected.  

 

Paediatric population 

The European Medicines Agency has deferred the obligation to submit the results of studies with 

Bosulif in one or more subsets of the paediatric population in CML (see section 4.2 for information 

on paediatric use). 

 

Conditional approval 

This medicinal product has been authorised under a so-called “conditional approval” scheme. This 

means that further evidence on this medicinal product is awaited. 

 

The European Medicines Agency will review new information on this medicinal product at least 

every year and this SmPC will be updated as necessary. 

 

5.2 Pharmacokinetic properties 

 

Absorption 

Following administration of a single dose of bosutinib (500 mg) with food in healthy subjects, the 

absolute bioavailability was 34%. Absorption was relatively slow, with a median time-to-peak 

concentration (tmax) reached after 6 hours. Bosutinib exhibits dose proportional increases in AUC 

and Cmax, over the dose range of 200 to 600 mg. Food increased bosutinib Cmax 1.8-fold and 

bosutinib AUC 1.7-fold compared to the fasting state. In CML patients at steady state, Cmax 
(geometric mean, coefficient of variation [CV]%) was 145 (14) ng/mL, and AUCss (geometric 



 

20 

mean, CV%) was 2,700 (16) ng•h/mL after daily administration of bosutinib at 400 mg with food. 

After 500 mg bosutinib daily with food, Cmax was 200 (6) ng/mL and AUCss was 

3,640 (12) ng•h/mL. The solubility of bosutinib is pH-dependent and absorption is reduced when 

gastric pH is increased (see section 4.5). 

 

Distribution  

Following administration of a single intravenous dose of 120 mg bosutinib to healthy subjects, 

bosutinib had a mean (% coefficient of variation [CV]) volume of distribution of 2,331 (32) L, 

suggesting that bosutinib is extensively distributed to extra vascular tissue.  

 

Bosutinib was highly bound to human plasma proteins in vitro (94%) and ex vivo in healthy 

subjects (96%), and binding was not concentration-dependent. 

 

Biotransformation 

In vitro and in vivo studies indicated that bosutinib (parent compound) undergoes predominantly 

hepatic metabolism in humans. Following administration of single or multiple doses of bosutinib 

(400 or 500 mg) to humans, the major circulating metabolites appeared to be oxydechlorinated (M2) 

and N-desmethylated (M5) bosutinib, with bosutinib N-oxide (M6) as a minor circulating metabolite. 

The systemic exposure of N-desmethylated metabolite was 25% of the parent compound, while the 

oxydechlorinated metabolite was 19% of the parent compound. All 3 metabolites exhibited activity 

that was  5% that of bosutinib in a Src-transformed fibroblast anchorage-independent proliferation 

assay. In faeces, bosutinib and N-desmethyl bosutinib were the major drug-related components. 

In vitro studies with human liver microsomes indicated that the major cytochrome P450 isozyme 

involved in the metabolism of bosutinib is CYP3A4 and drug interaction studies have shown that 

ketoconazole and rifampicin had marked effect on the pharmacokinetics of bosutinib (see 

section 4.5). No metabolism of bosutinib was observed with CYPs 1A2, 2A6, 2B6,  2C8, 2C9, 
2C19, 2D6, 2E1, or 3A5.  

 

Elimination 

In healthy subjects given a single intravenous dose of 120 mg bosutinib, the mean (%CV) terminal 

elimination half-life was 35.5 (24) hours, and the mean (%CV) clearance was 61.9 (26) L/h. In a 

mass-balance study with oral bosutinib, an average of 94.6% of the total dose was recovered in 

9 days; faeces (91.3%) was the major route of excretion, with 3.29% of the dose recovered in 

urine. Seventy-five percent of the dose was recovered within 96 hours. Excretion of unchanged 

bosutinib in urine was low with approximately 1% of the dose in both healthy subjects and those 

with advanced malignant solid tumours. 

 

Special populations  

 

Hepatic impairment 

A 200 mg dose of bosutinib administered with food was evaluated in a cohort of 18 hepatically 

impaired subjects (Child-Pugh classes A, B, and C) and 9 matched healthy subjects. Cmax of 

bosutinib in plasma increased 2.4-fold, 2-fold, and 1.5-fold, respectively, in Child-Pugh classes A, 

B, and C; and bosutinib AUC in plasma increased 2.3-fold, 2-fold, and 1.9-fold, respectively. The t½ 
of bosutinib increased in hepatic impaired patients as compared to the healthy subjects.  

 

Renal impairment 

In a renal impairment study, a single dose of 200 mg bosutinib was administered with food to 

26 subjects with mild, moderate, or severe renal impairment and to 8 matching healthy volunteers. 

Renal impairment was based on CLCr (calculated by the Cockcroft-Gault formula) of < 30 mL/min 

(severe renal impairment), 30  CLCr  50 mL/min (moderate renal impairment), or 

50 < CLCr  80 mL/min (mild renal impairment). Subjects with moderate and severe renal 

impairment had an increase in AUC over healthy volunteers of 35% and 60%, respectively. Maximal 

exposure Cmax increased by 28% and 34% in the moderate and severe groups, respectively. 



 

21 

Bosutinib exposure was not increased in subjects with mild renal impairment. The elimination 

half-life of bosutinib in subjects with renal impairment was similar to that in healthy subjects.   

 

Dose adjustments for renal impairment were based on the results of this study, and the known 

linear pharmacokinetics of bosutinib in the dose range of 200 to 600 mg. 

 

Age, gender and race 

No formal studies have been performed to assess the effects of these demographic factors. 

Population pharmacokinetic analyses in patients with Ph+ leukaemia or malignant solid tumour 

indicate that there are no clinically relevant effects of age, gender, body weight, race.  

 

Paediatric population 

Bosulif has not yet been studied in children and adolescents less than 18 years of age.  

 

5.3 Preclinical safety data 

 

Bosutinib has been evaluated in safety pharmacology, repeated dose toxicity, genotoxicity, 

reproductive toxicity, and photoxicity studies. 

 

Safety pharmacology 

Bosutinib did not have effects on respiratory functions. In a study of the central nervous system 

(CNS), bosutinib treated rats displayed decreased pupil size and impaired gait. A no observed effect 

level (NOEL) for pupil size was not established, but the NOEL for impaired gait occurred at 

exposures approximately 11-times the human exposure resulting from the clinical dose of 400 mg 

and 8-times the human exposure resulting from the clinical dose of 500 mg (based on unbound Cmax 

in the respective species). Bosutinib activity in vitro in hERG assays suggested a potential for 

prolongation of cardiac ventricular repolarisation (QTc). In an oral study of bosutinib in dogs, 

bosutinib did not produce changes in blood pressure, abnormal atrial or ventricular arrhythmias, or 

prolongation of the PR, QRS, or QTc of the ECG at exposures up to 3-times the human exposure 

resulting from the clinical dose of 400 mg and 2-times the human exposure resulting from the 

clinical dose of 500 mg (based on unbound Cmax in the respective species). A delayed increase in 

heart rate was observed. In an intravenous study in dogs, transient increases in heart rate and 

decreases in blood pressure and minimal prolongation of the QTc (< 10 msec) were observed at 

exposures ranging from approximately 6-times to 20-times the human exposure resulting from the 

clinical dose of 400 mg and 4-times to 15-times the human exposure resulting from the clinical dose 

of 500 mg (based on unbound Cmax in the respective species). The relationship between the 

observed effects and medicinal product treatment were inconclusive. 

 

Repeated-dose toxicity 

Repeated-dose toxicity studies in rats of up to 6 months in duration and in dogs up to 9 months in 

duration revealed the gastrointestinal system to be the primary target organ of toxicity of bosutinib. 

Clinical signs of toxicity included foecal changes and were associated with decreased food 

consumption and body weight loss which occasionally led to death or elective euthanasia.  

 

Histopathologically, luminal dilation, goblet cell hyperplasia, haemorrhage, erosion, and oedema of 

the intestinal tract, and sinus erythrocytosis and haemorrhage in the mesenteric lymph nodes, were 

observed. The liver was also identified as a target organ in rats. Toxicities were characterised by an 

increase in liver weights in correlation with hepatocellular hypertrophy which occurred in the 

absence of elevated liver enzymes or microscopic signs of hepatocellular cytotoxicity, and is of 

unknown relevance to humans. The exposure camparison across species indicates that exposures 

that did not elicit adverse events in the 6- and 9-month toxicity studies in rats and dogs, 

respectively, were similar to the human exposure resulting from a clinical dose of 400 mg or 

500 mg (based on unbound AUC in the respective species). 

 



 

22 

Genotoxicity 

Genotoxicity studies in bacterial in vitro systems and in mammalian in vitro and in vivo systems 

with and without metabolic activation did not reveal any evidence for a mutagenic potential of 

bosutinib. 

 

Reproductive toxicity and development toxicity 

In a rat fertility study, fertility was slightly decreased in males. Females were observed with 

increased embryonic resorptions, and decreases in implantations and viable embryos. The dose at 

which no adverse reproductive effects were observed in males (30 mg/kg/day) and females 

(3 mg/kg/day) resulted in exposures equal to 0.6-times and 0.3-times, respectively, the human 

exposure resulting from the clinical dose of 400 mg, and 0.5-times and 0.2-times, respectively, the 

human exposure resulting from the clinical dose of 500 mg (based on unbound AUC in the 

respective species). An effect on male fertility cannot be excluded (see section 4.6). 

 

Foetal exposure to bosutinib-derived radioactivity during pregnancy was demonstrated in a placental 

transfer study in gravid Sprague-Dawley rats. In a rat pre- and postnatal development study, there 

were reduced number of pups born at ≥ 30 mg/kg/day, and increased incidence of total litter loss 

and decreased growth of offspring after birth occurred at 70 mg/kg/day. The dose at which no 

adverse development effects were observed (10 mg/kg/day) resulted in exposures equal to 

1.3-times and 1.0-times human exposure resulting from the clinical dose of 400 mg and 500 mg, 

respectively (based on unbound AUC in the respective species). In a rabbit developmental toxicity 

study at the maternally toxic dose, there were foetal anomalies observed (fused sternebrae, and 

2 foetuses had various visceral observations), and a slight decrease in foetal body weight. The 

exposure at the highest dose tested in rabbits (10 mg/kg/day) that did not result in adverse foetal 

effects was 0.9-times and 0.7-times the human exposure resulting from the clinical dose of 400 mg 

or 500 mg, respectively (based on unbound AUC in the respective species). 

 

Following a single oral (10 mg/kg) administration of [14C] radiolabelled bosutinib to lactating 

Sprague-Dawley rats, radioactivity was readily excreted into breast milk as early as 0.5 hr after 

dosing. Concentration of radioactivity in milk was up to 8-fold higher than in plasma. This allowed 

measurable concentrations of radioactivity to appear in the plasma of nursing pups.  

 

Carcinogenicity 

Bosutinib was not carcinogenic in the 2-year rat carcinogenicity study. 

 

Phototoxicity 

Bosutinib has demonstrated the ability to absorb light in the UV-B and UV-A range and is distributed 

into the skin and uveal tract of pigmented rats. However, bosutinib did not demonstrate a potential 

for phototoxicity of the skin or eyes in pigmented rats exposed to bosutinib in the presence of 

UV radiation at bosutinib exposures up to 3-times and 2-times the human exposure resulting from 

the clinical dose of 400 or 500 mg, respectively (based on unbound Cmax in the respective species). 

 

 

6. PHARMACEUTICAL PARTICULARS 

 

6.1 List of excipients 

 

Tablet core  

Microcrystalline cellulose (E460) 

Croscarmellose sodium (E468) 

Poloxamer 188 

Povidone (E1201) 

Magnesium stearate (E470b) 

 



 

23 

Film coating 

  

Bosulif 100 mg film-coated tablets  

Polyvinyl alcohol 

Titanium dioxide (E171)  

Macrogol 3350 

Talc (E553b) 

Iron oxide yellow (E172) 

 

Bosulif 400 mg film-coated tablets  

Polyvinyl alcohol 

Titanium dioxide (E171)  

Macrogol 3350 

Talc (E553b) 

Iron oxide yellow (E172) 

Iron oxide red (E172) 

 

Bosulif 500 mg film-coated tablets  

Polyvinyl alcohol 

Titanium dioxide (E171)  

Macrogol 3350 

Talc (E553b) 

Iron oxide red (E172) 

 

6.2 Incompatibilities 

 

Not applicable. 

 

6.3 Shelf life 

 

4 years.  

 

6.4 Special precautions for storage 

 

This medicinal product does not require any special storage conditions.  

 

6.5 Nature and contents of container  

 

White opaque 3-ply PVC/Polychlorotrifluoroethene/PVC blister sealed with push-through foil 

backing containing either 14 or 15 tablets.  

 

Bosulif 100 mg film-coated tablets 

Each carton contains 28, 30 or 112 tablets. 

 

Bosulif 400 mg film-coated tablets  

Each carton contains 28 or 30 tablets. 

 

Bosulif 500 mg film-coated tablets 

Each carton contains 28 or 30 tablets. 

 

Not all pack sizes may be marketed. 

 



 

24 

6.6 Special precautions for disposal  

 

Any unused medicinal product or waste material should be disposed of in accordance with local 

requirements.  

 

 

7. MARKETING AUTHORISATION HOLDER 

 

Pfizer Europe MA EEIG 

Boulevard de la Plaine 17 

1050 Bruxelles 

Belgium 

 

 

8. MARKETING AUTHORISATION NUMBER(S)  

 

Bosulif 100 mg film-coated tablets 

EU/1/13/818/001 

EU/1/13/818/002 

EU/1/13/818/005 

 

Bosulif 400 mg film-coated tablets 

EU/1/13/818/006 

EU/1/13/818/007 

 

Bosulif 500 mg film-coated tablets 

EU/1/13/818/003 

EU/1/13/818/004 

 

 

9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION 

 

Date of first authorisation: 27 March 2013 

Date of latest renewal: 18 February 2019 

 

 

10. DATE OF REVISION OF THE TEXT 

 

 

 

Detailed information on this medicinal product is available on the website of the European Medicines 

Agency http://www.ema.europa.eu. 



 

25 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

ANNEX II 

 

A. MANUFACTURER(S) RESPONSIBLE FOR BATCH 

RELEASE 

 

B. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY 

AND USE 

 

C. OTHER CONDITIONS AND REQUIREMENTS OF THE 

MARKETING AUTHORISATION 

 

D. CONDITIONS OR RESTRICTIONS WITH REGARD TO 

THE SAFE AND EFFECTIVE USE OF THE MEDICINAL 

PRODUCT 

 

E. SPECIFIC OBLIGATION TO COMPLETE POST-

AUTHORISATION MEASURES FOR THE CONDITIONAL 

MARKETING AUTHORISATION 

 

 

 

 

 



 

26 

A. MANUFACTURER(S) RESPONSIBLE FOR BATCH RELEASE 

 

Name and address of the manufacturer(s) responsible for batch release 

 

Pfizer Manufacturing Deutschland GmbH 

Betriebsstӓtte Freiburg 

Mooswaldallee 1 

79090 Freiburg 

Germany 

 

 

B. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY AND USE 

 

Medicinal product subject to restricted medical prescription (see Annex I: Summary of Product 

Characteristics, section 4.2). 

 

 

C.  OTHER CONDITIONS AND REQUIREMENTS OF THE MARKETING 

AUTHORISATION  

 

• Periodic Safety Update Reports  
 

The requirements for submission of periodic safety update reports for this medicinal product are 

set out in the list of Union reference dates (EURD list) provided for under Article 107c(7) of 

Directive 2001/83/EC and any subsequent updates published on the European medicines 

web-portal. 

 

 

D. CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE AND EFFECTIVE 

USE OF THE MEDICINAL PRODUCT 

 

• Risk Management Plan (RMP) 
 

The MAH shall perform the required pharmacovigilance activities and interventions detailed in the 

agreed RMP presented in Module 1.8.2 of the Marketing Authorisation and any agreed 

subsequent updates of the RMP. 

 

An updated RMP should be submitted: 

• At the request of the European Medicines Agency; 

• Whenever the risk management system is modified, especially as the result of new 
information being received that may lead to a significant change to the benefit/risk profile 

or as the result of an important (pharmacovigilance or risk minimisation) milestone being 

reached.  

 

 



 

27 

E. SPECIFIC OBLIGATION TO COMPLETE POST-AUTHORISATION MEASURES 

FOR THE CONDITIONAL MARKETING AUTHORISATION  

 

This being a conditional marketing authorisation and pursuant to Article 14(7) of Regulation (EC) 

No 726/2004, the MAH shall complete, within the stated timeframe, the following measures: 

 

Description Due date 

To conduct a single-arm open-label, multi-centre efficacy and safety study of 

bosutinib in patients with Philadelphia chromosome-positive chronic 

myelogenous leukaemia (Ph+ CML) previously treated with one or more 

tyrosine kinase inhibitor(s) and for whom imatinib, nilotinib and dasatinib are not 

considered appropriate treatment options.   

Final Clinical 

Study Report: 

 

31 May 2022 

 



 

28 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

ANNEX III 

 

LABELLING AND PACKAGE LEAFLET 

 

 



 

29 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

A. LABELLING 



 

30 

 

PARTICULARS TO APPEAR ON THE OUTER PACKAGING 

 

CARTON 

 

 

1. NAME OF THE MEDICINAL PRODUCT 

 

Bosulif 100 mg film-coated tablets 

bosutinib 

 

 

2. STATEMENT OF ACTIVE SUBSTANCE(S) 

 

Each film-coated tablet contains 100 mg bosutinib (as monohydrate). 

 

 

3. LIST OF EXCIPIENTS 

 

 

 

4. PHARMACEUTICAL FORM AND CONTENTS 

 

28 film-coated tablets. 

30 film-coated tablets. 

112 film-coated tablets. 

 

 

5. METHOD AND ROUTE(S) OF ADMINISTRATION 

 

Read the package leaflet before use. 

Oral use. 

 

 

6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT OF 

THE SIGHT AND REACH OF CHILDREN 

 

Keep out of the sight and reach of children. 

 

 

7. OTHER SPECIAL WARNING(S), IF NECESSARY 

 

 

 

8. EXPIRY DATE 

 

EXP  

 

 



 

31 

9. SPECIAL STORAGE CONDITIONS 

 

 

 

10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS 

OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF 

APPROPRIATE 

 

Dispose unused medicinal product in accordance with local requirements. 

 

 

11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER 

 

Pfizer Europe MA EEIG 

Boulevard de la Plaine 17 

1050 Bruxelles 

Belgium 

 

 

12. MARKETING AUTHORISATION NUMBER(S)  

 

EU/1/13/818/001  (28 film-coated tablets) 

EU/1/13/818/002  (30 film-coated tablets) 

EU/1/13/818/005  (112 film-coated tablets) 

 

 

13. BATCH NUMBER 

 

Lot 

 

 

14. GENERAL CLASSIFICATION FOR SUPPLY 

 

 

 

15. INSTRUCTIONS ON USE 

 

 

 

16. INFORMATION IN BRAILLE 

 

Bosulif 100 mg 

 

17. UNIQUE IDENTIFIER – 2D BARCODE 

 

2D barcode carrying the unique identifier included. 

 



 

32 

18. UNIQUE IDENTIFIER - HUMAN READABLE DATA 

 

PC:  

SN:  

NN:  



 

33 

 

MINIMUM PARTICULARS TO APPEAR ON BLISTERS OR STRIPS 

 

BLISTER 

 

 

1. NAME OF THE MEDICINAL PRODUCT 

 

Bosulif 100 mg film-coated tablets 

bosutinib 

 

 

2. NAME OF THE MARKETING AUTHORISATION HOLDER 

 

Pfizer  

 

 

3. EXPIRY DATE 

 

EXP 

 

 

4. BATCH NUMBER 

 

Lot 

 

 

5. OTHER 

 

 



 

34 

PARTICULARS TO APPEAR ON THE OUTER PACKAGING 

 

CARTON 

 

 

1. NAME OF THE MEDICINAL PRODUCT 

 

Bosulif 400 mg film-coated tablets 

bosutinib 

 

 

2. STATEMENT OF ACTIVE SUBSTANCE(S) 

 

Each film-coated tablet contains 400 mg bosutinib (as monohydrate). 

 

 

3. LIST OF EXCIPIENTS 

 

 

 

4. PHARMACEUTICAL FORM AND CONTENTS 

 

28 film-coated tablets. 

30 film-coated tablets. 

 

 

5. METHOD AND ROUTE(S) OF ADMINISTRATION 

 

Read the package leaflet before use. 

Oral use. 

 

 

6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT OF 

THE SIGHT AND REACH OF CHILDREN 

 

Keep out of the sight and reach of children. 

 

 

7. OTHER SPECIAL WARNING(S), IF NECESSARY 

 

 

 

8. EXPIRY DATE 

 

EXP  

 

 

9. SPECIAL STORAGE CONDITIONS 

 

 



 

35 

 

10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS 

OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF 

APPROPRIATE 

 

Dispose unused medicinal product in accordance with local requirements.  

 

 

11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER 

 

Pfizer Europe MA EEIG 

Boulevard de la Plaine 17 

1050 Bruxelles 

Belgium 

 

 

12. MARKETING AUTHORISATION NUMBER(S)  

 

EU/1/13/818/006  (28 film-coated tablets) 

EU/1/13/818/007  (30 film-coated tablets) 

 

 

13. BATCH NUMBER 

 

Lot 

 

 

14. GENERAL CLASSIFICATION FOR SUPPLY 

 

 

 

15. INSTRUCTIONS ON USE 

 

 

 

16. INFORMATION IN BRAILLE 

 

Bosulif 400 mg 

 

 

17. UNIQUE IDENTIFIER – 2D BARCODE 

 

2D barcode carrying the unique identifier included. 

 

 

18. UNIQUE IDENTIFIER - HUMAN READABLE DATA 

 

PC:  

SN:  

NN:  



 

36 

 

MINIMUM PARTICULARS TO APPEAR ON BLISTERS OR STRIPS 

 

BLISTER 

 

 

1. NAME OF THE MEDICINAL PRODUCT 

 

Bosulif 400 mg film-coated tablets 

bosutinib 

 

 

2. NAME OF THE MARKETING AUTHORISATION HOLDER 

 

Pfizer  

 

 

3. EXPIRY DATE 

 

EXP 

 

 

4. BATCH NUMBER 

 

Lot 

 

 

5. OTHER 

 

 



 

37 

PARTICULARS TO APPEAR ON THE OUTER PACKAGING 

 

CARTON 

 

 

1. NAME OF THE MEDICINAL PRODUCT 

 

Bosulif 500 mg film-coated tablets 

bosutinib 

 

 

2. STATEMENT OF ACTIVE SUBSTANCE(S) 

 

Each film-coated tablet contains 500 mg bosutinib (as monohydrate). 

 

 

3. LIST OF EXCIPIENTS 

 

 

 

4. PHARMACEUTICAL FORM AND CONTENTS 

 

28 Film-coated tablets. 

30 Film-coated tablets. 

 

 

5. METHOD AND ROUTE(S) OF ADMINISTRATION 

 

Read the package leaflet before use. 

Oral use. 

 

 

6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT OF 

THE SIGHT AND REACH OF CHILDREN 

 

Keep out of the sight and reach of children. 

 

 

7. OTHER SPECIAL WARNING(S), IF NECESSARY 

 

 

 

8. EXPIRY DATE 

 

EXP  

 

 

9. SPECIAL STORAGE CONDITIONS 

 

 



 

38 

 

10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS 

OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF 

APPROPRIATE 

 

Dispose unused medicinal product in accordance with local requirements.  

 

 

11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER 

 

Pfizer Europe MA EEIG 

Boulevard de la Plaine 17 

1050 Bruxelles 

Belgium 

 

 

12. MARKETING AUTHORISATION NUMBER(S)  

 

EU/1/13/818/003   28 film-coated tablets 

EU/1/13/818/004   30 film-coated tablets 

 

 

13. BATCH NUMBER 

 

Lot 

 

 

14. GENERAL CLASSIFICATION FOR SUPPLY 

 

 

 

15. INSTRUCTIONS ON USE 

 

 

 

16. INFORMATION IN BRAILLE 

 

Bosulif 500 mg 

 

17. UNIQUE IDENTIFIER – 2D BARCODE 

 

2D barcode carrying the unique identifier included. 

 

 

18. UNIQUE IDENTIFIER - HUMAN READABLE DATA 

 

PC: 

SN: 

NN: 



 

39 

 

MINIMUM PARTICULARS TO APPEAR ON BLISTERS OR STRIPS 

 

BLISTER 

 

 

1. NAME OF THE MEDICINAL PRODUCT 

 

Bosulif 500 mg film-coated tablets 

bosutinib 

 

 

2. NAME OF THE MARKETING AUTHORISATION HOLDER 

 

Pfizer  

 

 

3. EXPIRY DATE 

 

EXP 

 

 

4. BATCH NUMBER 

 

Lot 

 

 

5. OTHER 

 

 



 

40 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

B. PACKAGE LEAFLET 



 

41 

 

Package leaflet: Information for the user 

 

Bosulif 100 mg film-coated tablets 

Bosulif 400 mg film-coated tablets 

Bosulif 500 mg film-coated tablets 

bosutinib 

 

This medicine is subject to additional monitoring. This will allow quick identification of new 

safety information. You can help by reporting any side effects you may get. See the end of 

section 4 for how to report side effects. 

 

Read all of this leaflet carefully before you start taking this medicine  because it contains 

important information for you. 

- Keep this leaflet. You may need to read it again. 

- If you have any 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 get any side effects, talk to your doctor. This includes any possible side effects not 

listed in this leaflet. See section 4. 

 

What is in this leaflet 

 

1. What Bosulif is and what it is used for 

2. What you need to know before you take Bosulif 

3. How to take Bosulif 

4. Possible side effects 

5. How to store Bosulif 

6. Content of the pack and other information 

 

 

1. What Bosulif is and what it is used for 

 

Bosulif contains the active substance bosutinib. It is used to treat adult patients who have a type of 

leukaemia called Philadelphia chromosome-positive (Ph-positive) Chronic Myeloid Leukaemia 

(CML) and are newly-diagnosed or for whom previous medicines to treat CML have either not 

worked or are not suitable. Ph-positive CML is a cancer of the blood which makes the body 

produce too many of a specific type of white blood cell called granulocytes.  

 

If you have any questions about how Bosulif works or why this medicine has been prescribed for 

you, ask your doctor. 

 

 

2. What do you need to know before you take 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 your liver has been damaged and is not working normally. 

 

Warnings and precautions  

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



 

42 

- if you have, or have had in the past, liver problems. Tell your doctor if you have a history 

of liver problems including hepatitis (liver infection or inflammation) of any kind, or a history 

of any of the following signs and symptoms of liver problems: itching, yellow eyes or skin, 

dark urine, and pain or discomfort in the right upper stomach area. Your doctor should do 

blood tests to check your liver function prior to your starting treatment with Bosulif and for 

the first 3 months of treatment with Bosulif, and as clinically indicated.  

 

- if you have diarrhoea and vomiting. Tell your doctor if you develop any of the following 

signs and symptoms: an increase in the number of stools (bowel movements) per day over 

normal, an increase in episodes of vomiting, blood in your vomit, stools (bowel movements) 

or urine, or have black stools (tarry black bowel movements). You should ask your doctor if 

use of your treatment for vomiting may result in a greater risk of heart arrhythmias. In 

particular, you should ask your doctor if you want to use a medicine containing domperidone 

for the treatment of nausea and/or vomiting. Treatment of nausea or vomiting with such 

medicines together with Bosulif may result in a greater risk of dangerous heart arrhythmias. 

 

- if you suffer from bleeding problems. Tell your doctor if you develop any of the following 

signs and symptoms such as abnormal bleeding or bruising without having an injury. 

 

- if you have an infection. Tell your doctor if you develop any of the following signs and 

symptoms such as fever, problems with urine such as burning on urination, a new cough, or 

a new sore throat. 

 

- if you have fluid retention. Tell your doctor if you develop any of the following signs and 

symptoms of fluid retention during Bosulif treatment such as swelling of the ankles, feet or 

legs; difficulty breathing chest pain or a cough (these may be signs of fluid retention in the 

lungs or chest). 

 

- if you have heart problems. Tell your doctor if you have a heart disorders, such as 

arrhythmias or an abnormal electrical signal called “prolongation of the QT  interval”. This is 

always important, but especially if you are experiencing frequent or prolonged diarrhoea as 

described above. If you faint (loss of consciousness) or have an irregular heartbeat while 

taking Bosulif, tell your doctor immediately, as this may be a sign of a serious heart condition.  

 

- if you have been told that you have problems with your kidneys. Tell your doctor if you 

are urinating more frequently and producing larger amounts of urine with a pale colour or if 

you are urinating less frequently and producing smaller amounts of urine with a dark colour. 

Also tell your doctor if you are losing weight or have experienced swelling of your feet, 

ankles, legs, hands or face.  

 

-  if you have ever had or might now have a hepatitis  B infection. This is because Bosulif 

could cause hepatitis B to become active again, which can be fatal in some cases. Patients 

will be carefully checked by their doctor for signs of this infection before treatment is started. 

 

- if you have or have had pancreas problems. Tell your doctor if you develop abdominal 

pain or discomfort. 

 

- if you have any of these symptoms: serious skin rashes. Tell your doctor if you develop 

any of the following signs and symptoms of painful red or purplish rash that spreads and 

blisters and/or other lesions begin to appear in the mucous membrane (e.g., mouth and lips).  

 



 

43 

- if you notice any of these symptoms: pain in your side, blood in your urine or reduced 

amount of urine. When your disease is very severe, your body may not be able to clear all 

the waste products from the dying cancer cells. This is called tumour lysis syndrome and can 

cause kidney failure and heart problems within 48 hours of the first dose of Bosulif. Your 

doctor will be aware of this and may ensure you are adequately hydrated and give you other 

medicines to help prevent it. 

 

Children and adolescents 

Bosulif is not recommended for people whose age is under 18 years. This medicine has not been 

studied in children and adoloscents. 

 

Other medicines and Bosulif 

Tell your doctor or pharmacist if you are taking, have recently taken or might take any other 

medicines, including medicines obtained without a prescription, vitamins, and herbal medicines. 

Some medicines can affect the levels of Bosulif in your body. You should inform your doctor if you 

are taking medicines containing active substances such as those listed below: 

 

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 human immunodeficiency virus (HIV)/AIDS. 

- boceprevir and telaprevir, used to treat hepatitis C. 

- aprepitant, used to prevent and control nausea (feeling sick) 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 lower high blood pressure in the lungs (pulmonary artery hypertension). 

- nafcillin, an antibiotic used to treat bacterial infections. 

- St. John’s Wort (a herbal preparation obtained without a prescription), used to treat 

depression. 

- efavirenz and etravirine, used to treat HIV infections/AIDS. 

- modafinil, used to treat certain types of sleep disorders. 

 

These medicines should be avoided during your treatment with Bosulif. If you are taking any of 

them, tell your doctor. Your doctor may change the dose of these medicines, change the dose of 

Bosulif, or switch you to a different medicine. 

 

The following active substances may affect the heart rhythm: 

- amiodarone, disopyramide, procainamide, quinidine and sotalol used to treat heart disorder.  

- chloroquine, halofantrine used to treat malaria.  

- clarithromycin and moxifloxacin antibiotics used to treat bacterial infections.  

- haloperidol, used to treat psychotic disease such as schizophrenia.   

- domperidone, used to treat nausea and vomiting or to stimulate breast milk production.  

- methadone, used to treat pain.  



 

44 

 

These medicines should be taken with caution during your treatment with Bosulif. If you are taking 

any of them, tell your doctor. 

 

The medicines listed here may not be the only ones that could interact with Bosulif.  

 

Bosulif with food and drink 

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

 

Pregnancy, breast-feeding and fertility 

Bosulif is not to be used during pregnancy, unless clearly necessary, because Bosulif could harm an 

unborn baby. Ask your doctor for advice before taking Bosulif if you are pregnant or might become 

pregnant.  

 

Women taking Bosulif will be advised to use effective contraception during treatment and for at 

least 1 month after the last dose. Vomiting or diarrhoea may reduce the effectiveness of oral 

contraceptives. 

 

There is a risk that treatment with Bosulif will lead to decreased fertility and you may wish to seek 

advice about sperm storage before the treatment starts. 

 

If you are breast-feeding, tell your doctor. Do not breast-feed during treatment with Bosulif as it 

could harm your baby. 

 

Driving and using machines 

If you experience dizziness, have blurred vision or feel unusually tired, do not drive or operate 

machines until these side effects have gone away. 

 

 

3. How to take Bosulif 

 

Always take this medicine exactly as your doctor has told you. Check with your doctor or 

pharmacist if you are not sure. 

 

Bosulif will only be prescribed to you by a doctor with experience in medicines to treat leukaemia. 

 

Dose and method of administration  

The recommended dose is 400 mg once daily for patients with newly-diagnosed CML. The 

recommended dose is 500 mg once daily for patients whose previous medicines to treat CML have 

either not worked or are not suitable. In the event that you have moderate or severe kidney 

problems, your doctor will reduce your dose by 100 mg once daily for moderate kidney problems 

and by an additional 100 mg once daily for severe kidney problems. Your doctor may adjust the 

dose using the 100 mg tablets depending upon your medical conditions, upon your response to 

treatment and/or on any side effect you may experience.  Take the tablet(s) in the morning with 

food. Swallow the tablet(s) whole with water. 

 

If you take more Bosulif than you should 

If you accidentally take too many Bosulif tablets or a higher dose than you need, contact a doctor 

for advice right away. If possible, show the doctor the pack, or this leaflet. You may require 

medical attention. 

 



 

45 

If you forget to take Bosulif 

If dose is missed by less than 12 hours, take your recommended dose. If a dose is missed by more 

than 12 hours, take your next dose at your regular time on the following day.  

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

 

If you stop taking Bosulif 

Do not stop taking Bosulif unless your doctor tells you to do so. If you are not able to take the 

medicine as your doctor prescribed or you feel you do not need it anymore, contact your doctor 

right away. 

 

If you have any further questions on 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. 

 

You must immediately contact your doctor if you experience any of those serious side effects (see 

also section 2 “What you need to know before you take Bosulif”): 

 

Blood disorders. Tell your doctor right away if you have any of these symptoms: bleeding, fever or 

easy bruising (you might have blood or lymphatic system disorder). 

 

Liver disorders. Tell your doctor right away if you have any of these symptoms: itching, yellow 

eyes or skin, dark urine, and pain or discomfort in the right upper stomach area or fever. 

 

Stomach/intestinal disorders. Tell your doctor if you develop stomach pain, heartburn, diarrhoea, 

constipation, nausea and vomiting. 

 

Heart problems. Tell your doctor if you have a heart disorder, such as an abnormal electrical 

signal called “prolongation of the QT interval”, or if you faint (loss of consciousness) or have an 

irregular heart beat while taking Bosulif. 

 

Hepatitis B reactivation. Recurrence (reactivation) of hepatitis B infection when you have had 

hepatitis B in the past (a liver infection). 

 

Severe skin reactions. Tell your doctor right away if you have any of these symptoms: painful red 

or purplish rash that spreads and blisters and/or other lesions begin to appear in the mucous 

membrane (e.g. mouth and lips). 

 

Side effects with Bosulif may include: 

 

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

- reduction in the number of platelets, red blood cells and/or neutrophils (type of white blood 

cells). 

- diarrhoea, vomiting, stomach pain, nausea. 

- fever, swelling of hands, feet or face, fatigue, weakness. 

- respiratory tract infection. 

- nasopharyngitis. 

- changes in blood test to determine if Bosulif is affecting your liver and/or pancreas.  

- decrease of appetite. 

- joint pain, back pain. 

- headache. 

- skin rash, which may be itchy and/or generalised. 



 

46 

- cough.  

- shortness of breath. 
 

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

- low white blood cells count (leukopenia).  

- stomach irritation (gastritis), bleeding from the stomach or intestine. 

- chest pain, pain. 

- toxic damage to the liver, abnormal hepatic function including liver disorder. 

- infection of the lung (pneumonia), influenza, bronchitis. 

- defect in cardiac rhythm that predisposes to fainting, dizziness and palpitation. 

- increase in blood pressure. 

- high level of potassium in the blood, low level of phosphorus in the blood, excessive loss of 

body fluid (dehydration). 

- pain in the muscles. 

- feeling of instability (dizziness), alteration of the sense of taste (dysgeusia).  

- acute kidney failure, kidney failure, kidney impairment. 

- fluid on the lungs (pleural effusion).  

- fluid around the heart (pericardial effusion). 

- ringing in the ears (tinnitus). 

- itching, urticaria (hives), acne. 
 

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

- fever associated with low white blood cell count (febrile neutropenia). 

- acute inflammation of the pancreas (acute pancreatitis). 

- damage to the liver. 

- life-threatening allergic reaction (anaphylactic shock). 

- abnormal build-up of fluid in the lungs (acute pulmonary oedema). 

- respiratory failure.  

- allergic reaction.  

- abnormally high blood pressure in the arteries of the lungs (pulmonary hypertension). 

- skin eruption. 

- inflammation of the sac-like covering of the heart (pericarditis).  

- a marked decrease in the number of granulocytes (a type of white blood cells).  
 

Rare side effects (may affect up to 1 in 1,000 people): 

- severe skin disorder (erythema multiforme, Stevens-Johnson syndrome, toxic epidermal 

necrolysis) due to an allergic reaction, exfoliative (scaly, peeling) rash. 

 

Reporting of side effects 

If you get any side effects, talk to your doctor or pharmacist or nurse. This includes any possible 

side effects not listed in this leaflet. You can also report side effects directly via the national 

reporting system listed in Appendix 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 foil 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 pack is damaged or shows signs of tampering.  



 

47 

- Do not throw away any medicines via wastewater or household waste. Ask your pharmacist 

how to throw away medicines you no longer use. These measures will help protect the 

environment. 

 

 

6. Content of the pack and other information 

 

What Bosulif contains  

- The active substance is bosutinib. Bosulif film-coated tablets come in different strengths. 

Bosulif 100 mg: each film-coated tablet contains 100 mg bosutinib (as monohydrate). 

Bosulif 400 mg: each film-coated tablet contains 400 mg bosutinib (as monohydrate). 

Bosulif 500 mg: each film-coated tablet contains 500 mg bosutinib (as monohydrate). 

 

- The other ingredients are: microcrystalline cellulose (E460), croscarmellose sodium (E468), 

poloxamer 188, povidone (E1201) and magnesium stearate (E470b). The tablet film-coating 

contains polyvinyl alcohol, titanium dioxide (E171), macrogol 3350, talc (E553b) and iron 

oxide yellow (E172, for Bosulif 100 mg and 400 mg) or iron oxide red (E172, for Bosulif 

400 mg and 500 mg). 

 

What Bosulif looks like and contents of the pack  

Bosulif 100 mg film-coated tablets are yellow, oval biconvex, debossed with “Pfizer” on one side 

and “100” on the other side.  

Bosulif 100 mg is available in blisters containing either 14 or 15 film-coated tablets in cartons of 28 

or 30 film-coated tablets or 112 film-coated tablets. 

 

Bosulif 400 mg film-coated tablets are orange, oval biconvex, debossed with “Pfizer” on one side 

and “400” on the other side. 

Bosulif 400 mg is available in blisters containing either 14 or 15 film-coated tablets in cartons of 28 

or 30 film-coated tablets. 

 

Bosulif 500 mg film-coated tablets are red, oval biconvex, debossed with “Pfizer” on one side and 

“500” on the other side. 

Bosulif 500 mg is available in blisters containing either 14 or 15 film-coated tablets in cartons of 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 Bruxelles 

Belgium 

 

Manufacturer 

Pfizer Manufacturing Deutschland GmbH 

Betriebsstӓtte Freiburg 

Mooswaldallee 1 

79090 Freiburg 

Germany 

 



 

48 

For any information about this medicine, please contact the local representative of the Marketing 

Authorisation Holder: 

 

Belgique / België /Belgien 

Pfizer S.A. / N.V. 

Tél/Tel: +32 (0)2 554 62 11 

Lietuva 

Pfizer Luxembourg SARL filialas Lietuvoje 

Tel. + 370 52 51 4000 

 

България  

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

Luxembourg/Luxemburg 

Pfizer S.A. 

Tél/Tel: +32 (0)2 554 62 11 

 

Česká republika 

Pfizer PFE, spol. s r.o. 

Tel.: +420 283 004 111 

Magyarország 

Pfizer Kft. 

Tel.: +36-1-488-37-00 

Danmark 

Pfizer ApS 

Tlf: +45 44 20 11 00 

 

Malta 

Vivian Corporation Ltd. 

Tel: +356 21344610 

Deutschland 

Pfizer Pharma GmbH 

Tel: +49 (0)30 550055 51000 

  

Nederland 

Pfizer BV 

Tel: +31 (0)10 406 43 01 

 

Eesti 

Pfizer Luxembourg SARL Eesti filiaal  

Tel: +372 666 7500 

Norge 

Pfizer Norge AS 

Tlf: +47 67 52 61 00 

 

Ελλάδα 

Pfizer Ελλάς A.E. 

Τλ: +30 210 6785 800 

 

Österreich 

Pfizer Corporation Austria Ges.m.b.H. 

Tel: +43 (0)1 521 15-0 

 

España 

Pfizer, S.L. 

Tél: +34 91 490 99 00 

Polska 

Pfizer Polska Sp. z o.o. 

Tel.:+48 22 335 61 00 

 

France 

Pfizer  

Tél: +33 (0)1 58 07 34 40 

Portugal 

Pfizer Biofarmacêutica, Sociedade Unipessoal Lda 

Tel: +351 21 423 5500 

Hrvatska 

Pfizer Croatia d.o.o. 

Tel: + 385 1 3908 777 

România 

Pfizer Romania S.R.L. 

Tel: +40 (0) 21 207 28 00 

 

Ireland 

Pfizer Healthcare Ireland 

Tel: 1800 633 363 (toll free) 

+44 (0)1304 616161 

Slovenija 

Pfizer Luxembourg SARL 

Pfizer, podružnica za svetovanje s področja 

farmacevtske dejavnosti, Ljubljana 

Tel.: + 386 (0)1 52 11 400 

 

Ísland 

Icepharma hf. 

Sími: +354 540 8000 

Slovenská republika 

Pfizer Luxembourg SARL, organizačná zložka  

Tel.: + 421 2 3355 5500 

 



 

49 

Italia 

Pfizer S.r.l. 

Tel: +39 06 33 18 21 

Suomi/Finland 

Pfizer Oy 

Puh./Tel: +358 (0)9 43 00 40 

Kύπρος 

Pfizer Ελλάς Α.Ε. (Cyprus Branch) 

Tηλ+357 22 817690 

Sverige  

Pfizer Innovations AB 

Tel: +46 (0)8 550 520 00 

Latvija 

Pfizer Luxembourg SARL filiāle Latvijā 

Tel.: + 371 670 35 775 

 

United Kingdom 

Pfizer Limited 

Tel: +44 (0) 1304 616161 

 

 

This leaflet was last revised in  

 

This medicine has been given “conditional approval”. 

This means that there is more evidence to come about this medicine. 

The European Medicines Agency will review new information on this medicine at least every year 

and this leaflet will be updated as necessary. 

 

Detailed information on this medicine is available on the European Medicines Agency web site: 

http://www.ema.europa.eu.  

 


	SUMMARY OF PRODUCT CHARACTERISTICS
	A. MANUFACTURER(S) RESPONSIBLE FOR BATCH RELEASE
	B. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY AND USE
	C. OTHER CONDITIONS AND REQUIREMENTS OF THE MARKETING AUTHORISATION
	D. CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE AND EFFECTIVE USE OF THE MEDICINAL PRODUCT
	A. LABELLING
	B. PACKAGE LEAFLET