BOSULIF 100mg tablets medication leaflet

Bosulif 100 mg film-coated tablets

Bosulif 400 mg film-coated tablets

Bosulif 500 mg film-coated tablets

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.

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” onone 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” onone 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” onone side and “500” on the other side.

Bosulif is indicated for the treatment of adult patients with:

* newly-diagnosed chronic phase (CP) Philadelphia chromosome-positive chronic myelogenousleukaemia (Ph+ CML).

* CP, accelerated phase (AP), and blast phase (BP) Ph+ CML previously treated with one ormore tyrosine kinase inhibitor(s) [TKI(s)] and for whom imatinib, nilotinib and dasatinib arenot considered appropriate treatment options.

Therapy should be initiated by a physician experienced in the diagnosis and the treatment of patientswith CML.

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 orintolerance to therapy.

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 todemonstrate 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 theinvestigational product. In the Phase 3 clinical study in patients with newly-diagnosed CP CMLtreated with bosutinib 400 mg, dose escalations by 100 mg increments to a maximum of 600 mg oncedaily 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 ofescalation, and all Grade 2 non-haematological toxicities were resolved to at least Grade 1. In the

Phase 4 clinical study in patients with Ph+ CML previously treated with 1 or more TKI(s), doseescalations from 500 mg to 600 mg once daily with food were allowed in patients with unsatisfactoryresponse or with signs of disease progression in the absence of any Grade 3 or 4 or persistent Grade 2adverse events.

In the Phase 1/2 study in patients with CML who were resistant or intolerant to prior therapy whostarted 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 at400 mg, a total of 58 patients (21.6%) received dose escalations to 500 mg daily. In addition, 10.4% ofpatients in the bosutinib treatment group had further dose escalations to 600 mg daily.

In the Phase 4 study in patients with Ph+ CML previously treated with 1 or more TKI(s) who startedbosutinib treatment at 500 mg daily, 1 patient (0.6%) had a dose escalation up to 600 mg daily.

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 beinterrupted, and may be resumed at a dose reduced by 100 mg taken once daily after the toxicity hasresolved. If clinically appropriate, re-escalation to the dose prior to the dose reduction taken once dailyshould 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 ofnormal (ULN) occur, bosutinib should be interrupted until recovery to ≤ 2.5 × ULN and may beresumed at 400 mg once daily thereafter. If recovery takes longer than 4 weeks, discontinuation ofbosutinib should be considered. If transaminase elevations ≥ 3 × ULN occur concurrently withbilirubin 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 3-4diarrhoea, bosutinib should be interrupted and may be resumed at 400 mg once daily upon recovery tograde ≤ 1 (see section 4.4).

Haematological adverse reactions

Dose reductions are recommended for severe or persistent neutropenia and thrombocytopenia asdescribed in Table 1:

Table 1 - Dose adjustments for neutropenia and thrombocytopenia

ANCa < 1.0 × 109/L Hold bosutinib until ANC  1.0 × 109/L and platelets 50 × 109/L.

and/or

Resume treatment with bosutinib at the same dose if recovery

Platelets < 50 × 109/L occurs within 2 weeks. If blood counts remain low for> 2 weeks, upon recovery reduce dose by 100 mg and resumetreatment.

If cytopoenia recurs, reduce dose by an additional 100 mg uponrecovery and resume treatment.

Doses less than 300 mg/day have been used; however, efficacyhas not been established.a ANC = absolute neutrophil count

Elderly patients (≥ 65 years)

No specific dose recommendation is necessary in the elderly. Since there is limited information in theelderly, caution should be exercised in these patients.

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 wasobserved.

Newly-diagnosed CP Ph+ CML

In patients with moderate renal impairment (creatinine clearance [CLCr] 30 to 50 mL/min, estimatedby the Cockcroft-Gault formula), the recommended dose of bosutinib is 300 mg daily with food (seesections 4.4 and 5.2).

In patients with severe renal impairment (CLCr < 30 mL/min, estimated by the Cockcroft-Gaultformula), 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 to300 mg once daily for patients with severe renal impairment may be considered if they do notexperience severe or persistent moderate adverse reactions and if they do not achieve an adequatehaematological, cytogenetic, or molecular response.

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-Gaultformula), 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-Gaultformula), 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 oncedaily in patients with severe renal impairment may be considered in those who did not experiencesevere or persistent moderate adverse reactions, and if they do not achieve an adequatehaematological, cytogenetic, or molecular response.

In clinical studies, patients with uncontrolled or significant cardiac disease (e.g., recent myocardialinfarction, congestive heart failure or unstable angina) were excluded. Caution should be exercised inpatients 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 withrecent or ongoing clinically significant gastrointestinal disorder (see section 4.4).

The safety and efficacy of bosutinib in children and adolescents less than 18 years of age have notbeen established. No data are available.

Bosulif should be taken orally once daily with food (see section 5.2). If a dose is missed by more than12 hours, the patient should not be given an additional dose. The patient should take the usualprescribed dose on the following day.

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).

Liver function abnormalities

Treatment with bosutinib is associated with elevations in serum transaminases (alanineaminotransferase [ALT], aspartate aminotransferase [AST]).

Transaminase elevations generally occurred early in the course of treatment (of the patients whoexperienced transaminase elevations of any grade, > 80% experienced their first event within the first3 months). Patients receiving bosutinib should have liver function tests prior to treatment initiation andmonthly for the first 3 months of treatment, and as clinically indicated.

Patients with transaminase elevations should be managed by withholding bosutinib temporarily (withconsideration given to dose reduction after recovery to Grade 1 or baseline), and/or discontinuation ofbosutinib. 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 managedappropriately (see sections 4.2 and 4.8).

Diarrhoea and vomiting

Treatment with bosutinib is associated with diarrhoea and vomiting; therefore, patients with recent orongoing clinically significant gastrointestinal disorder should use this medicinal product with cautionand only after a careful benefit-risk assessment as respective patients were excluded from the clinicalstudies. 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, hasthe 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 assessmentis mandatory and patients should be monitored for occurrence of QTc prolongation.

Treatment with bosutinib is associated with myelosuppression, defined as anaemia, neutropenia, andthrombocytopenia. Complete blood counts should be performed weekly for the first month and thenmonthly thereafter, or as clinically indicated. Myelosuppression should/can be managed bywithholding bosutinib temporarily, dose reduction, and/or discontinuation of bosutinib (seesections 4.2 and 4.8).

Fluid retention

Treatment with bosutinib may be associated with fluid retention including pericardial effusion, pleuraleffusion, pulmonary oedema and/or peripheral oedema. Patients should be monitored and managedusing standard-of-care treatment. In addition, fluid retention can also be managed by withholdingbosutinib 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 previoushistory of pancreatitis. In case lipase elevations are accompanied by abdominal symptoms, bosutinibshould be interrupted and appropriate diagnostic measures considered to exclude pancreatitis (seesection 4.2).

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

Cardiovascular toxicity

Bosulif can cause cardiovascular toxicity including cardiac failure and cardiac ischaemic events.

Cardiac failure events occurred more frequently in previously treated patients than in patients withnewly diagnosed CML and were more frequent in patients with advanced age or risk factors, includingprevious medical history of cardiac failure. Cardiac ischaemic events occurred in both previouslytreated patients and in patients with newly diagnosed CML and were more common in patients withcoronary artery disease risk factors, including history of diabetes, body mass index greater than 30,hypertension and vascular disorders.

Patients should be monitored for signs and symptoms consistent with cardiac failure and cardiacischaemia and treated as clinically indicated. Cardiovascular toxicity can also be managed by doseinterruption, dose reduction and/or discontinuation of bosutinib.

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 myocardialinfarction, congestive heart failure, unstable angina or clinically significant bradycardia, or who aretaking medicinal products that are known to prolong the QTc (e.g., anti-arrhythmic medicinal productsand other substances that may prolong QTc [see section 4.5]). The presence of hypokalaemia andhypomagnesaemia may further enhance this effect.

Monitoring for an effect on the QTc is advisable and a baseline electrocardiogram (ECG) isrecommended prior to initiating therapy with bosutinib and as clinically indicated. Hypokalaemia orhypomagnesaemia must be corrected prior to bosutinib administration and should be monitoredperiodically during therapy.

Treatment with bosutinib may result in a clinically significant decline in renal function in CMLpatients. A decline over time in estimated glomerular filtration rate (eGFR) has been observed inpatients treated with bosutinib in clinical studies. In patients with newly-diagnosed CP CML treatedwith 400 mg, the median decline from baseline in eGFR was 11.1 ml/min/1.73 m2 at 1 year and14.1 ml/min/1.73 m2 at 5 years for patients on treatment. Treatment-naïve CML patients treated with500 mg showed a median eGFR decline of 9.2 ml/min/1.73 m2 at 1 year, 12.0 ml/min/1.73 m2 at5 years and 16.6 ml/min/1.73 m2 at 10 years for patients on treatment. In pre-treated patients with CPand advanced stage CML treated with 500 mg the median eGFR decline was 7.6 ml/min/1.73 m2 at1 year, 12.3 ml/min/1.73 m2 at 5 years and 15.9 ml/min/1.73 m2 at 10 years for patients on treatment.

In patients with Ph+ CML previously treated with 1 or more TKI(s) treated with 500 mg, the medianeGFR decline from baseline was 9.2 ml/min/1.73 m2 at 1 year and 14.5 ml/min/1.73 m2 at 4 years forpatients on treatment.

It is important that renal function is assessed prior to treatment initiation and closely monitored duringtherapy with bosutinib, with particular attention in those patients who have pre-existing renalcompromise or in those patients exhibiting risk factors for renal dysfunction, including concomitantuse of medicinal products with potential for nephrotoxicity, such as diuretics, angiotensin-convertingenzyme (ACE) inhibitors, angiotensin receptor blockers, and nonsteroidal anti-inflammatory drugs(NSAIDs).

In a renal impairment study, bosutinib exposures were increased in subjects with moderately andseverely impaired renal function. Dose reduction is recommended for patients with moderate or severerenal impairment (see sections 4.2 and 5.2).

Patients with serum creatinine > 1.5 × ULN were excluded from the CML studies. Based on apopulation pharmacokinetic analysis increasing exposure (AUC) in patients with moderate and severerenal 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 anescalated dose of 600 mg bosutinib.

Asian race

According to population pharmacokinetic analyses, Asians had a lower clearance resulting inincreased exposure. Therefore, these patients should be closely monitored for adverse reactionsespecially in case of dose escalation.

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 skinreaction during treatment.

Due to the possible occurrence of tumour lysis syndrome (TLS), correction of clinically significantdehydration and treatment of high uric acid levels are recommended prior to initiation of bosutinib(see section 4.8).

Reactivation of hepatitis B (HBV) in patients who are chronic carriers of this virus has occurred afterthese patients received BCR-ABL TKIs. Some cases resulted in acute hepatic failure or fulminanthepatitis leading to liver transplantation or a fatal outcome.

Patients should be tested for HBV infection before initiating treatment with bosutinib. Experts in liverdisease and in the treatment of HBV should be consulted before treatment is initiated in patients withpositive 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 beclosely monitored for signs and symptoms of active HBV infection throughout therapy and for severalmonths following termination of therapy (see section 4.8).

Exposure to direct sunlight or ultraviolet (UV) radiation should be avoided or minimised due to therisk of photosensitivity associated with bosutinib treatment. Patients should be instructed to usemeasures such as protective clothing and sunscreen with high sun protection factor (SPF).

Cytochrome P-450 (CYP)3A inhibitors

The concomitant use of bosutinib with strong or moderate CYP3A inhibitors should be avoided, as anincrease in bosutinib plasma concentration will occur (see section 4.5).

Selection of an alternate concomitant medicinal product with no or minimal CYP3A inhibitionpotential, if possible, is recommended.

If a strong or moderate CYP3A inhibitor must be administered during bosutinib treatment, aninterruption of bosutinib therapy or a dose reduction in bosutinib should be considered.

The concomitant use of bosutinib with strong or moderate CYP3A inducers should be avoided as adecrease in bosutinib plasma concentration will occur (see section 4.5).

Grapefruit products, including grapefruit juice and other foods that are known to inhibit CYP3Ashould be avoided (see section 4.5).

Dietary sodium

This medicinal product contains less than 1 mmol sodium (23 mg) per 100 mg, 400 mg, or 500 mgtablet. Patients on low sodium diets should be informed that this product is essentially ‘sodium-free’.

Effects of other medicinal products on bosutinib

The concomitant use of bosutinib with strong CYP3A inhibitors (including, but not limited toitraconazole, 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 notlimited to fluconazole, ciprofloxacin, erythromycin, diltiazem, verapamil, amprenavir, atazanavir,darunavir/ritonavir, fosamprenavir, aprepitant, crizotinib, imatinib) should be avoided, as an increasein 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 enzymeinhibition potential, if possible, is recommended.

If a strong or moderate CYP3A inhibitor must be administered during bosutinib treatment, aninterruption 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 CYP3Ainhibitor) 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, ascompared with administration of bosutinib alone.

In a study of 20 healthy subjects, in whom a single dose of 125 mg aprepitant (a moderate CYP3Ainhibitor) was co-administered with a single dose of 500 mg bosutinib under fed conditions, aprepitantincreased bosutinib Cmax by 1.5-fold, and bosutinib AUC in plasma by 2.0-fold, as compared withadministration of bosutinib alone.

The concomitant use of bosutinib with strong CYP3A inducers (including, but not limited tocarbamazepine, phenytoin, rifampicin, St. John’s Wort), or moderate CYP3A inducers (including, butnot limited to bosentan, efavirenz, etravirine, modafinil, nafcillin) should be avoided, as a decrease inbosutinib plasma concentration will occur.

Based on the large reduction in bosutinib exposure that occurred when bosutinib was co-administeredwith 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 mgrifampicin, in 24 healthy subjects in fed state bosutinib exposure (Cmax and AUC in plasma) decreasedto 14% and 6%, respectively, of the values when bosutinib 500 mg was administered alone.

Proton pump inhibitors (PPIs)

Caution should be exercised when administering bosutinib concomitantly with PPIs. Short-actingantacids should be considered as an alternative to PPIs and administration times of bosutinib andantacids should be separated (i.e. take bosutinib in the morning and antacids in the evening) wheneverpossible. Bosutinib displays pH-dependent aqueous solubility in vitro. When a single oral dose ofbosutinib (400 mg) was co-administered with multiple-oral doses of lansoprazole (60 mg) in a study of24 healthy fasting subjects, bosutinib Cmax and AUC decreased to 54% and 74%, respectively, of thevalues 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-administeredwith a single dose of 150 mg dabigatran etexilate mesylate (a P-glycoprotein [P-gp] substrate) underfed conditions, bosutinib did not increase Cmax or AUC of dabigatran in plasma, as compared withadministration of dabigatran etexilate mesylate alone. The study results indicate that bosutinib doesnot exhibit clinically relevant P-gp inhibitory effects.

An in vitro study indicates that drug-drug interactions are unlikely to occur at therapeutic doses as aresult 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 dosesas 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 aniontransporter (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 prolongationsuch as chloroquine, halofantrine, clarithromycin, domperidone, haloperidol, methadone, andmoxifloxacin (see section 4.4).

Women of childbearing potential should be advised to use effective contraception during treatmentwith bosutinib and for at least 1 month after the last dose and to avoid becoming pregnant whilereceiving bosutinib. In addition, the patient should be advised that vomiting or diarrhoea may reducethe efficacy of oral contraceptives by preventing full absorption.

There are limited amount of data in pregnant women from the use of bosutinib. Studies in animalshave shown reproductive toxicity (see section 5.3). Bosutinib is not recommended for use duringpregnancy, or in women of childbearing potential not using contraception. If bosutinib is used duringpregnancy, or the patient becomes pregnant while taking bosutinib, she should be apprised of thepotential hazard to the foetus.

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. Breast-feedingshould be discontinued during treatment with bosutinib.

Based on non-clinical findings, bosutinib has the potential to impair reproductive function and fertilityin humans (see section 5.3). Men being treated with bosutinib are advised to seek advice onconservation of sperm prior to treatment because of the possibility of decreased fertility due to therapywith bosutinib.

Bosutinib has no or negligible influence on the ability to drive and use machines. However, if a patienttaking bosutinib experiences dizziness, fatigue, visual impairment or other undesirable effects with apotential impact on the ability to drive or use machines safely, the patient should refrain from theseactivities for as long as the undesirable effects persist.

A total of 1,372 leukaemia patients received at least 1 dose of single-agent bosutinib. The medianduration of therapy was 26.30 months (range: 0.03 to 170.49 months). These patients were eithernewly-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 inpreviously untreated CML patients, 60 (400 mg starting dose) are from a Phase 2 study in previouslyuntreated CML patients, 570 and 63 (Phase 2: 500 mg starting dose) are from 2 Phase 1/2 studies inpreviously treated Ph+ leukaemias, and 163 (500 mg starting dose) are from a Phase 4 study inpreviously treated CML. The median duration of therapy was 55.1 months (range: 0. 2 to60.05 months), 61.6 months (0.03 to 145.86 months), 15.3 months (range: 0.3 to 21.8 months),11.1 months (range: 0.03 to 170.49 months), 30.2 months (range: 0.2 to 85.6 months), and37.80 months (range: 0.16 to 50.0 months), respectively. The safety analyses included data from acompleted extension study.

At least 1 adverse reaction of any toxicity grade was reported for 1,349 (98.3%) patients. The mostfrequent adverse reactions reported for  20% of patients were diarrhoea (80.4%), nausea (41.5%),abdominal pain (35.6%), thrombocytopenia (34.4%), vomiting (33.7%), rash (32.8%), ALT increased(28.0%), anaemia (27.2%), pyrexia (23.4%), AST increased (22.5%), fatigue (32.0%), and headache(20.3%). At least 1 Grade 3 or Grade 4 adverse reaction was reported for 943 (68.7%) patients. The

Grade 3 or Grade 4 adverse reactions reported for  5% of patients were thrombocytopenia (19.7%),

ALT increased (14.6%), neutropenia (10.6%), diarrhoea (10.6%), anaemia (10.3%), lipase increased(10.1%), AST increased (6.7%), and rash (5.0%).

The following adverse reactions were reported in patients in bosutinib clinical studies (Table 2). Theserepresent an evaluation of the adverse reaction data from 1,372 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 arepresented 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). Withineach frequency grouping, adverse reactions are presented in order of decreasing seriousness.

Table 2 - Adverse reactions for bosutinib

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

Respiratory tract infection viral, Upper respiratory tract infection, Viral upperrespiratory tract infection), Nasopharyngitis

Common Pneumonia (including Atypical pneumonia, Pneumonia bacterial, Pneumoniafungal, Pneumonia necrotising, Pneumonia streptococcal), Influenza(including Influenza H1N1), Bronchitis

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

Uncommon Tumour lysis syndrome**

Very common Thrombocytopenia (including Platelet count decreased), Neutropenia(including Neutrophil count decreased), Anaemia (including haemoglobindecreased, Red blood cell count decreased)

Common Leukopenia (including White blood cell count decreased)

Uncommon Febrile neutropenia, Granulocytopenia

Common Drug hypersensitivity

Uncommon Anaphylactic shock

Very common Decreased appetite

Common Dehydration, Hyperkalaemia (including Blood potassium increased),

Hypophosphataemia (including Blood phosphorus decreased)

Very common Dizziness, Headache

Common Dysgeusia

Ear and labyrinth disorders

Common Tinnitus

Common Pericardial effusion, Cardiac failure (including Cardiac failure, Cardiac failureacute, Cardiac failure chronic, Cardiac failure congestive, Cardiogenic shock,

Cardiorenal syndrome, Ejection fraction decreased, Left ventricular failure),

Cardiac ischaemic events (including Acute coronary syndrome, Acutemyocardial infarction, Angina pectoris, Angina unstable, Arteriosclerosiscoronary artery, Coronary artery disease, Coronary artery occlusion, Coronaryartery stenosis, Myocardial infarction, Myocardial ischaemia, Troponinincreased)

Uncommon Pericarditis

Common Hypertension (including Blood pressure increased, Blood pressure systolicincreased, Essential hypertension, Hypertensive crisis)

Very common Pleural effusion, Dyspnoea, Cough

Common Pulmonary hypertension (including Pulmonary arterial hypertension,

Pulmonary arterial pressure increased), Respiratory failure

Uncommon Acute pulmonary oedema (including Pulmonary oedema)

Not known Interstitial lung disease

Very common Diarrhoea, Vomiting, Nausea, Abdominal pain (including Abdominaldiscomfort, Abdominal pain lower, Abdominal pain upper, Abdominaltenderness, Gastrointestinal pain)

Common Gastrointestinal haemorrhage (including Anal haemorrhage, Gastrichaemorrhage, Intestinal haemorrhage, Lower gastrointestinal haemorrhage,

Rectal haemorrhage, Upper gastrointestinal haemorrhage), Pancreatitis(including Pancreatitis acute), Gastritis

Common Hepatotoxicity (including Hepatitis, Hepatitis toxic, Liver disorder), Hepaticfunction abnormal (including Hepatic enzyme increased, Liver function testabnormal, Liver function test increased, Transaminases increased)

Uncommon Liver injury (including Drug-induced liver injury, Hepatocellular injury)

Very common Rash (including Rash macular, Rash maculo-papular, Rash papular, Rashpruritic), Pruritus

Common Photosensitivity reaction (including Polymorphic light eruption), Urticaria,

Acne

Uncommon Erythema multiforme, Exfoliative rash, Drug eruption

Not known Stevens-Johnson Syndrome**, Toxic epidermal necrolysis**

Very common Arthralgia, Back pain

Common Myalgia

Common Acute kidney injury, Renal failure, Renal impairment

Very common Oedema (including Eyelid oedema, Face oedema, Generalised oedema,

Localised oedema, Oedema peripheral, Periorbital oedema, Periorbitalswelling, Peripheral swelling, Swelling, Swelling of eyelid), Pyrexia, Fatigue(including Asthenia, Malaise)

Common Chest pain (including Chest discomfort), Pain

Very common Lipase increased (including Hyperlipasaemia), Alanine aminotransferaseincreased (including Alanine aminotransferase abnormal), Aspartateaminotransferase increased, Blood creatinine increased

Common Electrocardiogram QT prolonged (including Long QT syndrome) , Amylaseincreased (including Hyperamylasaemia), Blood creatine phosphokinaseincreased, Gamma-glutamyltransferase increased, Blood bilirubin increased(including Hyperbilirubinaemia, Bilirubin conjugated increased, Bloodbilirubin unconjugated increased)

** Adverse reaction identified post marketing.

The descriptions included below are based on the safety population of 1,372 patients who received atleast 1 dose of bosutinib and had either newly-diagnosed CP CML or were resistant or intolerant toprior therapy with CP, AP, or BP CML, or Ph+ ALL.

Of the 372 (27.1%) patients with reports of adverse reactions of anaemia, 6 patients discontinuedbosutinib due to anaemia. Maximum toxicity of Grade 1 occurred in 95 (25.5%) patients, Grade 2 in135 (36.3%) patients, Grade 3 in 113 patients (30.4%), and Grade 4 in 29 (7.8%) patients. Amongthese patients, the median time to first event was 29 days (range: 1 to 3,999 days) and the medianduration per event was 22 days (range: 1 to 3,682 days).

Of the 209 (15.2%) patients with reports of adverse reactions of neutropenia, 19 patients discontinuedbosutinib due to neutropenia. Maximum toxicity of Grade 1 occurred in 19 patients (9.1%), Grade 2 in45 (21.5%) patients, Grade 3 in 95 (45.5%) patients, and Grade 4 in 50 (23.9%) patients. Among thesepatients, the median time to first event was 56 days (range: 1 to 1,769 days), and the median durationper event was 15 days (range: 1 to 913 days).

Of the 472 (34.4%) patients with reports of adverse reactions of thrombocytopenia, 42 patientsdiscontinued bosutinib due to thrombocytopenia. Maximum toxicity of Grade 1 occurred in114 (24.2%) patients, Grade 2 in 88 (18.6%) patients, Grade 3 in 172 (36.4%) patients, and Grade 4 in98 (20.8%) patients. Among these patients, the median time to first event was 28 days (range: 1 to1,688 days), and median duration per event was 15 days (range: 1 to 3,921 days).

Among patients with reports of adverse reactions of elevations in either ALT or AST (all grades), themedian time of onset observed was 29 days with a range of onset 1 to 3,995 days for ALT and AST.

The median duration of an event was 17 days (range: 1 to 1,148 days), and 15 days (range: 1 to803 days) for ALT and AST, respectively.

Two cases consistent with drug-induced liver injury (defined as concurrent elevations in ALT or AST≥ 3 × ULN with total bilirubin > 2 × ULN and with alkaline phosphatase < 2 × ULN) withoutalternative causes have occurred in 2/1,711 (0.1%) subjects treated with bosutinib.

Hepatitis B reactivation has been reported in association with BCR-ABL TKIs. Some cases resulted inacute hepatic failure or fulminant hepatitis leading to liver transplantation or a fatal outcome (seesection 4.4).

Of the 1,103 (80.4%) patients that experienced diarrhoea, 14 patients discontinued bosutinib due tothis event. Concomitant medicinal products were given to treat diarrhoea in 756 (68.5%) patients.

Maximum toxicity of Grade 1 occurred in 575 (52.1%) patients, Grade 2 in 383 (34.7%) patients,

Grade 3 in 144 (13.1%) patients; 1 patient (0.1%) experienced a Grade 4 event. Among patients withdiarrhoea, the median time to first event was 2 days (range: 1 to 2,702 days) and the median durationof any grade of diarrhoea was 2 days (range: 1 to 4,247 days).

Among the 1,103 patients with diarrhoea, 218 patients (19.8%) were managed with treatmentinterruption and of these 208 (95.4%) were rechallenged with bosutinib. Of those who wererechallenged, 201 (96.6%) did not have a subsequent event or did not discontinue bosutinib due to asubsequent event of diarrhoea.

Among 1372 patients, cardiac failure occurred in 50 (3.6%) patients and cardiac ischaemic events in57 (4.2%) patients.

Seven patients (0.5%) experienced QTcF prolongation (greater than 500 ms). Eleven (0.8%) patientsexperienced QTcF increase > 60 ms from baseline. Patients with uncontrolled or significantcardiovascular disease including QTc prolongation, at baseline, were not included in clinical studies(see sections 5.1 and 5.3).

Reporting suspected adverse reactions after authorisation of the medicinal product is important. Itallows continued monitoring of the benefit/risk balance of the medicinal product. Healthcareprofessionals are asked to report any suspected adverse reactions via the national reporting systemlisted in Appendix V.

Experience with bosutinib overdose in clinical studies was limited to isolated cases. Patients who takean overdose of bosutinib should be observed and given appropriate supportive treatment.

Pharmacotherapeutic group: Antineoplastic agents, protein kinase inhibitors, ATC code: L01EA04.

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

Bosutinib inhibits the abnormal BCR-ABL kinase that promotes CML. Modelling studies indicate thatbosutinib binds the kinase domain of BCR-ABL. Bosutinib is also an inhibitor of Src family kinasesincluding 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 of18 imatinib-resistant forms of BCR-ABL expressed in murine myeloid cell lines. Bosutinib treatmentreduced the size of CML tumours growing in nude mice and inhibited growth of murine myeloidtumours expressing imatinib-resistant forms of BCR-ABL. Bosutinib also inhibits receptor tyrosinekinases 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 ofthe Ste20 family, and 2 calmodulin-dependent protein kinases.

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-labelmoxifloxacin-controlled study in healthy subjects.

The data from this study indicate that bosutinib does not prolong the QTc in healthy subjects at thedose of 500 mg daily with food, and under conditions that give rise to supratherapeutic plasmaconcentrations. 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 ofbosutinib) in healthy subjects, the upper bound of the 1-sided 95% confidence interval (CI) around themean change in QTc was less than 10 ms at all post-dose time points, and no adverse eventssuggestive of QTc prolongation were observed.

In a study in liver impaired subjects, an increasing frequency of QTc prolongation > 450 ms withdeclining hepatic function was observed. In the Phase 1/2 clinical study in patients with previouslytreated Ph+ leukaemias treated with bosutinib 500 mg, QTcF increase > 60 ms from baseline wasobserved in 9 (1.6%) of 570 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(N=268) with a QTcF increase of > 60 ms from baseline. In the Phase 3 clinical study in patients withnewly-diagnosed Ph+ CP CML treated with bosutinib 500 mg, QTcF increase > 60 ms from baselinewas observed in 2 (0.8%) of 248 patients receiving bosutinib. In the Phase 4 clinical study in patientswith Ph+ CML previously treated with 1 or more TKI(s) treated with bosutinib 500 mg (N=163), therewere no patients with a QTcF increase > 60 ms from baseline. A proarrhythmic potential of bosutinibcannot be ruled out.

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 efficacyand safety of bosutinib 400 mg once daily alone compared with imatinib 400 mg once daily alone inadult patients with newly-diagnosed Ph+ CP CML. The trial randomised 536 patients (268 in eachtreatment 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 treatmentgroup in the mITT population. MMR was defined as ≤ 0.1% BCR-ABL/ABL ratio by internationalscale (corresponding to ≥ 3 log reduction from standardised baseline) with a minimum of 3,000 ABLtranscripts as assessed by the central laboratory.

Key secondary endpoints included complete cytogenetic response (CCyR) by 12 months, duration of

CCyR, duration of MMR, event-free survival (EFS), and overall survival (OS). CCyR by Month 12,was defined as the absence of Ph+ metaphases in chromosome banding analysis of ≥ 20 metaphasesderived 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 beenadjusted for multiple comparisons.

Baseline characteristics for the mITT population were well balanced between the 2 treatment groupswith respect to age (median age was 52 years for the bosutinib group and 53 years for the imatinibgroup with 19.5% and 17.4% of patients 65 years of age or older, respectively); gender (women 42.3%and 44.0%, respectively); race (Caucasian 78.0% and 77.6%, Asian 12.2% and 12.4%, Black or

African American 4.1% and 4.1%, and Other 5.7% and 5.4%, respectively, and 1 unknown in theimatinib group); and Sokal risk score (low risk 35.0% and 39.4%, intermediate risk 43.5% and 38.2%,high risk 21.5% and 22.4%, respectively).

After 60 months of follow-up in the mITT population, 60.2% of patients treated with bosutinib(N=246) and 59.8% of patients treated with imatinib (N=239) were still receiving first-line treatment.

After 60 months of follow-up in the mITT population, discontinuations due to disease progression to

AP or BP CML for bosutinib-treated patients were 0.8% compared to 1.7% for imatinib-treatedpatients. Six (2.4%) bosutinib patients and 7 (2.9%) imatinib patients transformed to AP CML or

BP CML. Discontinuations due to suboptimal response or treatment failure as assessed by theinvestigator occurred for 5.3% of patients in the bosutinib-treated group compared to 15.5% ofpatients in the imatinib-treated group. Twelve (4.9%) patients on bosutinib and 14 (5.8%) patients onimatinib died while on study. No additional transformations occurred in the ITT population, there were2 additional deaths in the bosutinib arm in the ITT population.

The efficacy results of MMR and CCyR are summarised in Table 3.

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

Bosutinib Imatinib Odds ratio

Response (N=246) (N=241) (95% CI)a

Major molecular response

MMR at Month 12, n (%) 116 (47.2)b 89 (36.9) 1.55 (1.07,2.23)(95% CI) (40.9,53.4) (30.8,43.0)1-sided p-value 0.0100b

MMR at Month 18, n (%) 140 (56.9) 115 (47.7) 1.45 (1.02,2.07)(95% CI) (50.7,63.1) (41.4,54.0)1-sided p-value 0.0208c

Complete cytogenetic response

CCyR by Month 12, n (%) 190 (77.2)b 160 (66.4) 1.74 (1.16,2.61)(95% CI) (72.0,82.5) (60.4,72.4)1-sided p-value 0.0037b

Note: MMR was defined as ≤ 0.1% BCR-ABL/ABL ratio by international scale (corresponding to ≥ 3 logreduction from standardised baseline) with a minimum of 3,000 ABL transcripts assessed by the centrallaboratory. Complete cytogenetic response was defined as the absence of Ph+ metaphases in chromosomebanding analysis of ≥ 20 metaphases derived from bone marrow aspirate or MMR if an adequate cytogeneticassessment 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 Adjusted for geographical region and Sokal score at randomisation.b Statistically significant comparison at the pre-specified significance level; based on CMH test stratified bygeographical region and Sokal score at randomisation.c 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 fromstandardised baseline] with a minimum of 9,800 ABL transcripts) was higher in the bosutinibtreatment 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, odds ratio (OR) 1.88 [95% CI:

1.15, 3.08], 1-sided p-value=0.0052).

At Months 3, 6, and 9, the proportion of patients with MMR was higher in the bosutinib treatmentgroup compared to the imatinib treatment group (Table 4).

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

Number (%) of subjects with MMR

Bosutinib Imatinib Odds ratio

Time (N=246) (N=241) (95% CI)a

Month 3 10 (4.1) 4 (1.7) 2.48 (0.77,7.98)(95% CI) (1.6,6.5) (0.0,3.3)1-sided p-valueb 0.0578

Month 6 86 (35.0) 44 (18.3) 2.42 (1.59,3.69)(95% CI) (29.0,40.9) (13.4,23.1)1-sided p-valueb <0.0001

Month 9 104 (42.3) 71 (29.5) 1.78 (1.22,2.60)(95% CI) (36.1,48.4) (23.7,35.2)1-sided p-valueb 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 aminimum of 3,000 ABL transcripts assessed by the central laboratory.

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

CMH=Cochran-Mantel-Haenszel; mITT=modified intent-to-treat; MMR=major molecular response; N=number ofpatients.a Adjusted for geographical region and Sokal score at randomisation.b Based on CMH test stratified by geographical region and Sokal score at randomisation.

By Month 60 in the mITT population, the proportion of patients with MMR, MR4 and MR4.5 washigher in the bosutinib group compared to the imatinib group (Table 5). MMR rates by Month 60across Sokal risk subgroups are summarised in Table 6.

Table 5 - Summary of molecular response by Month 60 in the mITT population

Response Bosutinib Imatinib Odds ratio(N=246) (N=241) (95% CI)a

Molecular responseby Month 60, n (%)(95% CI)

MMR 182 (74.0) 158 (65.6) 1.52 (1.02,2.25)(68.5,79.5) (59.6,71.6)

MR4 145 (58.9) 120 (49.8) 1.46 (1.02,2.09)(52.8,65.1) (43.5,56.1)

MR4.5 119 (48.4) 93 (38.6) 1.50 (1.05,2.16)(42.1,54.6) (32.4,44.7)

Note: MMR/MR4/MR4.5 were defined as ≤ 0.1/0.01/0.0032% BCR-ABL/ABL ratio on international scale(corresponding to ≥ 3/4/4.5 log reduction from standardised baseline) with a minimum of3,000/9,800/30,990 ABL transcripts assessed by the central laboratory.

Abbreviations: BCR-ABL=breakpoint cluster region-Abelson; CI=confidence interval; mITT=modifiedintent-to-treat; MMR=major molecular response; MR=molecular response; N/n=number of patients.a Adjusted for geographical region and Sokal score at randomisation.

Table 6 - Summary of MMR by Month 60 by Sokal risk score in the mITT population

Response Bosutinib Imatinib Odds ratio(95% CI)

Low Sokal risk N=86 N=95 1.40 (0.71,2.76)

MMR, n (%) 67 (77.9) 68 (71.6)( 95% CI) (69.1,86.7) (62.5,80.6)

Intermediate Sokal risk N=107 N=92 1.37 (0.74,2.52)

MMR, n (%) 79 (73.8) 62 (67.4)( 95% CI) (65.5,82.2) (57.8,77.0)

High Sokal risk N=53 N=54 1.97 (0.90,4.32)

MMR, n (%) 36 (67.9) 28 (51.9)( 95% CI) (55.4,80.5) (38.5,65.2)

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) witha minimum of 3,000 ABL transcripts assessed by the central laboratory.

Abbreviations: BCR-ABL=breakpoint cluster region-Abelson; CI=confidence interval; mITT=modifiedintent-to-treat; MMR=major molecular response; N/n=number of patients.

The cumulative incidence of CCyR adjusted for the competing risk of treatment discontinuationwithout CCyR was higher in the bosutinib treatment group compared to the imatinib treatment groupin the mITT population (83.3% [95% CI: 78.1%, 87.4%] versus 76.8% [95% CI: 70.9%, 81.6%] at

Month 60; hazard ratio [HR] from a stratified proportional sub distributional hazards model: 1.35,[95% CI: 1.11, 1.64]). The median time to CCyR (responders only) was 24.0 weeks (range: 11.4 to120.7) in the bosutinib group compared to the 24.3 weeks (range: 11.4 to 96.6) in the imatinib group.

The median time to MMR, MR4 and MR4.5 (responders only) was 36.1 weeks (range: 11.9 to 241.9),83.7 weeks (range: 12.4 to 244.3), and 108.0 weeks (range: 24.1 to 242.1), respectively, for thebosutinib treatment group versus 47.7 weeks (range: 12.1 to 216.1), 84.4 weeks (range: 23.6 to 241.9),and 120.4 weeks (range: 24.6 to 240.7), respectively, for the imatinib treatment group in the mITTpopulation.

The cumulative incidence of MMR, MR4 and MR4.5 adjusted for the competing risk of treatmentdiscontinuation without the event was higher with bosutinib compared to imatinib as shown in

Figures 1 to 3.

Figure 1 - Cumulative incidence of MMR (mITT population)

Figure 2 - Cumulative incidence of MR4 (mITT population)

Figure 3 - Cumulative incidence of MR4.5 (mITT population)

In the mITT population, among patients who achieved CCyR, the Kaplan-Meier estimate ofmaintaining a response at Year 4 was 97.4% (95% CI: 93.9%, 98.9%) and 93.7% (95% CI: 88.9%,96.5%) in the bosutinib and imatinib groups (HR 0.39 [95% CI: 0.14, 1.13]), respectively. Amongpatients who achieved MMR, the Kaplan-Meier estimate of maintaining a response at Year 4 was92.2% (95% CI: 86.8%, 95.4%) and 92.0% (95% CI: 85.9%, 95.5%) in the bosutinib and imatinibgroups (HR 1.09 [95% CI: 0.49, 2.44]), respectively.

By Month 60, 43.9% (95% CI: 37.7%, 50.1%) and 38.6% (95% CI: 32.4%, 44.7%) of bosutinib- andimatinib-treated patients (OR 1.24 [95% CI: 0.87, 1.78]) in the mITT population, respectively, hadsustained MR4 defined by the following criteria: treatment for at least 3 years with at least MR4 at allassessments during a 1-year period.

The cumulative incidence of on-treatment EFS events at Month 60 in the mITT population was 6.9%(95% CI: 4.2%, 10.5%) in the bosutinib arm and 10.4% (95% CI: 6.9%, 14.6%) in the imatinib arm(HR 0.64, 95% CI: 0.35, 1.17).

The Kaplan-Meier estimates of OS at Month 60 for bosutinib and imatinib patients in themITT population were 94.9% (95% CI: 91.1%, 97.0%) and 94.0% (95% CI: 90.1%, 96.4%),respectively (HR 0.80, 95% CI: 0.37, 1.73).

In a retrospective analysis, among evaluable patients in the ITT population, more patients in thebosutinib arm 200/248 (80.6%) achieved early molecular response (BCR-ABL transcripts ≤ 10% at3 months) compared to patients in the imatinib arm 153/253 (60.5%), OR 2.72 (95% CI: 1.82, 4.08).

MMR and EFS at Month 60 in bosutinib patients with and without early molecular response aresummarised in Table 7.

Table 7 - Outcomes at Month 60 in bosutinib patients with BCR-ABL ≤ 10% vs > 10% at Month3 in the ITT population

Bosutinib (N=248) Patients with Patients with Hazard Ratio

BCR-ABL ≤ 10% at BCR-ABL > 10% at (95% CI)a3 Months 3 Months(N=200) (N=48)

Cumulative incidence 84.0 (78.1,88.4) 56.5 (41.1,69.4) 2.67 (1.90,3.75)of MMR, % (95% CI)

Cumulative incidence 5.5 (2.9,9.3) 12.5 (5.1,23.4) 0.40 (0.14,1.17)of EFS events, %(95% CI)

Abbreviations: BCR-ABL=breakpoint cluster region-Abelson; CI=confidence interval; ITT=intent-to-treat;

MMR=major molecular response; EFS=event free survival; N=number of patients with ≥ 3000 ABL copies at

Month 3.a Adjusted for geographical region and Sokal score at randomisation.

Fewer patients in the bosutinib arm [6 (2.4%) bosutinib and 12 (5.0%) imatinib] had newly detectablemutations at 60 months in the mITT population.

Phase 1/2 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 safetyof bosutinib 500 mg once daily in patients with imatinib-resistant or -intolerant CML with separatecohorts 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 previouslytreated with only 1 prior TKI (imatinib), CP CML patients previously treated with imatinib and at least1 additional TKI (dasatinib and/or nilotinib), CML patients in accelerated or blast phase previouslytreated with at least 1 TKI (imatinib) and patients with Ph+ ALL previously treated with at least 1 TKI(imatinib).

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 cytogenetic and molecular response rates,time to and duration of cytogenetic and molecular responses, response in baseline mutations,transformation to AP/BP, progression free survival and OS for all cohorts.

Patients who were still receiving bosutinib at the end of the Phase 1/2 study and were benefiting frombosutinib treatment as judged by the investigator, as well as those patients who had alreadydiscontinued bosutinib as part of the Phase 1/2 study and were in long-term follow-up for survival orhad completed the Phase 1/2 study, were eligible for enrollment into the extension study. Each patientremained in the extension study, either on bosutinib treatment or in long-term survival follow-up, untilthe last patient reached 10 years of follow-up, as calculated from the date of his/her first dose ofbosutinib administered in the Phase 1/2 study.

Extension study efficacy endpoints included duration of cytogenetic and molecular responses,transformation to AP/BP, progression free survival, and OS.

The efficacy analyses included data from this completed extension study.

CP CML Patients

The efficacy results for Ph+ CP CML patients previously treated with imatinib and at least 1 additional

TKI (minimum follow-up 120 months, median treatment duration of 9 months (range: 0.23 to164.28 months) and 20.2% and 7.6% still on-treatment at 60 and 120 months, respectively) and theresults for Ph+ CP CML patients previously treated with only imatinib (minimum follow-up120 months, median treatment duration of 26 months (range: 0.16 to 170.49 months) and 40.5% and19.4% still on-treatment at 60 and 120 months, respectively) are presented in Table 8.

AP and BP CML patients

The efficacy results for AP (minimum follow-up 120 months, median treatment duration of 10 months(range: 0.10 to 156.15 months) and 12.7% and 7.6% still on-treatment at 60 and 120 months,respectively) and BP (minimum follow-up 120 months, median treatment duration of 2.8 months(range: 0.03 to 71.38 months) and 3.1% and 0% still on-treatment at 60 and 120 months, respectively)

Ph+ CML patients are present in Table 8.

Table 8 - Efficacy results in previously treated patients with chronic and advanced phase CML*

Ph+ CP CML Ph+ CP CML Accelerated Blast phasewith prior with prior phase with with priorimatinib treatment prior treatment oftreatment with imatinib treatment of at leastonly and dasatinib at least imatinibor nilotinib imatinib

Cumulative cytogenetic N=262 N=112 N=72 N=54responsea 59.9 42.0 40.3 37.0

MCyR, % (95% CI) (53.7,65.9) (32.7,51.7) (28.9,52.5) (24.3,51.3)

CCyR, % (95% CI) 49.6 32.1 30.6 27.8(43.4,55.8) (23.6,41.6) (20.2,42.5) (16.5,41.6)

Cumulative molecular N=197 N=107 N=54 N=48responsea 42.1 17.8 16.7 (7.9,29.3) 10.4 (3.5,22.7)

MMR, % (95% CI) (35.1,49.4) (11.0,26.3) 13.0 (5.4,24.9) 10.4 (3.5,22.7)

MR4, % (95% CI) 37.1 15.0 (8.8,23.1)(30.3,44.2)

Time to MCyR for 12.3 12.3 12.0 8.2 (3.9,25.1)responders onlyb, median (4.0,346.0) (3.9,550.6) (3.9,144.7)(range), weeks

Duration of MCyRb N=157 N=47 N=29 N=20

K-M at year 5, % (95% CI) 70.7 66.6 40.8 21.2 (0.1,42.3)

K-M at year 10, % (95% (63.1,78.3) (51.5,81.7) (20.9,60.7) N/E

CI) 65.3 55.3 40.8 29.1

Median, weeks (95% CI) (56.6,74.0) (36.3,74.4) (20.9,60.7) (11.9,38.3)

N/R N/R 84.0 (24.0,N/E)

Time to CCyR for 24.0 24.0 23.8 8.4 (3.9,25.1)responders onlyb, median (7.7,240.6) (11.6,216.0) (4.1,120.0)(range), weeks

Duration of CCyRb N=130 N=36 N=22 N=15

K-M at year 5, % (95% CI) 69.7 54.4 40.0 24.9 (0.9,48.9)

K-M at year 10, % (95% (61.3,78.2) (36.7,72.1) (18.5,61.5) N/E

CI) 63.4 40.8 40.0 20.0 (9.1,29.6)

Median, weeks (95% CI) (54.0,72.8) (22.0,59.6) (18.5,61.5)

N/R 252.0 72.0 (36.1,N/E)(24.0,N/E)

Time to MMR for responders 35.6 12.4 36.1 4.7 (3.9,168.9)onlyb, median (range), weeks (3.1,367.1) (4.0,171.7) (12.1,144.1)

Duration of MMRb N=83 N=19 N=9 N=5

K-M at year 5, % (95% CI) 74.1 70.0 66.7 60.0

K-M at year 10, % (95% (64.2,83.9) (47.5,92.5) (35.9,97.5) (17.1,100.0)

CI) 63.4 70.0 66.7 N/E

Median, weeks (95% CI) (50.2,76.6) (47.5,92.5) (35.9,97.5) N/R

N/R N/R N/R

Time to MR4 for responders 28.0 23.8 24.1 4.7 (3.9,284.9)onlyb, median (range), weeks (3.1,583.1) (4.0,240.1) (22.9,96.0)

Duration of MR4b,e N=73 N/A N/A N/A

K-M at year 5, % (95% CI) 74.7

K-M at year 10, % (95% (64.2,85.2)

CI) 60.8

Median, weeks (95% CI) (46.1,75.4)

N/R

Transformation to AP/ BPc N=284 N=119 N=79 N/A

On--treatment 15 5 3transformation, n

Progression-free survivalc N=284 N=119 N=79 N=64

CumInc at year 5, % (95% 19.7 24.4 41.8 67.2

CI)d (15.6,24.9) (17.8,33.4) (32.2,54.2) (56.6,79.7)

CumInc at year 10, % (95% 23.9 26.9 41.8 N/E

CI)d (19.5,29.5) (20.0,36.2) (32.2,54.2)

Overall survivalc N=284 N=119 N=79 N=64

K-M at year 5, % (95% CI) 83.5 74.1 58.5 22.5 (7.1,37.9)

K-M at year 10, % (95% (78.7,88.3) (64.8,83.4) (46.9,70.2) 22.5 (7.1,37.9)

CI) 71.5 60.4 50.7 10.9 (8.7,19.7)

Median, months (95% CI) (64.4,78.7) (47.2,73.7) (36.5,65.0)

N/R N/R N/R

Snapshot date: Phase 1/2 Study 02Oct2015, Extension Study 02Sep2020.

Cytogenetic Response criteria: MCyR 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 bonemarrow sample. FISH analysis (≥ 200 cells) could be used for post-baseline cytogenetic assessments if≥ 20 metaphases were not available. In the extension study, CCyR was imputed from MMR if a valid cytogeneticassessment was not available on a specific date.

Molecular response criteria: In the Phase 1/2 Study, MMR/MR4 was defined as ≤0.1/0.01% BCR-ABL transcriptsas assessed by a central laboratory (not on the international scale). In the extension study, responders had

MMR/MR4 denoted on the case report form as assessed by a local laboratory.

Abbreviations: AP=accelerated phase; BP=blast phase; Ph+=Philadelphia chromosome-positive; CP=chronicphase; 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=majorcytogenetic response; CCyR=complete cytogenetic response; CumInc=cumulative incidence; MMR=majormolecular response; BCR-ABL=breakpoint cluster region-Abelson.a Includes patients (N) with a valid baseline assessment for cytogenetic and patients not from China, South Africa,

India, or Russia for molecular as samples could not be exported for molecular assessment in those countries.

The analyses allow baseline responders who maintained response post-baseline to be responders. Minimumfollow-up time (time from last patient first dose to data snapshot date) of 120 months.b Includes patients (N) who attained or maintained response.c Including patients (N) who received at least 1 dose of bosutinib.d Cumulative incidence analysis adjusting for the competing risk of treatment discontinuation without the event.e Not analysed for groups with limited numbers.

The Overall Survival in the CP, AP and BP cohorts is displayed graphically in Figure 4.

Figure 4 - Kaplan-Meier Estimate of Overall Survival (OS) in CP2L, CP3L, AP, and BP

Based on the limited clinical information from the Phase 1/2 study, some evidence of clinical activitywas observed in patients with BCR-ABL mutations (see Table 9).

Table 9 - 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 Incidence at baseline MCyR attained or maintainedbaseline n (%)a Resp/Evalb (%)

N=112

Mutation assessed 98 (100.0) 36/92 (39.1)

No mutation 59 (60.2) 23/55 (41.8)

At least 1 mutation 39 (39.8) 13/37 (35.1)

Dasatinib resistant mutations 10 (10.2) 1/9 (11.1)

E255K/V 2 (2.0) 0/2

F317L 8 (8.2) 1/7 (14.3)

Nilotinib resistant mutationsc13 (13.3) 8/13 (61.5)

Y253H 6 (6.1) 5/6 (83.3)

E255K/V 2 (2.0) 0/2

F359C/I/V 7 (7.1) 5/7 (71.4)

Snapshot date: Phase 1/2 Study 02Oct2015, Extension Study 02Sep2020

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 myelogenousleukaemia; 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.

Phase 4 Clinical study in Ph+ CML previously treated with 1 or more TKI(s)

A single-arm, Phase 4 open-label, non-randomised, multi-centre study was conducted to evaluate theefficacy and safety of bosutinib 500 mg once daily in patients with TKI-resistant or TKI-intolerant

CML with separate cohorts for CP, AP or BP disease previously treated with 1 or more prior TKIs.

There were 163 patients treated with bosutinib in this trial including 46 patients with CP Ph+ CMLand treated previously with 1 prior TKI (imatinib or dasatinib or nilotinib), 61 CP Ph+ CML patientspreviously treated with 2 prior TKIs (imatinib and/or dasatinib and/or nilotinib), 49 CP Ph+ CMLpatients treated with 3 prior TKIs (imatinib and dasatinib and nilotinib), 4 patients with AP Ph+ CMLpreviously treated with at least 1 TKI (2 patients treated with 2 prior TKIs and 2 patients treated with3 prior TKIs) and 3 patients with Ph- CML treated with at least 1 prior TKI.

The primary efficacy endpoint was cumulative confirmed MCyR by 1 year (Week 52) in patients with

CP Ph+ CML previously treated with 1 or 2 prior TKIs and patients with CP Ph+ CML previouslytreated with 3 prior TKIs. For patients with AP and BP Ph+ CML with any prior TKI therapy, theprimary efficacy endpoint was cumulative confirmed overall haematological response (OHR) by1 year (Week 52). Other efficacy endpoints in Ph+ CP CML patients include cumulative cytogeneticand molecular response, the duration of cytogenetic and molecular responses, response in baselinemutations, transformation to AP/BP, PFS, and OS. Additional endpoints in the Ph+ AP/BP cohortinclude cumulative cytogenetic and molecular responses rates, PFS and OS.

CP CML patients

The primary endpoint of cumulative confirmed MCyR (95% CI) rate by 1 year (52 weeks) was76.5% (66.9, 84.5) in patients treated with 1 or 2 prior TKIs and 62.2% (46.5, 76.2) in patients treatedwith 3 prior TKIs.

Additional efficacy results at study closure, after a minimum follow-up of 3 years, in Ph+ CP CMLpatients treated with 1 (median treatment duration 47.5 months (range: 0.9 to 50.1 months) and60.9% still on-treatment), 2 (median treatment duration 41.9 months (range: 0.4 to 48.9 months) and45.9% still on-treatment) and 3 (median treatment duration 20.0 months (range: 0.2 to 48.9 months)and 38.8% still on-treatment) prior TKIs are presented in Table 10.

Table 10 - Efficacy results in previously treated patients with chronic phase Ph+ CML

Ph+ CP CML Ph+ CP CML Ph+ CP CML Total Ph+treated with treated with treated with CP CML cohort1 prior TKI 2 prior TKIs 3 prior TKIs

Cumulative confirmed N=43 N=55 N=45 N=143

MCyRa by 1 year, % 83.7 (69.3,93.2) 70.9 (57.1,82.4) 62.2 (46.5,76.2) 72.0 (63.9,79.2)(95% CI)

Cumulative N=43 N=55 N=45 N=143cytogenetic responsea,b

MCyR, % (95% CI) 88.4 (74.9,96.1) 85.5 (73.3,93.5) 77.8 (62.9,88.8) 83.9 (76.9,89.5)

CCyR, % (95% CI) 86.0 (72.1,94.7) 83.6 (71.2,92.2) 73.3 (58.1,85.4) 81.1 (73.7,87.2)

Cumulative molecular N=46 N=55 N=48 N=149responsea,b

MMR, % (95% CI) 82.6 (68.6,92.2) 76.4 (63.0,86.8) 56.3 (41.2,70.5) 71.8 (63.9,78.9)

MR4, % (95% CI) 73.9 (58.9,85.7) 63.6 (49.6,76.2) 41.7 (27.6,56.8) 59.7 (51.4,67.7)

MR4.5, % (95% CI) 58.7 (43.2,73.0) 50.9 (37.1,64.6) 35.4 (22.2,50.5) 48.3 (40.1,56.6)

Time to cytogeneticresponse forresponders onlyb,median (range),months

MCyR 3.0 (1.0,11.8) 2.9 (0.3,6.4) 3.0 (1.8,8.8) 3.0 (0.3,11.8)

CCyR 3.0 (1.0,17.6) 2.9 (0.3,6.4) 3.0 (1.8,8.8) 3.0 (0.3,17.6)

Duration ofcytogenetic responseb

MCyR, K-M at year 3, 96.6 (77.9,99.5) 94.4 (79.2,98.6) 96.9 (79.8,99.6) 95.6 (88.7,98.4)% (95% CI)

CCyR, K-M at year 3, 96.4 (77.2,99.5) 94.4 (79.2,98.6) 100.0 96.5 (89.5,98.9)% (95% CI) (100.0,100.0)

Time to molecularresponse forresponders only,median (range),months

MMR 3.0 (2.8,23.3) 3.0 (1.0,35.9) 3.1 (1.8,9.3) 3.0 (1.0,35.9)

MR4 6.0 (2.8,47.4) 3.1 (1.0,36.1) 3.2 (1.8,47.9) 5.5 (1.0,47.9)

MR4.5 9.2 (2.8,47.6) 6.0 (2.8,36.2) 5.8 (1.8,18.0) 6.0 (1.8,47.6)

Duration of molecularresponseb

MMR, K-M at year 3, 90.7 (73.9,96.9) 81.5 (63.2,91.3) 90.2 (65.9,97.5) 87.2 (78.0,92.7)% (95% CI)

MR4, K-M at year 3, 89.5 (70.9,96.5) 68.7 (48.0,82.5) 85.2 (51.9,96.2) 80.7 (69.4,88.1)% (95% CI)

Snapshot date: 23Nov2020.

Abbreviations: Ph+=Philadelphia chromosome-positive; CP=chronic phase; CML=chronic myelogenous leukaemia;

K-M=Kaplan-Meier; N=number of patients; CI=confidence interval; MCyR=major cytogenetic response;

CCyR=complete cytogenetic response; MMR=major molecular response; MR4=≥ 4 log-reduction in BCR-ABLtranscripts from standardised baseline; MR4.5=≥ 4.5 log-reduction in BCR-ABL transcripts from standardisedbaseline.

Cumulative Confirmed MCyR criteria: Response is confirmed with 2 consecutive evaluations at least 28 days apart.

To be considered a responder, the patient must have maintained a baseline response for at least 52 weeks orimproved from baseline. Patients with partial cytogenetic response (PCyR) at baseline must attain CCyRon-treatment to be counted as a cytogenetic responder. Patients with at least MMR and a deeper molecular responsethan baseline are counted as confirmed CCyR.

Cumulative Cytogenetic Response criteria: Major Cytogenetic Response included Complete [0% Ph+ metaphasesfrom 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 to assess CCyR if≥ 20 metaphases were not available. Patients without a valid bone marrow or FISH assessment and with at least

MMR are counted as CCyR.

Cumulative Molecular Response criteria: MMR, MR4, and MR4.5 were defined as ≤ 0.1%, ≤ 0.01%, and ≤ 0.0032%

BCR-ABL/ABL ratio on international scale, respectively (corresponding to ≥ 3, ≥ 4, and ≥ 4.5 log-reduction fromstandardised baseline) with a minimum of 10,000, 10,000, and 32,000 ABL transcripts assessed by the centrallaboratory, respectively.a Includes patients (N) with a valid baseline assessment. Minimum follow-up time (time from last patient first dose todata snapshot date) of 36 months.b Includes patients (N) who attained or maintained response.

The cumulative incidence of MMR, MR4 and MR4.5 adjusted for the competing risk of treatmentdiscontinuation without the event are shown in Figure 5.

Figure 5 - Cumulative Incidence of Molecular Response (CP Evaluable Population)

Achieved molecular responses by line of treatment are shown in Table 11.

Table 11 - Achieved molecular responses

Ph+ CP CML Ph+ CP CML Ph+ CP CML Total Ph+treated with treated with treated with CP CML1 prior TKI 2 prior TKIs 3 prior TKIs cohort

Patients without MMR at N=25 N=28 N=26 N=79baselinea

MMR, % (95% CI) 76.0 (54.9,90.6) 64.3 (44.1,81.4) 38.5 (20.2,59.4) 59.5 (47.9,70.4)

Patients without MR4 at N=37 N=38 N=37 N=112baselinea

MR4, % (95% CI) 70.3 (53.0,84.1) 55.3 (38.3,71.4) 32.4 (18.0,49.8) 52.7 (43.0,62.2)

Patients without MR4.5 at N=42 N=46 N=43 N=131baselinea

MR4.5, % (95% CI) 54.8 (38.7,70.2) 43.5 (28.9,58.9) 30.2 (17.2,46.1) 42.7 (34.1,51.7)

Patients with MMR at N=21 N=27 N=22 N=70baselinea

Deeper MR, % (95% CI) 85.7 (63.7,97.0) 66.7 (46.0,83.5) 63.6 (40.7,82.8) 71.4 (59.4,81.6)

Snapshot date: 23Nov2020.

Abbreviations: Ph+=Philadelphia chromosome-positive; CP=chronic phase; CML=chronic myelogenous leukaemia;

N=number of patients; CI=confidence interval; MMR=major molecular response; MR=molecular response;

MR4=≥ 4 log-reduction in BCR-ABL transcripts from standardised baseline; MR4.5=≥ 4.5 log-reduction in

BCR-ABL transcripts from standardised baseline.a Includes patients (N) with a valid baseline assessment. To be considered a responder, patients must have achievedan improved response from baseline. Molecular Response criteria: MMR, MR4, and MR4.5 were defined as ≤ 0.1%,≤ 0.01%, and ≤ 0.0032% BCR-ABL/ABL ratio on international scale, respectively (corresponding to ≥ 3, ≥ 4, and≥ 4.5 log-reduction from standardised baseline) with a minimum of 10,000, 10,000, and 32,000 ABL transcriptsassessed by the central laboratory, respectively.

In CP patients, there were no on-treatment progressions to AP or BP CML.

AP CML patients

In patients with Ph+ AP CML, the median duration of treatment was 22.1 months (range: 1.6 to50.1 months), the cumulative confirmed OHR by 1 year (52 weeks) was 75.0% (95% CI: 19.4, 99.4),as was the cumulative CCyR rate, all 3 patients maintained their CCyR on treatment.

Response by BCR-ABL Mutations at baseline

Ten patients in the CP cohort had mutations at baseline (A365V, E453K, E255K, E255V,

Q252H, L298V [n=1 each], Y253F and G250E [n=2 each]). One patient in the CP cohort hada F359I mutation identified on study day 8. One patient in the AP cohort had 2 mutations(F311L and L387F) at baseline. In the CP cohort, among patients with mutations, molecularresponses were observed in 4/11 (36.4%) patients, 1 patient with a E255V mutation achieved

MMR and 3 patients with F359I, Y253F and A365V respectively achieved MR4.5. The patientwith mutations in the AP cohort did not achieve any response.

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 onpaediatric use).

Following administration of a single dose of bosutinib (500 mg) with food in healthy subjects, theabsolute bioavailability was 34%. Absorption was relatively slow, with a median time-to-peakconcentration (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 mean, CV%) was2,700 (16) ng*h/mL after daily administration of bosutinib at 400 mg with food. After 500 mgbosutinib daily with food, Cmax was 200 (6) ng/mL and AUCss was 3,640 (12) ng*h/mL. The solubilityof bosutinib is pH-dependent and absorption is reduced when gastric pH is increased (see section 4.5).

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.

In vitro and in vivo studies indicated that bosutinib (parent compound) undergoes predominantlyhepatic 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 theoxydechlorinated metabolite was 19% of the parent compound. All 3 metabolites exhibited activitythat was  5% that of bosutinib in a Src-transformed fibroblast anchorage-independent proliferationassay. 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 isozymeinvolved in the metabolism of bosutinib is CYP3A4 and drug interaction studies have shown thatketoconazole 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, or3A5.

In healthy subjects given a single intravenous dose of 120 mg bosutinib, the mean (%CV) terminalelimination half-life was 35.5 (24) hours, and the mean (%CV) clearance was 61.9 (26) L/h. In amass-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 inurine was low with approximately 1% of the dose in both healthy subjects and those with advancedmalignant solid tumours.

A 200 mg dose of bosutinib administered with food was evaluated in a cohort of 18 hepaticallyimpaired subjects (Child-Pugh classes A, B, and C) and 9 matched healthy subjects. Cmax of bosutinibin plasma increased 2.4-fold, 2-fold, and 1.5-fold, respectively, in Child-Pugh classes A, B, and C; andbosutinib AUC in plasma increased 2.3-fold, 2-fold, and 1.9-fold, respectively. The t½ of bosutinibincreased in hepatic impaired patients as compared to the healthy subjects.

In a renal impairment study, a single dose of 200 mg bosutinib was administered with food to26 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), or50 < CLCr  80 mL/min (mild renal impairment). Subjects with moderate and severe renal impairmenthad 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. Bosutinib exposurewas not increased in subjects with mild renal impairment. The elimination half-life of bosutinib insubjects 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 linearpharmacokinetics of bosutinib in the dose range of 200 to 600 mg.

No formal studies have been performed to assess the effects of these demographic factors. Populationpharmacokinetic analyses in patients with Ph+ leukaemia or malignant solid tumour and in healthysubjects indicate that there are no clinically relevant effects of age, gender or body weight. Populationpharmacokinetic analyses revealed that Asians had a 18% lower clearance corresponding to anapproximately 25% increase in bosutinib exposure (AUC).

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

Bosutinib has been evaluated in safety pharmacology, repeated dose toxicity, genotoxicity,reproductive toxicity, and phototoxicity 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 effectlevel (NOEL) for pupil size was not established, but the NOEL for impaired gait occurred at exposuresapproximately 11-times the human exposure resulting from the clinical dose of 400 mg and 8-timesthe human exposure resulting from the clinical dose of 500 mg (based on unbound Cmax in therespective species). Bosutinib activity in vitro in hERG assays suggested a potential for prolongationof cardiac ventricular repolarisation (QTc). In an oral study of bosutinib in dogs, bosutinib did notproduce 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 theclinical 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 anintravenous study in dogs, transient increases in heart rate and decreases in blood pressure andminimal prolongation of the QTc (< 10 msec) were observed at exposures ranging from approximately6-times to 20-times the human exposure resulting from the clinical dose of 400 mg and 4-times to15-times the human exposure resulting from the clinical dose of 500 mg (based on unbound Cmax in therespective species). The relationship between the observed effects and medicinal product treatmentwere inconclusive.

Repeated-dose toxicity

Repeated-dose toxicity studies in rats of up to 6 months in duration and in dogs up to 9 months induration 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 foodconsumption and body weight loss which occasionally led to death or elective euthanasia.

Histopathologically, luminal dilation, goblet cell hyperplasia, haemorrhage, erosion, and oedema ofthe intestinal tract, and sinus erythrocytosis and haemorrhage in the mesenteric lymph nodes, wereobserved. The liver was also identified as a target organ in rats. Toxicities were characterised by anincrease in liver weights in correlation with hepatocellular hypertrophy which occurred in the absenceof elevated liver enzymes or microscopic signs of hepatocellular cytotoxicity, and is of unknownrelevance to humans. The exposure comparison across species indicates that exposures that did notelicit adverse events in the 6- and 9-month toxicity studies in rats and dogs, respectively, were similarto the human exposure resulting from a clinical dose of 400 mg or 500 mg (based on unbound AUC inthe respective species).

Genotoxicity studies in bacterial in vitro systems and in mammalian in vitro and in vivo systems withand 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 increasedembryonic resorptions, and decreases in implantations and viable embryos. The dose at which noadverse 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 resultingfrom the clinical dose of 400 mg, and 0.5-times and 0.2-times, respectively, the human exposureresulting from the clinical dose of 500 mg (based on unbound AUC in the respective species). Aneffect on male fertility cannot be excluded (see section 4.6).

Foetal exposure to bosutinib-derived radioactivity during pregnancy was demonstrated in a placentaltransfer study in gravid Sprague-Dawley rats. In a rat pre- and postnatal development study, therewere reduced number of pups born at ≥ 30 mg/kg/day, and increased incidence of total litter loss anddecreased growth of offspring after birth occurred at 70 mg/kg/day. The dose at which no adversedevelopment effects were observed (10 mg/kg/day) resulted in exposures equal to 1.3-times and1.0-times human exposure resulting from the clinical dose of 400 mg and 500 mg, respectively (basedon unbound AUC in the respective species). In a rabbit developmental toxicity study at the maternallytoxic dose, there were foetal anomalies observed (fused sternebrae, and 2 foetuses had various visceralobservations), and a slight decrease in foetal body weight. The exposure at the highest dose tested inrabbits (10 mg/kg/day) that did not result in adverse foetal effects was 0.9-times and 0.7-times thehuman 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 allowedmeasurable concentrations of radioactivity to appear in the plasma of nursing pups.

Bosutinib was not carcinogenic in the 2-year rat and 6-month rasH2 mouse carcinogenicity studies.

Bosutinib has demonstrated the ability to absorb light in the UV-B and UV-A range and is distributedinto the skin and uveal tract of pigmented rats. However, bosutinib did not demonstrate a potential forphototoxicity 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 theclinical dose of 400 or 500 mg, respectively (based on unbound Cmax in the respective species).

Microcrystalline cellulose (E460)

Croscarmellose sodium (E468)

Poloxamer 188

Povidone (E1201)

Magnesium stearate (E470b)

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)

Not applicable.

4 years.

This medicinal product does not require any special storage conditions.

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

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

Pfizer Europe MA EEIG

Boulevard de la Plaine 171050 Bruxelles

Belgium

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

Date of first authorisation: 27 March 2013

Date of latest renewal: 31 March 2022

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

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