4.1. Therapeutic indications

Bosutinib is indicated for the treatment of:

• Adult and paediatric patients aged 6 years and older with newly‑diagnosed (ND) chronic phase (CP) Philadelphia chromosome‑positive chronic myelogenous leukaemia (Ph+ CML).

• Adult and paediatric patients aged 6 years and older with CP 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.

• Adult patients with 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.

4.2. Posology and method of administration

Posology

Adult patients with newly-diagnosed CP Ph+ CML

The recommended dose is 400 mg bosutinib once daily.

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

The recommended dose is 500 mg bosutinib once daily.

In clinical studies for both indications, treatment with bosutinib continued until disease progression or intolerance to therapy.

Paediatric patients with newly-diagnosed CP Ph+ CML or with CP Ph+ CML with resistance or intolerance to prior therapy

The recommended dosage of bosutinib for newly-diagnosed paediatric patients is 300 mg/m2 body surface area (BSA) orally once daily and the recommended dosage for paediatric patients resistant or intolerant (R/I) to prior therapies is 400 mg/m2 BSA orally once daily; dose recommendations are provided in Table 1. As appropriate, the desired dose can be attained by combining different strengths of bosutinib film-coated tablets and/or hard capsules.

Table 1 – Dosing of bosutinib for paediatric patients with newly-diagnosed CP Ph+ CML or with CP Ph+ CML with resistance or intolerance to prior therapy

BSA

ND Recommended Dose

R/I Recommended Dose

0.55–<0.63 m2

200 mg

250 mg

0.63–<0.75 m2

200 mg

300 mg

0.75–<0.9 m2

250 mg

350 mg

0.9–<1.1 m2

300 mg

400 mg

≥ 1.1 m2

400 mg*

500 mg*

* maximum starting dose (corresponding to maximum starting dose in adult indication)

Abbreviations: AP=accelerated phase; BP=blast phase; BSA=body surface area; CML=chronic myeloid leukaemia; CP=chronic phase; ND=newly‑diagnosed; Ph+=Philadelphia chromosome-positive; R/I=resistant or intolerant.

Dose adjustments

In adult patients with CML who are resistant or intolerant to prior therapy, doses can be escalated to 600 mg in those with unsatisfactory response or with signs of progression and in the absence of any Grade 3 or 4 or persistent Grade 2 adverse events.

In adult patients with newly-diagnosed CP CML, doses can be escalated by 100 mg increments to a maximum of 600 mg once daily if patients fail to demonstrate breakpoint cluster region Abelson (BCR-ABL) transcripts ≤ 10% at months 3 and do not have a grade 3 or 4 adverse reaction at the time of escalation and all Grade 2 non-haematological toxicities are resolved to at least Grade 1.

In paediatric patients with BSA < 1.1 m2 and an insufficient response after 3 months consider increasing dose by 50 mg increments up to maximum of 100 mg above BSA-adjusted recommended dose. In paediatric patients with BSA ≥1.1 m2 and an insufficient response after 3 months consider increasing dose similarly to adult recommendations in 100 mg increments. If there is inadequate clinical response and further dose escalation cannot be performed in paediatric patients, treatment will be stopped.

The maximum dose in paediatric patients is 600 mg once daily in previously treated CML and 500 mg once daily in newly-diagnosed CML.

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

Dose adjustments for 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 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).

In paediatric patients, dose adjustments for non-haematologic toxicities can be conducted similarly to adults, however the dose reduction increments may differ. For paediatric patients with BSA < 1.1 m2, consider dose reduction by 50 mg initially followed by additional 50 mg reductions if the adverse drug reaction (ADR) persists, in line with recommendations from Table 2. For paediatric patients with BSA ≥ 1.1 m2 reduce dose similarly to adults.

Haematological adverse reactions

Dose reductions are recommended for severe or persistent neutropenia and thrombocytopenia as described in Table 2:

Table 2 – Dose adjustments for neutropenia and thrombocytopenia in adult and paediatric patients

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 in adult patients and paediatric patients with BSA ≥ 1.1 m2 or by 50 mg in paediatric patients with BSA < 1.1 m2 and resume treatment.

If cytopoenia recurs, reduce dose by an additional 100 mg in adult patients and paediatric patients with BSA ≥ 1.1 m2 upon recovery, or by an additional 50 mg in paediatric patients with BSA < 1.1 m2 and resume treatment.

Doses less than 300 mg/day have been used in adult patients and paediatric patients with BSA ≥ 1.1 m2; however, efficacy has not been established. Doses less than 300 mg/m2 have been used in paediatric patients however efficacy has not been established.

a ANC = absolute neutrophil count; BSA=body surface area

Missed dose

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.

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 adult 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 adult 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 adult 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.

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

In adult 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 adult 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 paediatric patients below the age of 1 year with newly diagnosed, or resistant or intolerant Ph+ CML in CP have not been established. No data are available. The information from paediatric patients below the age of 6 years are too limited so that no dose recommendations can be made (see section 5.1).

Method of administration

Bosulif should be taken orally once daily with food (see section 5.2).

The film-coated tablets should be swallowed whole. Do not cut, crush, break or chew the film-coated tablets.

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 in adult and paediatric patients 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).

Diarrhoea and vomiting

Treatment with bosutinib in adult and paediatric patients 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 in adult and paediatric patients 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 in adult patients may be associated with fluid retention including pericardial effusion, pleural effusion, pulmonary oedema and/or peripheral oedema. Treatment with bosutinib in paediatric patients may be associated with low-grade pericardial effusion and 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.

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 with newly-diagnosed CML and were more frequent in patients with advanced age or risk factors, including previous medical history of cardiac failure. Cardiac ischaemic events occurred in both previously treated patients and in patients with newly-diagnosed CML and were more common in patients with coronary 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 cardiac ischaemia and treated as clinically indicated. Cardiovascular toxicity can also be managed by dose interruption, 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 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 adult and paediatric patients. A decline over time in estimated glomerular filtration rate (eGFR) has been observed in patients treated with bosutinib in clinical studies (see section 4.8).

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(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.

Asian race

According to population pharmacokinetic analyses, Asians had a lower clearance resulting in increased exposure. Therefore, these patients should be closely monitored for adverse reactions especially 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 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).

Photosensitivity

Exposure to direct sunlight or ultraviolet (UV) radiation should be avoided or minimised due to the risk of photosensitivity associated with bosutinib treatment. Patients should be instructed to use measures 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 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.

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).

Sodium

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

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.

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. 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 1,372 leukaemia adult patients received at least 1 dose of single‑agent bosutinib. The median duration of therapy was 26.30 months (range: 0.03 to 170.49 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). The safety analyses included data from a completed extension study.

At least 1 adverse reaction of any toxicity grade was reported for 1,349 (98.3%) patients. The most frequent 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%).

Tabulated list of adverse reactions

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.

Table 4 – Adverse reactions for bosutinib

Infections and infestations

Very common

Nasopharyngitis

Respiratory tract infectiona

Common

Influenzab

Pneumoniac

Bronchitis

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

Uncommon

Tumour lysis syndrome**

Blood and lymphatic system disorders

Very common

Thrombocytopeniad

Anaemiae

Neutropeniaf

Common

Leukopeniag

Uncommon

Febrile neutropenia

Granulocytopenia

Immune system disorders

Common

Drug hypersensitivity

Uncommon

Anaphylactic shock

Metabolism and nutrition disorders

Very common

Decreased appetite

Common

Hypophosphataemiah

Dehydration

Hyperkalaemiai

Nervous system disorders

Very common

Headache

Dizziness

Common

Dysgeusia

Ear and labyrinth disorders

Common

Tinnitus

Cardiac disorders

Common

Pericardial effusion, Cardiac failurej, Cardiac ischaemick

Uncommon

Pericarditis

Vascular disorders

Common

Hypertensionl

Respiratory, thoracic and mediastinal disorders

Very common

Cough

Dyspnoea

Pleural effusion

Common

Pulmonary hypertensionm

Uncommon

Respiratory failure

Acute pulmonary oedeman

Not known

Interstitial lung disease

Gastrointestinal disorders

Very common

Diarrhoea

Nausea

Abdominal paino

Vomiting

Common

Gastritis

Gastrointestinal haemorrhagep

Pancreatitis acuteq

Hepatobiliary disorders

Common

Hepatic function abnormalr

Hepatotoxicitys

Uncommon

Liver injuryt

Skin and subcutaneous tissue disorders

Very common

Rashu

Common

Pruritus

Acne

Urticaria

Photosensitivity reactionv

Uncommon

Drug eruption

Exfoliative rash

Erythema multiforme

Cutaneous vasculitis**

Not known

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

Fatiguew

Pyrexia

Oedemax

Common

Chest painy

Pain

Investigations

Very common

Alanine aminotransferase increasedz

Aspartate aminotransferase increased

Lipase increasedaa

Blood creatinine increased

Common

Amylase increasedbb

Blood creatine phosphokinase increased

Blood bilirubin increasedcc

Gamma‑glutamyltransferase increased

Electrocardiogram QT prolongeddd

a Respiratory tract infection includes Lower respiratory tract infection, Respiratory tract infection, Respiratory tract infection viral, Upper respiratory tract infection, Viral upper respiratory tract infection

b Influenza includes H1N1 influenza, Influenza

c Pneumonia includes Atypical pneumonia, Pneumonia, Pneumonia bacterial, Pneumonia fungal, Pneumonia necrotising, Pneumonia streptococcal

d Thrombocytopenia includes Platelet count decreased, Thrombocytopenia

e Anaemia includes Anaemia, Haemoglobin decreased, Red blood cell count decreased

f Neutropenia includes Neutropenia, Neutrophil count decreased

g Leukopenia includes Leukopenia, White blood cell count decreased

h Hypophosphataemia includes Blood phosphorus decreased, Hypophosphataemia

i Hyperkalaemia includes Blood potassium increased, Hyperkalaemia

j Cardiac failure includes Cardiac failure, Cardiac failure acute, Cardiac failure chronic, Cardiac failure congestive, Cardiogenic shock, Cardiorenal syndrome, Ejection fraction decreased, Left ventricular failure

k Cardiac ischaemic includes Acute coronary syndrome, Acute myocardial infarction, Angina pectoris, Angina unstable, Arteriosclerosis coronary artery, Coronary artery disease, Coronary artery occlusion, Coronary artery stenosis, Myocardial infarction, Myocardial ischaemia, Troponin increased

l Hypertension includes the Blood pressure increased, Blood pressure systolic increased, Essential hypertension, Hypertension, Hypertensive crisis

m Pulmonary hypertension includes Pulmonary arterial hypertension, Pulmonary arterial pressure increased, Pulmonary hypertension

n Acute pulmonary oedema includes Acute pulmonary oedema, Pulmonary oedema

o Abdominal pain includes Abdominal discomfort, Abdominal pain, Abdominal pain lower, Abdominal pain upper, Abdominal tenderness, Gastrointestinal pain

p Gastrointestinal haemorrhage includes Anal haemorrhage, Gastric haemorrhage, Gastrointestinal haemorrhage, Intestinal haemorrhage, Lower gastrointestinal haemorrhage, Rectal haemorrhage, Upper gastrointestinal haemorrhage

q Pancreatitis acute includes Pancreatitis, Pancreatitis acute

r Hepatic function abnormal includes Hepatic enzyme increased, Hepatic function abnormal, Liver function test abnormal, Liver function test increased, Transaminases increased

s Hepatotoxicity includes Hepatitis, Hepatitis toxic, Hepatotoxicity, Liver disorder

t Liver injury includes Drug-induced liver injury, Hepatocellular injury, Liver injury

u Rash includes Rash, Rash macular, Rash maculo-papular, Rash papular, Rash pruritic

v Photosensitivity reaction includes Photosensitivity reaction, Polymorphic light eruption

w Fatigue includes Asthenia, Fatigue, Malaise

x Oedema includes Eyelid oedema, Face oedema, Generalised oedema, Localised oedema, Oedema, Oedema peripheral, Periorbital oedema, Periorbital swelling, Peripheral swelling, Swelling, Swelling of eyelid

y Chest pain includes Chest discomfort, Chest pain

z Alanine aminotransferase increased includes Alanine aminotransferase abnormal, Alanine aminotransferase increased

aa Lipase increased includes Hyperlipasaemia, Lipase increased

bb Amylase increased includes Amylase increased, Hyperamylasaemia

cc Blood bilirubin increased includes Bilirubin conjugated increased, Blood bilirubin increased, Blood bilirubin unconjugated increased, Hyperbilirubinaemia

dd Electrocardiogram QT prolonged includes Electrocardiogram QT prolonged, Long QT syndrome

**Adverse reaction identified post marketing in adults.

Paediatric populations

A total of 55 paediatric patients ≥ 1 year of age received at least 1 dose of bosutinib in the Phase I/II, multicentre, international, single-arm, open-label BCHILD study. The median duration of treatment was 13.5 months (range: 0.2 to 60.9 months). These patients were either newly-diagnosed CP Ph+ CML or resistant or intolerant Ph+ CML-CP and CML-AP.

At least 1 adverse reaction of any toxicity grade was reported for 54 (98.2%) paediatric patients. The most frequent adverse reactions reported were diarrhoea (82%), abdominal pain (65%), vomiting (56%), nausea (51%), rash (36%), fatigue (35%), thrombocytopenia (35%), headache (33%), pyrexia (33%), ALT increased (29%), and decreased appetite (24%).

The most frequent Grade 3 or Grade 4 adverse reactions reported were thrombocytopenia (18%), ALT increased (15%) and diarrhoea (13%).

Blood and lymphatic system disorders

Blood and lymphatic events in 55 paediatric patients in the BCHILD study include thrombocytopenia in 19 (34.5%) patients, anaemia in 10 patients (18.2%), and neutropenia in 7 patients (12.7%). One patient discontinued treatment due to Grade 4 neutropenia. Among patients with blood and lymphatic events, 37.5% were managed with treatment interruption and 16.7% required dose reduction. Among patients with dose interruptions, none had a positive rechallenge when bosutinib was restarted. The median time to first event was 13 days (range: 1 to 757 days) and the median cumulative duration of grade 3/4 events was 16.0 (range: 4 to 47) days.

Hepatobiliary disorders

Of the 55 participants, the incidence based on laboratory data of ALT and AST increased was 67.3% and 63.6%, respectively and 43 (78.2% participants experienced an increase in either ALT or AST). Most cases of transaminase elevation occurred early in treatment; of participants who experienced transaminase elevations of any grade, 83.7% experienced their first event within 3 months. The median time to onset of ALT and AST increased was 22.0 days (range: 9 to 847 days) and 18.5 days (range: 9 to 169 days), respectively. The median duration of Grade 3/4 events was 18.0 days (range: 2 to 132 days) and 12 days (range: 5 to 19 days) for ALT and AST increased, respectively.

Gastrointestinal disorders

Gastrointestinal disorders of diarrhoea, vomiting and nausea occurred in 81.8%, 56.4%, and 50.9% of the 55 paediatric patients treated with bosutinib in the BCHILD study, respectively. Three (5.5%) patients discontinued bosutinib treatment due to diarrhoea (n=3), abdominal pain (n=2), nausea (n=1) and/or vomiting (n=1). Among paediatric patients with gastrointestinal disorders, 9 (19%) were managed with treatment interruption and 4 (8.3%) required dose reduction. Among the 9 patients who required a treatment interruption, 8 (88.9%) were rechallenged. Of these, 55.6% were successfully rechallenged. The median time to onset for diarrhoea was 2 days and the median duration of any grade diarrhoea was 2 days.

Renal disorders

In the paediatric study, 45 (82%) of the total 55 patients had normal eGFR (≥ 90 mL/min/1.73 m2 estimated by Bedside Schwartz Equation) at baseline. Among these 45 patients, 19 (34.5%) experienced a decline in eGFR to Grade 1 (60 < 90 mL/min/1.73 m2) and 1 (1.8%) patient to Grade 2 (30 < 60 mL/min/1.73 m2) at 13.47 months. No participant had a post‑baseline eGFR < 45 mL/min/1.73 m2 regardless of baseline values.

Description of selected adverse reactions

Blood and lymphatic system disorders

Of the 372 (27.1%) adult patients with reports of adverse reactions of anaemia, 6 patients discontinued bosutinib due to anaemia. Maximum toxicity of Grade 1 occurred in 95 (25.5%) patients, Grade 2 in 135 (36.3%) patients, Grade 3 in 113 patients (30.4%), and Grade 4 in 29 (7.8%) patients. Among these patients, the median time to first event was 29 days (range: 1 to 3 999 days) and the median duration per event was 22 days (range: 1 to 3 682 days).

Of the 209 (15.2%) adult patients with reports of adverse reactions of neutropenia, 19 patients discontinued bosutinib due to neutropenia. Maximum toxicity of Grade 1 occurred in 19 patients (9.1%), Grade 2 in 45 (21.5%) patients, Grade 3 in 95 (45.5%) patients, and Grade 4 in 50 (23.9%) patients. Among these patients, the median time to first event was 56 days (range: 1 to 1 769 days), and the median duration per event was 15 days (range: 1 to 913 days).

Of the 472 (34.4%) adult patients with reports of adverse reactions of thrombocytopenia, 42 patients discontinued bosutinib due to thrombocytopenia. Maximum toxicity of Grade 1 occurred in 114 (24.2%) patients, Grade 2 in 88 (18.6%) patients, Grade 3 in 172 (36.4%) patients, and Grade 4 in 98 (20.8%) patients. Among these patients, 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 3 921 days).

Hepatobiliary disorders

Among adult 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 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 to 803 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) without alternative causes have occurred in 2/1 711 (0.1%) adult subjects treated with bosutinib.

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 1 103 (80.4%) patients that experienced diarrhoea, 14 patients discontinued bosutinib due to this 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 with diarrhoea, the median time to first event was 2 days (range: 1 to 2 702 days) and the median duration of 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 treatment interruption and of these 208 (95.4%) were rechallenged with bosutinib. Of those who were rechallenged, 201 (96.6%) did not have a subsequent event or did not discontinue bosutinib due to a subsequent event of diarrhoea.

Cardiac disorders

Among 1372 patients, cardiac failure occurred in 50 (3.6%) patients and cardiac ischaemic events in 57 (4.2%) patients.

Seven patients (0.5%) experienced QTcF prolongation (greater than 500 ms). Eleven (0.8%) patients experienced QTcF increase > 60 ms from baseline. 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).

Renal disorders

In patients with newly-diagnosed‑ CP CML treated with 400 mg, the median decline from baseline in eGFR (estimated by MDRD Equation) was 11.1 mL/min/1.73 m2 at 1 year and 14.1 mL/min/1.73 m2 at 5 years for patients on‑treatment. Treatment-naïve CML patients treated with 500 mg showed a median eGFR decline of 9.2 mL/min/1.73 m2 at 1 year, 12.0 mL/min/1.73 m2 at 5 years and 16.6 mL/min/1.73 m2 at 10 years for patients on-treatment. In pre‑treated patients with CP and advanced stage CML treated with 500 mg the median eGFR decline was 7.6 mL/min/1.73 m2 at 1 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 median eGFR 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 for patients on-treatment.

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 Yellow Card Scheme at: www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store.

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.