4.1. Therapeutic indications

Bosutinib is indicated for the treatment of adult patients with:

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

• CP, accelerated phase (AP), and blast phase (BP) Ph+ CML previously treated with one or more tyrosine kinase inhibitor(s) [TKI(s)] and for whom imatinib, nilotinib and dasatinib are not considered appropriate treatment options.

4.2. Posology and method of administration

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

Posology

Newly-diagnosed CP Ph+ CML

The recommended dose is 400 mg bosutinib once daily.

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

The recommended dose is 500 mg bosutinib once daily.

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

Dose adjustments

In the Phase 1/2 clinical study in patients with CML who were resistant or intolerant to prior therapy dose escalations from 500 mg to 600 mg once daily with food were allowed in patients who failed to demonstrate complete haematological response (CHR) by Week 8 or complete cytogenetic response (CCyR) by Week 12 and did not have Grade 3 or higher adverse events possibly-related to the investigational product. In the Phase 3 clinical study in patients with newly-diagnosed CP CML treated with bosutinib 400 mg, dose escalations by 100 mg increments to a maximum of 600 mg once daily with food were permitted if the patient failed to demonstrate breakpoint cluster region-Abelson (BCR-ABL) transcripts ≤ 10% at Month 3, did not have a Grade 3 or 4 adverse reaction at the time of escalation, and all Grade 2 non-haematological toxicities were resolved to at least Grade 1. In the Phase 4 clinical study in patients with Ph+ CML previously treated with 1 or more TKI(s), dose escalations from 500 mg to 600 mg once daily with food were allowed in patients with unsatisfactory response or with signs of disease progression in the absence of any Grade 3 or 4 or persistent Grade 2 adverse events.

In the Phase 1/2 study in patients with CML who were resistant or intolerant to prior therapy who started treatment at ≤ 500 mg, 93 (93/558; 16.7%) patients had dose escalations to 600 mg daily.

In the Phase 3 study in patients with newly-diagnosed CP CML who started bosutinib treatment at 400 mg, a total of 58 patients (21.6%) received dose escalations to 500 mg daily. In addition, 10.4% of patients 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 started bosutinib 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 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).

Haematological adverse reactions

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

Table 1 – Dose adjustments for neutropenia and thrombocytopenia

ANCa < 1.0 × 109/L

and/or

Platelets < 50 × 109/L

Hold bosutinib until ANC ≥ 1.0 × 109/L and platelets ≥ 50 × 109/L.

Resume treatment with bosutinib at the same dose if recovery occurs within 2 weeks. If blood counts remain low for > 2 weeks, upon recovery reduce dose by 100 mg and resume treatment.

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

Doses less than 300 mg/day have been used; however, efficacy has not been established.

aANC = absolute neutrophil count

Special populations

Elderly patients (≥ 65 years)

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

Renal impairment

Patients with serum creatinine > 1.5×ULN were excluded from CML studies. Increasing exposure (area under curve [AUC]) in patients with moderate and severe renal impairment during studies was observed.

Newly-diagnosed CP Ph+ CML

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

In patients with severe renal impairment (CLCr < 30 ml/min, estimated by the Cockcroft-Gault formula), the recommended dose of bosutinib is 200 mg daily with food (see sections 4.4 and 5.2).

Dose escalation to 400 mg once daily with food for patients with moderate renal impairment or to 300 mg once daily for patients with severe renal impairment may be considered if they do not experience severe or persistent moderate adverse reactions and if they do not achieve an adequate haematological, cytogenetic, or molecular response.

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

In patients with moderate renal impairment (CLCr 30 to 50 ml/min, calculated by the Cockcroft-Gault formula), the recommended dose of bosutinib is 400 mg daily (see sections 4.4 and 5.2).

In patients with severe renal impairment (CLCr < 30 ml/min, calculated by the Cockcroft-Gault formula), the recommended dose of bosutinib is 300 mg daily (see sections 4.4 and 5.2).

Dose escalation to 500 mg once daily for patients with moderate renal impairment or to 400 mg once daily in patients with severe renal impairment may be considered in those who did not experience severe or persistent moderate adverse reactions, and if they do not achieve an adequate haematological, cytogenetic, or molecular response.

Cardiac disorders

In clinical studies, patients with uncontrolled or significant cardiac disease (e.g., recent myocardial infarction, congestive heart failure or unstable angina) were excluded. Caution should be exercised in patients with relevant cardiac disorders (see section 4.4).

Recent or ongoing clinically significant gastrointestinal disorder

In clinical studies, patients with recent or ongoing clinically significant gastrointestinal disorder (e.g., severe vomiting and/or diarrhoea) were excluded. Caution should be exercised in patients with recent or ongoing clinically significant gastrointestinal disorder (see section 4.4).

Paediatric population

The safety and efficacy of bosutinib in children and adolescents less than 18 years of age have not been established. No data are available.

Method of administration

Bosutinib should be taken orally once daily with food (see section 5.2). If a dose is missed by more than 12 hours, the patient should not be given an additional dose. The patient should take the usual prescribed dose on the following day.

4.3. Contraindications

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

Hepatic impairment (see sections 5.1 and 5.2).

4.4. Special warnings and precautions for use

Liver function abnormalities

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

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

Patients with transaminase elevations should be managed by withholding bosutinib temporarily (with consideration given to dose reduction after recovery to Grade 1 or baseline), and/or discontinuation of bosutinib. Elevations of transaminases, particularly in the setting of concomitant increases in bilirubin, may be an early indication of drug-induced liver injury and these patients should be managed appropriately (see sections 4.2 and 4.8).

Diarrhoea and vomiting

Treatment with bosutinib is associated with diarrhoea and vomiting; therefore, patients with recent or ongoing clinically significant gastrointestinal disorder should use this medicinal product with caution and only after a careful benefit-risk assessment as respective patients were excluded from the clinical studies. Patients with diarrhoea and vomiting should be managed using standard-of-care treatment, including an antidiarrhoeal or antiemetic medicinal product and/or fluid replacement. In addition, diarrhoea and vomiting can also be managed by withholding bosutinib temporarily, dose reduction, and/or discontinuation of bosutinib (see sections 4.2 and 4.8). The antiemetic agent, domperidone, has the potential to increase QT interval (QTc) prolongation and to induce “torsade de pointes”- arrhythmias; therefore, co-administration with domperidone should be avoided. It should only be used, if other medicinal products are not efficacious. In these situations an individual benefit-risk assessment is mandatory and patients should be monitored for occurrence of QTc prolongation.

Myelosuppression

Treatment with bosutinib is associated with myelosuppression, defined as anaemia, neutropenia, and thrombocytopenia. Complete blood counts should be performed weekly for the first month and then monthly thereafter, or as clinically indicated.

Myelosuppression should/can be managed by withholding bosutinib temporarily, dose reduction, and/or discontinuation of bosutinib (see sections 4.2 and 4.8).

Fluid retention

Treatment with bosutinib may be associated with fluid retention including pericardial effusion, pleural effusion, pulmonary oedema and/or peripheral oedema. Patients should be monitored and managed using standard-of-care treatment. In addition, fluid retention can also be managed by withholding bosutinib temporarily, dose reduction, and/or discontinuation of bosutinib (see sections 4.2 and 4.8).

Serum lipase

Elevation in serum lipase has been observed. Caution is recommended in patients with previous history of pancreatitis. In case lipase elevations are accompanied by abdominal symptoms, bosutinib should be interrupted and appropriate diagnostic measures considered to exclude pancreatitis (see section 4.2).

Infections

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

Proarrhythmic potential

Automated machine-read QTc prolongation without accompanying arrhythmia has been observed. Bosutinib should be administered with caution to patients who have a history of or predisposition for QTc prolongation, who have uncontrolled or significant cardiac disease including recent myocardial infarction, congestive heart failure, unstable angina or clinically significant bradycardia, or who are taking medicinal products that are known to prolong the QTc (e.g., anti-arrhythmic medicinal products and other substances that may prolong QTc [see section 4.5]). The presence of hypokalaemia and hypomagnesaemia may further enhance this effect.

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

Renal impairment

Treatment with bosutinib may result in a clinically significant decline in renal function in CML patients. A decline over time in estimated glomerular filtration rate (eGFR) has been observed in patients treated with bosutinib in clinical studies. In patients with newly-diagnosed CP CML treated with 400 mg, the median decline from baseline in eGFR 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 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.

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

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

Patients with serum creatinine > 1.5 × ULN were excluded from the CML studies. Based on a population pharmacokinetic analysis increasing exposure (AUC) in patients with moderate and severe renal impairment at initiation of treatment during studies was observed (see sections 4.2 and 5.2).

Clinical data are very limited (n = 3) for CML patients with moderate renal impairment receiving an escalated dose of 600 mg bosutinib.

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).

Dietary sodium

This medicinal product contains less than 1 mmol sodium (23 mg) per 100 mg, 400 mg, or 500 mg 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 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). Of these patients, 268 (400 mg starting dose) and 248 (500 mg starting dose) are from the 2 Phase 3 studies in previously untreated CML patients, 60 (400 mg starting dose) are from a Phase 2 study in previously untreated CML patients, 570 and 63 (Phase 2: 500 mg starting dose) are from 2 Phase 1/2 studies in previously treated Ph+ leukaemias, and 163 (500 mg starting dose) are from a Phase 4 study in previously treated CML. The median duration of therapy was 55.1 months (range: 0. 2 to 60.05 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), and 37.80 months (range: 0.16 to 50.0 months), respectively. 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

The following adverse reactions were reported in patients in bosutinib clinical studies (Table 2). These represent an evaluation of the adverse reaction data from 1,372 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 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 2 - Adverse reactions for bosutinib

Infections and infestations

Very common

Respiratory tract infection (including Lower respiratory tract infection, Respiratory tract infection viral, Upper respiratory tract infection, Viral upper respiratory tract infection), Nasopharyngitis

Common

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

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

Uncommon

Tumour lysis syndrome**

Blood and lymphatic system disorders

Very common

Thrombocytopenia (including Platelet count decreased), Neutropenia (including Neutrophil count decreased), Anaemia (including haemoglobin decreased, Red blood cell count decreased)

Common

Leukopenia (including White blood cell count decreased)

Uncommon

Febrile neutropenia, Granulocytopenia

Immune system disorders

Common

Drug hypersensitivity

Uncommon

Anaphylactic shock

Metabolism and nutrition disorders

Very common

Decreased appetite

Common

Dehydration, Hyperkalaemia (including Blood potassium increased), Hypophosphataemia (including Blood phosphorus decreased)

Nervous system disorders

Very common

Dizziness, Headache

Common

Dysgeusia

Ear and labyrinth disorders

Common

Tinnitus

Cardiac disorders

Common

Pericardial effusion

Uncommon

Pericarditis

Vascular disorders

Common

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

Respiratory, thoracic and mediastinal disorders

Very common

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

Gastrointestinal disorders

Very common

Diarrhoea, Vomiting, Nausea, Abdominal pain (including Abdominal discomfort, Abdominal pain lower, Abdominal pain upper, Abdominal tenderness, Gastrointestinal pain)

Common

Gastrointestinal haemorrhage (including Anal haemorrhage, Gastric haemorrhage, Intestinal haemorrhage, Lower gastrointestinal haemorrhage, Rectal haemorrhage, Upper gastrointestinal haemorrhage), Pancreatitis (including Pancreatitis acute), Gastritis

Hepatobiliary disorders

Common

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

Uncommon

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

Skin and subcutaneous tissue disorders

Very common

Rash (including Rash macular, Rash maculo-papular, Rash papular, Rash pruritic), Pruritus

Common

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

Uncommon

Erythema multiforme, Exfoliative rash, Drug eruption, 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

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

Common

Chest pain (including Chest discomfort), Pain

Investigations

Very common

Lipase increased (including Hyperlipasaemia), Alanine aminotransferase increased (including Alanine aminotransferase abnormal), Aspartate aminotransferase increased, Blood creatinine increased

Common

Electrocardiogram QT prolonged (including Long QT syndrome) , Amylase increased (including Hyperamylasaemia), Blood creatine phosphokinase increased, Gamma-glutamyltransferase increased, Blood bilirubin increased (including Hyperbilirubinaemia, Bilirubin conjugated increased, Blood bilirubin unconjugated increased)

** Adverse reaction identified post marketing.

Description of selected adverse reactions

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

Blood and lymphatic system disorders

Of the 372 (27.1%) 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%) 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 themedian duration per event was 15 days (range: 1 to 913 days).

Of the 472 (34.4%) 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 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%) 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

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 significant cardiovascular disease including QTc prolongation, at baseline, were not included in clinical studies (see sections 5.1 and 5.3).

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via Yellow Card Scheme Website: 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.