EXPECTATIONS - pfizer.no HCP guide.pdf · Figure made by Pfizer from data in ref. 6. Figure 2. BFORE: proportion of patients achieving BCR-ABL1 ≤10% at 3 months. Figure made by

Raise Your EXPECTATIONS

BOSULIF® is indicated for the treatment of adult patients with • newly-diagnosed chronic phase (CP) Ph+ CML.

• CP, accelerated phase (AP), and blast phase (BP) Ph+ CML previously treated with one or more tyrosine kinase inhibitors (TKIs) and for whom imatinib, nilotinib and dasatinib

are not considered appropriate treatment options.1

A healthcare professional’s guide to treatment with BOSULIF (bosutinib)qq

19975_Bosulif_HCP_guide_A4_NO.indd 119975_Bosulif_HCP_guide_A4_NO.indd 1 29.05.2020 13.0729.05.2020 13.07

2


3

Introduction 05

Clinical efficacy of BOSULIF® 06–09

Dosing of BOSULIF 10–11

Key interactions 12–13

Safety profile of BOSULIF 14–15

Cardiovascular and pulmonary safety profile of BOSULIF 16–19

BOSULIF management

Diarrhoea 20–23

Nausea and vomiting 24–26

Liver enzyme abnormalities 27–29

Myelosuppression 30–32

Renal impairment 33–34

Rash 35–36

Fatigue 37

Pleural and pericardial effusions 38–39

QTc interval prolongation 40–41

Other special warnings and precautions for use 42

Fertility, pregnancy and lactation 43

References 44–45

Prescribing information 46-47

Notes 45

Contents


4

A healthcare professional’s guide to treatment with BOSULIF® (bosutinib)

The first version of this guide was prepared in collaboration with:

• Professor Jane Apperley, Imperial College, London, United Kingdom

• Professor Tim H. Brümmendorf, University Hospital, RWTH Aachen, Aachen, Germany

• Professor Carlo Gambacorti-Passerini, University of Milano Bicocca, Monza, Italy


5

BOSULIF® is indicated for the treatment of adult patients with:1

• Newly diagnosed chronic phase (CP) Philadelphia chromosome-positive chronic

myeloid leukaemia (Ph+ CML), and

• CP, accelerated phase (AP) or blast phase (BP) Ph+ CML previously treated with

one or more tyrosine kinase inhibitors (TKIs), and for whom imatinib, nilotinib and

dasatinib are not considered appropriate treatment options

Due to the median age of patients at diagnosis, cardiovascular and pulmonary

comorbidities that negatively impact overall survival and are relevant to TKI therapy,

are prevalent in patients with CML.2,3

Life expectancy in CML now approaches that of the general population.4 As a result,

many patients with CML now receive long-term TKI therapy.4 Therefore, there is a

need to offer patients who have CML therapeutic options that have manageable

safety profiles and do not compromise cardiovascular or pulmonary health over time.

BOSULIF is a second-generation, dual SRC/ABL TKI. Unlike imatinib and dasatinib,

BOSULIF does not significantly inhibit c-KIT or PDGFR (platelet-derived growth

factor receptor).5

Randomised controlled clinical trial data with BOSULIF shows (at 12 months):• Molecular responses that are superior to those with imatinib in newly diagnosed

CP Ph+ CML, irrespective of Sokal risk score6

• Fewer patients experiencing disease progression, and fewer deaths on study,

versus imatinib in newly diagnosed CP Ph+ CML6

• A distinct and manageable safety profile, with low impact on cardiovascular health7

BOSULIF is taken once daily, with food.1

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

treatment of patients with CML.1

Adequate and appropriate management of adverse events (AEs) associated with

treatment, and appropriate scheduling of follow-up visits to review reported AEs,

could help to improve patient adherence to therapy, and therefore ensure that

patients gain optimal clinical benefit from their TKI therapy.7,8

This booklet provides an overview of the benefits and safety profile of BOSULIF, and includes guidance for management of AEs.

Introduction


6

Clinical efficacy of BOSULIF®

Newly diagnosed CP Ph+ CML

The BFORE trial (a phase III, open label, multicentre study) was conducted to investigate the efficacy and safety of BOSULIF 400 mg once daily compared with imatinib 400 mg once daily in adult patients with newly diagnosed CP Ph+ CML.1,6

The primary efficacy endpoint was the proportion of patients demonstrating a major molecular response (MMR) at 12 months in the modified intent-to-treat (mITT) population.6

Patients randomised to BOSULIF had superior rates of MMR versus imatinib after both 12 and 18 months of treatment (Table 1 and Figure 1).1,6 Responses to BOSULIF were more rapid than with imatinib: more patients in the BOSULIF versus the imatinib group achieved BCR-ABL1 ≤10% at 3 months (Figure 2).6 Furthermore, BOSULIF induced deeper molecular responses than imatinib, with significantly higher rates of MR4.5 at 12 months than imatinib (Figure 3).6

The clinical use of BOSULIF is supported by evidence from clinical trials in patients with Ph+ CML.


7

Figure 1. BFORE: rate of MMR for BOSULIF vs imatinib in newly diagnosed CP Ph+ CML at 12 and 18 months. Figure is made by Pfizer from data in product resume.1

Table 1. Summary of the main efficacy results of the BFORE trial (mITT population). Figure made by Pfizer from data in ref. 1 and 6.

Parameter

MMR (n, %)

Month 12(95% CI)

Month 18(95% CI)

CCyR by Month 12 (n, %)(95% CI)

BOSULIF® (n=246)

116 (47.2)(40.9, 53.4)

140 (56.9)(50.7, 63.1)

190 (77.2)(72.0, 82.5)

Imatinib (n=241)

89 (36.9)(30.8, 43.0)

115 (47.7)(41.4, 54.0)

160 (66.4)(60.4, 72.4)

1-sided p value

0.0100

0.0208

0.0037

MMR was defined as ≤0.1% BCR-ABL/ABL ratio by international scale (corresponding to ≥3 log reduction from standardised baseline), with a minimum of 3,000 ABL transcripts assessed by the central laboratory. CCyR was defined as the absence of Ph+ metaphases in chromosome banding analysis of ≥20 metaphases derived from bone marrow aspirate, or MMR if an adequate cytogenetic assessment was unavailable.

BCR-ABL1, breakpoint cluster region Abelson murine leukaemia viral oncogene 1; CI, confidence interval; CCyR, complete cytogenetic response; MMR, major molecular response; NA, not available; Ph+, Philadelphia chromosome-positive.

CI, confidence interval; CML, chronic myeloid leukaemia; CP, chronic phase; MMR, major molecular response; OR, odds ratio; Ph+, Philadelphia chromosome-positive.

0

10

20

30

40

50

60

Maj

or m

olec

ular

resp

onse

(MM

R, %

)

Month

P=0.0100OR 1.55 (95% CI 1.07–2.23)

12

47.2

36.9

P=0.0208

18

56.9

47.7

BOSULIF(n=246)

Imatinib(n=241)


8

Figure 3. BFORE: proportion of patients achieving MR4.5 at 12 months.Figure made by Pfizer from data in ref. 6.

Figure 2. BFORE: proportion of patients achieving BCR-ABL1 ≤10% at 3 months. Figure made by Pfizer from data in ref. 6.

BCR-ABL1, breakpoint cluster region – Abelson murine leukaemia viral oncogene 1.

MR4.5: ≤0.0032% BCR-ABL1 transcripts on the international scale with ≥30,990 ABL1 assessed.

0

2

4

6

8

10

Mol

ecul

ar re

spon

se (M

R4.

5 , %

)

Month

P=0.02

12

8.1

3.3

BOSULIF(n=246)

Imatinib(n=241)

≤10%

BC

R-A

BL1

, (%

)

0

10

20

30

40

50

60

70

80

57.3

75.2

Month

3

BOSULIF(n=246)

Imatinib(n=241)


9

Imatinib-resistant or intolerant Ph+ CML in CP, AP and BP

A single-arm, phase I/II open label, multicentre trial was conducted to evaluate the efficacy and safety of BOSULIF® 500 mg once daily in patients with CP, AP, and BP CML previously treated with at least one TKI.1

570 patients were treated with BOSULIF in this trial, including: CP Ph+ CML patients previously treated with only one prior TKI (imatinib); CP Ph+ CML patients previously treated with imatinib and at least one additional TKI (dasatinib and/or nilotinib); and CML patients in AP or BP previously treated with at least one TKI (imatinib).1

At long-term follow-up (a minimum of 48 months, unless otherwise noted):

• CP Ph+ CML resistant/intolerant to imatinib alone (minimum follow-up 60 months) – cumulative major cytogenetic response (MCyR) rate was 59.5%, with 49.6% achieving or maintaining CCyR. Transformation to AP/BP CML was reported in 15 of 284 evaluable patients. Progression-free survival (PFS) and overall survival (OS) rates at year 4/5 were 72.5% and 83.1%, respectively1

• CP Ph+ CML resistant/intolerant to imatinib and dasatinib and/or nilotinib – cumulative MCyR rate was 40.2%, with 32.1% achieving or maintaining a CCyR. Transformation to AP/BP CML was reported in 5 of 119 evaluable patients. PFS and OS rates at year 4/5 were 65.1% and 77.0%, respectively1

• AP CML – cumulative MCyR was 40.3% with 30.6% achieving or maintaining a CCyR. Cumulative overall haematologic response (OHR) rate was 56.9%. Transformation to BP CML was reported in 3 of 79 evaluable patients. PFS and OS rates at year 4/5 were 40.8% and 58.4%, respectively1

• BP CML – cumulative OHR rate was 28.3%. PFS and OS rates at year 4/5 were 8.0% and 20.1%, respectively1


10

Dosing of BOSULIF®

In patients with newly diagnosed CP Ph+ CML, the recommended dose of BOSULIF is 400 mg once daily with food.1

• In the BFORE trial, dose escalation in 100 mg increments to a maximum of 600 mg once daily was permitted in patients who did not achieve BCR-ABL transcripts ≤10% at month 3, provided they did not have a Grade 3 or 4 adverse reaction at the time of escalation, and all Grade 2 non-haematological toxicities had resolved to at least Grade 1.1

In patients with CP, AP or BP Ph+ CML with resistance or intolerance to prior therapy, the recommended dose of BOSULIF is 500 mg once daily with food.1

• In phase I/II trials in patients with resistance or intolerance to prior therapy, dose escalation to 600 mg once daily was allowed in patients who did not achieve complete haematological response (CHR) by week 8, or CCyR by week 12, and had not experienced Grade 3 or higher adverse reactions1

• Doses greater than 600 mg/day have not been studied and, therefore, should not be given1

Detailed guidance for dose interruption, reduction and re-escalation are provided in the relevant AE sections later in this guide. 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.1

Doses less than 300 mg/day have been used in patients; however, efficacy has not been established.1

In clinical trials, treatment with BOSULIF continued until disease progression (transformation to AP or BP, or loss of previously attained response), or until BOSULIF was no longer tolerated by the patient.6,9–12

Patients should receive information and education about the importance of treatment adherence in order to optimise their clinical outcome.8


11

Special populations• Elderly patients (≥65 years of age) – no specific dose recommendation

is necessary. Caution is advised in this population, as data are limited1

• Paediatric population – the safety and efficacy of BOSULIF® in children <18 years of age have not been established1

• Renal impairment – patients with serum creatinine >1.5 x upper limit of normal (ULN) were excluded from clinical trials of BOSULIF. Increasing exposure to BOSULIF (as measured by area under the curve [AUC]) in patients with moderate or severe renal impairment has been observed1

– In patients with moderate renal impairment (creatinine clearance [CrCl] 30 to 50 ml/min, calculated by the Cockcroft-Gault formula), the recommended dose of BOSULIF is 300 mg once daily in patients with newly diagnosed CP Ph+ CML, and 400 mg once daily in patients with CP, AP or BP Ph+ CML with resistance or intolerance to prior therapy1

– In patients with severe renal impairment (CrCl <30 ml/min, calculated by the Cockcroft-Gault formula), the recommended dose of BOSULIF is 200 mg once daily in patients with newly diagnosed CP Ph+ CML, and 300 mg once daily in patients with CP, AP or BP Ph+ CML with resistance or intolerance to prior therapy1

– In patients with newly diagnosed CP Ph+ CML, dose escalation to 400 mg once daily for patients with moderate renal impairment, or to 300 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 response1

– In patients with CP, AP or BP Ph+ CML with resistance or intolerance to prior therapy, 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 response1

• Cardiac disorders – patients with uncontrolled or significant cardiac disease were excluded from clinical trials of BOSULIF. Caution should be exercised in such patients1

• Recent or ongoing clinically significant gastrointestinal disorders – patients with recent or ongoing clinically significant gastrointestinal disorders were excluded from clinical trials of BOSULIF. Caution should be exercised in such patients1

• Hepatic impairment – BOSULIF is contraindicated in these patients1


12

Key interactionsCytochrome P450 (CYP) 3A inhibitors:• The concomitant use of BOSULIF® with potent or moderate CYP3A

inhibitors should be avoided, as an increase in plasma BOSULIF concentration will occur. Selection of an alternative concomitant medicinal product with no or minimal CYP3A inhibition potential, if possible, is recommended. If a potent or moderate CYP3A inhibitor must be administered during BOSULIF treatment, an interruption of BOSULIF therapy or a reduction in the dose of BOSULIF should be considered1

• Caution should be exercised if mild CYP3A inhibitors are used concomitantly with BOSULIF1

CYP3A inducers:• The concomitant use of BOSULIF with potent or moderate CYP3A inducers

(including St John’s wort) should be avoided, as a decrease in plasma BOSULIF concentration will occur1

• Based on the large reduction in BOSULIF exposure that occurs when BOSULIF is 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 exposure1

• Caution is warranted if mild CYP3A inducers are used concomitantly with BOSULIF1

Proton pump inhibitors (PPIs):• Caution should be exercised when administering BOSULIF concomitantly

with PPIs. Short-acting antacids should be considered as an alternative to PPIs, and the administration times of BOSULIF and antacids should be separated (e.g. by taking BOSULIF in the morning and antacids in the evening) whenever possible1


13

Anti-arrhythmic medicines and other substances that may prolong the QT interval:• BOSULIF® should be used with caution in patients who have, or who may

develop, prolongation of the QT interval, including those taking anti-arrhythmic medicines or other medicinal products that may lead to QT interval prolongation1

Food effect• Grapefruit products, including grapefruit juice, and other foods that are

known to inhibit CYP3A (e.g. Seville oranges, tangelos), should be avoided1,13


14

Safety profile of BOSULIF®

BOSULIF has a manageable safety profile. Most adverse events are of mild-to-moderate severity, are manageable and improve over time.6

Gastrointestinal events (diarrhoea, abdominal pain, nausea, vomiting), thrombocytopenia and rash are among the AEs most commonly associated with BOSULIF.1,6,12 Advise patients of the common occurrence of these AEs before treatment.

AEs reported in the BFORE trial of newly diagnosed patients with CP Ph+ CML are shown in Table 2.6

A 4-year follow-up analysis of a phase I/II clinical trial including adults with CP Ph+ CML who had received prior imatinib treatment identified no new safety signals with BOSULIF after the first treatment year.14

• Individual treatment-emergent adverse events (TEAEs; occurring in ≥10% of patients overall) were generally most frequent in Year 114

• Discontinuations due to AEs were most common in the first year (17%)14

– In years 2, 3 and 4, discontinuations due to AEs were 4%, 2% and 2%, respectively14


15

Table 2. Adverse events that occurred in ≥10% of patients in either arm of the BFORE trial which compared BOSULIF with imatinib in newly diagnosed patients with CP Ph+ CML. Figure made by Pfizer from data in ref. 6.

Any AEGastrointestinal Diarrhoea

Nausea

Vomiting

Abdominal pain

Haematologic Thrombocytopenia

Anaemia

Neutropenia

Leukopenia

Musculoskeletal Muscle spasms

Arthralgia

Myalgia

Pain in extremity

Infections Upper respiratory tract infection

Liver function

ALT increase

AST increase

Other Fatigue

Rash

Headache

Increased lipase

Pyrexia

Peripheral oedema

Asthenia

Periorbital oedema

Decreased appetite

98.1

81.3

70.1

35.1

17.9

17.9

45.5

35.1

18.7

11.2

5.6

29.5

2.2

11.2

3.0

4.5

44.4

8.6

39.9

30.6

22.8

19.4

19.8

18.7

13.4

13.1

4.1

11.2

1.5

10.1

56.3

10.8

7.8

0

1.1

1.9

16.4

13.8

3.4

6.7

1.1

1.9

0

0.7

0.4

0.4

3.4

0.4

24.3

19.0

9.7

0.4

0.4

1.1

9.7

0.7

0

0

0

0.4

Adverse event, % All Grades Grade ≥3

BOSULIF (n=268)

97.0

61.5

33.6

38.5

16.2

7.2

43.4

19.6

18.9

20.8

10.9

58.5

26.4

13.2

15.5

12.5

47.2

10.2

13.6

5.7

6.4

17.7

13.2

12.8

8.3

8.3

13.6

6.4

14.0

6.0

42.6

3.4

0.8

0

0

0.4

19.6

5.7

4.5

12.1

3.0

2.3

0.4

0

0.8

0

4.9

0

4.2

1.5

1.9

0

1.1

1.1

5.3

0

0.4

0

0

0

All Grades Grade ≥3

Imatinib (n=265)

AE, adverse event; ALT, alanine aminotransferase; AST, aspartate aminotransferase; CML, chronic myeloid leukaemia; CP, chronic phase; Ph+, Philadelphia chromosome-positive.


16

Figure 4. Prevalence of comorbid conditions relevant to TKI treatment choice among patients with CML (n=2,296) in a real-world setting. Figure made by Pfizer from data in ref. 2.

0

20

Heart disease

18–44 years

45–54 years

55–64 years

≥65 years

6%

15%

24%

45%

2%

3%

5%

16%

7%

14%

23%

25%

0.0%

0.5%

0.4%

0.4%

1%

2%

2%

4%

5%

11%

12%

23%

15%

33%

47%

65%

40

60

80

100

P<0.001

Arrhythmia

P<0.001

Diabetes

P<0.001

Pancreatitis

P=0.50

Pleural effusion

P=0.01

Lung disease

P<0.001

Any of evaluatedconditions

P<0.001

Pro

porti

on o

f pat

ient

s (%

)Cardiovascular and pulmonary safety profile of BOSULIF®

Cardiovascular and pulmonary comorbidities relevant to TKI therapy are highly prevalent in patients with CML due to the median age of patients at CML diagnosis (Figure 4).2 The presence of cardiovascular comorbidities has been shown to negatively affect all-cause mortality in patients with CML.3

CML, chronic myeloid leukaemia; TKI, tyrosine kinase inhibitor.


17

In the BFORE trial, rates of cardiovascular and pulmonary AEs were relatively low with BOSULIF® at 12 months.6

• Cardiovascular events were reported in 3.0% of patients receiving BOSULIF and 0.4% of patients receiving imatinib, 1.5% and 0% of which were Grade ≥3, respectively6,

• One patient who received imatinib experienced a cerebrovascular event; no patients treated with BOSULIF reported a cerebrovascular event6

• Peripheral vascular events occurred in 1.5% of patients receiving BOSULIF and 1.1% of patients receiving imatinib6

• Pleural effusion events were reported in 1.9% of patients treated with BOSULIF and 1.5% treated with imatinib, none of which were Grade ≥36

• There were no deaths due to cardiovascular toxicity in either treatment arm6

Cardiac events (any grade) occurred in 5.2% and 5.3% of patients who received BOSULIF or imatinib, respectively.

• Grade ≥3 events occurred in 1.1% of patients in each arm6

• Events of Grade ≥3 considered to be treatment-related occurred in 0.7% and 0.4% of patients receiving BOSULIF and imatinib, respectively6

Long-term follow-up of patients enrolled in BELA, a randomised phase III trial comparing BOSULIF 500 mg* with imatinib in newly diagnosed CP Ph+ CML, indicates that rates of vascular (including cardiovascular) and cardiac AEs remain relatively low during long-term treatment with BOSULIF (Figure 5).7

*BOSULIF 500 mg is not an approved starting dose for patients with newly diagnosed CP Ph+ CML.


18

Figure 5. Rates of vascular (including cardiovascular) and cardiac TEAEs are relatively low with BOSULIF® during long-term treatment. Figure made by Pfizer from data in ref. 7.

0.50.5

0.5

0.5

0.40.400

0.6

0.6

0.40.5

0.40000

0.5000.400.4000.400

2.8 3.2

Vasc

ular

TEA

Es

Car

diac

TEA

Es

Cerebrovasculardisorders

Cardiovasculardisorders

Peripheralvasculardisorders

Cerebral haemorrhage 0.40000.4 0.6

0.60.5

0.60.5

000.4

00000.4

00000

00.8

00000

Subarachnoid haemorrhage

Angina pectoris

Angina unstable

Coronary artery disease

Coronary artery stenosis

Coronary artery arteriosclerosis

Acute myocardial infarction

Year 1 (n=248) Year 2 (n=183) Year 3 (n=168) Year 4 (n=154)

Year 1 (n=251)

BOSULIF

Imatinib Year 2 (n=209) Year 3 (n=183) Year 4 (n=176)

Myocardial infarction

Myocardial ischaemia

Aortic arteriosclerosis

Peripheral coldness

Venous insufficiency

Deep vein thrombosis

0.40.4

Atrial fibrillation

Tachycardia

Bradycardia

Sinus bradycardia

Right bundle branch block

Arrhythmia

Complete atrioventricular block

Supraventricular extrasystoles

Ventricular extrasystoles

Congestive cardiac failure

Cardiac failure

Chronic cardiac failure

Prolonged ECG QT


19

0.50.5

0.5

0.5

0.40.400

0.6

0.6

0.40.5

0.40000

0.5000.400.4000.400

2.8 3.2

Vasc

ular

TEA

Es

Car

diac

TEA

Es

Cerebrovasculardisorders

Cardiovasculardisorders

Peripheralvasculardisorders

Cerebral haemorrhage 0.40000.4 0.6

0.60.5

0.60.5

000.4

00000.4

00000

00.8

00000

Subarachnoid haemorrhage

Angina pectoris

Angina unstable

Coronary artery disease

Coronary artery stenosis

Coronary artery arteriosclerosis

Acute myocardial infarction

Year 1 (n=248) Year 2 (n=183) Year 3 (n=168) Year 4 (n=154)

Year 1 (n=251)

BOSULIF

Imatinib Year 2 (n=209) Year 3 (n=183) Year 4 (n=176)

Myocardial infarction

Myocardial ischaemia

Aortic arteriosclerosis

Peripheral coldness

Venous insufficiency

Deep vein thrombosis

0.40.4

Atrial fibrillation

Tachycardia

Bradycardia

Sinus bradycardia

Right bundle branch block

Arrhythmia

Complete atrioventricular block

Supraventricular extrasystoles

Ventricular extrasystoles

Congestive cardiac failure

Cardiac failure

Chronic cardiac failure

Prolonged ECG QT

TEAE, treatment-emergent adverse event.


20

Table 3. CTCAE grading scale version 5.0 for diarrhoea. Table made by Pfizer from data in ref. 15.

BOSULIF® management

Classification

The severity of AEs can be classified according to the National Cancer Institute’s grading scale, commonly referred to as the Common Terminology Criteria for Adverse Events (CTCAE).15 The CTCAE grading scale for diarrhoea is shown in Table 3.

Diarrhoea(AE frequency category: Very common, ≥1/101)

Grade

1 Mild

2 Moderate

3 Severe

4 Life-threatening

Increase of 1–3 stools per day over baseline

Increase of 4–6 stools per day over baseline

Increase of ≥7 stools per day over baseline; hospitalisation

indicated

Life-threatening consequences;

urgent intervention indicated

CTCAE, Common Terminology Criteria for Adverse Events.


21

Characterisation

Diarrhoea is the most common AE with BOSULIF®; patients with recent or ongoing clinically significant gastrointestinal disorder should use BOSULIF with caution and only after a careful benefit–risk assessment as these patients were excluded from the clinical studies.1

In the BFORE trial, diarrhoea events with BOSULIF occurred early, were transient and generally of low severity.6 The incidence of diarrhoea of any grade with BOSULIF was 70.1% (188/268) and the incidence of Grade ≥3 diarrhoea was 7.8% (21/268).6 This was consistent with the rate and severity reported in Study 200, where BOSULIF was given as a second or subsequent line therapy in CP CML patients.9

Among the 188 patients who experienced drug-related diarrhoea in the BFORE trial:6

• The median time to first event was 3 days

• The median cumulative duration was 15 days

• Dose interruptions and reductions for the management of diarrhoea were required in 13.3% and 3.2% of affected patients, respectively

• Of the patients who had interruptions to BOSULIF treatment because of diarrhoea, 88.0% were re-challenged successfully; none of these patients discontinued treatment permanently because of diarrhoea

• Overall, only two patients discontinued treatment because of diarrhoea, emphasising the tolerability and manageability of this common AE

Management

Before treatment

It is very important to advise patients that:

• Diarrhoea is a common occurrence, especially during the first few days and weeks of treatment with BOSULIF1,6

• Consider discontinuation of medications such as bulk laxatives, stool softeners and motility-promoting agents that may exacerbate diarrhoea16

On treatment

Diarrhoea should be treated with an appropriateanti-diarrhoeal medication at the first occurrence of an event. Exclude other causes of diarrhoea (e.g. infection, use of medicines that exacerbate diarrhoea).16,17


22

Initial management strategies should include oral hydration (8–10 large glasses of clear liquids containing water, salt and sugar daily) and dietary modification:16,17

• During the episode, encourage patients to avoid spicy, fatty or high-fibre foods, caffeine and alcohol, dairy products, and raw fruits and vegetables (except for bananas)16-18

• Encourage patients to eat foods that are high in sodium (such as clear soups) and potassium (such as bananas, canned apricots, and potatoes without their skins), and low-fibre starchy foods such as white toast, rice and pasta, and apple sauce, which may help resolve symptoms18

• Patients should be encouraged to eat small meals, snack frequently, and avoid very hot or very cold foods and drinks18

• A balanced diet that includes high-fibre foods, fruit and vegetables, should be re-introduced once diarrhoea has resolved17

• Patients should be advised to contact a healthcare professional if diarrhoea persists or worsens18

For Grade 3/4 diarrhoea, fluid replacement therapy should continue (orally or intravenously, as clinically indicated) and treatment with BOSULIF® should be interrupted.1 Appropriate anti-diarrhoeal therapy should be administered.1,17 Treatment may be resumed at 400 mg once daily, upon recovery to Grade ≤1 diarrhoea.1 If clinically appropriate, re-escalation of BOSULIF to the original dose should be considered.1

Encourage patients to report abdominal pain.1

Recommendations are summarised in Figure 6.


23

Figure 6. Management recommendations for patients with diarrhoea. Figure made by Pfizer from data in ref. 1, 16 and 17.

*Patients with diarrhoea should drink 8–10 large glasses of clear liquids daily and avoid spicy, fatty and high-fibre foods, alcohol and caffeine, dairy products, and raw fruits and vegetables (except bananas).16-18

Upon initiation of BOSULIF®: 1. Discontinue medicines that may exacerbate diarrhoea 2. Advise patients of the common occurrence of

diarrhoea and to treat with over-the-counter anti-diarrhoeal therapy at first occurence

Treat immediately with anti-diarrhoeal therapy. Modify diet and monitor patient.

Promote oral hydration and encourage avoidance of foods and supplements that cause gastrointestinal irritation*

Diarrhoea

Treat immediately with anti-diarrhoeal therapy

until event resolves

Interrupt BOSULIFAdminister appropriate anti-diarrhoeal therapy

Consider discontinuation

of BOSULIF

Resume BOSULIF at 400 mg once daily

If clinically appropriate re-escalate

dose

Escalation of diarrhoea to Grade 3/4

Grade 1/2 diarrhoea Grade 3/4 diarrhoea

Recovery to Grade ≤1No

No

Yes

Yes


24

Grade

1 Mild

2 Moderate

3 Severe

4 Life-threatening

Loss of appetite without alteration in eating habits

Oral intake decreased without significant weight loss, dehydration or malnutrition

Inadequate oral caloric or fluid intake; tube feeding, TPN or hospitalisation indicated

N/A

Intervention not indicated

Outpatient IV hydration; medical intervention indicated

Tube feeding, TPN orhospitalisation indicated

Life-threatening consequences

Table 4. CTCAE grading scale version 5.0 for nausea and vomiting. Figure made by Pfizer from data in ref. 15.

Classification

The CTCAE grading scales for nausea and vomiting are shown in Table 4.

Nausea and vomiting(AE frequency category: Very common, ≥1/101)

Event

Nausea

Vomiting

CTCAE, Common Terminology Criteria for Adverse Events; TPN, total parenteral nutrition; IV, intravenous; N/A, not applicable.


25

Characterisation

Nausea and vomiting are very common AEs with BOSULIF®; patients with recent or ongoing clinically significant gastrointestinal disorder should use BOSULIF with caution and only after a careful benefit–risk assessment as respective patients were excluded from the clinical studies.1

The majority of nausea and vomiting events in the BFORE trial were mild to moderate in severity.6

• The results for BFORE are similar to the rates of nausea and vomiting reported in Study 200, BOSULIF as second or subsequent line therapy in patients with CP CML, (any grade 43% and 32% respectively)9

• The incidence of nausea events of any grade was 35.1% (94/268) in the BFORE trial; there were no Grade 3 nausea events reported6

• The incidence of vomiting events of any grade was 17.9% (48/268); the incidence of Grade ≥3 vomiting events was 1.1% (3/268)6

Management

Possible risk factors for nausea and vomiting, such as bowel obstruction, vestibular dysfunction, electrolyte imbalance and concomitant medication(s), should be assessed and managed accordingly.19

Patients experiencing nausea and vomiting should be managed using supportive care, which includes the following advice and strategies:

1. Remind patients that BOSULIF should be taken with food1

2. Dietary modification

• Patients should be encouraged to eat small meals and snack frequently, avoid food and drinks that are very hot or very cold, and try to eat foods that are gentle on the stomach18

• Patients should spread their fluid intake throughout the day and sip slowly. Some patients may find it beneficial to only drink small amounts of fluid at meal times, to avoid feeling bloated as a result of eating and drinking at the same time18

• Eating dry toast before getting up can help alleviate nausea in the morning18

• Patients should be encouraged to eat what appeals to them and should not miss snacks or meals, as nausea can be worse with an empty stomach18


26

3. Anti-emetic therapy

• If nausea and vomiting cannot be managed conservatively, it is recommended that appropriate anti-emetic therapy be prescribed, to be used on an ‘as needed’ basis. Long-term daily use of anti-emetics is not recommended.19 Patients should be advised to contact a healthcare professional if nausea or vomiting persists or worsens

• Anti-emetics should be selected for their anti-emetic potential, but only after ascertaining that their safety profile is appropriate

– Use of the anti-emetic domperidone should be avoided due to its potential to induce QT interval prolongation and torsades de pointes arrhythmias1

– Some anti-emetika increase gut mobility and may cause diarrhoea.19 Choose an alternative anti-emetic in patients with diarrhoea, if appropriate

When supportive care does not resolve nausea and vomiting, these events can be managed by dose interruption and modification.1

In BOSULIF®-treated patients experiencing clinically significant (moderate or severe) nausea or vomiting, BOSULIF treatment should be interrupted, and may be resumed at a dose reduced by 100 mg taken once daily following resolution of the event. If clinically appropriate, re-escalation to the original dose should be considered.1


27

Classification

The CTCAE grading scale for liver enzyme elevations is shown in Table 5.

Characterisation

Liver abnormalities involving elevated levels of the enzymes ALT or AST are associated with BOSULIF® treatment.1

Elevated transaminase levels, particularly in the setting of concomitant increases in bilirubin levels, may be an early indication of drug-induced liver injury, and such patients should be managed appropriately.1

Events involving ALT or AST in patients who received BOSULIF in the BFORE trial:6

• The incidence of ALT elevations of any grade was 30.6% (n= 82/268), and that of Grade ≥3 events was 19.0% (51/268)6

• The incidence of AST elevations of any grade was 22.8% (n= 61/268), and that of Grade ≥3 events was 9.7% (26/268)6

Liver enzyme abnormalities(AE frequency category: alanine transaminase (ALT) increased/aspartate transaminase (AST) increased, very common ≥1/10; bilirubin increased/gamma-glutamyltransferase increased, common ≥1/100 to <1/101)

Grade

1 Mild

2 Moderate

3 Severe

4 Life-threatening

>ULN – 3 x ULN >3–5 x ULN >5–20 x ULN >20 x ULN

Table 5. CTCAE grading scale version 5.0 for elevated liver enzymes (ALT and AST). Figure made by Pfizer from data in ref. 15.

ALT, alanine transaminase; AST; aspartate transaminase; CTCAE, Common Terminology Criteria for Adverse Events; ULN, upper limit of normal.


28

• These findings are consistent with the rates reported in Study 200, BOSULIF® as second or subsequent line therapy in patients with CP CML; ALT elevations any grade were 49%, Grade 3/4 events were 7%; AST elevations any grade were 41%, Grade 3/4 events were 3%9

Transaminase elevations generally occurred early in the course of treatment.1,6 Among the 143 patients who reported elevations of either ALT or AST in the BFORE trial:6

• The median time to first event was 30 days

• The median duration of an event was 18 days

23 patients (8.6%) had dose reductions because of liver function AEs. Of the 25.7% of patients who interrupted BOSULIF because of liver function AEs, 91.3% were re-challenged (84.1% successfully).6

BOSULIF was discontinued in 4.9% and 2.2% of patients because of elevated ALT and AST levels, respectively.6

Management

Before treatment

It is essential to assess liver function before commencing treatment with BOSULIF.1

BOSULIF is contraindicated in patients with hepatic impairment.1

On treatment

Liver function should be monitored monthly for the first 3 months, and as clinically indicated.1

In patients with liver transaminase levels >5 x ULN, treatment with BOSULIF should be interrupted until recovery to ≤2.5 x ULN, and may be resumed at 400 mg once daily thereafter. Re-escalation of BOSULIF to the original dose should be considered if clinically appropriate. If recovery takes longer than 4 weeks, discontinuation of BOSULIF should be considered.1

Treatment with BOSULIF should be discontinued in patients with transaminase levels ≥3 x ULN who also have bilirubin elevations >2 x ULN and alkaline phosphatase levels <2 x ULN.1 In the entire BOSULIF clinical programme, this occurred in only one patient, who was receiving treatment with letrozole for concomitant metastatic breast cancer.1

Recommendations are summarised in Figure 7.


29

Figure 7. Management recommendations for patients with elevated liver transaminases. Figure made by Pfizer from data in ref. 1.

Elevated liver transaminase: >5 x ULN

Interrupt BOSULIF® until recovery to ≤2.5 x ULN and consider resuming at 400 mg/day

Recovery >4 weeks

Consider discontinuation of BOSULIF

Liver transaminases ≥3 x ULN and

bilirubin >2 x ULN and

alkaline phosphatase <2 x ULN

Discontinue BOSULIF

ULN, upper limit of normal.


30

Grade

1 Mild

2 Moderate

3 Severe

4 Life-threatening

<LLN – 100 g/L <100–80 g/L<80 g/L

Transfusion indicated

Urgent interventionindicated

<LLN – 1.5 x 109/L <1.5–1.0 x 109/L <1.0–0.5 x 109/L <0.5 x 109/L

<LLN – 75.0 x 109/L

<75.0–50.0 x 109/L

<50.0–25.0 x 109/L <25.0 x 109/L

Table 6. CTCAE grading scale version 5.0 for myelosuppression events15

Classification

The CTCAE grading scale for myelosuppression events (i.e. anaemia, neutropenia and thrombocytopenia) is shown in Table 6.

Myelosuppression

Event

Anaemia*

Neutropenia (ANC)

Thrombocytopenia†

*LLN for haemoglobin is 130 g/L for men and 120 g/L for women.†LLN is approximately 140 x 109/L for platelets. ANC, absolute neutrophil count; CTCAE, Common Terminology Criteria for Adverse Events; LLN, lower limit of normal.


31

Table 7. Incidence of myelosuppression events with BOSULIF in the BFORE trial (n=268). Figure made by Pfizer from data in ref. 6.

Characterisation

Myelosuppression has been reported in trials of BOSULIF®.1,6,12,20

In the BFORE trial, thrombocytopenia, anaemia and neutropenia were reported in 35.1% (94/268), 18.7% (50/268) and 11.2% (30/268) of patients receiving BOSULIF, respectively. Thrombocytopenia was the second most common Grade ≥3 AE (13.8%) among BOSULIF recipients, after ALT elevations.6 By comparison the rates reported for thrombocytopenia, anaemia and neutropenia in Study 200, BOSULIF as second or subsequent line therapy in patients with CP CML; were any grade 58%, 84% and 46% respectively.9 The rates of Grade 3/4 AEs for thrombocytopenia, anaemia and neutropenia were 25%, 8% and 19% respectively.9

The incidence of myelosuppression events in the BFORE trial is shown in Table 7.

*Reported among 268 patients with CP CML who received at least one dose of BOSULIF.6

Parameter, %

Thrombocytopenia

Anaemia

Neutropenia

Leukopenia

BOSULIF (n=268)

All gradesn (%)

Grade ≥3n (%)

94 (35.1) 37 (13.8)

50 (18.7) 9 (3.4)

30 (11.2) 18 (6.7)

15 (5.6) 3 (1.1)


32

Management

Complete blood counts should be performed weekly for the first month and then monthly thereafter, or as clinically indicated.1

In patients with absolute neutrophil count (ANC) <1.0 x 109/L and/or platelets <50 x 109/L, withhold BOSULIF® treatment until ANC ≥1.0 x 109/L and platelets ≥50 x 109/L. Resume BOSULIF therapy at the same dose if recovery occurs within 2 weeks. If blood counts remain low for more than 2 weeks, reduce the dose by 100 mg/day and resume treatment. If cytopenia recurs, reduce the dose by 100 mg/day upon recovery and resume treatment. Doses less than 300 mg/day have been used; however, efficacy has not been evaluated.1

Growth factors can be used in combination with BOSULIF for patients with resistant neutropenia and thrombocytopenia.8


33

Table 8. Cockcroft-Gault formula grading for renal impairment. Figure made by Pfizer from data in ref. 1

Classification

Assessment of renal function in patients receiving BOSULIF® is based on CrCl (calculated using the Cockcroft-Gault formula; Table 8).1

Renal impairment

Characterisation

Treatment with BOSULIF may result in a clinically significant decline in renal function in patients with CML. A decline over time in estimated glomerular filtration rate (eGFR) has been observed in patients treated with BOSULIF in clinical studies.1

In a renal impairment study, BOSULIF exposures were increased in subjects with moderately and severely impaired renal function. Dose reduction is recommended for patients with moderate or severe renal impairment.1

Patients with serum creatinine >1.5 x ULN were excluded from the CML studies. Based on a population pharmacokinetic analysis, patients with moderate or severe renal impairment at initiation of treatment were observed to have increased exposure (AUC) to BOSULIF.1

Grade

Mild renal impairment

Moderate renal impairment

Severe renal impairment

CrCl >50–80 mL/min CrCl 30–50 mL/min CrCl <30 mL/min

CrCl, creatinine clearance.


34

Management

Before treatment

Renal function should be assessed before treatment initiation, and closely monitored during therapy with BOSULIF®. Particular attention should be paid in patients with pre-existing renal compromise or risk factors for renal dysfunction. This includes concomitant use of potentially nephrotoxic medications, such as diuretics, angiotensin-converting enzyme (ACE) inhibitors, angiotensin receptor blockers, and non-steroidal anti-inflammatory drugs (NSAIDs).1

Recommended dosage of BOSULIF in renal impairment

Dose escalation guidelines


Dose escalation to 400 mg (moderate renal impairment) or 300 mg (severe renal impairment) once daily with food may be considered for patients who do not experience severe or persistent moderate adverse reactions, and have not achieved an adequate haematological, cytogenetic or molecular response.1

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

Dose escalation to 500 mg (moderate renal impairment) or 400 mg (severe renal impairment) once daily with food may be considered for patients who do not experience severe or persistent moderate adverse reactions, and have not achieved an adequate haematological, cytogenetic or molecular response.1

Table 9. Recommended dosage of BOSULIF for patients with moderate or severe renal impairment. Figure made by Pfizer from data in ref. 1.

*Calculated using the Cockcroft-Gault formula.AP, acute phase; BP, blast phase; CML, chronic myeloid leukaemia; CP, chronic phase; CrCl, creatinine clearance; Ph+, Philadelphia chromosome-positive.

Recommended dosage of BOSULIF


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

300 mg once daily 400 mg once daily

200 mg once daily 300 mg once daily

Degree of impairment*

Moderate (CrCl 30–50 mL/min)

Severe (CrCl <30 mL/min)


35

Classification

The CTCAE grading scale for maculopapular rash is shown in Table 10.

Rash

Table 10. CTCAE grading scale version 5.0 for maculopapular rash. Figure made by Pfizer from data in ref. 15.

Grade

1 Mild

2 Moderate

3 Severe

4 Life-threatening

Macules/papules covering <10% BSA

with or without symptoms (e.g.

pruritus, burning, tightness)

Macules/papules covering 10–30%

BSA with or without

symptoms (e.g. pruritus, burning, tightness); limiting instrumental ADL;

papules and or pustules covering >30% BSA with or without mild

symptoms

Macules/papules covering >30% BSA with moderate or severe symptoms; limiting self-care

ADL

N/A

ADL, activities of daily living; BSA, body surface area; CTCAE, Common Terminology Criteria for Adverse Events; N/A, not applicable.

Characterisation

The majority of rash AEs in the BFORE trial were mild to moderate in severity. The incidence of rash of any grade among BOSULIF® recipients was 19.8% (53/268). Incidence of Grade ≥3 rash was <1%.6 This was consistent with the findings of Study 200, BOSULIF as second or subsequent line therapy for patients with CP CML.9 In Study 200, the frequency of rash of all grades was 22% and for Grade 3/4 rash was 4%.9


36

Management

Before treatment

Promote basic skin care. Advise patients to use mild soaps, and to avoid products that contain alcohol or perfume. Showers and baths should be brief and taken in warm rather than hot water. Wet skin should be patted dry. Sun avoidance and sun protection should be encouraged.21

On treatment

Rash occurring during BOSULIF treatment may be treated with topical or systemic steroids.8 Consultation with a dermatologist should be considered.

If a clinically significant moderate or severe rash develops, BOSULIF treatment should be interrupted. BOSULIF may be resumed at a dose reduced by 100 mg taken once daily, after the rash has resolved. Re-escalation to the original dose should be considered, if clinically appropriate.1

Figure 8. Examples of more common types of rash observed with BOSULIF®

Figure 9. Example of a less common type of rash observed with BOSULIF

27

Figure 4. Example of a less common type of rash observed with BOSULIF®:

Management

Before treatment

Inform patients that a balanced diet and adequate hydration (with, if possible, a daily fluid intake of at least 2–3 L)*20 will assist in the maintenance of healthy skin.

Promote basic skin care. Advise the patient to use only mild soaps, and to avoid products that contain alcohol or perfume. Showers and baths should be brief and taken in warm rather than hot water. Wet skin should be patted dry. Sun avoidance and sun protection should be encouraged.21

On treatment

Rash occurring during BOSULIF® treatment may be treated with topical or systemic steroids.4 Consultation with a dermatologist should be considered.

If a clinically significant moderate or severe rash develops, BOSULIF® treatment should be interrupted. BOSULIF® may be resumed at 400 mg once daily following resolution of the event. Re-escalation of the dose to 500 mg once daily should be considered if clinically appropriate.1

* Total water intake includes drinking water, either on its own or as part of a mixed beverage, and intake of water through food.20

Classification


Characterisation

The majority of rash AEs in the pivotal study were mild to moderate in severity. The in-cidence of rash of any grade was 33% (185/570). Incidence of Grade 3/4 rash was 6%.3


Rash

Grade

1Mild

2Moderate

3Severe

4Life-threatening

Macules/papules covering <10% BSA with or without symptoms (e.g. pruritus,

burning, tightness)

Macules/papules covering 10–30% BSA with or with-

out symptoms (e.g. pruritus, burning, tightness); limiting

instrumental ADL

Macules/papules covering >30% BSA with or without

associated symptoms; limiting self-care ADL

N/A

Table 9. CTCAE grading scale version 4.03 for maculopapular rash.10


Reproduced with kind permission from Professor Carlo Gambacorti-Passerini, Italy



27

Figure 4. Example of a less common type of rash observed with BOSULIF®:

Management

Before treatment

Inform patients that a balanced diet and adequate hydration (with, if possible, a daily fluid intake of at least 2–3 L)*20 will assist in the maintenance of healthy skin.

Promote basic skin care. Advise the patient to use only mild soaps, and to avoid products that contain alcohol or perfume. Showers and baths should be brief and taken in warm rather than hot water. Wet skin should be patted dry. Sun avoidance and sun protection should be encouraged.21

On treatment

Rash occurring during BOSULIF® treatment may be treated with topical or systemic steroids.4 Consultation with a dermatologist should be considered.

If a clinically significant moderate or severe rash develops, BOSULIF® treatment should be interrupted. BOSULIF® may be resumed at 400 mg once daily following resolution of the event. Re-escalation of the dose to 500 mg once daily should be considered if clinically appropriate.1

* Total water intake includes drinking water, either on its own or as part of a mixed beverage, and intake of water through food.20

Classification


Characterisation

The majority of rash AEs in the pivotal study were mild to moderate in severity. The in-cidence of rash of any grade was 33% (185/570). Incidence of Grade 3/4 rash was 6%.3


Rash

Grade

1Mild

2Moderate

3Severe

4Life-threatening

Macules/papules covering <10% BSA with or without symptoms (e.g. pruritus,

burning, tightness)

Macules/papules covering 10–30% BSA with or with-

out symptoms (e.g. pruritus, burning, tightness); limiting

instrumental ADL

Macules/papules covering >30% BSA with or without

associated symptoms; limiting self-care ADL

N/A

Table 9. CTCAE grading scale version 4.03 for maculopapular rash.10





37

Classification

The CTCAE grading scale for fatigue is shown in Table 11.

Fatigue

Table 11. CTCAE grading scale version 5.0 for fatigue. Figure made by Pfizer from data in ref. 15.

Grade

1 Mild

2 Moderate

3 Severe

4 Life-threatening

Fatigue relieved by rest

Fatigue not relieved by rest; limiting

instrumental ADL

Fatigue not relieved by rest; limiting self-care ADL

N/A

ADL, activities of daily living; CTCAE, Common Terminology Criteria for Adverse Events; N/A, not applicable.

Characterisation

In the BFORE trial, the incidence of fatigue events of any grade was 19.4% (52/268); however, the incidence of Grade ≥3 fatigue events was <1% (1/268).6 Rates of fatigue were similar in the BOSULIF® and imatinib groups (19.4% vs 17.7% for any grade, respectively).6

Management

Contributing factors other than cancer treatment, such as anaemia, malnutrition, thyroid dysfunction and infection, should be excluded or treated accordingly.22

Encourage light-to-moderate exercise in patients for whom it is appropriate.22,23 Promote the use of: energy-conserving techniques (e.g. prioritising important activities when energy levels are highest, taking short naps if they don’t interfere with sleeping well at night); distraction through engaging in pleasurable activities; and techniques to maximise sleep and deal with emotional stress.22,23 Patients with fatigue should be periodically assessed and referred to support services as required.23


38

Classification

The CTCAE grading scales for pleural and pericardial effusions are shown in Table 12.

Pleural and pericardial effusions

Table 12. CTCAE grading scale version 5.0 for pleural and pericardial effusions. Figure made by Pfizer from data in ref. 15.

CTCAE, Common Terminology Criteria for Adverse Events; N/A, not applicable.

Grade

1 Mild

2 Moderate

3 Severe

4 Life-threatening

Asymptomatic; clinical or diagnostic observations only; intervention not indicated

Symptomatic; intervention indicated (e.g. diuretics or limited therapeuticthoracentesis)

Symptomatic with respiratory distress and hypoxia; operative intervention,including chest tube or pleurodesis indicated

Life-threatening respiratory or haemodynamic compromise;intubation or urgent intervention indicated

N/A Asymptomatic effusion, size small to moderate

Effusion with physiological consequences

Urgent intervention indicated

Pleural effusion

Pericardial effusion


39

Table 13. Incidence of pleural and pericardial effusion events in the BOSULIF arm of the BFORE trial (n=268). Figure made by Pfizer from data in ref. 6.

Characterisation

The frequencies of pleural and pericardial effusions reported with BOSULIF® in the BFORE trial are shown in Table 13.

Management

Risk factors for effusions and pulmonary oedema should be excluded.

Patients who develop signs and symptoms of effusions or pulmonary oedema during BOSULIF treatment (e.g. difficulty breathing, chest pain or a cough)should undergo evaluation with appropriate techniques.1

Monitor and manage patients using the standard-of-care treatment that is clinically indicated for effusions or pulmonary oedema (e.g. diuretics, supportive care).8

In the case of moderate-to-severe events, interrupt treatment with BOSULIF and consider resuming at 100 mg/day below the previous dose, following resolution of the event. If clinically appropriate, re-escalation to the original dose should be considered.1

In patients with CP, AP or BP Ph+ CML with resistance or intolerance to imatinib, treatment-emergent pleural effusions of any grade were reported in 10% (57/570) of BOSULIF treated patients.12

Adverse event

Pericardial effusion

Pleural effusion

BOSULIF (n=268)

All gradesn (%)

Grade ≥3n (%)

1 (0.4) 1 (0.4)

5 (1.9) 0 (0)


40

Classification

QTc interval prolongation is defined as ‘a finding of a cardiac dysrhythmia by abnormally long corrected QT interval’.15

Patients with a prolonged QTc interval are at higher risk of ventricular tachyarrhythmias, such as torsades de pointes.15

The CTCAE grading scale for QTc prolongation is shown in Table 14.

QTc interval prolongation

Table 14. CTCAE grading scale version 5.0 for QTc prolongation. Figure made by Pfizer from data in ref. 15.

Grade

1 Mild

2 Moderate

3 Severe

4 Life-threatening

QTc 450–480 ms QTc 481–500 msQTc ≥501 ms;

>60 ms change from baseline

Torsades de pointes or

polymorphic ventriculartachycardia

or signs/symptoms of seriousarrhythmia

CTCAE, Common Terminology Criteria for Adverse Event; QTc, QT-corrected.

Characterisation

Patients with uncontrolled or significant cardiovascular disease, including QTc interval prolongation at baseline, were not included in clinical studies.1

Automated machine-read QTc prolongation without accompanying arrhythmia has been observed.1 In the safety population of 1,272 patients who received at least one dose of BOSULIF® for newly diagnosed CP CML, previously treated CP, AP, or BP CML, or Ph+ ALL, four patients (0.3%) experienced QT corrected by Fridericia’s formula (QTcF) interval prolongation (>500 ms). Nine patients (0.8%) experienced QTcF increase >60 ms from baseline.1


41

Management

Before treatment

A baseline electrocardiogram (ECG) is recommended prior to initiating therapy with BOSULIF®.1

Hypokalaemia or hypomagnesaemia must be corrected prior to BOSULIF administration.1

BOSULIF has not been studied in patients with uncontrolled or significant cardiovascular disease (including QT interval prolongation) at baseline.1

BOSULIF should be administered with caution in patients:

• With a history of, or predisposition to, QTc prolongation1

• With uncontrolled or significant cardiac disease, including recent myocardial infarction, congestive heart failure, unstable angina or clinically significant bradycardia1

• Who are taking medications that are known to prolong the QT interval, such as (but not limited to) amiodarone, disopyramide, procainamide, quinidine and sotalol1

• Who are taking other medicinal products that may lead to QT prolongation, such as chloroquine, halofantrine, clarithromycin, haloperidol, methadone, domperidone and moxifloxacin1

On treatment

The use of ECG to monitor for an effect on the QTc interval is advisable, as clinically indicated. Potassium and magnesium levels should be monitored periodically during therapy.1


42

Serum lipase:• Elevation in serum lipase has been observed. Caution is recommended

in patients with previous history of pancreatitis1

• In case lipase elevations are accompanied by abdominal symptoms, BOSULIF® should be interrupted and appropriate diagnostic measures considered to exclude pancreatitis1

Infections:• BOSULIF may predispose patients to bacterial, fungal, viral,

or protozoan infections1

Severe skin reactions:• BOSULIF can induce severe skin reactions such as Stevens-Johnson

Syndrome and Toxic Epidermal Necrolysis1

• BOSULIF should be permanently discontinued in patients who experience a severe skin reaction during treatment1

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 BOSULIF1

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 outcome1

• Patients should be tested for HBV infection before initiating treatment with BOSULIF1

• 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 treatment1

• Carriers of HBV who require treatment with BOSULIF should be closely monitored for signs and symptoms of active HBV infection throughout therapy and for several months following termination of therapy1

Other special warnings and precautions for use


43

Women of childbearing potential:• Women of childbearing potential should be advised to use effective

contraception and avoid becoming pregnant while receiving BOSULIF®1

• In addition, the patient should be advised that vomiting or diarrhoea may reduce the efficacy of oral contraceptives by preventing full absorption1

Pregnancy:• BOSULIF is not recommended for use during pregnancy, or in women of

childbearing potential not using contraception1

• If BOSULIF is used during pregnancy, or the patient becomes pregnant while taking bosutinib, she should be apprised of the potential hazard to the foetus1

Breastfeeding:• It is unknown whether BOSULIF and its metabolites are excreted in human

milk. A potential risk to the breastfed infant cannot be excluded1

• Breastfeeding should be discontinued during treatment with BOSULIF1

Fertility• Men being treated with BOSULIF are advised to seek advice on

conservation of sperm prior to treatment because of the possibility of decreased fertility due to therapy with BOSULIF1

Fertility, pregnancy and lactation


44

1. BOSULIF®. Summary of Product Characteristics. 13th of November 2019. Available at: https://www.ema.europa.eu/en/documents/product-information/bosulif-epar-product-information_no.pdf. Accessed March 2020.

2. Jabbour EJ, Makenbaeva D, Lingohr-Smith L, et al. Use of real-world claim data to assess prevalence of comorbid conditions relevant to the treatment of chronic myelogenous leukemia based on National Comprehensive Cancer Network treatment guidelines. Clin Lymphoma Myeloma and Leuk. 2015;15(12):797–802.

3. Mohammadi M, Cao Y, Glimelius I, et al. The impact of comorbid disease history on all-cause and cancer-specific mortality in myeloid leukemia and myeloma – a Swedish population-based study. BMC Cancer 2015;15:850.

4. Bower H, Björkholm M, Dickman PW, et al. Life expectancy of patients with chronic myeloid leukemia approaches the life expectancy of the general population. J Clin Oncol. 2016;34:2851–2857.

5. Keller G, Schafhausen P, Brümmendorf TH. Bosutinib: a dual SRC/ABL kinase inhibitor for the treatment of chronic myeloid leukaemia. Expert Rev Hematol. 2009;2:489–497.

6. Cortes JE, Gambacorti-Passerini C, Deininger MW, et al. Bosutinib versus imatinib for newly-diagnosed chronic myeloid leukemia: results from the randomized BFORE trial. Including Cortes data supplement_2017.747162.docx J Clin Oncol. 2018;36(3):231–237.

7. Cortes JE, Khoury HJ, Kantarjian H, et al. Long-term evaluation of cardiac and vascular toxicity in patients with Philadelphia chromosome-positive leukemias treated with bosutinib. Am J Hematol. 2016;91(6):606–616.

8. National Comprehensive Cancer Network. Clinical practice guidelines in oncology. Chronic myelogenous leukemia version 3.2020. Available at: www.nccn.org/professionals/physician_gls/pdf/cml.pdf. Accessed March 2020.

9. Khoury HJ, Cortes JE, Kantarjian HM, et al. Bosutinib is active in chronic phase chronic myeloid leukemia after imatinib and/or nilotinib therapy failure. Blood 2012;119:3403–3412.

10. Cortes JE, Hagop M, Kantarjian HM. Safety and efficacy of bosutinib (SKI-606) in chronic phase Philadelphia chromosome-positive CML patients with resistance or intolerance to imatinib. Blood 2011;118:4567–4576.

11. Gambacorti-Passerini C, Brümmendorf TH, Kim D-W, et al. Bosutinib efficacy and safety in chronic phase chronic myeloid leukemia after imatinib resistance or intolerance: minimum 24-month follow-up. Am J Hematol. 2014;89:732–742.

12. Kantarjian HM, Cortes JE, Kim DW, et al. Bosutinib safety and management of toxicity in leukemia patients with resistance or intolerance to imatinib and other tyrosine kinase inhibitors. Blood 2014;123:1309–18.

13. US Food and Drug Administration. Don’t take this with that! Version 17th of December 2015. Available at: www.fda.gov/drugs/special-features/dont-take. Accessed March 2020.

14. Brümmendorf TH, Cortes JE, Khoury HJ, et al. Factors influencing long-term efficacy and tolerability of bosutinib in chronic phase chronic myeloid leukemia resistant or intolerant to imatinib. Including appendix Br J Haematol 2016.docx. Br J Haematol. 2016;172:97–110.

15. National Cancer Institute. Common terminology criteria for adverse events v5.0. Last updated 3rd of January 2018. Available at: ctep.cancer.gov/protocoldevelopment/electronic_applications/ctc.htm. Accessed March 2020

16. National Cancer Institute. Gastrointestinal complications (PDQ): health professional version. Version 28th of November 2018. Available at: www.cancer.gov/about-cancer/treatment/side-effects/constipation/gi-complications-hp-pdq#_8. Accessed March 2020.

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17. Benson AB III, Ajani JA, Catalano RB, et al. Recommended guidelines for the treatment of cancer treatment-induced diarrhea. J Clin Oncol. 2004;22:2918–2926.

18. National Cancer Institute. Eating hints: before, during, and after cancer treatment. Version January 2018. Available at: www.cancer.gov/publications/patient-education/eating-hints. Accessed March 2020.

19. National Comprehensive Cancer Network Clinical Practice Guidelines In Oncology. Antiemesis version 1.2020. Available at: www.nccn.org/professionals/physician_gls/pdf/antiemesis.pdf. Accessed March 2020.

20. Cortes JE, Kim DW, Kantarjian HM. Bosutinib versus imatinib in newly diagnosed chronic-phase chronic myeloid leukemia: results from the BELA trial. J Clin Oncol. 2012;30:3486–3492.

21. National Cancer Institute. Managing chemotherapy side effects. Skin and nail changes. 2009. Version 14th of June 2019. Available at: www.cancer.gov/about-cancer/treatment/side-effects/skin-nail-changes. Accessed March 2020.

22. Wagner LI, Cella D. Fatigue and cancer: causes, prevalence and treatment approaches. Br J Cancer 2004;91:822–828.

23. National Comprehensive Cancer Network Clinical Practice Guidelines in Oncology. Fatigue version 1.2020. Available at: www.nccn.org/professionals/physician_gls/pdf/fatigue.pdf. Accessed March 2020.

PP-BOS-NOR-0032Preparation date: April 23rd 2020


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Proteinkinasehemmer.ATC-nr.: L01X E14

TABLETTER, filmdrasjerte 100 mg, 400 mg og 500 mg: Hver tablett inneh.: Bosutinib 100 mg, resp. 400 mg og 500 mg, hjelpestoffer. Fargestoff: Titandioksid (E 171). 100 mg: Gult jernoksid (E 172). 400 mg: Gult og rødt jernoksid (E 172). 500 mg: Rødt jernoksid (E 172).

Indikasjoner: Behandling av voksne med nydiagnostisert Philadelphiakromosom-positiv kronisk myelogen leukemi (Ph+ KML) i kronisk fase (KF), samt Ph+ KML i KF, akselerert fase (AF) og blastfase (BF) som tidligere er behandlet med én eller flere tyrosinkinasehemmere (TKI) og hvor imatinib, nilotinib og dasatinib ikke anses som egnede behandlingsalternativer.

Dosering: Behandling bør startes opp av lege med erfaring i diagnostisering og behandling av KML. Nydiagnostisert KF Ph+ KML: Anbefalt dose 400 mg 1 gang daglig. KF, AF eller BF Ph+ KML med resistens/intoleranse mot tidligere behandling: Anbefalt dose 500 mg 1 gang daglig. I kliniske studier fortsatte behandlingen ved begge indikasjoner inntil sykdomsprogresjon eller til intoleranse. Dosejustering: Doser >600 mg/dag er ikke undersøkt og bør ikke gis. Doser <300 mg/dag er brukt, men effekt ikke fastslått. Dosejustering ved ikke-hematologiske bivirkninger: Dersom klinisk signifikant moderat eller alvorlig ikke-hematologisk toksisitet utvikles, bør behandlingen avbrytes, og kan gjenopptas med en dose redusert med 100 mg 1 gang daglig når toksisiteten er opphørt. Hvis hensiktsmessig, bør opptrapping til aktuell dagsdose før dosenedtrapping vurderes. Ved økning i levertransaminaser >5 × ULN, bør behandlingen avbrytes inntil forbedring til ≤2,5 × ULN, og deretter gjenopptas med 400 mg 1 gang daglig. Hvis bedring tar >4 uker bør seponering vurderes. Bør seponeres ved økning i transaminaser ≥3 × ULN samtidig med økning av bilirubin >2 × ULN og alkalisk fosfatase <2 × ULN. Ved diaré NCI CTCAE grad 3-4 bør behandlingen avbrytes, og gjenopptas med 400 mg 1 gang daglig ved bedring til grad ≤1. Dosejustering ved alvorlig eller vedvarende nøytropeni og trombocytopeni: Ved absolutt nøytrofiltall (ANC) <1 × 109/liter og/eller blodplater <50 × 109/liter: Avvent behandling inntil ANC ≥1 × 109/liter og blodplater ≥50 × 109/liter. Ved bedring innen 2 uker gjenopptas behandlingen med samme dose. Hvis blodverdiene forblir lave >2 uker gjenopptas behandlingen med dose redusert med 100 mg ved bedring. Ved gjentatt cytopeni gjenopptas behandlingen med dose redusert med ytterligere 100 mg ved bedring. Glemt dose: En ekstra dose skal ikke tas hvis det har gått >12 timer, men den vanlige dosen tas påfølgende dag. Spesielle pasientgrupper: Nedsatt nyrefunksjon: Tendens til økt eksponering ved moderat/alvorlig nedsatt nyrefunksjon. Ved moderat nedsatt nyrefunksjon (ClCR 30-50 ml/minutt) er anbefalt dose 300 mg eller 400 mg 1 gang daglig ved hhv. nydiagnostisert KF Ph+ KML og KF, AF eller BF Ph+ KML med resistens/intoleranse mot tidligere behandling. Ved alvorlig nedsatt nyrefunksjon (ClCR <30 ml/minutt) er anbefalt dose 200 mg eller 300 mg 1 gang daglig ved hhv. nydiagnostisert KF Ph+ KML og KF, AF eller BF Ph+ KML med resistens/intoleranse mot tidligere behandling. Doseopptrapping til 400 mg eller 500 mg 1 gang daglig ved moderat nedsatt nyrefunksjon (ved hhv. nydiagnostisert KF Ph+ KML og KF, AF eller BF Ph+ KML med resistens/intoleranse mot tidligere behandling), eller til 300 mg eller 400 mg 1 gang daglig ved alvorlig nedsatt nyrefunksjon (ved hhv. nydiagnostisert KF Ph+ KML og KF, AF eller BF Ph+ KML med resistens/intoleranse mot tidligere behandling), kan vurderes for de som ikke har opplevd alvorlige eller vedvarende moderate bivirkninger, og ved utilstrekkelig hematologisk, cytogenetisk eller molekylær respons. Barn og ungdom <18 år: Sikkerhet og effekt ikke fastslått. Data mangler. Eldre: Forsiktighet bør utvises. Hjertesykdom: Forsiktighet bør utvises. Nylig eller pågående klinisk signifikant gastrointestinal sykdom: Forsiktighet bør utvises. Administrering: Tas 1 gang daglig om morgenen. Skal tas med mat, men samtidig inntak av grapefrukt/grapefruktjuice skal unngås. Skal svelges hele med vann. Skal ikke deles eller knuses.

Kontraindikasjoner: Overfølsomhet for innholdsstoffene. Nedsatt leverfunksjon.

Forsiktighetsregler: Unormal leverfunksjon: Behandling er assosiert med økt ALAT- og ASAT-nivå. Leverfunksjonstester bør tas før behandlingsstart og månedlig de første 3 behandlingsmånedene, og som klinisk indisert. Forhøyede transaminaser bør håndteres med midlertidig behandlingsavbrudd (dosereduksjon vurderes etter bedring til grad 1 eller baseline) og/eller seponering. Økte transaminaser, spesielt samtidig med økt bilirubin, kan være tidlig tegn på legemiddelindusert leverskade. Diaré og oppkast: Forsiktighet bør utvises, spesielt ved nylig eller pågående klinisk signifikant gastrointestinal sykdom. Standardbehandling gis, inkl. legemidler som motvirker diaré, kvalmestillende midler og/eller væskeerstatning. Kan håndteres med midlertidig avbrudd, dosereduksjon og/eller seponering. Samtidig bruk av domperidon bør unngås, og kun brukes dersom andre legemidler ikke har effekt. Myelosuppresjon: Blodtelling bør utføres ukentlig 1. behandlingsmåned, deretter månedlig eller som klinisk indisert. Bør håndteres med midlertidig avbrudd, dosereduksjon og/eller seponering. Væskeretensjon: Kan være assosiert med behandlingen, inkl. perikardial effusjon, pleuraeffusjon, lungeødem og/eller perifert ødem. Pasienten bør monitoreres og gis standardbehandling. Kan håndteres med midlertidig avbrudd, dosereduksjon og/eller seponering. Serumlipase: Forsiktighet anbefales ved tidligere pankreatitt. Ved forhøyet lipase ledsaget av abdominale symptomer, bør behandlingen avbrytes og pankreatitt utelukkes. Infeksjoner: Kan predisponere for infeksjoner med bakterier, sopp, virus eller parasitter. Proarytmisk potensiale: Forsiktighet bør utvises ved tidligere eller predisposisjon for QTC-forlengelse, ved ukontrollert eller signifikant hjertesykdom, inkl. nylig hjerteinfarkt, kongestiv hjertesvikt, ustabil angina eller klinisk signifikant bradykardi, eller ved bruk av legemidler kjent for å forlenge QTC. Hypokalemi og hypomagnesemi kan forsterke effekten ytterligere. Monitorering av effekt på QTC og EKG ved baseline anbefales før behandlingsstart. Hypokalemi og hypomagnesemi skal korrigeres før bosutinibadministrering, og bør monitoreres periodisk under behandlingen. Nedsatt nyrefunksjon: Behandling kan gi klinisk signifikant nedsatt nyrefunksjon hos KML-pasienter. Reduksjon over tid i estimert GFR er sett i kliniske studier, både hos pasienter med allerede behandlet og avansert KML og hos behandlingsnaive. Vurdering av nyrefunksjon før behandlingsstart og nøye overvåkning under behandling er viktig. Spesielt ved eksisterende nyreproblemer, eller ved risiko for renal dysfunksjon, inkl. ved samtidig bruk av legemidler med potensiale for nefrotoksisitet, f.eks. diuretika, ACE-hemmere, angiotensinreseptorblokkere og NSAID. Økt bosutinibeksponering ved moderat og alvorlig nedsatt nyrefunksjon er sett, og dosereduksjon anbefales. I en farmakokinetisk populasjonsanalyse på KML-pasienter ble det sett en tendens til økt eksponering (AUC) ved moderat og alvorlig nedsatt nyrefunksjon. Kliniske data er svært begrensede hos KML-pasienter med moderat nedsatt nyrefunksjon som får en opptrappet dose med 600 mg. Alvorlige hudreaksjoner: Kan fremkalles, f.eks. Stevens-Johnsons syndrom (SJS) og toksisk epidermal nekrolyse (TEN). Skal seponeres permanent ved alvorlig hudreaksjon under behandling.


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Tumorlysesyndrom: Pga. risiko for tumorlysesyndrom, anbefales korrigering av klinisk signifikant dehydrering og behandling av høye urinsyrenivåer før behandlingsstart. Hepatitt B-reaktivering: Reaktivering av hepatitt B hos kroniske bærere av viruset har oppstått etter behandling med Bcr-Abl-TKI. Noen tilfeller resulterte i akutt leversvikt eller fulminant hepatitt, som igjen førte til levertransplantasjon eller død. Pasienten bør testes for HBV-infeksjon før oppstart. Ekspert på leversykdom og behandling av HBV bør konsulteres før oppstart ved positiv HBV-serologi (inkl. de med aktiv sykdom) og hos de som tester positivt på HBV-infeksjon i løpet av behandlingen. Hvis bosutinibbehandling er nødvendig ved positiv HBV-serologi, bør pasienten overvåkes nøye for symptomer på aktiv HBV-infeksjon under behandling og i flere måneder etter avsluttet behandling. Bilkjøring og bruk av maskiner: Bør unngås ved svimmelhet, fatigue, synsforstyrrelser eller andre bivirkninger med potensiell innvirkning på evnen til å kjøre bil eller bruke maskiner.

Interaksjoner: For utfyllende informasjon om relevante interaksjoner, bruk interaksjonsanalyse.

Samtidig bruk av kraftige eller moderate CYP3A-hemmere bør unngås, da de øker plasmakonsentrasjonen av bosutinib. Vis forsiktighet ved samtidig bruk av svake CYP3A-hemmere. Dersom kraftig eller moderat CYP3A-hemmer må administreres under behandling, bør behandlingsavbrudd eller dosereduksjon vurderes. Samtidig bruk av kraftige eller moderate CYP3A-induktorer bør unngås, da de reduserer plasmakonsentrasjonen av bosutinib. Vis forsiktighet ved samtidig bruk av svake CYP3A-induktorer. Forsiktighet bør utvises ved samtidig bruk av protonpumpehemmere (PPI). Korttidsvirkende antacida bør vurderes som et alternativ til PPI, og bosutinib og antacida bør gis til forskjellig tid (dvs. ta bosutinib om morgenen og antacida på kvelden) dersom mulig. Bør brukes med forsiktighet sammen med andre legemidler som kan føre til QT-forlengelse.

Graviditet, amming og fertilitet: Graviditet: Begrensede data. Dyrestudier viser reproduksjonstoksisitet. Bør ikke brukes under graviditet eller til fertile kvinner som ikke bruker antikonsepsjon. Amming: Skal ikke brukes. Overgang i morsmelk er ukjent. Risiko for barn som ammes kan ikke utelukkes. Fertilitet: Kan potensielt svekke reproduksjonsfunksjon og fertilitet. Fertile kvinner bør bruke sikker prevensjon under behandlingen og i minst 1 måned etter siste dose for å unngå graviditet. Menn bør søke råd om oppbevaring av sæd før behandling.

Bivirkninger: Svært vanlige (≥1/10): Blod/lymfe: Trombocytopeni (inkl. redusert platetall), nøytropeni (inkl. redusert antall nøytrofile), anemi (inkl. redusert hemoglobin). Gastrointestinale: Diaré, oppkast, kvalme, abdominale smerter (inkl. abdominalt ubehag, øvre og nedre abdominalsmerter, abdominal ømhet, gastrointestinal smerte). Hud: Utslett (inkl. generalisert, makulært, makulopapulært, papulært og kløende utslett). Infeksiøse: Luftveisinfeksjon (inkl. øvre/nedre, samt viral luftveisinfeksjon), nasofaryngitt. Lever/galle: Økt ALAT og ASAT. Luftveier: Dyspné, hoste. Muskel-skjelettsystemet: Artralgi, ryggsmerter. Nevrologiske: Hodepine. Stoffskifte/ernæring: Nedsatt appetitt. Undersøkelser: Økt lipase (inkl. hyperlipasemi). Øvrige: Pyreksi, asteni, ødem (inkl. ansiktsødem, lokalt ødem, perifert ødem), fatigue (inkl. malaise). Vanlige (≥1/100 til <1/10): Blod/lymfe: Leukopeni (inkl. redusert antall hvite blodceller). Gastrointestinale: Gastritt, gastrointestinal blødning (inkl. analblødning, mageblødning, tarmblødning, nedre gastrointestinal blødning, rektalblødning). Hjerte/kar: Perikardial effusjon, QTC-forlengelse på EKG (inkl. langt QTC-syndrom), hypertensjon (inkl. økt blodtrykk, økt systolisk blodtrykk, essensiell hypertensjon, hypertensiv krise). Hud: Urticaria, akne, pruritus. Infeksiøse: Pneumoni (inkl. atypisk pneumoni), influensa, bronkitt. Lever/galle: Hepatotoksisitet (inkl. hepatitt, toksisk hepatitt, leversykdom), unormal leverfunksjon (inkl. unormal leverfunksjonstest, økt leverfunksjon, økt transaminase), økt bilirubin i blod (inkl. hyperbilirubinemi), økt γ-GT. Luftveier: Pleuraeffusjon. Muskel-skjelettsystemet: Myalgi. Nevrologiske: Svimmelhet, dysgeusi. Nyre/urinveier: Akutt nyresvikt, nyresvikt, nedsatt nyrefunksjon. Stoffskifte/ernæring: Dehydrering, hyperkalemi, hypofosfatemi. Undersøkelser: Økt blodkreatinin, økt amylase, økt CK i blod. Øre: Tinnitus. Øvrige: Brystsmerter (inkl. ubehag i brystet), smerter. Mindre vanlige (≥1/1000 til <1/100): Blod/lymfe: Febril nøytropeni, granulocytopeni. Gastrointestinale: Pankreatitt (inkl. akutt pankreatitt). Hjerte/kar: Perikarditt. Hud: Eksfoliativt utslett, legemiddelutslett. Immunsystemet: Anafylaktisk sjokk, hypersensitivitet. Lever/galle: Leverskade (inkl. legemiddelindusert leverskade). Luftveier: Pulmonal hypertensjon, respirasjonssvikt, akutt lungeødem. Svulster/cyster: Tumorlysesyndrom. Sjeldne (≥1/10 000 til <1/1000): Hud: Erythema multiforme. Ukjent frekvens: Hud: SJS, TEN.

Overdosering/Forgiftning: Begrenset erfaring. Behandling: Pasienten bør overvåkes og støttebehandling igangsettes. Se Giftinformasjonens anbefalinger for proteinkinasehemmere L01X E på www.felleskatalogen.no.

Egenskaper: Virkningsmekanisme: Hemmer BCR-ABL-kinase som fører til KML. Er i tillegg hemmer av Src-kinasefamilien, inkl. Src, Lyn og Hck. Absorpsjon: Etter en enkeltdose bosutinib (500 mg) med mat til friske er absolutt biotilgjengelighet 34%. Gjennomsnittlig Tmax er 6 timer. En proporsjonal økning i AUC og Cmax er vist over et doseområde fra 200-600 mg. Mat øker Cmax

1,8 ganger og AUC med 1,7 ganger. Proteinbinding: Ca. 96% hos friske. Fordeling: Vd ca. 2331 liter. Halveringstid: Ca. 35,5 timer. Clearance ca. 61,9 liter/time. Metabolisme: Primært i lever. Utskillelse: Primært via feces, noe i urin.

Pakninger og priser: 100 mg: 28 stk.1 (blister) 479904. 400 mg: 28 stk.1 (blister) 558417. 500 mg: 28 stk.1 (blister) 492377.

Refusjon:

1H-resept: L01X E14_1 Bosutinib

Sist endret: 30.07.2019

Basert på SPC godkjent av SLV/EMA: 13.11.2019


PP-BOS-NOR-0032Preparation date: April 23rd 2020.


Documents

EXPECTATIONS - pfizer.no HCP guide.pdf · Figure made by Pfizer from data in ref. 6. Figure 2. BFORE: proportion of patients achieving BCR-ABL1 ≤10% at 3 months. Figure made by