Special Warning : אזהרת שימוש

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/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’.

Cardiovascular Toxicity
BOSULIF can cause cardiovascular toxicity including cardiac failure, left ventricular dysfunction, and cardiac ischaemic events. Cardiac failure events occurred more frequently in previously treated patients than in patients with newly diagnosed CML and were more frequent in patients with advanced age or risk factors, including previous medical history of cardiac failure. Cardiac ischaemic events occurred in both previously treated patients and in patients with newly diagnosed CML. Monitor patients for signs and symptoms consistent with cardiac failure and cardiac ischaemia and treat as clinically indicated.
Interrupt, dose reduce, or discontinue BOSULIF as necessary.

Effects on Driving

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.