Bosulif

/ Pfizer

Therapy should be initiated by a physician experienced in the diagnosis and the treatment of patients with CML.
Newly-diagnosed CP Ph+ CML: The recommended dose is 400 mg bosutinib once daily.
CP, AP, or BP Ph+ CML with resistance or intolerance to prior therapy: The recommended dose is 500 mg Bosutinib once daily.
In clinical trials for both indications, treatment with bosutinib continued until disease progression 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. 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.
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.
Haematological adverse reactions: Dose reductions are recommended for severe or persistent neutropenia and thrombocytopenia as described in Table 1 at the attached doctor’s leaflet.
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.
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.
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.
In patients with severe renal impairment (CLcr < 30 mL/min, calculated by the Cockroft-Gault formula), the recommended dose of bosutinib is 300 mg daily.
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.
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.
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: Bosulif should be taken orally once daily with food. 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.

Treatment of adult patients with:
– newly-diagnosed chronic phase (CP) Philadelphia chromosome-positive chronic myelogenous leukaemia (Ph+ CML).
– chronic phase (CP), accelerated phase (AP), and blast phase (BP) Philadelphia chromosome positive chronic myelogenous leukaemia (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.

Hypersensitivity to the active substance or to any of the excipients. Hepatic impairment.

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.
Diarrhea 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 .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.
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.
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 excluding pancreatitis
Infections: Bosutinib may predispose patients to bacterial, fungal, viral or protozoan infections.
Pro-arrhythmic 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). 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.
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.
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.
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.
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.
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.
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.
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.
Cardiovascular Toxicity: Bosutinib can cause cardiovascular toxicity including cardiac failure and cardiac ischaemic events. Cardiac failure events occurred more frequently in previously treated patients than in patients with newly diagnosed CML and were more frequent in patients with advanced age or risk factors, including previous medical history of cardiac failure. Cardiac ischaemic events occurred in both previously treated patients and in patients with newly diagnosed CML and were more common in patients with coronary artery disease risk factors, including history of diabetes, body mass index greater than 30, hypertension and vascular disorders.
Patients should be monitored for signs and symptoms consistent with cardiac failure and cardiac ischaemia and treated as clinically indicated. Cardiovascular toxicity can also be managed by dose interruption, dose reduction and/or discontinuation of bosutinib.
See prescribing information for full details.

Very common: Respiratory tract infection (including lower respiratory tract infection, respiratory tract infection viral, upper respiratory tract infection, viral upper respiratory tract infection), nasopharyngitis, thrombocytopenia (including platelet count decreased), neutropenia (including neutrophil count decreased), anaemia (including haemoglobin decreased, red blood cell count decreased), decreased appetite, dizziness, headache, pleural effusion, dyspnoea, cough, diarrhoea, vomiting, nausea, abdominal pain (including abdominal discomfort, abdominal pain lower, abdominal pain upper, abdominal tenderness, gastrointestinal pain), rash (including rash macular, rash maculo-papular, rash papular, rash pruritic), pruritus, arthralgia, back pain, 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), lipase increased (including hyperlipasaemia), alanine aminotransferase increased (including alanine aminotransferase abnormal), aspartate aminotransferase increased, blood creatinine increased,
Common: Pneumonia (including atypical pneumonia, pneumonia bacterial, pneumonia fungal, pneumonia necrotising, pneumonia streptococcal), influenza (including influenza h1n1), bronchitis, leukopenia (including white blood cell count decreased), drug hypersensitivity, dehydration, hyperkalaemia (including blood potassium increased), hypophosphataemia (including blood phosphorus decreased), dysgeusia, tinnitus, hypertension (including blood pressure increased, blood pressure systolic increased, essential hypertension, hypertensive crisis), pericardial effusion, Cardiac failure (including Cardiac failure, Cardiac failure acute, Cardiac failure chronic, Cardiac failure congestive, Cardiogenic shock, Cardiorenal syndrome, Ejection fraction decreased, Left ventricular failure), Cardiac ischaemic events (including Acute coronary syndrome, Acute myocardial infarction, Angina pectoris, Angina unstable, Arteriosclerosis coronary artery, Coronary artery disease, Coronary artery occlusion, Coronary artery stenosis, Myocardial infarction, Myocardial ischaemia, Troponin increased), pulmonary hypertension (including pulmonary arterial hypertension, pulmonary arterial pressure increased), respiratory failure, gastrointestinal haemorrhage (including anal haemorrhage, gastric haemorrhage, intestinal haemorrhage, lower gastrointestinal haemorrhage, rectal haemorrhage, upper gastrointestinal haemorrhage), pancreatitis (including pancreatitis acute), gastritis, hepatotoxicity (including hepatitis, hepatitis toxic, liver disorder), hepatic function abnormal (including hepatic enzyme increased, liver function test abnormal, liver function test increased, transaminases increased), photosensitivity reaction (including polymorphic light eruption), urticaria, acne, myalgia, acute kidney injury, renal failure, renal impairment, chest pain (including chest discomfort), pain, 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)
See prescribing information for full details.

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.

Pregnancy: 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 this drug. In addition, the patient should be advised that vomiting or diarrhea may reduce the efficacy of oral contraceptives by preventing full absorption. This drug is not recommended for use during pregnancy, or in women of childbearing potential not using contraception.
Lactation: It is unknown whether bosutinib and its metabolites are excreted in human milk. A potential risk to the breast-feeding infant cannot be excluded. Breast-feeding should be discontinued during treatment with bosutinib.
See prescribing information for full details.

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.

Before/after meal: should be taken with food.
Fertility: Based on non-clinical findings, Bosutinib has the potential to impair reproductive function and fertility in humans.
Effects on ability to drive and use machines: This drug 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.