Bosulif 100 mg film-coated tablets

Bosulif 500 mg film-coated tablets

Bosulif 100 mg film-coated tablets

Each film-coated tablet contains 100 mg bosutinib (as monohydrate).

Bosulif 500 mg film-coated tablets

Each film-coated tablet contains 500 mg bosutinib (as monohydrate).

For the full list of excipients, see section 6.1.

Film-coated tablet.

Bosulif 100 mg film-coated tablets

Yellow oval biconvex, film-coated tablet debossed with “Pfizer” on one side and “100” on the other side.

Bosulif 500 mg film-coated tablets

Red oval biconvex, film-coated tablet debossed with “Pfizer” on one side and “500”on the other side.

Bosulif is indicated for the treatment of adult patients with 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) and for whom imatinib, nilotinib and dasatinib are not considered appropriate treatment options.

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

Posology

The recommended dose is 500 mg bosutinib once daily. In clinical trials, treatment with bosutinib continued until disease progression or until it was no longer tolerated by the patient.

Dose adjustments

In the Phase 2 clinical trial of adult patients with previously treated Ph+ leukaemia, dose escalation to 600 mg once daily with food was allowed in patients who did not experience severe or persistent moderate-adverse reactions, under any of the following circumstances. A total of 85 patients (15.2%) who started treatment at </= 500 mg (n=558) received dose escalations to 600 mg of bosutinib.

Circumstances for dose escalation

- Failure to achieve complete haematologic response (CHR) by week 8

- Failure to achieve complete cytogenetic response (CCyR) by week 12

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

Dose adjustments for adverse reactions

Dose adjustments for non-haematologic adverse reactions

If clinically significant moderate or severe non-haematological toxicity develops, bosutinib should be interrupted, and may be resumed at 400 mg once daily once the toxicity has resolved. If clinically appropriate, re-escalation of the dose to 500 mg once daily should be considered (see section 4.4).

Elevated liver transaminases: If elevations in liver transaminases > 5 x institutional upper limit of normal (ULN) occur, bosutinib should be interrupted until recovery to ≤ 2.5xULN 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 ≥ 3xULN occur concurrently with bilirubin elevations >2xULN and alkaline phosphatase <2xULN, bosutinib should be discontinued (see section 4.4).

Diarrhoea: For NCI CTCAE Grade 3-4 diarrhoea, bosutinib should be interrupted and may be resumed at 400 mg once daily upon recovery to grade ≤1 (see section 4.4).

Dose adjustments for haematologic adverse reactions

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

Table 1 – Dose adjustments for neutropenia and thrombocytopenia

^a ANC = absolute neutrophil count

Special populations

Elderly patients (≥65 years)

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

Renal impairment

Patients with serum creatinine >1.5xULN were excluded from CML studies. Increasing exposure (AUC) in patients with moderate and severe renal impairment during studies was observed.

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

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

Dose escalation to 500 mg once daily for patients with moderate renal impairment or to 400 mg once daily in patients with severe renal impairment may be considered in those who did not experience severe or persistent moderate adverse reactions, under any of the following circumstances.

Circumstances for dose escalation

- Failure to achieve complete haematologic response (CHR) by week 8

- Failure to achieve complete cytogenetic response (CCyR) by week 12

Cardiac disorders

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

Recent or ongoing clinically significant gastrointestinal disorder

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

Paediatric population

The safety and efficacy of bosutinib in children 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 (see section 5.2). If a dose is missed the patient should not be given an additional dose. The patient should take the usual prescribed dose on the following day.

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

Hepatic impairment (see sections 5.1 and 5.2).

Liver function abnormalities

Treatment with bosutinib is associated with elevations in serum transaminases (ALT, 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 three 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, these events 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 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 QT 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 and pulmonary oedema. Patients should be monitored and managed using standard-of-care treatment. In addition, these events 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

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

Proarrhythmic potential

Automated machine-read QTc prolongation without accompanying arrhythmia has been observed. Bosulif 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 QT interval (e.g., anti-arrhythmic medicinal products and other substances that may prolong QT [section 4.5]). The presence of hypokalaemia and hypomagnesaemia may further enhance this effect.

Monitoring for an effect on the QTc interval is advisable and a baseline ECG is recommended prior to initiating therapy with Bosulif and as clinically indicated. Hypokalaemia or hypomagnesaemia must be corrected prior to Bosulif 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. Patients with pretreated and advanced stage Ph+ leukemias in the global single-arm Phase 1/2 clinical trial showed a median decline from baseline in eGFR of 5.29 ml/min/1.73 m2 at 3 months, of 7.11 ml/min/1.73 m2 at 6 months and of 10.92 ml/min/1.73 m2 at 36 months. Treatment-naïve CML patients showed a median decline from baseline in eGFR of 5.06 ml/min/1.73 m2 at 3 months, of 7.65 ml/min/1.73 m2 at 6 months and of 15.62 ml/min/1.73 m² at 48 months. 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 preexisting 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, 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 > 1.5xULN 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 is very limited (n = 3) for CML patients with moderate renal impairment receiving an escalated dose of 600 mg 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 tyrosine kinase inhibitors. 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 Bosulif. Experts in liver disease and in the treatment of hepatitis B should be consulted before treatment is initiated in patients with positive hepatitis B serology (including those with active disease) and for patients who test positive for HBV infection during treatment. 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 therapy (see section 4.8).

CYP3A inhibitors

The concomitant use of Bosulif 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 Bosulif treatment, an interruption of Bosulif therapy or a dose reduction in Bosulif should be considered.

CYP3A inducers

The concomitant use of Bosulif 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).

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 Bosulif treatment, an interruption of Bosulif therapy or a dose reduction in Bosulif should be considered.

In a study of 24 healthy subjects in whom five 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 C_max 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 C_max 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 Bosulif 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 Bosulif 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 Bosulif.

Following concomitant administration of a single dose bosutinib with six daily doses of 600 mg rifampicin, in 24 healthy subjects in fed state bosutinib exposure (C_max 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 Bosulif concomitantly with proton pump inhibitors (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 C_max 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 C_max 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.

Anti-arrhythmic medicinal products and other substances that may prolong QT

Bosutinib should be used with caution in patients who have or may develop prolongation of QT, including those patients taking anti-arrhythmic medicinal products such as amiodarone, disopyramide, procainamide, quinidine and sotalol or other medicinal products that may lead to QT prolongation such as chloroquine, halofantrine, clarithromycin, domperidone, haloperidol, methadone and moxifloxacin (see section 4.4).

Women of childbearing potential

Women of childbearing potential should be advised to use effective contraception and avoid becoming pregnant while receiving Bosulif. In addition, the patient should be advised that vomiting or diarrhoea may reduce the efficacy of oral contraceptives by preventing full absorption.

Pregnancy

There are limited amount of data in pregnant women from the use of Bosulif. Studies in animals have shown reproductive toxicity (see section 5.3). Bosulif is not recommended for use during pregnancy, or in women of childbearing potential not using contraception. If Bosulif is used during pregnancy, or the patient becomes pregnant while taking Bosulif, she should be apprised of the potential hazard to the foetus.

Breast-feeding

It is unknown whether bosutinib and its metabolites are excreted in human milk. A study of [¹⁴C] radiolabelled bosutinib in rats demonstrated excretion of bosutinib-derived radioactivity in breast milk (see section 5.3). A potential risk to the breast-feeding infant cannot be excluded. Breast-feeding should be discontinued during treatment with bosutinib.

Fertility

Based on non-clinical findings, bosutinib has the potential to impair reproductive function and fertility in humans (see section 5.3).

Bosulif 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.

Summary of safety profile

A total of 870 Ph+ leukaemia patients received at least 1 dose of single-agent bosutinib. These patients were either newly diagnosed, Ph+ chronic phase CML or were resistant or intolerant to prior therapy with Ph+ chronic, accelerated, or blast phase CML or Ph+ acute lymphoblastic leukaemia (ALL). Of these patients, 248 are from the Phase 3 study in previously untreated CML patients, 570 and 52 are from two Phase 1/2 studies in previously treated Ph+ leukaemias. The median duration of therapy was 16.6 months (range: 0.03 to 30.4 months), 11 months (range: 0.03 to 55.1 months), and 5.5 months (range: 0.3 to 30.4 months), respectively.

At least 1 adverse reaction of any toxicity grade was reported for 848 (97.5%) patients. The most frequent adverse reactions reported for ≥20% of patients were diarrhoea (78.5%), nausea (42.1%), thrombocytopenia (38.5%), vomiting (37.1%), abdominal pain (33.4%), rash (32.4%), anaemia (27.4%), pyrexia (23.4%), and alanine aminotranserase increased (22.3%). At least 1 Grade 3 or Grade 4 adverse reaction was reported for 531 (61.0%) patients. The Grade 3 or Grade 4 adverse reactions reported for ≥5% of patients were thrombocytopenia (25.4%), anaemia (12.3%), neutropenia (11.5%), alanine aminotransferase increased (10.2%), diarrhoea (9.1%), rash (6.1%), lipase increased (5.2%) and aspartate aminotransferase increased (5.0%).

Tabulated list of adverse reactions

The following adverse reactions were reported in patients in bosutinib clinical studies (Table 2). These represent an eva luation of the adverse reaction data from 870 patients with newly diagnosed Ph+ chronic phase CML or with Ph+ chronic, accelerated, or blast phase CML or Ph+ acute lymphoblastic leukaemia (ALL) resistant or intolerant to prior therapy and who have received at least 1 dose of single-agent bosutinib. These adverse reactions are presented by system organ class and frequency. Frequency categories are defined as: very common (≥ 1/10), common (≥ 1/100 to < 1/10), uncommon (≥ 1/1,000 to < 1/100), rare (≥ 1/10,000 to < 1/1,000), very rare (< 1/10,000), not known (cannot be estimated from the available data). Within each frequency grouping, adverse reactions are presented in order of decreasing seriousness.

Table 2 - Adverse reactions for bosutinib

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