Bozulif

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT BOZULIF (BOSULIF®)

Composition:

Active substance: bosutinib;

1 tablet of 100 mg contains 103.40 mg of bosutinib monohydrate, equivalent to 100 mg of bosutinib;

1 tablet of 500 mg contains 516.98 mg of bosutinib monohydrate, equivalent to 500 mg of bosutinib;

Excipients: microcrystalline cellulose, sodium croscarmellose, poloxamer 188, povidone, magnesium stearate;

coating of 100 mg tablet: Opadry II Yellow 85F12390 (polyvinyl alcohol, titanium dioxide, macrogol/polyethylene glycol 3350, talc, iron oxide yellow (E 172));

coating of 500 mg tablet: Opadry II Red 85F15642 (polyvinyl alcohol, titanium dioxide, macrogol/polyethylene glycol 3350, talc, iron oxide red (E 172)).

Pharmaceutical form. Film-coated tablets.

Main physicochemical properties:

100 mg tablets:

yellow, oval, biconvex film-coated tablets, imprinted with "Pfizer" on one side and "100" on the other;

500 mg tablets:

red, oval, biconvex film-coated tablets, imprinted with "Pfizer" on one side and "500" on the other.

Pharmacotherapeutic group.

Antineoplastic agents. Protein kinase inhibitors. BCR-ABL tyrosine kinase inhibitors. Bosutinib. ATC code L01E A04.

Pharmacological Properties

Mechanism of Action

Bosutinib belongs to the pharmacological class of kinase inhibitors. The drug inhibits the breakpoint cluster region-Abelson (BCR-ABL) kinase, which is responsible for the development of chronic myeloid leukemia (CML). Additionally, bosutinib is an inhibitor of the Src family of kinases, including Src, Lyn, and Hck kinases. Bosutinib has minimal inhibitory activity against PDGF and c-Kit receptors.

In in vitro studies, bosutinib inhibited proliferation and survival of established CML cell lines, Ph+ acute lymphoblastic leukemia (ALL) cell lines, and primary primitive CML cells isolated from patients. Furthermore, bosutinib inhibited 16 out of 18 imatinib-resistant forms of BCR-ABL expressed in murine myeloid cell lines. In nude mice, bosutinib treatment resulted in reduced tumor size (CML), and inhibited the growth of myeloid tumors expressing imatinib-resistant forms of BCR-ABL in mice. Bosutinib also inhibits tyrosine kinase receptors c-Fms, EphA and EphB, Trk family kinases, Axl family kinases, Tes family kinases, several members of the ErbB family, the non-receptor tyrosine kinase Csk, serine/threonine kinases of the Ste20 family, and two calmodulin-dependent kinases.

Pharmacodynamics

An exposure–response analysis for efficacy in clinical trials showed a relationship between drug exposure and higher probability of response. An exposure–response analysis for safety in clinical trials demonstrated a link between drug exposure and increased likelihood of adverse reactions.

Cardiac Electrophysiology

Following a single oral 500 mg dose of Bosulif in combination with ketoconazole (a strong CYP3A inhibitor), Bosulif did not clinically significantly prolong the QT interval.

Clinical Studies

Chronic Phase Philadelphia Chromosome-Positive Chronic Myeloid Leukemia (CP Ph+ CML), Newly Diagnosed

The efficacy of Bosulif in patients with newly diagnosed CP Ph+ CML was evaluated in the BFORE study (an open-label, multicenter, phase III trial involving adult patients with newly diagnosed CML in chronic phase, compared to imatinib treatment).

The BFORE study was a double-open, randomized, multicenter trial designed to assess the efficacy and safety of monotherapy with Bosulif 400 mg once daily compared to monotherapy with imatinib 400 mg once daily in adult patients with newly diagnosed CP Ph+ CML. A total of 536 patients (268 patients in each group) with Ph+ or Ph- CP CML, newly diagnosed (intent-to-treat [ITT] population), were randomized, including 487 patients with Ph+ CML who had expression of b2a2 and/or b3a2 transcripts and BCR-ABL copy number > 0 prior to study initiation (modified intent-to-treat [mITT] population).

Randomization was stratified by Sokal score and geographic region. All patients received treatment and/or were followed for up to 5 years (240 weeks). Efficacy was evaluated in the mITT population. The primary efficacy endpoint was major molecular response (MMR) at month 12 (week 48) of the study, defined as BCR-ABL ≤ 0.1% on the international scale (corresponding to a ≥ 3-log reduction from standardized baseline levels), with assessment of at least 3000 ABL transcripts by a central laboratory. Additional efficacy endpoints included complete cytogenetic response (CCyR) at 12 months, defined as absence of Ph+ metaphases in the analysis of ≥ 20 metaphases of stained chromosomes obtained from bone marrow aspirate, or MMR in the absence of adequate cytogenetic assessment, and MMR at month 18 (week 72) of the study.

In this study, 57% of the mITT population were male, 78% were Caucasian, and 19% were aged 65 years or older. The median age was 53 years. At baseline, the distribution of Sokal risk groups was similar between patients receiving bosutinib and those receiving imatinib (low risk: 35% and 39%; intermediate risk: 44% and 38%; high risk: 22% and 22%, respectively). After at least 12 months of follow-up, 78% of 246 patients receiving bosutinib and 72% of 239 patients receiving imatinib continued treatment; after at least 60 months of follow-up, 60% and 60% of patients, respectively, were still continuing treatment. The median duration of treatment was 55.1 months for Bosulif and 55.0 months for imatinib.

Efficacy results from the BFORE study are presented in Table 1.

Table 1. Summary of major molecular response (MMR) and complete cytogenetic response (CCyR) by treatment group in the mITT population

The MMR rate at month 12 for all randomized patients (ITT population) corresponded to the rate in the mITT population (47% [95% CI: 41; 53] in the bosutinib treatment group and 36% [95% CI: 30; 42] in the imatinib treatment group; odds ratio 1.57 [95% CI: 1.10; 2.22]). The MMR rate at month 60 (week 240) in the mITT population was 74% (95% CI: 69; 80) in the bosutinib treatment group and 66% (95% CI: 60; 72) in the imatinib treatment group; odds ratio 1.52 (95% CI: 1.02; 2.25). The MMR rate at month 60 in the ITT population also corresponded to the mITT population results (1.57 [95% CI: 1.08; 2.28]).

After 60 months of follow-up, the median time to MMR among patients achieving a response was 9.0 months for bosutinib and 11.9 months for imatinib.

At month 60, MMR rates within each Sokal risk group for patients receiving bosutinib and imatinib, respectively, were 78% and 72% for low risk, 74% and 67% for intermediate risk, and 68% and 52% for high risk.

After 60 months of observation, progression to accelerated phase or blast crisis of CML occurred in 6 patients (2%) in the bosutinib group and in 7 patients (3%) in the imatinib group.

After 60 months of follow-up, the overall survival rate was 95% (95% CI: 91; 97) in the bosutinib group and 94% (95% CI: 90; 96) in the imatinib group.

Chronic myeloid leukemia (CML) with Philadelphia chromosome-positive (Ph+) in accelerated phase, blast crisis, and chronic phase in cases of intolerance or ineffectiveness of imatinib

Study 200 (NCT00261846) – a non-comparative, open-label, multicenter study involving patients with CML resistant or intolerant to prior therapy – was conducted to evaluate the efficacy and safety of bosutinib 500 mg once daily in patients with CML who were intolerant or resistant to imatinib therapy. The trial included separate patient cohorts with CML in accelerated phase, blast crisis, or chronic phase who had previously received either one tyrosine kinase inhibitor (TKI) (imatinib) or multiple TKIs (treatment with dasatinib and/or nilotinib after imatinib). Imatinib resistance was defined as failure to achieve or maintain any hematologic improvement within 4 weeks; inability to achieve complete hematologic response (CHR) after 3 months of therapy, cytogenetic response after 6 months of therapy, or major cytogenetic response (MCyR) after 12 months of therapy; disease progression after achieving prior cytogenetic or hematologic response; or presence of a BCR-ABL gene mutation associated with imatinib resistance. Imatinib intolerance was defined as inability to tolerate imatinib treatment due to toxicity, disease progression during therapy, or inability to receive higher doses due to toxicity. Definitions of resistance or intolerance to dasatinib and nilotinib were analogous to those for imatinib. After 396 patients were enrolled in the trial, the study protocol was amended to exclude patients with known T315I mutation.

The efficacy endpoints for patients with chronic phase CML previously treated with one TKI (imatinib) were the rate of achievement of MCyR by week 24 of therapy and duration of MCyR. The efficacy endpoints for patients with chronic phase CML previously treated with imatinib and at least one additional TKI were cumulative rate of achievement of MCyR by week 24 of therapy and duration of MCyR. The efficacy endpoints for patients with accelerated phase or blast crisis CML previously treated were confirmed complete hematologic response (CHR) and overall hematologic response (HCR).

A total of 546 patients with CML in accelerated phase, blast crisis, or chronic phase were enrolled in the trial. 73% of study participants were imatinib-resistant, 27% were imatinib-intolerant. In this study, 53% of patients were male, 65% were Caucasian, and 20% were aged 65 years or older. 506 out of 546 patients receiving treatment were considered evaluable for assessment of cytogenetic or hematologic response. Evaluable patients were those who received at least one dose of bosutinib and had a reliable baseline assessment of response. Among evaluable patients, 262 had chronic phase CML previously treated with one TKI (imatinib); 112 had chronic phase CML previously treated with imatinib and at least one additional TKI; 132 had progressive CML previously treated with at least one TKI.

The median duration of treatment with bosutinib was 26 months for patients with chronic phase CML previously treated with one TKI (imatinib); 9 months for patients with chronic phase CML previously treated with imatinib and at least one additional TKI; 10 months for patients with accelerated phase CML previously treated with at least imatinib; and 3 months for patients with blast crisis CML previously treated with at least imatinib.

Efficacy results at 24 weeks and MCyR at any time are presented in Table 2.

Table 2. Efficacy results in patients with Philadelphia chromosome-positive (Ph+) chronic phase chronic myeloid leukemia (CML) who were intolerant or resistant to imatinib therapy

CI – confidence interval, MCyR – major cytogenetic response, N/n – number of patients.

The long-term follow-up analysis was based on monitoring data with a minimum of 60 months for CML patients in chronic phase who had previously received one TKI (imatinib), and a minimum of 48 months for CML patients in chronic phase who had previously received imatinib and at least one additional TKI. In 59.5% of CML patients in chronic phase who had previously received one TKI (imatinib) and achieved MCyR at any time, the median duration of MCyR was not reached. In 65.4% and 42.9% of such patients, MCyR lasted at least 18 and 54 months, respectively. In 40.2% of CML patients in chronic phase who had previously received imatinib and at least one additional TKI and achieved MCyR at any time, the median duration of MCyR was not reached. Among these patients, MCyR lasted at least 9 and 42 months in 64.4% and 35.6% of patients, respectively. Among 403 CML patients in chronic phase who received treatment, 20 patients had a confirmed disease progression to the accelerated phase or blast crisis during bosutinib therapy.

The efficacy results of 48-week therapy in patients with CML in accelerated phase or blast crisis who had previously received at least imatinib are presented in Table 3.

Table 3. Efficacy results of therapy in patients with CML in accelerated phase or blast crisis who had previously received at least imatinib

CI – confidence interval, CHR – complete hematologic response, GCyR – major cytogenetic response, n/N – number of patients

a Major hematologic response (MHR) – complete hematologic response (CHR) or no evidence of leukemia. All responses were confirmed after 4 weeks of therapy.

Complete hematologic response (CHR) for CML in accelerated phase or blast crisis: white blood cell count less than or equal to the upper limit of normal (ULN) as defined by the treating institution; platelet count 100,000/mm³ or higher and less than 450,000/mm³; absolute neutrophil count (ANC) 1.0 × 10⁹/L or higher; absence of blasts or promyelocytes in peripheral blood; less than 5% myelocytes and metamyelocytes in bone marrow; less than 20% basophils in peripheral blood; no evidence of extramedullary disease. No evidence of leukemia: patient status meets all other CHR criteria; thrombocytopenia (platelet count 20,000/mm³ or higher and less than 100,000/mm³) and/or neutropenia (ANC 0.5 × 10⁹/L or higher and less than 1.0 × 10⁹/L) are permitted. Return to chronic phase: disappearance of features of accelerated phase or blast crisis while maintaining characteristics of chronic phase.

Long-term follow-up data analysis was based on monitoring data with a minimum duration of 48 months for patients with CML in accelerated phase or blast crisis. Among 79 patients with accelerated phase CML who received treatment, 3 patients had a confirmed progression to blast phase during Bosulif therapy.

Pharmacokinetics

The pharmacokinetics of bosutinib were evaluated following oral administration with food, unless otherwise specified.

Bosutinib demonstrated dose-proportional increases in AUC and Cmax following oral administration over the range of 200 to 800 mg (0.33 to 1.3 times the maximum approved recommended dose of 600 mg). The mean (standard deviation [SD]) Cmax was 146 (20) ng/mL and the mean (SD) AUC was 2720 (442) ng·h/mL after multiple oral doses of Bosulif 400 mg in patients with CML; Cmax was 200 (12) ng/mL and AUC was 3650 (425) ng·h/mL after multiple oral doses of Bosulif 500 mg in patients with CML.

Absorption

Following a single 500 mg dose of Bosulif with food in patients with CML, the median (minimum, maximum) time to reach maximum concentration (tmax) was 6.0 (6.0; 6.0) hours. Absolute bioavailability in healthy volunteers was 34%.

When administered with a high-fat meal, bosutinib Cmax increased by 1.8-fold and AUC by 1.7-fold in healthy volunteers. A high-fat meal (800–1000 calories) consisted of approximately: protein (150 calories), carbohydrates (250 calories), fat (500–600 calories).

Distribution

After intravenous administration of a single 120 mg dose of bosutinib (0.2 times the maximum approved recommended oral dose of 600 mg) to healthy volunteers, the mean (SD) volume of distribution was 2441 (796) L. The mean (SD) apparent volume of distribution after administration of a single 500 mg dose of Bosulif to patients with CML was 6080 (1230) L.

Protein binding is 94% in vitro and 96% ex vivo, and is independent of drug concentration.

Elimination

After intravenous administration of a single 120 mg dose of bosutinib (0.2 times the maximum approved recommended oral dose of 600 mg) to healthy volunteers, the mean (SD) terminal half-life (t1/2) was 35.5 (8.5) hours and the mean (SD) clearance (Cl) was 63.6 (14.1) L/h. After administration of a single oral dose of Bosulif to patients with CML, the mean t1/2 was 22.5 (1.7) hours and the mean (SD) clearance (Cl) was 189 (48) L/h.

Metabolism

Bosutinib is primarily metabolized by CYP3A4.

Excretion

After administration of a single oral dose of [14C]-radiolabeled bosutinib without food, 91.3% of the dose was recovered in feces and 3.3% in urine.

Special patient populations

Renal impairment

Following a single 200 mg oral dose of Bosulif (0.33 times the maximum approved recommended dose of 600 mg), bosutinib AUC increased by 1.4-fold in subjects with moderate renal impairment (creatinine clearance (Clcr) 30–50 mL/min, calculated by Cockcroft-Gault (C-G)) and by 1.6-fold in subjects with severe renal impairment (Clcr < 30 mL/min), compared to subjects with normal renal function (Clcr > 80 mL/min, C-G). No clinically significant differences in bosutinib pharmacokinetics were observed in subjects with mild renal impairment (Clcr 51–80 mL/min, C-G).

Patients with moderate or severe renal impairment should have their initial dose reduced prior to starting treatment. For patients whose renal function deteriorates while receiving Bosulif at an initial dose of 500 mg, dose adjustments should be made according to toxicity recommendations (see section "Dosage and administration"). The use of Bosulif in patients undergoing hemodialysis has not been studied.

Hepatic impairment

Following a single 200 mg oral dose of Bosulif (0.33 times the maximum approved recommended dose of 600 mg), bosutinib Cmax increased by 2.4-, 2-, and 1.5-fold, and AUC increased by 2.3-, 2-, and 1.9-fold, respectively, in patients with mild (Child-Pugh class A), moderate (Child-Pugh class B), and severe (Child-Pugh class C) hepatic impairment.

Age, gender, and race

No dedicated studies were conducted to evaluate the impact of demographic factors. Population pharmacokinetic analysis in patients with Ph+ leukemia or solid malignancies and healthy volunteers demonstrated no clinically significant effect of age, gender, or body weight on bosutinib pharmacokinetics. Population pharmacokinetic analysis also indicated that Asian patients had an 18% lower clearance, corresponding to an approximately 25% increase in bosutinib exposure (AUC).

Clinical Characteristics

Indications

Bosulif is indicated for the treatment of adult patients with:

• newly diagnosed chronic myeloid leukemia (CML) positive for the Philadelphia chromosome (Ph+) in the chronic phase;
• chronic myeloid leukemia (CML) positive for the Philadelphia chromosome (Ph+) in the chronic phase, accelerated phase, or blast phase, in cases of intolerance or ineffectiveness of prior therapy.

Contraindications

Hypersensitivity to the active substance or to any of the excipients of the medicinal product.

Hepatic impairment (see section "Pharmacokinetics").

Safety precautions

All unused medicinal products and waste materials must be disposed of in accordance with local requirements.

Interaction with other medicinal products and other forms of interaction

CYP3A inhibitors

Concomitant use of bosutinib with strong CYP3A inhibitors, including itraconazole, ketoconazole, posaconazole, voriconazole, clarithromycin, telithromycin, nefazodone, mibefradil, indinavir, lopinavir/ritonavir, nelfinavir, ritonavir, saquinavir, boceprevir, telaprevir, grapefruit-containing products, including grapefruit juice, or with moderate CYP3A inhibitors, including fluconazole, ciprofloxacin, erythromycin, diltiazem, verapamil, amprenavir, atazanavir, darunavir/ritonavir, fosamprenavir, aprepitant, crizotinib, imatinib, should be avoided, as these may lead to increased plasma concentrations of bosutinib.

Bosutinib should be used with caution when administered concomitantly with weak CYP3A inhibitors.

Where possible, it is recommended to prescribe an alternative concomitant medicinal product without CYP3A inhibitory effect or with minimal inhibitory effect.

If use of a strong or moderate CYP3A inhibitor is necessary during bosutinib therapy, temporary interruption of therapy or dose reduction of bosutinib should be considered.

In a study involving 24 healthy volunteers who received 5 daily doses of 400 mg ketoconazole (a strong CYP3A inhibitor) concomitantly with a single 100 mg dose of bosutinib under fasting conditions, ketoconazole increased the Cmax of bosutinib by 5.2-fold and the AUC of bosutinib in plasma by 8.6-fold compared to bosutinib monotherapy.

In a study involving 20 healthy volunteers who received a single 125 mg dose of aprepitant (a moderate CYP3A inhibitor) together with a single 500 mg dose of bosutinib after food intake, aprepitant increased the Cmax of bosutinib by 1.5-fold and the AUC of bosutinib in plasma by 2-fold compared to bosutinib monotherapy.

CYP3A inducers

Concomitant use of bosutinib with strong CYP3A inducers, including carbamazepine, phenytoin, rifampicin, St. John’s wort, or with moderate CYP3A inducers, including bosentan, efavirenz, etravirine, modafinil, nafcillin, should be avoided, as these may lead to reduced plasma concentrations of bosutinib.

Due to the pronounced decrease in bosutinib exposure observed with concomitant administration of bosutinib and rifampicin, increasing the bosutinib dose when co-administered with strong or moderate CYP3A inducers is unlikely to sufficiently compensate for the reduction in exposure.

Bosutinib should be used with caution when administered concomitantly with weak CYP3A inducers.

Following concomitant administration after food intake of a single dose of bosutinib and 6 daily doses of 600 mg rifampicin in 24 healthy volunteers, bosutinib exposure (Cmax and AUC in plasma) decreased to 14% and 6%, respectively, of the values observed with 500 mg bosutinib monotherapy.

Proton pump inhibitors (PPIs)

Bosutinib should be used with caution when co-administered with PPIs. As an alternative to PPIs, short-acting antacids should be considered; however, whenever possible, bosutinib and antacids should be taken at different times (e.g., bosutinib in the morning and antacids in the evening). Bosutinib demonstrates pH-dependent aqueous solubility in vitro. When a single oral dose of bosutinib (400 mg) was administered fasting concomitantly with multiple oral doses of lansoprazole (60 mg) in a study involving 24 healthy volunteers, the Cmax and AUC of bosutinib decreased to 54% and 74%, respectively, of the values observed with bosutinib (400 mg) monotherapy.

Effect of bosutinib on other medicinal products

In a study involving 27 healthy volunteers who received a single 500 mg dose of bosutinib concomitantly with a single 150 mg dose of dabigatran etexilate mesylate (a P-glycoprotein [P-gp] substrate) after food intake, bosutinib did not increase the Cmax or AUC of dabigatran in plasma compared to dabigatran etexilate mesylate monotherapy. The study results indicate that bosutinib does not exhibit clinically relevant inhibitory effects on P-gp.

In vitro studies have shown that drug interactions at therapeutic doses are unlikely due to the effect of bosutinib on the metabolism of medicinal products that are substrates of CYP1A2, CYP2B6, CYP2C9, CYP2C19, and CYP3A4.

In vitro studies have demonstrated that drug interactions at therapeutic doses are unlikely due to inhibition by bosutinib of the metabolism of medicinal products that are substrates of CYP1A2, CYP2A6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, or CYP3A4/5.

In vitro studies have shown that bosutinib has low potential to inhibit breast cancer resistance protein (BCRP, systemic), organic anion transporting polypeptide (OATP)1B1, OATP1B3, organic anion transporter (OAT)1, OAT3, or organic cation transporter (OCT)2 at clinically relevant concentrations, but may potentially inhibit BCRP in the gastrointestinal tract and OCT1.

Antiarrhythmic drugs and other drugs that prolong the QT interval

Bosutinib should be used with caution in patients who have or may develop QT interval prolongation, particularly in patients receiving antiarrhythmic drugs such as amiodarone, disopyramide, procainamide, quinidine, and sotalol, or other medicinal products that may lead to QT interval prolongation, such as chloroquine, halofantrine, clarithromycin, domperidone, haloperidol, methadone, and moxifloxacin (see section "Special precautions for use").

Special precautions for use

Hepatic impairment

Elevated plasma levels of transaminases (alanine aminotransferase [ALT], aspartate aminotransferase [AST]) have been observed during bosutinib therapy.

Elevations in transaminases occurred predominantly early in the course of therapy (in > 80% of cases, the first episode of any-grade transaminase elevation occurred within the first 3 months of treatment). Patients receiving bosutinib require monitoring of liver function before starting therapy and once monthly during the first 3 months of treatment, and as clinically indicated thereafter.

In case of transaminase elevation, temporary interruption of bosutinib therapy (with dose reduction upon recovery to grade 1 or baseline levels) and/or permanent discontinuation of bosutinib may be necessary. Transaminase elevation, particularly when accompanied by increased bilirubin levels, may be an early sign of drug-induced liver injury. Such patients should receive appropriate management (see sections "Posology and method of administration" and "Undesirable effects").

Diarrhea and vomiting

Diarrhea and vomiting may occur in patients receiving bosutinib. Therefore, patients with recent or clinically significant gastrointestinal disorders should use this medicinal product cautiously and only after careful benefit-risk assessment, as such patients were not included in clinical trials. Patients experiencing diarrhea or vomiting should receive standard supportive therapy, including antidiarrheal and antiemetic agents and/or fluid volume replacement. Temporary interruption of bosutinib therapy, dose reduction, and/or permanent discontinuation of the drug may also be considered (see sections "Posology and method of administration" and "Undesirable effects"). The antiemetic agent domperidone may prolong the QT interval (QTc) and induce torsade de pointes ventricular arrhythmia. Therefore, concomitant use of bosutinib and domperidone should be avoided. Domperidone may be prescribed only if other antiemetic agents are ineffective. In such cases, a careful benefit-risk assessment should be performed, and ECG monitoring for QT interval prolongation should be conducted.

Myelosuppression

Myelosuppression, including anemia, neutropenia, and thrombocytopenia, may occur in patients treated with bosutinib. A complete blood count is recommended weekly during the first month of therapy and monthly thereafter or as clinically indicated. Depending on the clinical situation, dose reduction, temporary or permanent discontinuation of Bosulif may be required to manage myelosuppression (see sections "Posology and method of administration" and "Undesirable effects").

Fluid retention

Fluid retention, including pericardial effusion, pleural effusion, pulmonary edema, and/or peripheral edema, may occur during bosutinib therapy. Patients should be managed and monitored according to standard therapeutic practices. Additionally, dose reduction, temporary or permanent discontinuation of bosutinib may be considered (see sections "Posology and method of administration" and "Undesirable effects").

Increased serum lipase levels

Elevated serum lipase levels have been reported. Bosutinib should be used with caution in patients with a history of pancreatitis. If elevated lipase levels occur in combination with abdominal symptoms, bosutinib should be discontinued and diagnostic evaluation should be performed to rule out pancreatitis (see section "Posology and method of administration").

Infections

Use of bosutinib may predispose patients to bacterial, fungal, viral, or protozoal infections.

Proarrhythmic potential

Cases of QTc interval prolongation without associated arrhythmia have been reported. Bosutinib should be used cautiously in patients with a history of QTc prolongation or predisposition to it, in patients with uncontrolled or severe cardiovascular diseases, including recent myocardial infarction, congestive heart failure, unstable angina, or clinically significant bradycardia, and in patients taking medicinal products that may prolong the QTc interval (e.g., antiarrhythmic agents and other substances known to prolong QTc interval (see section "Interaction with other medicinal products and other forms of interaction")). Hypokalemia and hypomagnesemia may potentiate this effect.

Monitoring of QTc interval prolongation and ECG assessment are recommended before starting bosutinib therapy and as clinically indicated. Hypokalemia and hypomagnesemia should be corrected prior to initiating bosutinib therapy and periodically monitored during treatment.

Renal impairment

Bosutinib treatment may lead to clinically significant decline in renal function in patients with CML. During clinical trials, a gradual decline in estimated glomerular filtration rate (eGFR) was observed in patients receiving bosutinib. In patients with newly diagnosed chronic phase CML receiving a 400 mg dose, the median decline in eGFR from baseline was 11.1 mL/min/1.73 m² at 1 year and 14.1 mL/min/1.73 m² at 5 years of treatment. In treatment-naïve CML patients receiving 500 mg bosutinib, the median decline in eGFR was 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 of treatment. In previously treated CML patients with advanced phase CML receiving 500 mg bosutinib, the median decline in eGFR 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 of treatment. In previously treated Ph+ CML patients receiving 500 mg bosutinib, the median decline in eGFR from baseline was 9.2 mL/min/1.73 m² at 1 year and 14.5 mL/min/1.73 m² at 4 years of treatment.

Renal function should be monitored at the start of therapy and periodically throughout treatment in patients receiving bosutinib; particular attention should be paid to patients with pre-existing renal impairment or risk factors for renal dysfunction, including concomitant use of potentially nephrotoxic medicinal products such as diuretics, angiotensin-converting enzyme (ACE) inhibitors, angiotensin receptor blockers, and nonsteroidal anti-inflammatory drugs (NSAIDs).

In a renal impairment study, increased bosutinib exposure was observed in patients with moderate and severe renal impairment. Dose reduction is recommended for patients with moderate or severe renal impairment (see sections "Posology and method of administration" and "Pharmacokinetics").

Patients with serum creatinine levels > 1.5 × ULN were excluded from CML studies. Based on population pharmacokinetic analysis during clinical trials, increased exposure (AUC) was observed in patients with moderate and severe renal impairment at treatment initiation (see sections "Posology and method of administration" and "Pharmacokinetics").

There are very limited clinical data (n = 3) in CML patients with moderate renal impairment receiving the higher 600 mg dose of bosutinib.

Asian race

According to population pharmacokinetic analysis, Asians have lower clearance, resulting in higher exposure. Therefore, these patients should be monitored more closely for adverse reactions, especially when dose escalation is considered.

Severe skin reactions

Bosutinib may cause severe skin reactions, such as Stevens-Johnson syndrome and toxic epidermal necrolysis. Bosutinib should be discontinued in patients who develop severe skin reactions during treatment.

Tumor lysis syndrome

Due to the potential for tumor lysis syndrome (TLS), correction of clinically significant dehydration and treatment of elevated uric acid levels are recommended prior to initiating bosutinib therapy (see section "Undesirable effects").

Hepatitis B reactivation

Hepatitis B virus (HBV) reactivation has been observed in patients who are chronic carriers of the virus after treatment with BCR-ABL tyrosine kinase inhibitors (TKIs). In some cases, acute liver failure or fulminant hepatitis occurred, requiring liver transplantation or resulting in fatal outcomes.

Before initiating bosutinib therapy, patients should be tested for HBV. Patients with positive serological markers for HBV (including those with active infection) and patients diagnosed with HBV infection during treatment should be referred to specialists in liver diseases and HBV management for guidance. In HBV carriers requiring bosutinib treatment, careful monitoring for signs of active HBV infection is recommended during treatment and for several months after treatment completion (see section "Undesirable effects").

Photosensitivity

Exposure to direct sunlight and ultraviolet radiation should be avoided or minimized due to the risk of photosensitivity associated with bosutinib use. Patients are advised to use protective measures such as protective clothing and high sun protection factor (SPF) sunscreen.

Cytochrome P450 (CYP)3A inhibitors

Concomitant use of bosutinib with strong or moderate CYP3A inhibitors should be avoided, as this may increase bosutinib plasma concentrations (see section "Interaction with other medicinal products and other forms of interaction").

If possible, alternative concomitant medications without CYP3A inhibitory effects or with minimal inhibition should be prescribed.

If concomitant use of a strong or moderate CYP3A inhibitor is necessary during bosutinib therapy, temporary interruption or dose reduction of bosutinib should be considered.

CYP3A inducers

Concomitant use of bosutinib with strong or moderate CYP3A inducers should be avoided, as this may reduce bosutinib plasma concentrations (see section "Interaction with other medicinal products and other forms of interaction").

Interaction with food

Products containing grapefruit or grapefruit juice and other products that inhibit CYP3A should be avoided (see section "Interaction with other medicinal products and other forms of interaction").

Low-sodium diet

This medicinal product contains less than 1 mmol sodium (23 mg) per 100 mg or 500 mg tablet, i.e., essentially "sodium-free".

Use during pregnancy and breastfeeding

Females of reproductive potential/Contraception

Women of reproductive potential should be advised to use effective contraception during bosutinib therapy and for at least 1 month after the last dose, and to avoid pregnancy while taking bosutinib. Patients should also be informed that vomiting or diarrhea may reduce the effectiveness of oral contraceptives due to decreased absorption.

Pregnancy

Data on bosutinib use in pregnant women are limited. Reproductive toxicity was observed in animal studies. Bosutinib is not recommended for use in pregnant women or women of reproductive potential who are not using contraception. If bosutinib is used during pregnancy or if a patient becomes pregnant while taking bosutinib, the patient should be informed of the potential risk to the fetus.

Breastfeeding

It is unknown whether bosutinib or its metabolites are excreted in human breast milk. In a study with [14C]-labeled bosutinib in rats, radioactivity associated with bosutinib was detected in milk. A potential risk to the breastfed infant cannot be excluded. Breastfeeding should be discontinued during bosutinib therapy.

Fertility

Based on non-clinical data, bosutinib may impair reproductive function and fertility in humans. Men are therefore advised to consult on sperm preservation prior to starting Bosulif due to the potential for reduced fertility with bosutinib use.

Ability to drive and use machines

Bosulif has no or negligible influence on the ability to drive or operate machinery. However, if patients experience dizziness, fatigue, visual disturbances, or other adverse reactions that may affect their ability to drive or operate machinery, they should refrain from such activities during the occurrence of these reactions.

Method of Administration and Dosage

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

Method of Administration

The recommended dose should be taken orally once daily with food (see section "Pharmacokinetics"). If a dose is missed and more than 12 hours have passed, that dose should not be taken; the patient should take the next scheduled dose on the following day.

Dosage

Newly diagnosed Ph+ CML in chronic phase

The recommended dose is 400 mg of bosutinib once daily.

Ph+ CML in chronic phase, accelerated phase, or blast phase following intolerance or lack of efficacy of prior therapy

The recommended dose is 500 mg of bosutinib once daily.

In clinical studies for both indications, treatment with bosutinib was continued until disease progression or until occurrence of therapy intolerance.

Dose Adjustment

In a phase I/II clinical study in patients with CML who were intolerant of or resistant to prior therapy, the dose could be increased from 500 mg to 600 mg once daily with food if complete hematologic response (CHR) was not achieved by week 8 or complete cytogenetic response (CCyR) by week 12, and no drug-related adverse reactions of grade 3 or higher were observed. In a phase III clinical study in patients with newly diagnosed chronic phase CML receiving 400 mg of bosutinib, dose escalation by 100 mg increments up to a maximum of 600 mg once daily with food was permitted if BCR-ABL transcript levels were >10% at month 3, no adverse reactions of grade 3 or 4 were present at the time of dose escalation, and all grade 2 non-hematologic toxicities had been resolved to at least grade 1. In a phase IV clinical study involving patients with Ph+ CML previously treated with one or more tyrosine kinase inhibitors (TKIs), dose escalation from 500 mg to 600 mg once daily with food was allowed for patients with suboptimal response or signs of disease progression in the absence of any grade 3 or 4 adverse reactions or persistent grade 2 adverse reactions.

In the phase I/II study involving patients with CML who were intolerant of or resistant to prior therapy and initiated treatment at doses ≤500 mg, 93 patients (93 of 558; 16.7%) had their dose escalated to 600 mg daily.

In the phase III study involving patients with newly diagnosed chronic phase CML initiated on 400 mg of bosutinib, a total of 58 patients (21.6%) had their dose escalated to 500 mg daily. Additionally, 10.4% of patients subsequently had their dose increased to 600 mg daily.

In the phase IV study involving patients with Ph+ CML previously treated with one or more TKIs and initiated on bosutinib 500 mg daily, 1 patient (0.6%) had dose escalation to 600 mg daily.

Dosing above 600 mg daily has not been studied and therefore should not be used.

Dose Adjustment for Adverse Reactions

Non-hematologic Adverse Reactions

In the event of clinically significant non-hematologic toxicity of moderate or severe intensity, bosutinib should be withheld; after resolution of toxicity, treatment may be resumed at a dose reduced by 100 mg once daily. If clinically appropriate, re-escalation to the dose level prior to reduction should be considered (see section "Special Warnings and Precautions for Use"). Doses lower than 300 mg daily have been used in patients, but the efficacy of such doses has not been established.

Elevated liver transaminases: If liver transaminase levels increase to more than 5 times the upper limit of normal (ULN), bosutinib treatment should be temporarily discontinued. Upon reduction of transaminase levels to ≤2.5 × ULN, treatment may be resumed at a dose of 400 mg once daily. If levels do not decrease within 4 weeks, permanent discontinuation of bosutinib should be considered. If transaminase levels increase to ≥3 × ULN accompanied by bilirubin increase to ≥2 × ULN and alkaline phosphatase <2 × ULN, bosutinib treatment should be discontinued (see section "Special Warnings and Precautions for Use").

Diarrhea: If grade 3–4 diarrhea occurs according to the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTC), bosutinib administration should be temporarily withheld. After diarrhea severity decreases to grade 1 or lower, bosutinib therapy may be resumed at a dose of 400 mg daily (see section "Special Warnings and Precautions for Use").

Hematologic Adverse Reactions

Dose reduction guidelines for patients with severe or persistent neutropenia or thrombocytopenia are provided below (Table 4).

Table 4. Dose Adjustment for Patients with Neutropenia and Thrombocytopenia

and Absolute neutrophil count.

Special populations

Elderly patients (aged 65 years and older)

There are no specific dosage recommendations for elderly patients. Since data on use in elderly patients are limited, therapy should be administered with caution in this patient group.

Renal impairment

Patients with creatinine levels above 1.5 × ULN were not included in CML studies. Increased exposure (AUC) was observed in patients with moderate and severe renal impairment in clinical trials.

Newly diagnosed Ph+ CML in chronic phase

For patients with moderate renal impairment (creatinine clearance [CrCl] 30–50 mL/min calculated by the Cockcroft-Gault formula), the recommended dose of bosutinib is 300 mg once daily with food (see sections "Special instructions for use" and "Pharmacokinetics").

For patients with severe renal impairment (CrCl < 30 mL/min calculated by the Cockcroft-Gault formula), the recommended dose of bosutinib is 200 mg once daily with food (see sections "Special instructions for use" and "Pharmacokinetics").

Dose escalation of bosutinib to 400 mg once daily with food in patients with moderate renal impairment, and to 300 mg once daily in patients with severe renal impairment, may be considered only if they do not experience serious or persistent moderate adverse reactions and have not achieved adequate hematologic, cytogenetic, or molecular responses.

Ph+ CML in chronic phase, accelerated phase, or blast phase after intolerance or lack of response to prior therapy

For patients with moderate renal impairment (creatinine clearance [CrCl] 30–50 mL/min calculated by the Cockcroft-Gault formula), the recommended dose of bosutinib is 400 mg once daily (see sections "Special instructions for use" and "Pharmacokinetics").

For patients with severe renal impairment (CrCl < 30 mL/min calculated by the Cockcroft-Gault formula), the recommended dose of bosutinib is 300 mg once daily (see sections "Special instructions for use" and "Pharmacokinetics").

Dose escalation of bosutinib to 500 mg once daily with food in patients with moderate renal impairment, and to 400 mg once daily in patients with severe renal impairment, may be considered only if they do not experience serious or persistent moderate adverse reactions and have not achieved adequate hematologic, cytogenetic, or molecular responses.

Cardiac disorders

Patients with uncontrolled or severe cardiac disease (e.g., recent myocardial infarction, congestive heart failure, or unstable angina) were not included in clinical studies. The drug should be used with caution in patients with cardiac disorders (see section "Special instructions for use").

Recent or ongoing clinically significant gastrointestinal disorders

Patients with recent or ongoing clinically significant gastrointestinal disorders (e.g., severe vomiting and/or diarrhea) were not included in clinical studies. The drug should be used with caution in patients with recent or ongoing clinically significant gastrointestinal disorders (see section "Special instructions for use").

Pediatric population

The safety and efficacy of Bosulif in patients under 18 years of age have not been established. No data are available.

Overdose

Isolated cases of Bosulif overdose have been reported in clinical studies. There are no reports of any serious adverse events related to overdose. In case of overdose, appropriate supportive treatment and monitoring should be implemented.

Adverse Reactions

Summary of safety profile

A total of 1372 patients with leukemia received at least one dose of bosutinib as monotherapy. The median duration of treatment was 26.30 months (range 0.03–170.49 months).

These patients included subjects with newly diagnosed chronic phase (CP) chronic myeloid leukemia (CML) or subjects with Philadelphia chromosome-positive (Ph+) CML in chronic phase, accelerated phase, or blast phase, or with Ph+ acute lymphoblastic leukemia (ALL) and resistance or intolerance to prior therapy. Among them, 268 (with initial dose of 400 mg) and 248 (with initial dose of 500 mg) subjects participated in two phase III studies in patients with previously untreated CML; 60 (with initial dose of 400 mg) subjects participated in a phase II study in patients with previously untreated CML; 570 and 63 (phase II: with initial dose of 500 mg) subjects were participants in two phase I and II studies in patients with previously treated Ph+ leukemia; and 163 (with initial dose of 500 mg) patients participated in a phase IV study in previously treated patients. The median duration of therapy was 55.1 months (range 0.2–60.05 months), 61.6 months (range 0.03–145.86 months), 15.3 months (range 0.3–21.8 months), 11.1 months (range 0.03–170.49 months), 30.2 months (range 0.2–85.6 months), and 37.80 months (range 0.16–50.0 months), respectively. The safety data analysis included data from the completed extension study.

1349 (98.3%) patients reported at least one adverse drug reaction of any severity. The most commonly reported adverse effects, observed in ≥ 20% of patients, were diarrhea (80.4%), nausea (41.5%), abdominal pain (35.6%), thrombocytopenia (34.4%), vomiting (33.7%), rash (32.8%), elevated alanine aminotransferase (ALT) levels (28.0%), anemia (27.2%), fever (23.4%), increased aspartate aminotransferase (AST) levels (22.5%), fatigue (32.0%), and headache (20.3%). At least one grade 3 or 4 adverse reaction was observed in 943 (68.77%) patients. Adverse effects of grade 3 or 4 severity reported in ≥ 5% of patients were: thrombocytopenia (19.7%), increased ALT levels (14.6%), neutropenia (10.6%), diarrhea (10.6%), anemia (10.3%), increased lipase levels (10.1%), increased aspartate aminotransferase (AST) levels (6.7%), and rash (5.0%).

List of adverse reactions in tabular form

The adverse events listed below were observed in patients in clinical trials of bosutinib (Table 5). They represent an assessment of adverse effects in 1372 patients (who received at least one dose of bosutinib as monotherapy) with newly diagnosed chronic phase CML, as well as with Ph+ CML in chronic phase, accelerated phase, or blast phase, or Ph+ ALL and resistance or intolerance to prior therapy. These adverse reactions are listed by system organ class and frequency of occurrence. Frequency categories are defined as follows: 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), and not known (cannot be estimated from available data). Within each frequency group, adverse reactions are listed in decreasing order of severity.

Table 5. Adverse reactions associated with the use of bosutinib

| System Organ Class | 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 | |---------------------|----------------------|--------------------------|-------------------------------|------------------------------|------------------------|-----------| | Infections and infestations | Urinary tract infection, upper respiratory tract infection, nasopharyngitis, influenza, bronchitis, gastroenteritis, pneumonia, sepsis | | | | | | | Blood and lymphatic system disorders | Thrombocytopenia, anemia, neutropenia | Leukopenia, lymphopenia | | | | | | Immune system disorders | Hypersensitivity | | | | | Anaphylactic reaction | | Metabolism and nutrition disorders | Decreased appetite | | | | | | | Psychiatric disorders | Insomnia | | | | | | | Nervous system disorders | Headache, dizziness | | | | | Convulsion, posterior reversible encephalopathy syndrome | | Eye disorders | Blurred vision | | | | | | | Cardiac disorders | | | | | | QT prolongation, ventricular arrhythmia, atrial fibrillation, atrial flutter | | Vascular disorders | Hypertension | | | | | | | Respiratory, thoracic and mediastinal disorders | Dyspnea, cough, epistaxis | | | | | Interstitial lung disease, pulmonary hypertension | | Gastrointestinal disorders | Diarrhea, nausea, vomiting, abdominal pain, constipation, dyspepsia, stomatitis, dry mouth | | | | | Gastrointestinal perforation, colitis | | Hepatobiliary disorders | Increased ALT, increased AST | | | | | Hepatic failure, hepatitis | | Skin and subcutaneous tissue disorders | Rash, pruritus, alopecia, dry skin | | | | | Stevens-Johnson syndrome, toxic epidermal necrolysis, erythema multiforme, palmar-plantar erythrodysesthesia syndrome | | Musculoskeletal and connective tissue disorders | Arthralgia, myalgia, back pain | | | | | | | Renal and urinary disorders | Renal failure | | | | | | | General disorders and administration site conditions | Fatigue, pyrexia, edema | | | | | | | Investigations | Increased lipase, increased amylase | | | | | | | Injury, poisoning and procedural complications | Falls | | | | | |

** Adverse reactions identified in post-marketing studies

Description of selected adverse reactions

The description below is based on data from the safety study population consisting of 1372 patients who received at least 1 dose of bosutinib as monotherapy, with either newly diagnosed chronic phase chronic myeloid leukemia (CML) or resistance or intolerance to prior CML therapy in chronic phase, accelerated phase, blast phase, or Ph+ ALL.

Blood and lymphatic system disorders

Of the 372 (27.1%) patients with anemia as an adverse reaction, 6 patients discontinued bosutinib due to anemia. Maximum toxicity Grade 1 was observed in 95 (25.5%) patients, Grade 2 in 135 (36.3%) patients, Grade 3 in 113 (30.4%) patients, and Grade 4 in 29 (7.8%) patients. The median time to first occurrence of anemia was 29 days (range: 1–3999 days), and the median duration was 22 days (range: 1–3682 days).

Of the 209 (15.2%) patients reporting neutropenia as an adverse reaction, 19 patients discontinued bosutinib due to neutropenia. Maximum toxicity Grade 1 was observed in 19 (9.1%) patients, Grade 2 in 45 (21.5%) patients, Grade 3 in 95 (45.5%) patients, and Grade 4 in 50 (23.9%) patients. In these patients, the median time to first occurrence was 56 days (range: 1–1769 days), and the median duration of an event was 15 days (range: 1–913 days).

Of the 472 (34.4%) patients with thrombocytopenia as an adverse reaction, 42 subjects discontinued bosutinib due to thrombocytopenia. Maximum toxicity Grade 1 was observed in 114 (24.2%) patients, Grade 2 in 88 (18.6%) patients, Grade 3 in 172 (36.4%) patients, and Grade 4 in 98 (20.8%) patients. In these patients, the median time to first occurrence was 28 days (range: 1–1688 days), and the median duration of the event was 15 days (range: 1–3921 days).

Hepatobiliary disorders

In patients with increased ALT or AST levels (all grades) as an adverse reaction, the median time to detection of this reaction was 29 days (range: 1–3995 days) for both ALT and AST. The median duration was 17 days (range: 1–1148 days) for ALT and 15 days (range: 1–803 days) for AST, respectively.

Two cases (2/1711; 0.1%) of drug-induced liver injury without obvious causes were reported in patients treated with bosutinib (defined as concurrent elevation of ALT or AST ≥ 3 × ULN with total bilirubin > 2 × ULN and alkaline phosphatase < 2 × ULN).

Hepatitis B reactivation

Hepatitis B reactivation has been reported and associated with BCR-ABL tyrosine kinase inhibitors (TKIs). In some cases, acute liver failure or fulminant hepatitis occurred, requiring liver transplantation or resulting in fatal outcomes (see section "Special warnings and precautions for use").

Gastrointestinal disorders

Of the 1103 (80.4%) patients who developed diarrhea, 14 patients discontinued bosutinib due to this event. Concomitant medications were prescribed for the treatment of diarrhea in 756 (68.5%) patients. Maximum toxicity Grade 1 was observed in 575 (52.1%) patients, Grade 2 in 383 (34.7%) patients, Grade 3 in 144 (13.1%) patients, and Grade 4 in 1 (0.1%) patient. In patients with diarrhea, the median time to first occurrence was 2 days (range: 1–2702 days), and the median duration of diarrhea of any severity grade was 2 days (range: 1–4247 days).

Of the 1103 patients with diarrhea, treatment was interrupted in 218 (19.8%) patients to manage this adverse event, of whom 208 (95.4%) were re-challenged with bosutinib. Of the 208 re-challenged patients, 201 (96.6%) did not experience recurrence of diarrhea or did not discontinue bosutinib due to recurrent diarrhea.

Cardiac disorders

QTcF prolongation (>500 ms) was observed in 7 patients (0.5%). An increase in QTcF > 60 ms from baseline was observed in 11 (0.8%) patients. Patients with uncontrolled or significant cardiovascular disease, including QTc prolongation, were excluded from clinical trials prior to study enrollment (see section "Pharmacodynamics").

Reporting suspected adverse reactions

Reporting of suspected adverse reactions after authorization of the medicinal product is important. It allows continued monitoring of the benefit-risk balance of the medicinal product. Healthcare and pharmacy professionals, as well as patients or their legal representatives, should report all suspected adverse reactions and lack of efficacy through the automated pharmacovigilance information system at the following link: https://aisf.dec.gov.ua.

Shelf life: 4 years.

Storage conditions.

Blister packs: No special storage conditions required. Keep out of the reach of children.

Vials: Store at 20 to 25 °C. Excursions permitted between 15 to 30 °C. Keep out of the reach of children.

Packaging.

100 mg tablets: 14 tablets in a blister; 2 blisters in a cardboard box;
120 tablets in a vial; 1 vial in a cardboard box.

500 mg tablets: 14 tablets in a blister; 2 blisters in a cardboard box;
30 tablets in a vial; 1 vial in a cardboard box.

Prescription status: Prescription only.

Manufacturer:

Pfizer Manufacturing Deutschland GmbH.

Manufacturer's address and place of business:

Mooswaldallee 1, 79108 Freiburg im Breisgau, Germany.