XORIAN

Bosutinib tablet contains bosutinib, a kinase inhibitor.

The chemical name for bosutinib is 3-Quinolinecarbonitrile, 4-[(2,4-dichloro-5-methoxyphenyl)amino]-6-methoxy-7-[3-(4-methyl-1-piperazinyl) propoxy.

Its chemical formula is

C 26 H 29 Cl 2 N 5 O 3; its molecular weight is 530.45.

Bosutinib has the following chemical structure

Bosutinib is a white to yellowish-tan powder.

Bosutinib is freely soluble in dimethyl sulfoxide, very slightly soluble in ethyl acetate and practically insoluble in water.

Bosutinib tablets are supplied for oral administration in two strengths: 100 mg and 500 mg. Each strength reflects the equivalent amount of bosutinib content (on anhydrous basis).

The tablets contain the following inactive ingredients: croscarmellose sodium, hypromellose, iron oxide red (for 500 mg tablet), iron oxide yellow (for 100 mg tablet), magnesium stearate, microcrystalline cellulose, poloxamer 188, polyethylene glycol 6000, povidone K-25, talc (for 500 mg tablet) and titanium dioxide. bosutinib-structure.jpg.

• adult and paediatric patients aged 6 years and older with chronic Philadelphia chromosome positive myeloid leukaemia (Ph+ CML) in the chronic phase (PC) newly diagnosed (ND);

• adult and paediatric patients aged 6 years and older with PC-based Ph+ CML previously treated with one or more tyrosine kinase inhibitors (ITK(s)) and for whom imatinib, nilotinib and dasatinib are not considered appropriate;

• adult patients with Ph+ CML, accelerated phase (PA) and blast crisis (CB) previously treated with one or more tyrosine kinase inhibitors (ITK(s)) and for whom imatinib, nilotinib and dasatinib are not considered appropriate treatments.

The use of this drug is not a risk-absorbing or a risk-absorbing or a risk-absorbing or a risk-absorbing or a risk-absorbing or a risk-absorbing or a risk-absorbing or a risk-absorbing or a risk-absorbing or a risk-absorbing or a risk-absorbing or a risk-absorbing or a risk-absorbing or a risk-absorbing or a risk-absorbing or a risk-absorbing or a risk-absorbing or a risk-absorbing or a risk-absorbing or a risk-absorbing or a risk-absorbing or a risk-absorbing or a risk-absorbing or a risk-absorbing or a risk-absorbing or a risk-absorbing or a risk-absorbing or a risk-absor.

Mechanism of Action Bosutinib is a

Bosutinib inhibits the BCR-ABLkinase that promotes

CML; it is also an inhibitor of Src-family kinases including Src, Lyn, and Hck.

Bosutinib inhibited of 18 imatinib-resistant forms of BCR-ABL kinase expressed in murine myeloid cell lines.

Bosutinib did not inhibit the

T315I and V299L mutant cells. 12.2 Pharmacodynamics A greater likelihood of response and a greater likelihood of safety events were observed with higher bosutinib exposure in clinical studies.

The time course of bosutinib pharmacodynamic response has not been fully characterized.

At a single oral dose of 500 mg bosutinib tablet with ketoconazole (a strong CYP3A inhibitor), bosutinib tablets does not prolong the QT interval to any clinically relevant extent. 12.3 Pharmacokinetics Bosutinib pharmacokinetics were assessed following oral dosing with food in adult patients with CML and were presented as geometric mean (CV%), unless otherwise specified.

Bosutinib exhibits dose proportional increases in C max and AUC over the oral dose range of to 800 mg (0.33 to 1.3 times the maximum approved recommended dosage of 600 mg).

Bosutinib steady state

C max was 127 ng/mL (31%), C trough was 68 ng/mL (39%) and AUC was 2370 ng•h/mL (34%) following multiple oral doses of bosutinib tablets 400 mg; Bosutinib steady state C max was 171 ng/mL (38%),C trough was 91 ng/mL (42%) and AUC was 3150 ng•h/mL (38%) following multiple oral doses of bosutinib tablets 500 mg. No clinically significant differences in the pharmacokinetics of bosutinib were observed following administration of either the tablet or capsule dosage forms of bosutinib at the same dose, under fed conditions.

The median bosutinib (minimum, maximum) time-to-C max (t max ) was 6 hours following oral administration of a single oral dose of bosutinib tablets 500 mg with food.

The absolute bioavailability was 34% in healthy subjects.

C max increased 1.8-fold and AUC increased 1.7-fold when bosutinib tablets were given with a high fat meal to healthy subjects compared to administration under fasted condition.

The high-fat meal (800 to 1000 total calories) consisted of approximately 150 protein calories, 250 carbohydrate calories, and to 600 fat calories.

The mean (SD) apparent bosutinib volume of distribution is 6080 L after an oral dose of 500 mg of bosutinib.

Bosutinib protein binding is 94% in vitro and 96% ex vivo, and is independent of concentration.

The mean (SD) bosutinib terminal phase elimination half-life (t ½ ) was 22.5 hours, and the mean (SD) apparent clearance was 189 L/h following a single oral dose of bosutinib tablets.

Metabolism Bosutinib is primarily metabolized by

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

Specific Populations Patients with Renal Impairment Bosutinib AUC increased 1.4-fold in subjects with moderate renal impairment (CL cr: 30 to 50 mL/min, estimated by Cockcroft-Gault (C-G)) and increased 1.6-fold in subjects with severe renal impairment (CL cr less than 30 mL/min) following a single oral dose of bosutinib tablets 200 mg (0.33 times the maximum approved recommended dosage of 600 mg).

No clinically significant difference in the pharmacokinetics of bosutinib was observed in subjects with mild renal impairment (CL cr: 51 to 80 mL/min, C-G).

Bosutinib tablets has not been studied in patients undergoing hemodialysis.

C max increased 2.4-fold, 2-fold, and 1.5-fold, and AUC increased 2.3-fold, 2-fold, and 1.9-fold in hepatic impairment Child-Pugh A, B, and C, respectively, following a single oral dose of bosutinib tablet 200 mg (0.33 times the maximum approved recommended dosage of 600 mg).

Drug Interaction Studies Clinical Studies Strong

CYP3A Inhibitors: Bosutinib C max increased 5.2-fold and AUC increased 8.6-fold following a single dose of bosutinib tablets 100 mg (0.17 times the maximum approved recommended dosage) without food when used concomitantly with 400 mg ketoconazole (a strong CYP3A inhibitor) administered over multiple daily doses.

CYP3A Inhibitors: Bosutinib C max increased 1.5-fold and AUC increased 2.0-fold following a single dose of bosutinib tablet 500 mg with food when administered concomitantly with 125 mg aprepitant (a moderate CYP3A inhibitor).

CYP3A Inducers: Bosutinib C max decreased by 86% and AUC decreased by 94% following a single dose of bosutinib tablet 500 mg with food administered concomitantly with multiple daily doses of 600 mg of rifampin (a strong CYP3A inducer).

Lansoprazole decreased bosutinib C max by 46% and AUC by 26% following a single oral dose of bosutinib tablet 400 mg without food when used concomitantly with lansoprazole 60 mg (proton pump inhibitor) administered over multiple daily doses.

Bosutinib displays pH-dependent aqueous solubility, in vitro.

No clinically significant differences in bosutinib pharmacokinetics were observed when used concomitantly with dabigatran etexilate mesylate (a P-glycoprotein (P-gp) substrate).

Bosutinib inhibits breast cancer resistance protein (BCRP) but, does not inhibit organic anion transporting polypeptide (OATP)1B1, OATP1B3, organic anion transporter (OAT)1, OAT3, organic cation transporter (OCT)1, and OCT2.

Pediatric use information is approved for PF PRISM CV’s BOSULIF® (bosutinib) tablets.

However, due to PF PRISM CV’s marketing exclusivity rights, this drug product is not labeled with that information.

Pharmacotherapeutic group: antineoplastic agents, protein kinase inhibitors, ATC code: L01EA04.

Bosutinib mechanism belongs to a pharmacological class of drugs called protein kinase inhibitors.

Bosutinib inhibits the abnormal kinase protein

BCR-ABL at the origin of the BMC.

Based on the modelling studies, bosutinib binds to the BCR-ABL kinase domain.

Bosutinib is also an inhibitor of

Src family kinases, including Src, Lyn and Hck; bosutinib inhibits the platelet-derived growth factor receptor (BMDF) and c-Kit.

In the in vitro studies, bosutinib inhibits the proliferation and survival of the laboratory-determinated cell lines, the laboratory-determinated renal-determinate cells, the laboratory-determinate cells of the BMC, the laboratory-determinate cells of the BMC.

Bosutinib inhibited of the 18 forms of BCR-ABL, expressed in the imatobb, the laboratory-determinated cells of the BEC, the laboratory-determinated cells of the cells of the.

The following are the most common adverse reactions: (i.e., 1 372 adult patients with leukaemia received at least one single dose of bosutinib monotherapy. The median duration of treatment was 26.30 months (range: 0.03-170.49 months).

These patients were either diagnosed with a newly diagnosed CML-PC, or resistant or intolerant to previous CML treatments in a chronic or accelerated phase, or blast crisis, or were affected by an acute lymphoblastic leukaemia (ALL) Ph+.

The safety analyses included data from a completed extension study.

At least one adverse drug reaction, all levels of toxicity were reported, including: (i.e., abs) (i.e., abs) (i.e., abs) (i.e., abs) (i.e., abs) (i.e., abs) (i.e., abs) (i., abs) (i., abs) (i., abs) (i., abs) (i., abs) (i., ab.

Experience with bosutinib tablets overdose in clinical studies was limited to isolated cases.

There were no reports of any serious adverse events associated with the overdoses.

Patients who take an overdose of bosutinib tablets should be observed and given appropriate supportive treatment.

Bosutinib tablet is contraindicated in patients with a history of hypersensitivity to bosutinib.

Reactions have included anaphylaxis.

Hypersensitivity to bosutinib tablets.

• Adult patients with chronic, accelerated, or blast phase Ph+ CML with resistance or intolerance to prior therapy: 500 mg orally once daily with food.

• Consider dose escalation by increments of 100 mg once daily to a maximum of 600 mg daily in adult patients who do not reach complete hematologic, cytogenetic, or molecular response and do not have Grade 3 or greater adverse reactions.

• Adjust dosage for toxicity and organ impairment 2.1 Recommended Dosage The recommended dosage is taken orally once daily with food.

Swallow tablets whole.

Do not cut, crush, break or chew tablets.

Continue treatment with bosutinib tablets until disease progression or intolerance to therapy.

If a dose is missed beyond 12 hours, the patient should skip the dose and take the usual prescribed dose on the following day. Dosage in Adult Patients with CP, AP, or BP Ph+ CML with Resistance or Intolerance to Prior Therapy The recommended dosage of bosutinib tablet is 500 mg orally once daily with food.

Pediatric use information is approved for PF PRISM CV’s BOSULIF® (bosutinib) tablets.

However, due to PF PRISM CV’s marketing exclusivity rights, this drug product is not labeled with that information. 2.2 Dose Escalation In clinical studies of adult patients with Ph+ CML, dose escalation by increments of 100 mg once daily to a maximum of 600 mg once daily was allowed in patients who did not achieve or maintain a hematologic, cytogenetic, or molecular response and who did not have Grade 3 or higher adverse reactions at the recommended starting dosage.

The maximum dose in adult patients is 600 mg once daily.

However, due to PF PRISM CV’s marketing exclusivity rights, this drug product is not labeled with that information. 2.3 Dosage Adjustments for Non-Hematologic Adverse Reactions Elevated liver transaminases: If elevations in liver transaminases greater than 5×institutional upper limit of normal (ULN) occur, withhold bosutinib tablets until recovery to less than or equal to 2.5×ULN and resume at 400 mg once daily thereafter.

If recovery takes longer than 4 weeks, discontinue bosutinib tablets.

If transaminase elevations greater than or equal to 3×ULN occur concurrently with bilirubin elevations greater than 2×ULN and alkaline phosphatase less than 2×ULN (Hy’s law case definition), discontinue bosutinib tablets.

For National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) Grade to 4 diarrhea (increase of greater than or equal to 7 stools/day over baseline/pretreatment), withhold bosutinib tablets until recovery to Grade less than or equal to 1.

Bosutinib tablets may be resumed at 400 mg once daily.

For other clinically significant, moderate or severe non-hematological toxicity, withhold bosutinib tablets until the toxicity has resolved, then consider resuming bosutinib tablets at a dose reduced by 100 mg taken once daily.

If clinically appropriate, consider re-escalating the dose of bosutinib tablets to the starting dose taken once daily.

However, due to PF PRISM CV’s marketing exclusivity rights, this drug product is not labeled with that information. 2.4 Dosage Adjustments for Myelosuppression Dose reductions for severe or persistent neutropenia and thrombocytopenia are described below (Table 3).

Table 3: Dose Adjustments for Neutropenia and Thrombocytopenia in Adult Patients ANC a less than 1000 x10 6 /L or Platelets less than 50,000 x10 6 /L Withhold bosutinib tablets until ANC greater than or equal to 1000x10 6 /L and platelets greater than or equal to 50,000x10 6 /L. Resume treatment with bosutinib tablets at the same dose if recovery occurs within 2 weeks.

If blood counts remain low for greater than 2 weeks, upon recovery, reduce dose by 100 mg and resume treatment.

If cytopenia recurs, reduce dose by an additional 100 mg upon recovery and resume treatment. a Absolute Neutrophil Count Pediatric use information is approved for PF PRISM CV’s BOSULIF® (bosutinib) tablets.

However, due to PF PRISM CV’s marketing exclusivity rights, this drug product is not labeled with that information. 2.5 Dosage Adjustments for Renal Impairment or Hepatic Impairment The recommended starting doses for patients with renal and hepatic impairment are described in Table 4 below.

Table 4: Dose Adjustments for Renal and Hepatic Impairment in Adult Patients Recommended Starting Dosage Chronic, accelerated, or blast phase Ph+ CML with resistance or intolerance to prior therapy Normal 500 mg daily Renal impairment Creatinine clearance to 50 mL/min 400 mg daily Creatinine clearance less than 30 mL/min 300 mg daily Hepatic impairment Mild (Child-Pugh A), Moderate (Child-Pugh B) or severe (Child-Pugh C) 200 mg daily.

However, due to PF PRISM CV’s marketing exclusivity rights, this drug product is not labeled with that information.

Bosutinib tablets are available in the following packaging configurations with a child-resistant (CR) closure.

Bottle contains desiccants.

Bosutinib tablets 100 mg are yellow colored, oval shaped, biconvex, film coated tablet, debossed with L603 on one side and plain on other side.

NDC 62332-311-35 bottle of 120 tablets Bosutinib tablets 500 mg are red colored, oval shaped, biconvex, film coated tablet debossed with L604 on one side and plain on the other.

NDC 62332-312-30 bottle of 30 tablets Storage Store at 20°C to 25°C (68°F to 77°F); excursions permitted to 15°C to 30°C (59°F to 86°F) .

Procedures for proper disposal of anticancer drugs should be considered.

Touching or handling crushed or broken tablets is to be avoided.

Any unused product or waste material should be disposed of in accordance with local requirements, or drug take back programs.

Based on findings from animal studies and its mechanism of action, bosutinib tablets can cause fetal harm when administered to a pregnant woman.

There are no available data in pregnant women to inform the drug-associated risk.

In animal reproduction studies conducted in rats and rabbits, oral administration of bosutinib during organogenesis caused adverse developmental outcomes, including structural abnormalities, embryo-fetal mortality, and alterations to growth at maternal exposures (AUC) as low as 1.2 times the human exposure at the dose of 500 mg/day.

Advise pregnant women of the potential risk to a fetus.

The background risk of major birth defects and miscarriage for the indicated population is unknown.

All pregnancies have a background risk of birth defect, loss, or other adverse outcomes.

In the

U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies are to 4% and to 20%, respectively.

In a rat fertility and early embryonic development study, bosutinib was administered orally to female rats for approximately to 6 weeks, depending on day of mating (2 weeks prior to cohabitation with untreated breeder males until gestation day [GD] 7).

Increased embryonic resorptions occurred at greater than or equal to 10 mg/kg/day of bosutinib (1.6 and 1.2 times the human exposure at the recommended doses of 400 or 500 mg/day, respectively), and decreased implantations and reduced number of viable embryos at 30 mg/kg/day of bosutinib (3.4 and 2.5 times the human exposure at the recommended doses of 400 or 500 mg/day, respectively).

In an embryo-fetal development study conducted in rabbits, bosutinib was administered orally to pregnant animals during the period of organogenesis at doses of and 30 mg/kg/day. At the maternally-toxic dose of 30 mg/kg/day of bosutinib, there were fetal anomalies (fused sternebrae, and 2 fetuses had various visceral observations), and an approximate 6% decrease in fetal body weight.

The dose of 30 mg/kg/day resulted in exposures (AUC) approximately 5.1 and 3.8 times the human exposures at the recommended doses of and 500 mg/day, respectively.

Fetal exposure to bosutinib-derived radioactivity during pregnancy was demonstrated in a placental-transfer study in pregnant rats.

In a rat pre-and postnatal development study, bosutinib was administered orally to pregnant animals during the period of organogenesis through lactation day at doses of 10, 30, and 70 mg/kg/day. Reduced number of pups born occurred at greater than or equal to 30 mg/kg/day bosutinib (3.4 and 2.5 times the human exposure at the recommended doses of 400 or 500 mg/day, respectively), and increased incidence of total litter loss and decreased growth of offspring after birth occurred at 70 mg/kg/day bosutinib (6.9 and 5.1 times the human exposure at the recommended doses of 400 or 500 mg/day, respectively).

The safety and effectiveness of bosutinib tablets in pediatric patients younger than 1 year of age with newly diagnosed CP Ph+ CML, pediatric patients younger than 1 year of age with CP Ph+ CML that is resistant or intolerant to prior therapy, and pediatric patients with AP Ph+ CML or BP Ph+ CML have not been established.

Pediatric use information is approved for PF PRISM CV’s BOSULIF® (bosutinib) tablets.

However, due to PF PRISM CV’s marketing exclusivity rights, this drug product is not labeled with that information.

In the single-arm study in patients with CML who were resistant or intolerant to prior therapy of bosutinib tablets in patients with Ph+ CML, 20% were age and over, 4% were and over.

No overall differences in safety or effectiveness were observed between these patients and younger patients, and other reported clinical experience has not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out.