XORIAN

Bosutinib is a 7-alkoxy-3-quinolinecarbonitrile that functions as a potent, dual SRC and ABL tyrosine kinase inhibitor indicated for chronic myelogenous leukemia (CML), specifically Philadelphia chromosome-positive (Ph+) CML.

Philadelphia chromosome is a hallmark of

CML due to the reciprocal translocation t(9;22)(q34;q11), resulting in a BCR-ABL fusion protein. 2, 3, 5 The first BCR-ABL inhibitor, imatinib, was introduced over a decade ago as a breakthrough in CML management; however, emerging resistance to imatinib poses challenges in achieving remission.

BCR-ABL inhibitors like bosutinib inhibit most resistance-conferring BCR-ABL mutations except V299 L and T315, thus providing more therapeutic options for patients. 1, 4 Bosutinib was first approved by the FDA in for the treatment of adult chronic, accelerated, or blast-phase Ph+ CML with resistance or intolerance to prior therapy.

On September 26, 2023, bosutinib was also approved by the FDA for the treatment of pediatric CML that is newly diagnosed or resistant/intolerant to prior therapy.

This approval was based on favorable results obtained from the open-label, randomized, multicenter trial BFORE that showed a significant improvement in major molecular response, defined as a ≤0.1% BCR ABL ratio on an international scale, with bosutinib treatment.

Bosutinib is indicated for the treatment of adult and pediatric patients 1 year of age and older with chronic phase Philadelphia chromosome-positive chronic myelogenous leukemia that is newly diagnosed or resistant or intolerant to prior therapy.

It is also indicated for the treatment of adult patients with accelerated or blast phase Philadelphia chromosome-positive chronic myelogenous leukemia that is newly diagnosed or resistant or intolerant to prior therapy.

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 with ketoconazole (a strong CYP3A inhibitor), bosutinib does not prolong the QT interval to any clinically relevant extent.

Tyrosine-protein kinase Lyn Inhibitor

Dual specificity mitogen-activated protein kinase kinase 1 Inhibitor Dual specificity mitogen-activated protein kinase kinase 2 Inhibitor + 6 more targets.

Bosutinib exhibits dose-proportional increases in C max and AUC over the oral dose range of 200-800 mg (0.33-1.3 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 400 mg.

The median bosutinib (minimum, maximum) t max was 6.0 hours following oral administration of a single oral dose of bosutinib 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 conditions.

C max increased 1.6-fold and AUC increased 1.5-fold when bosutinib capsules were given with a high-fat meal to healthy subjects compared to administration under fasted conditions.

The high-fat meal (800-1000 total calories) consisted of approximately 150 protein calories, 250 carbohydrate calories, and 500-600 fat calories.

The mean (SD) apparent bosutinib volume of distribution is 6080 ± 1230 L after an oral dose of 500 mg of bosutinib.

Bosutinib is primarily metabolized by

The major circulating metabolites identified in plasma are oxydechlorinated (M2) bosutinib (19% of parent exposure) and N-desmethylated (M5) bosutinib (25% of parent exposure), with bosutinib N-oxide (M6) as a minor circulating metabolite.

All the metabolites were deemed inactive.

Hover over products below to view reaction partners Bosutinib N-desmethylbosutinib Oxydechlorinated bosutinib.

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

The mean (SD) bosutinib terminal phase elimination half-life (t 1/2 ) was 22.5 ± 1.7 hours following a single oral dose of bosutinib.

The mean (SD) apparent clearance was 189 ± 48 L/h following a single oral dose of bosutinib.

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In a rat fertility and early embryonic development study, bosutinib was administered Oral to female rats for approximately 3-6 weeks, depending on the 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 Oral to pregnant animals during organogenesis at doses of 3, 10, 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 Oral 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).

Experience with bosutinib 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

BOSULIF should be observed and given appropriate supportive treatment.

Bosutinib was not carcinogenic in rats or transgenic mice.

The rat 2-year carcinogenicity study was conducted at bosutinib oral doses up to 25 mg/kg in males and 15 mg/kg in females.

Exposures at these doses were approximately 1.5 times (males) and 3.1 times (females) the human exposure at the 400 mg dose and 1.2 times (males) and 2.4 times (females) exposure in humans at the 500 mg dose.

The 6-month RasH2 transgenic mouse carcinogenicity study was conducted at bosutinib oral doses up to 60 mg/kg.

Bosutinib was not mutagenic or clastogenic in a battery of tests, including the bacteria reverse mutation assay (Ames Test), the in vitro assay using human peripheral blood lymphocytes and the micronucleus test in Oral treated male mice.

In a rat fertility study, drug-treated males were mated with untreated females or untreated males were mated with drug-treated females.

Females were administered the drug from pre-mating through early embryonic development.

The dose of 70 mg/kg/day of bosutinib resulted in reduced fertility in males as demonstrated by 16% reduction in the number of pregnancies.

There were no lesions in the male reproductive organs at this dose.

This dose of 70 mg/kg/day resulted in exposure (AUC) in male rats approximately 1.5 times and equal to human exposure at the recommended doses of and 500 mg/day, respectively.

Fertility (number of pregnancies) was not affected when female rats were treated with bosutinib.

However, there were increased embryonic resorptions 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 and 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).

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.