ORIONTINIB

Dasatinib is an

Oral available multikinase inhibitor indicated for the treatment of Philadelphia chromosome (Ph)-positive leukemias. 1, 7 Ph is a chromosomal abnormality found in patients with chronic myelogenous leukemia (CML) and acute lymphocytic leukemia (ALL), where the ABL tyrosine kinase and the breakpoint cluster region (BCR) gene transcribe the chimeric protein BCR-ABL.

BCR-ABL is associated with the uncontrolled activity of the ABL tyrosine kinase and is involved in the pathogenesis of CML and 15-30% of ALL cases. 5, 6 Dasatinib also inhibits a spectrum of kinases involved in cancer, including several SRC-family kinases.

Unlike imatinib, another tyrosine kinase used for the treatment of CML and Ph-positive ALL, dasatinib inhibits the active and inactive conformations of the ABL kinase domain. 2, 5 Also, mutations in the kinase domain of BCR-ABL may lead to relapse during imatinib treatment.

Since dasatinib does not interact with some of the residues involved in those mutations, the use of this drug represents a therapeutic alternative for patients with cancers that have developed imatinib-resistance.

The use of dasatinib was first approved by the FDA in 2006. 7, 9.

Dasatinib is indicated for the treatment of newly diagnosed adults with Philadelphia chromosome-positive (Ph+) chronic myeloid leukemia (CML) in chronic phase, as well as adults with chronic, accelerated, or myeloid or lymphoid blast phase Ph+ CML with resistance or intolerance to prior therapy including imatinib, and adults with Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL) with resistance or intolerance to prior therapy.

Dasatinib is also indicated for the treatment of pediatric patients 1 year of age and older with Ph+ CML in chronic phase or newly diagnosed Ph+ ALL in combination with chemotherapy.

Dasatinib is an

Oral available small-molecule multikinase inhibitor.

During clinical trials, less than 1% of patients treated with dasatinib had QTc prolongation as an adverse reaction, and 1% experienced a QTcF higher than 500 ms.

The use of dasatinib is also associated with myelosuppression, bleeding-related events, fluid retention, cardiovascular toxicity, pulmonary arterial hypertension, severe dermatologic reactions, tumor lysis syndrome and hepatotoxicity.

It may also cause embryo-fetal toxicity and lead to adverse reactions associated with bone growth and development in pediatric patients.

Tyrosine-protein kinase

ABL1 Inhibitor Multitarget Proto-oncogene tyrosine-protein kinase Src Inhibitor Multitarget Ephrin type-A receptor 2 Antagonist + 6 more targets.

Dasatinib has a dose-proportional pharmacokinetic profile and a linear elimination between 15 mg/day (0.15 times the lowest approved recommended dose) and 240 mg/day (1.7 times the highest approved recommended dose).

At 100 mg once a day, dasatinib has a C max and AUC of 82.2 ng/mL and 397 ng/mL*hr, respectively.

In healthy adult subjects given dasatinib as dispersed tablets in juice, the adjusted geometric mean ratio compared to intact tablets was 0.97 for C max, and 0.84 for AUC.

T max of dasatinib is between 0.5 and 6 hours following oral administration.

Following a single dose of 100 mg, a high-fat meal increases the AUC of dasatinib by 14%.

Dasatinib has an apparent volume of distribution of 2505 L.

In humans, dasatinib is mainly metabolized by CYP3A4, although flavin-containing monooxygenase 3 (FMO3) and uridine diphosphate-glucuronosyltransferase (UGT) enzymes are also involved in the formation of dasatinib metabolites.

Five pharmacologically active dasatinib metabolites have been identified: M4, M5, M6, M20 and M24.

M4, M20, and M24 are mainly generated by CYP3A4, M5 is generated by FMO3, and M6 is generated by a cytosolic oxidoreductase. 3, 4 M4 is equipotent to dasatinib and represents approximately 5% of the AUC.

However, it is unlikely to play a major role in the observed pharmacology of dasatinib. 3, 7 M5 and M6 are more than 10 times less active than dasatinib and are considered minor circulating metabolites.

Hover over products below to view reaction partners Dasatinib Dasatinib M4 metabolite Dasatinib M5 metabolite Dasatinib M24 metabolite Dasatinib M20 metabolite Dasatinib M6 metabolite.

Dasatinib is mainly eliminated via feces.

Within 10 days, 4% of dasatinib is recovered in urine, while 85% is recovered in feces.

Approximately 0.1% and 19% of the administered dasatinib dose was recovered unchanged in urine and feces, respectively, and the rest was recovered as metabolites.

The terminal half-life of dasatinib is 3-5 hours.

The clearance of dasatinib does not vary over time.

Dasatinib has an apparent oral clearance of 363.8 L/hr.

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Overdose cases with dasatinib occurred in isolated cases during clinical studies.

Patients that received 280 mg of dasatinib per day for 1 week developed severe myelosuppression and bleeding.

Since dasatinib is associated with severe myelosuppression, patients that ingest more than the recommended dosage should be monitored closely for myelosuppression and receive appropriate supportive treatment.

Acute overdose in animals was associated with cardiotoxicity.

In rodents, ventricular necrosis and valvular/ventricular/atrial hemorrhage were detected at single doses higher than or equal to 100 mg/kg (600 mg/m 2 ).

In monkeys receiving single doses higher than or equal to 10 mg/kg (120 mg/m 2 ), there was a tendency for increased systolic and diastolic blood pressure.

In rats, the oral LD of dasatinib is 50-100 mg/kg, and in monkeys, it is 25-45 mg/kg.

Chronic phase

CML in adults: 100 mg once daily.

Accelerated phase

CML, myeloid or lymphoid blast phase CML, or Ph+ ALL in adults: 140 mg once daily.

Chronic phase CML and

ALL in pediatrics: starting dose based on body weight.

Administer orally, with or without a meal.

Do not crush, cut, or chew tablets. 2.1 Dosage of Dasatinib Tablets in Adult Patients The recommended starting dosage of dasatinib tablets for chronic phase CML in adults is 100 mg administered orally once daily.

The recommended starting dosage of dasatinib tablets for accelerated phase CML, myeloid or lymphoid blast phase CML, or Ph+ ALL in adults is 140 mg administered orally once daily.

Tablets should not be crushed, cut, or chewed; they should be swallowed whole.

Dasatinib tablets can be taken with or without a meal, either in the morning or in the evening. 2.2 Dosage of Dasatinib Tablets in Pediatric Patients with CML or Ph+ ALL The recommended starting dosage for pediatrics is based on body weight as shown in Table 1.

The recommended dose should be administered orally once daily with or without food.

Recalculate the dose every 3 months based on changes in body weight, or more often if necessary.

Do not crush, cut or chew tablets.

Swallow tablets whole.

There are additional administration considerations for pediatric patients who have difficulty swallowing tablets whole.

Table 1: Dosage of Dasatinib Tablets for Pediatric Patients a Body Weight (kg) b Daily Dose (mg) 10 to less than 20 40 mg to less than 30 60 mg to less than 45 70 mg at least 45 100 mg a For pediatric patients with Ph+ ALL, begin dasatinib tablets therapy on or before day of induction chemotherapy, when diagnosis is confirmed and continue for 2 years. b Tablet dosing is not recommended for patients weighing less than 10 kg. Refer to Section 2.4 for recommendations on dose escalation in adults with CML and Ph+ ALL, and pediatric patients with CML. 2.3 Dose Modification Strong CYP3A4 Inducers Avoid the use of concomitant strong CYP3A4 inducers and St.

John’s wort.

If patients must be coadministered a strong CYP3A4 inducer, consider a dasatinib tablets dose increase.

If the dose of dasatinib tablets is increased, monitor the patient carefully for toxicity.

CYP3A4 Inhibitors Avoid the use of concomitant strong CYP3A4 inhibitors and grapefruit juice.

Recommend selecting an alternate concomitant medication with no or minimal enzyme inhibition potential, if possible.

If dasatinib tablets must be administered with a strong CYP3A4 inhibitor, consider a dose decrease to: 40 mg daily for patients taking dasatinib tablets 140 mg daily. 20 mg daily for patients taking dasatinib tablets 100 mg daily. 20 mg daily for patients taking dasatinib tablets 70 mg daily.

For patients taking dasatinib tablets 60 mg or 40 mg daily, consider interrupting dasatinib tablets until the inhibitor is discontinued.

Allow a washout period of approximately 1 week after the inhibitor is stopped before reinitiating dasatinib tablets.

These reduced doses of dasatinib tablets are predicted to adjust the area under the curve (AUC) to the range observed without CYP3A4 inhibitors; however, clinical data are not available with these dose adjustments in patients receiving strong CYP3A4 inhibitors.

If dasatinib tablets are not tolerated after dose reduction, either discontinue the strong CYP3A4 inhibitor or interrupt dasatinib tablets until the inhibitor is discontinued.

Allow a washout period of approximately 1 week after the inhibitor is stopped before the dasatinib tablets dose is increased. 2.4 Dose Escalation in Adults with CML and Ph+ ALL, and Pediatric Patients with CML For adult patients with CML and Ph+ ALL, consider dose escalation to 140 mg once daily (chronic phase CML) or 180 mg once daily (advanced phase CML and Ph+ ALL) in patients who do not achieve a hematologic or cytogenetic response at the recommended starting dosage.

For pediatric patients with

CML, consider dose escalation to 120 mg once daily.

Dose escalation is not recommended for pediatric patients with Ph+ ALL, where dasatinib tablets is administered in combination with chemotherapy.

Escalate the dasatinib tablets dose as shown in Table in pediatric patients with chronic phase CML who do not achieve a hematologic or cytogenetic response at the recommended starting dosage.

Table 2: Dose Escalation for Pediatric CML Formulation Dose (maximum dose per day) Starting Dose Escalation Tablets 40 mg 50 mg 60 mg 70 mg 70 mg 90 mg 100 mg 120 mg 2.5 Dose Adjustment for Adverse Reactions Myelosuppression In clinical studies, myelosuppression was managed by dose interruption, dose reduction, or discontinuation of study therapy.

Hematopoietic growth factor has been used in patients with resistant myelosuppression.

Guidelines for dose modifications for adult and pediatric patients are summarized in Tables and 4, respectively.

Table 3: Dose Adjustments for Neutropenia and Thrombocytopenia in Adults ANC: absolute neutrophil count Chronic Phase CML (starting dose 100 mg once daily) ANC <0.5 × 10 9 /L or Platelets <50 × 10 9 /L Stop dasatinib tablets until ANC ≥1.0 × 10 9 /L and platelets ≥50 × 10 9 /L. Resume treatment with dasatinib tablets at the original starting dose if recovery occurs in ≤7 days.

If platelets <25 × 10 9 /L or recurrence of ANC <0.5 × 10 9 /L for >7 days, repeat Step and resume dasatinib tablets at a reduced dose of 80 mg once daily for second episode.

For third episode, further reduce dose to 50 mg once daily (for newly diagnosed patients) or discontinue dasatinib tablets (for patients resistant or intolerant to prior therapy including imatinib).

CML, Blast Phase CML and Ph+ ALL (starting dose 140 mg once daily) ANC* <0.5 × 10 9 /L or Platelets <10 × 10 9 /L Check if cytopenia is related to leukemia (marrow aspirate or biopsy).

If cytopenia is unrelated to leukemia, stop dasatinib tablets until ANC ≥1.0 × 10 9 /L and platelets ≥20 × 10 9 /L and resume at the original starting dose.

If recurrence of cytopenia, repeat Step and resume dasatinib tablets at a reduced dose of 100 mg once daily (second episode) or 80 mg once daily (third episode).

If cytopenia is related to leukemia, consider dose escalation to 180 mg once daily.

Table 4: Dose Adjustments for Neutropenia and Thrombocytopenia in Pediatric Patients with Ph+ CML Dose (maximum dose per day) If cytopenia persists for more than 3 weeks, check if cytopenia is related to leukemia (marrow aspirate or biopsy).

If cytopenia is unrelated to leukemia, stop dasatinib tablets until ANC* ≥1.0 x 10 9 /L and platelets ≥75 x 10 9 /L and resume at the original starting dose or at a reduced dose.

If cytopenia recurs, repeat marrow aspirate/biopsy and resume dasatinib tablets at a reduced dose.

Original Starting Dose One-Level Dose Reduction Two-Level Dose Reduction Tablets 40 mg 20 mg * 60 mg 40 mg 20 mg 70 mg 60 mg 50 mg 100 mg 80 mg 70 mg ANC: absolute neutrophil count ** lower tablet dose not available For pediatric patients with chronic phase CML, if Grade ≥ 3 neutropenia or thrombocytopenia recurs during complete hematologic response (CHR), interrupt dasatinib tablets and resume at a reduced dose.

Implement temporary dose reductions for intermediate degrees of cytopenia and disease response as needed.

Ph+ ALL, if neutropenia and/or thrombocytopenia result in a delay of the next block of treatment by more than 14 days, interrupt dasatinib tablets and resume at the same dose level once the next block of treatment is started.

If neutropenia and/or thrombocytopenia persist and the next block of treatment is delayed another 7 days, perform a bone marrow assessment to assess cellularity and percentage of blasts.

If marrow cellularity is <10%, interrupt treatment with dasatinib tablets until ANC > 500/μL (0.5 x 10 9 /L), at which time treatment may be resumed at full dose.

If marrow cellularity is >10%, resumption of treatment with dasatinib tablets may be considered.

Non-Hematologic Adverse Reactions For adults with

Ph+ CML and ALL, and pediatric patients with Ph+ CML, if a severe non-hematologic adverse reaction develops with dasatinib tablets use, treatment must be withheld until the adverse reaction has resolved or improved.

Thereafter, treatment can be resumed as appropriate at a reduced dose depending on the severity and recurrence.

Ph+ ALL, interrupt treatment for cases of grade ≥ 3 non-hematologic adverse reactions with the exception of liver function test abnormalities, and resume at a reduced dose when resolved to grade ≤1.

For elevated direct bilirubin over 5 times the institutional upper limit of normal (ULN), interrupt treatment until improvement to baseline or grade ≤1.

For elevated

AST/ALT over 15 times the institutional ULN, interrupt treatment until improvement to baseline or grade <1.

For recurrent liver function test abnormalities as above, reduce the dose if this adverse reaction recurs after reinitiation of dasatinib tablets.

Dose reduction recommendations are described in

Table 5.

Table 5: Dose Adjustments for Non-Hematologic Toxicities in Pediatric Patients Dose (maximum dose per day) If a non-hematologic toxicity grade 2 occurs, consider interrupting dasatinib tablets if no recovery despite symptomatic therapy; once recovered to grade ≤1, resume at the original starting dose.

Resume dasatinib tablets at a reduced dose for recurrent events.

If a non-hematologic toxicity grade 3 occurs, stop dasatinib tablets until recovery to grade ≤1 and then resume at a reduced dose.

If direct bilirubin is >5 ULN or AST/ALT >15 ULN, interrupt dasatinib tablets until recovery to grade ≤1 and then resume dasatinib tablets at the original starting dose.

Resume dasatinib tablets at a reduced dose for recurrent hepatotoxicity.

Original Starting Dose One-Level Dose Reduction Two-Level Dose Reduction Tablets 40 mg 20 mg 60 mg 40 mg 20 mg 70 mg 60 mg 50 mg 100 mg 80 mg 70 mg lower tablet dose not available 2.6 Duration of Treatment In clinical studies, treatment with dasatinib tablets in adults and in pediatric patients with chronic phase CML was continued until disease progression or until no longer tolerated by the patient.

The effect of stopping treatment on long-term disease outcome after the achievement of a cytogenetic response (including complete cytogenetic response [CCyR]) or major molecular response (MMR and MR4.5) has not been established.

In clinical studies, treatment with dasatinib tablets in pediatric patients with Ph+ ALL was administered for a maximum duration of 2 years.

Dasatinib tablets are hazardous products.

Follow applicable special handling and disposal procedures.

Dasatinib tablets are available as described in Table 21.

Table 21: Dasatinib Tablets Trade Presentations NDC Number Strength Description Tablets per Bottle 68001-660-06 20 mg White to off-white, biconvex, round, film-coated tablet with “D8” debossed on one side and plain on the other side and free from physical defects. 60 68001-661-06 50 mg White to off-white, biconvex, oval, film-coated tablet with “D6” debossed on one side and plain on the other side and free from physical defects. 60 68001-662-06 70 mg White to off-white, biconvex, round, film-coated tablet with “D4” debossed on one side and plain on the other side and free from physical defects. 60 68001-663-04 80 mg White to off-white, biconvex, triangle, film-coated tablet with “D3” debossed on one side and plain on the other side and free from physical defects. 30 68001-664-04 100 mg White to off-white, biconvex, oval, film-coated tablet with “D2” debossed on one side and plain on the other side and free from physical defects. 30 68001-665-04 140 mg White to off-white, biconvex, round, film-coated tablet with “D1” debossed on one side and plain on the other side and free from physical defects.

Dasatinib tablets should be stored at 20°C to 25°C (68°F to 77°F); excursions permitted between 15°C and 30°C (59°F and 86°F) .

This package is child-resistant.

Dasatinib tablet is an antineoplastic product.

Follow special handling and disposal procedures.

Personnel who are pregnant should avoid exposure to crushed or broken tablets.

Dasatinib tablets consist of a core tablet, surrounded by a film coating to prevent exposure of healthcare professionals to the active substance.

The use of latex or nitrile gloves for appropriate disposal when handling tablets that are inadvertently crushed or broken is recommended, to minimize the risk of dermal exposure.

Based on limited human data, dasatinib can cause fetal harm when administered to a pregnant woman.

Adverse pharmacologic effects including hydrops fetalis, fetal leukopenia, and fetal thrombocytopenia have been reported with maternal exposure to dasatinib.

Animal reproduction studies in rats have demonstrated extensive mortality during organogenesis, the fetal period, and in neonates.

Skeletal malformations were observed in a limited number of surviving rat and rabbit conceptuses.

These findings occurred at dasatinib plasma concentrations below those in humans receiving therapeutic doses of dasatinib.

Advise a pregnant woman of the potential risk to a fetus.

The estimated background risk in the

U.S. general population of major birth defects is 2% to 4% and of miscarriage is 15% to 20% of clinically recognized pregnancies.

Fetal/Neonatal Adverse Reactions Transplacental transfer of dasatinib has been reported.

Dasatinib has been measured in fetal plasma and amniotic fluid at concentrations comparable to those in maternal plasma.

Hydrops fetalis, fetal leukopenia, and fetal thrombocytopenia have been reported with maternal exposure to dasatinib.

These adverse pharmacologic effects on the fetus are similar to adverse reactions observed in adult patients and may result in fetal harm or neonatal death.

Based on human experience, dasatinib is suspected to cause congenital malformations, including neural tube defects, and harmful pharmacological effects on the fetus when administered during pregnancy.

In nonclinical studies at plasma concentrations below those observed in humans receiving therapeutic doses of dasatinib, embryo-fetal toxicities were observed in rats and rabbits.

Fetal death was observed in rats.

In both rats and rabbits, the lowest doses of dasatinib tested (rat: 2.5 mg/kg/day [15 mg/m 2 /day] and rabbit: 0.5 mg/kg/day [6 mg/m 2 /day]) resulted in embryo-fetal toxicities.

These doses produced maternal

AUCs of 105 ng•h/mL and 44 ng•h/mL (0.1-fold the human AUC) in rats and rabbits, respectively.

Embryo-fetal toxicities included skeletal malformations at multiple sites (scapula, humerus, femur, radius, ribs, and clavicle), reduced ossification (sternum; thoracic, lumbar, and sacral vertebrae; forepaw phalanges; pelvis; and hyoid body), edema, and microhepatia.

In a pre.

• and postnatal development study in rats, administration of dasatinib from gestation day (GD) 16 through lactation day (LD) 20, GD 21 through LD 20, or LD 4 through LD 20 resulted in extensive pup mortality at maternal exposures that were below the exposures in patients treated with dasatinib at the recommended labeling dose.

Of the 2712 patients in clinical studies of dasatinib, 617 (23%) were 65 years of age and older, and 123 (5%) were 75 years of age and older.

No differences in confirmed Complete Cytogenetic

Response (cCCyR) and MMR were observed between older and younger patients.

While the safety profile of dasatinib in the geriatric population was similar to that in the younger population, patients aged 65 years and older are more likely to experience the commonly reported adverse reactions of fatigue, pleural effusion, diarrhea, dyspnea, cough, lower gastrointestinal hemorrhage, and appetite disturbance, and more likely to experience the less frequently reported adverse reactions of abdominal distention, dizziness, pericardial effusion, congestive heart failure, hypertension, pulmonary edema, and weight decrease, and should be monitored closely.