ELPIX

Dasatinib tablets are a kinase inhibitor.

The chemical name for dasatinib is

N-(2-chloro-6-methylphenyl)-2-[[6-[4-(2-hydroxyethyl)-1-piperazinyl]-2-methyl-4-pyrimidinyl]amino]-5-thiazolecarboxamide, monohydrate.

The molecular formula is

C 22 H 26 ClN 7 O 2 S.

• H 2 O, which corresponds to a formula weight of 506.02 (monohydrate).

The anhydrous free base has a molecular weight of 488.01.

Dasatinib has the following chemical structure

Dasatinib is a white to off-white powder.

The drug substance is soluble in

N,N-dimethylformamide and insoluble in acetonitrile.

Dasatinib tablets are white to off-white, biconvex, film-coated tablets containing dasatinib, administered orally, with the following inactive ingredients: anhydrous lactose, lactose monohydrate, microcrystalline cellulose, croscarmellose sodium, hydroxypropyl cellulose and magnesium stearate.

The tablet coating consists of polyvinyl alcohol, glycerol esters of fatty acids, talc, sodium lauryl sulfate and titanium dioxide. dasatinib-struct.jpg.

Dasatinib tablets are indicated for the treatment of adult patients with newly diagnosed Philadelphia chromosome-positive (Ph+) chronic myeloid leukemia (CML) in chronic phase. chronic, accelerated, or myeloid or lymphoid blast phase Ph+ CML with resistance or intolerance to prior therapy including imatinib.

Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL) with resistance or intolerance to prior therapy.

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

Dasatinib tablets are a kinase inhibitor indicated for the treatment of newly diagnosed adults with Philadelphia chromosome-positive (Ph+) chronic myeloid leukemia (CML) in chronic phase. adults with chronic, accelerated, or myeloid or lymphoid blast phase Ph+ CML with resistance or intolerance to prior therapy including imatinib. adults with Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL) with resistance or intolerance to prior therapy. pediatric patients 1 year of age and older with Ph+ CML in chronic phase. pediatric patients 1 year of age and older with newly diagnosed Ph+ ALL in combination with chemotherapy.

History of heart disease Cardiopathies Pleural effusion Female likely to be pregnant Hepatitis B Male of childbearing age Hypokalaemia Hypomagnesaemia Hepatic impairment Severe or unstable cardiovascular disease Presence of anti-HBc antibodies Elderly Subject at risk of heart Subject at risk of QT space prolongation Risk of pneumonitis Subject at risk of bleeding Treatment with high doses of anthracycline, history (de).

Dasatinib, at nanomolar concentrations, inhibits the following kinases: BCR-ABL, SRC family (SRC, LCK, YES, FYN), c-KIT, EPHA2, and PDGFRβ.

Based on modeling studies, dasatinib is predicted to bind to multiple conformations of the ABL kinase.

In vitro, dasatinib was active in leukemic cell lines representing variants of imatinib mesylate‑-sensitive and resistant disease.

Dasatinib inhibited the growth of chronic myeloid leukemia (CML) and acute lymphoblastic leukemia (ALL) cell lines overexpressing BCR-ABL.

Under the conditions of the assays, dasatinib could overcome imatinib resistance resulting from BCR-ABL kinase domain mutations, activation of alternate signaling pathways involving the SRC family kinases (LYN, HCK), and multi-drug resistance gene overexpression. 12.2 Pharmacodynamics Cardiac Electrophysiology Of 2440 patients treated with dasatinib at all doses tested in clinical trials, 16 patients (<1%) had QTc prolongation reported as an adverse reaction.

Twenty-two patients (1%) experienced a QTcF > 500 ms.

In 865 patients with leukemia treated with dasatinib 70 mg BID in five Phase 2 studies, the maximum mean changes in QTcF (90% upper bound CI) from baseline ranged from 7 ms to 13.4 ms.

An analysis of the data from five Phase 2 studies in patients (70 mg BID) and a Phase 1 study in healthy subjects (100 mg single dose) suggests that there is a maximum increase of to 6 milliseconds in Fridericia corrected QTc interval from baseline for subjects receiving therapeutic doses of dasatinib, with associated upper 95% confidence intervals <10 msec. 12.3 Pharmacokinetics The pharmacokinetics of dasatinib exhibits dose proportional increases in AUC and linear elimination characteristics over the dose range of 15 mg/day (0.15 times the lowest approved recommended dose) to 240 mg/day (1.7 times the highest approved recommended dose).

At 100 mg QD, the maximum concentration at steady state (C max ) is 82.2 ng/mL (CV% 69%), area under the plasma drug concentration time curve (AUC) is 397 ng/mL*hr (CV% 55%).

The clearance of dasatinib is found to be time-invariant.

When administered to adult healthy subjects as dispersed tablets in juice, the adjusted geometric mean ratio was 0.97 (90% CI: 0.85, 1.10) for Cmax and 0.84 (90% CI: 0.78, 0.91) for AUC as compared to intact tablets.

The maximum plasma concentrations (Cmax) of dasatinib are observed between 0.5 hours and 6 hours (Tmax) following oral administration.

Food Effect A high-fat meal increased the mean AUC of dasatinib following a single dose of 100 mg by 14%.

The total calorie content of the high-fat meal was 985 kcal.

The calories derived from fat, carbohydrates, and protein were 52%, 34%, and 14% for the high-fat meal.

The apparent volume of distribution is 2505 L (CV% 93%).

Binding of dasatinib to human plasma proteins in vitro was approximately 96% and of its active metabolite was 93%, with no concentration dependence over the range of 100 ng/mL to 500 ng/mL.

Dasatinib is a

P-gp substrate in vitro.

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

The mean apparent oral clearance is 363.8 L/hr (CV% 81.3%).

Dasatinib is metabolized in humans, primarily by CYP3A4.

CYP3A4 is the primary enzyme responsible for the formation of the active metabolite.

Flavin-containing monooxygenase 3 (FMO‑ - 3) and uridine diphosphate-glucuronosyltransferase (UGT) enzymes are also involved in the formation of dasatinib metabolites.

The exposure of the active metabolite, which is equipotent to dasatinib, represents approximately 5% of the AUC of dasatinib.

The active metabolite of dasatinib is unlikely to play a major role in the observed pharmacology of the drug.

Dasatinib also has several other inactive oxidative metabolites.

Elimination is primarily via the feces.

Following a single radiolabeled dose of oral dasatinib, 4% of the administered radioactivity was recovered in the urine and 85% in the feces within 10 days.

Unchanged dasatinib accounted for 0.1% of the administered dose in the urine and 19% of the administered dose in the feces with the remainder of the dose being metabolites.

Age (15 to 86 years old), sex, and renal impairment (creatinine clearance 21.6 mL/min to 342.3 mL/min as estimated by Cockcroft Gault) have no clinically relevant effect on the pharmacokinetics of dasatinib.

The pharmacokinetics of dasatinib were evaluated in 43 pediatric patients with leukemia or solid tumors at oral doses ranging from 60 mg/m to 120 mg/m 2 once daily, taken with or without food.

The pharmacokinetics showed dose proportionality with a dose-related increase in exposure.

The mean

T max was observed between 0.5 hours and 6 hours and the mean half-life was 2 hours to 5 hours.

The geometric mean (CV%) of body weight normalized clearance in these 43 pediatric patients is 5.98 (41.5%) L/h/kg. In pediatric patients with a dosing regimen of 60 mg/m 2, the model simulated geometric mean (CV%) steady-state plasma average concentrations of dasatinib were 14.7 (64.6%) ng/mL (for to <6 years old), 16.3 (97.5%) ng/mL (for to <12 years old), and 18.2 (67.7%) ng/mL (for 12 years and older) .

Dasatinib clearance and volume of distribution change with body weight in pediatric patients.

Dasatinib has not been studied in patients < 1 year old.

The bioavailability of dispersed tablets in pediatric patients was estimated to be 36% lower than that of intact tablets.

Compared to subjects with normal liver function, patients with moderate hepatic impairment (Child Pugh B) had decreases in mean Cmax by 47% and mean AUC by 8%.

Patients with severe hepatic impairment (Child Pugh C) had decreases in mean Cmax by 43% and in mean AUC by 28% compared to the subjects with normal liver function.

P450 Enzymes The coadministration of ketoconazole (strong CYP3A4 inhibitor) twice daily increased the mean Cmax of dasatinib by 4-fold and the mean AUC of dasatinib by 5-fold following a single oral dose of 20 mg. The coadministration of rifampin (strong CYP3A4 inducer) once daily decreased the mean Cmax of dasatinib by 81% and the mean AUC of dasatinib by 82%.

Dasatinib is a time-dependent inhibitor of

Dasatinib does not inhibit

CYP1A2, 2A6, 2B6, 2C8, 2C9, 2C19, 2D6, or 2E1.

Dasatinib does not induce

CYP enzymes.

The administration of 30 mL of aluminum hydroxide/magnesium hydroxide 2 hours prior to a single dose of dasatinib was associated with no relevant change in the mean AUC of dasatinib; however, the mean Cmax of dasatinib was increased by 26%.

The simultaneous administration of 30 mL of aluminum hydroxide/magnesium hydroxide with a single dose of dasatinib was associated with a 55% reduction in the mean AUC of dasatinib and a 58% reduction in the mean C max of dasatinib.

The administration of a single dose of dasatinib 10 hours following famotidine (H2 antagonist) reduced the mean AUC of dasatinib by 61% and the mean Cmax of dasatinib by 63%.

The administration of a single 100 mg dose of dasatinib 22 hours following a 40 mg dose of omeprazole (proton pump inhibitor) at steady state reduced the mean AUC of dasatinib by 43% and the mean C max of dasatinib by 42%.

Transporters Dasatinib is not an inhibitor of P-gp in vitro.

Mechanism of action Dasatinib inhibits the activity of BCR ( Breakpoint Cluster Region)-ABL (Abelson), SRC family kinases, a number of other selective oncogenous kinases including c-KIT, ephrine receptors (EPH), and the PDGF ( Platelet Derived Growth Factor) receptor.

Dasatinib is a potent inhibitor of

BCR-ABL kinase acting at subnanomolar concentrations of 0.6-0.8 nM.

It binds to both the active and inactive forms of BCR-ABL.

In vitro, dasatinib is active on various sensitive and resistant cell lines of the imatinib-like BCR-ABL kinase.

Non-clinical studies have shown that dasatinib can overcome resistance to imatinib caused by the hyperexpression of BCR-ABL.

In vitro, the enzyme-liked DNA-like cells of the complexes-like-determinary-determining the imatinib-like-like-determinable-determin-de-ms (the phystic-de-de.

• Hyperuricaemia (Common)
• Troponin (increase) (Uncommon)
• Gamma GT (increase) (Uncommon)
• Hypoalbuminaemia (Uncommon)
• KPC (increase) (Uncommon)
• Hypercholesterolaemia (Uncommon)
• Proteinuria (Uncommon)
• Neutropenia Blood creatinine (increase)
• Hypokalaemia Hyperbilirubinaemia
• Transaminases (increase)
• Hypophosphataemia Hypocalcaemia Natriuretic cerebral peptide increased
• Tumor lysis syndrome (Uncommon)
• Alopecia (Common)
• Dry skin (Common)
• Bully dermatosis (Uncommon)
• Pigmentation (amendment) (Uncommon)
• Urticaria (Common)
• Palmoplantary Erythrodysaesthesia (Uncommon)
• Hyperhidrosis (Common)
• Skin ulcer (Uncommon)
• Rash (Very common)
• Hair disorder (Uncommon)
• Pruritus (Common)
• Panniculitis (Uncommon)
• Dermatitis (Common)
• Onychopathy (Uncommon)
• Neutrophilic dermatosis (Uncommon)
• Acne (Common)
• Photosensitivity (Uncommon)
• Skin dysfunction (Rare)
• Reticular Livedo (Rare)
• Skin exfoliation Stevens-Johnson Syndrome Vesicular rash
• Eczema Milium Skin irritation Rash due to vasculitis Generalised Erythema Genital eruption
• Pustular psoriasis Erythrose Erythematous rash Pruriginous rash Skin Erythema Pustulous eruption
• Mucite Follicular Rash Maculopapulous eruption Vesicular urticaria Pétechie Polymorphic Erythema
• Fatigue (Very common)
• Generalised edema (Common)
• Asthenia (Common)
• Peripheral edema (Very common)
• Chest pain (Common)
• Frisher (Common)
• Pain (Common)
• Fever (Very common)
• Face edema (Very common)
• Swelling of the face Gravitational edema Tumef Localized edema Peripheral swelling
• Edema Genital edema Hypothyroidism (Uncommon)
• Gynecomastia (Uncommon)
• Thyroiditis (Rare)
• Hyperthyroidism (Rare)
• Menstrual disorder (Uncommon)
• Spontaneous abortion (Rare)
• Genital swelling Febrile neutropenia (Common)
• Haemorrhage (Very common)
• Adenopathies (Uncommon)
• Cardiac aplasia (Very common)
• Contusion (Common)
• Lymphopenia (Uncommon)
• Lymphadenopathy (Uncommon)
• Erythroblastopenia (Rare)
• Thrombocytopenia Anemia Cytopenia Cholestasis (Uncommon)
• Hepatitis (Uncommon)
• Cholecystitis (Uncommon)
• Hepatitis B (reactivation) fulminant hepatitis
• Acute hepatic impairment Hypersensitivity (Very common)
• Anaphylactic shock (Rare)
• Bacterial infection Bacterial pneumonitis Mycosis Fungal pneumonia Herpes virus infection (Common)
• Cytomegalovirus infection Viral pneumonitis Viral infection Infection (Very common)
• Sepsis (Common)
• Post-intervention edema Weight (variation) (Common)
• Dehydration (Uncommon)
• Appetizer disorder (Common)
• Dysphagia (Uncommon)
• Diabetes (Rare)
• Water inflation
• Waterproof detention Lacrymal hyposecretion (Common)
• Visual defects (Uncommon)
• Photophobia (Uncommon)
• Lacrimal hypersecretion (Uncommon)
• Vision disorder (Common)
• Conjunctivitis (Uncommon)
• Optical neurosis (Rare)
• Palpebral edema Eye edema Visual acuity (decrease)
• Orbitary edema
• Chemosis Macular edema Periorbital edema Eye swelling Blurty vision Vertigo (Common)
• Dysgueusia (Common)
• Flavoured tissue disorder of the mouth (Common)
• Oral inflammation (Common)
• Tinnitus (Common)
• Deafness (Uncommon)
• Oral edema Stomatitis Labial edema Epistaxis
• Libido (decrease) (Uncommon)
• Insomnia (Common)
• Anxiety (Uncommon)
• Mood disorder (Uncommon)
• Depression (Common)
• Mental confusion (Uncommon)
• Dementia (Rare)
• Angor (Uncommon)
• Hypertension (Common)
• Cardiomegaly (Uncommon)
• Palpitation (Common)
• Thrombosis (Uncommon)
• Heart failure (Common)
• Cardiac dysfunction (Common)
• Congestive heart failure (Common)
• Ventricular tachycardia (Uncommon)
• Arrhythmia (Common)
• Myocardial infarction (Uncommon)
• Malaise (Uncommon)
• Pericardial efanchement (Common)
• Abnormal T wave with electrocardiogram (Uncommon)
• Ventricular arrhythmia (Uncommon)
• Hypotension (Uncommon)
• Syncope (Uncommon)
• Congestive puff (Common)
• Pericarditis (Uncommon)
• QT space extension (Uncommon)
• Thrombophlebitis (Uncommon)
• Leukocytoclase vasculitis (Rare)
• Deep thrombophlebitis (Rare)
• Pulmonary heart (Rare)
• Embolie (Rare)
• Coronary disease (Rare)
• Cardiac arrest (Rare)
• Myocarditis (Rare)
• Lung embolism (Rare)
• Acute coronary syndrome (Rare)
• Extension of PR space (Rare)
• Tachycardia Diastolic dysfunction
• Thrombotic microangiopathy Atrial fibrillation Ventricular dysfunction Atrial flutter
• Cardiac-derived edema Ejection fraction decreased Ventricular impairment Ventricular hypokinesia
• Congestive Cardiomyopathy Cardiovascular disease Dyspepsia (Common)
• Nausea (Very common)
• Gastritis (Common)
• Vomiting (Very common)
• Gastrointestinal ulcer high (Uncommon)
• Ascite (Uncommon)
• Pancreatitis (Uncommon)
• Collision (Common)
• Abdominal distension (Common)
• Anal fissure (Uncommon)
• Esophagitis (Uncommon)
• Gastroesophageal reflux (Uncommon)
• Gastrointestinal haemorrhage (Common)
• Diarrhoea (Very common)
• Abdominal pain (Very common)
• Constipation (Common)
• Enterocolitis (Common)
• Ileus (Rare)
• Gastroenteropathy with protein loss (Rare)
• Anal fistula (Rare)
• Oedema of the viscera Acute Pancreatitis Neutropenic colitis
• Rapid satiety Gastrointestinal edema Arthritis (Uncommon)
• Rhabdomyolysis (Uncommon)
• Joint pain (Common)
• Muscle spasm (Common)
• Muscle pain (Common)
• Osteonecrosis (Uncommon)
• Tendinitis (Uncommon)
• Musculoskeletal pain (Very common)
• Muscle weakness (Common)
• Myositis (Uncommon)
• Musculoskeletal scarring (Common)
• Growth retardation (Rare)
• Delay in closure of epiphysis (Rare)
• Amnesia (Uncommon)
• Trembling (Uncommon)
• Central nervous system haemorrhage (Uncommon)
• Neuropathy (Common)
• Balance disorder (Uncommon)
• Somnolence (Common)
• Headache (Very common)
• Stroke (Rare)
• Ataxia (Rare)
• Convulsions (Rare)
• Transient ischemic accident (Rare)
• Walking disorder (Rare)
• Facial paralysis (Rare)
• Epidural hematoma Peripheral neuropathy
• Sub-arachnoid haemorrhage Subdural haemorrhage Blood-related stroke Brain hematoma
• Subdural hematoma Brain haemorrhage Intracranial haemorrhage Upper respiratory tract infection (Common)
• Pulmonary infiltration (Common)
• Pulmonary hypertension (Uncommon)
• Cough (Common)
• Pulmonary hypertension (Common)
• Bronchospasm (Uncommon)
• Asthma (Uncommon)
• Dyspnoea (Very common)
• Pleural effusion (Very common)
• Pulmonary edema (Common)
• Inflammation of the upper airways (Common)
• Pneumonia (Common)
• Chylothorax (Uncommon)
• Acute respiratory distress syndrome (Rare)
• Pleuropericarditis (Rare)
• Pre-capillary pulmonary hypertension.

Military Interstitial pneumopathy

Pollakiuria (Uncommon) Nephropathy (Uncommon) Testicular swelling Penile edema Penile swelling

Experience with overdose of dasatinib in clinical studies is limited to isolated cases.

The highest overdosage of 280 mg per day for 1 week was reported in two patients and both developed severe myelosuppression and bleeding.

Since dasatinib is associated with severe myelosuppression, monitor patients who ingest more than the recommended dosage closely for myelosuppression and give appropriate supportive treatment.

Acute overdose in animals was associated with cardiotoxicity.

Evidence of cardiotoxicity included ventricular necrosis and valvular/ventricular/atrial hemorrhage at single doses ≥100 mg/kg (600 mg/m 2 ) in rodents.

There was a tendency for increased systolic and diastolic blood pressure in monkeys at single doses ≥10 mg/kg (120 mg/m 2 ).

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.