Phyrago Drug Information

1. INDICATIONS AND USAGE PHYRAGO is 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.

PHYRAGO is 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.

2. DOSAGE AND ADMINISTRATION Chronic phase CML in adults: 100 mg orally once daily. Accelerated phase CML, myeloid or lymphoid blast phase CML, or Ph+ ALL in adults: 140 mg orally once daily.

Chronic phase CML and ALL in pediatrics: starting dose based on body weight. Administer with or without a meal. Do not crush, cut, or chew tablets. 2.1 Recommended Dosage in Adult Patients The recommended starting dosage of PHYRAGO for chronic phase CML in adults is 100 mg administered orally once daily.

Swallow PHYRAGO whole. PHYRAGO can be taken with or without a meal, either in the morning or in the evening. 2.2 Recommended Dosage 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 PHYRAGO for Pediatric Patients* For pediatric patients with Ph+ ALL, begin PHYRAGO therapy on or before day 15 of induction chemotherapy, when diagnosis is confirmed and continue for 2 years. Tablet dosing is not recommended for patients weighing less than 10 kg. See Dosage and Administration 2.4 below for recommendations on dose escalation in adults with CML and Ph+ ALL, and pediatric patients with CML. 2.3 Dosage Modifications for Drug Interactions Strong CYP3A4 Inducers Avoid the use of concomitant strong CYP3A4 inducers.

If patients must be coadministered a strong CYP3A4 inducer, consider a PHYRAGO dose increase. If the dose of PHYRAGO is increased, monitor the patient carefully for toxicity. Strong 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 PHYRAGO must be administered with a strong CYP3A4 inhibitor, consider a dose decrease to: daily, consider interrupting PHYRAGO until the inhibitor is discontinued. Allow a washout period of approximately 1 week after the inhibitor is stopped before reinitiating PHYRAGO.

These reduced doses of PHYRAGO 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 PHYRAGO is not tolerated after dose reduction, either discontinue the strong CYP3A4 inhibitor or interrupt PHYRAGO until the inhibitor is discontinued. Antacids Avoid concomitant use of PHYRAGO with antacids.

If concomitant use of an antacid cannot be avoided, administer the antacid at least 2 hours prior to or 2 hours after the dose of PHYRAGO. 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 (see Table 2 below). Dose escalation is not recommended for pediatric patients with Ph+ ALL, where PHYRAGO is administered in combination with chemotherapy.

Escalate the PHYRAGO dose as shown in Table 2 in pediatric patients with chronic phase CML who do not achieve a hematologic or cytogenetic response at the recommended starting dosage. Table 2: Dose 2.5 Dosage Modifications 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 3 and 4, respectively. Table 3: Dosage Modifications for Neutropenia and Thrombocytopenia in Adults ANC: absolute neutrophil count Table 4: Dosage Modifications for Neutropenia and Thrombocytopenia in Pediatric Patients with Ph+ CML 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 PHYRAGO and resume at a reduced dose. Implement temporary dose reductions for intermediate degrees of cytopenia and disease response as needed.

For pediatric patients with Ph+ ALL, if neutropenia and/or thrombocytopenia result in a delay of the next block of treatment by more than 14 days, interrupt PHYRAGO 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%, resumption of treatment with PHYRAGO 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 PHYRAGO 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. For pediatric patients with 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 PHYRAGO.

Dose reduction recommendations are described in Table 5. Table 5: Dosage Modifications for Non-Hematologic Toxicities in Pediatric Patients lower tablet dose not available 2.6 Duration of Treatment In clinical studies, treatment with dasatinib 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 ) or major molecular response (MMR and MR4.5) has not been established.

In clinical studies, treatment with dasatinib in pediatric patients with Ph+ ALL was administered for a maximum duration of 2 years. PHYRAGO is a hazardous drug. Follow applicable special handling and disposal procedures.

6. ADVERSE REACTIONS The following clinically significant adverse reactions are discussed in greater detail in other sections of the labeling: Myelosuppression. Bleeding-related events.

Fluid retention. Cardiovascular toxicity. Pulmonary arterial hypertension.

QT prolongation. Severe dermatologic reactions. Tumor lysis syndrome.

Effects on growth and development in pediatric patients. Hepatotoxicity. Most common adverse reactions (≥15%) in patients receiving dasatinib as single-agent therapy included myelosuppression, fluid retention events, diarrhea, headache, skin rash, hemorrhage, dyspnea, fatigue, nausea, and musculoskeletal pain.

Most common adverse reactions (≥30%) in pediatric patients receiving dasatinib in combination with chemotherapy included mucositis, febrile neutropenia, pyrexia, diarrhea, nausea, vomiting, musculoskeletal pain, abdominal pain, cough, headache, rash, fatigue, constipation, arrhythmia, hypertension, edema, infections (bacterial, viral and fungal), hypotension, decreased appetite, hypersensitivity, dyspnea, epistaxis, peripheral neuropathy, and altered state of consciousness. To report SUSPECTED ADVERSE REACTIONS, contact Cycle Pharmaceuticals Ltd at 1-844-784-1807 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. The data described below reflect exposure to dasatinib administered as single-agent therapy at all doses tested in clinical studies (n = 2809), including 324 adult patients with newly diagnosed chronic phase CML and 2388 adult patients with imatinib-resistant or -intolerant chronic or advanced phase CML or Ph+ ALL, and 97 pediatric patients with chronic phase CML.

In a randomized trial in patients with newly diagnosed chronic phase CML, the median duration of therapy was approximately 60 months. In the overall population of 2712 adult patients, 88% of patients experienced adverse reactions at some time and 19% experienced adverse reactions leading to treatment discontinuation. In the randomized trial in adult patients with newly diagnosed chronic phase CML, drug was discontinued for adverse reactions in 16% of patients with a minimum of 60 months of follow- up.

After a minimum of 60 months of follow-up, the cumulative discontinuation rate was 39%. Among the 97 pediatric subjects, drug-related adverse reactions leading to discontinuation were reported in 1 patient (1%). Adverse reactions reported in ≥ 10% of adult patients, and other adverse reactions of interest, in a randomized trial in patients with newly diagnosed chronic phase CML at a median follow-up of approximately 60 months are presented in Table 6.

Adverse reactions reported in ≥ 10% of adult patients treated at the recommended dose of 100 mg once daily (n=165), and other adverse reactions of interest, in a randomized dose-optimization trial of patients with chronic phase CML resistant or intolerant to prior imatinib therapy at a median follow-up of approximately 84 months are presented in Table 8. Adverse reactions reported in ≥10% of pediatric patients at a median follow-up of approximately 51.1 months are presented in Table 11. Drug-related serious adverse reactions (SARs) were reported for 16.7% of adult patients in the randomized trial of patients with newly diagnosed chronic phase CML.

Serious adverse reactions reported in 5% of patients included pleural effusion (5%). Drug-related SARs were reported for 26.1% of patients treated at the recommended dose of 100 mg once daily in the randomized dose-optimization trial of adult patients with chronic phase CML resistant or intolerant to prior imatinib therapy. Drug-related SARs were reported for 14.4% of pediatric patients.

Chronic Myeloid Leukemia (CML) Adverse reactions (excluding laboratory abnormalities) that were reported in at least 10% of adult patients are shown in Table 6 for newly diagnosed patients with chronic phase CML and Tables 8 and 10 for CML patients with resistance or intolerance to prior imatinib therapy. Table 6: Adverse Reactions Reported in ≥ 10% of Adult Patients with Newly Diagnosed Chronic Phase CML Minimum of a Includes cardiac failure acute, cardiac failure congestive, cardiomyopathy, diastolic dysfunction, ejection fraction decreased, and left ventricular dysfunction. b Includes erythema, erythema multiforme, rash, rash generalized, rash macular, rash papular, rash pustular, skin exfoliation, and rash vesicular. c Adverse reaction of special interest with <10% frequency. d Includes conjunctival hemorrhage, ear hemorrhage, ecchymosis, epistaxis, eye hemorrhage, gingival bleeding, hematoma, hematuria, hemoptysis, intra-abdominal hematoma, petechiae, scleral hemorrhage, uterine hemorrhage, and vaginal hemorrhage A comparison of cumulative rates of adverse reactions reported in ≥ 10% of patients with minimum follow-up of 1 and 5 years in a randomized trial of newly diagnosed patients with chronic phase CML treated with dasatinib are shown in Table 7. Table 7: Adverse Reactions Reported in ≥ 10% of Adult Patients with Newly Diagnosed Chronic Phase CML in the Dasatinib-Treated Arm n= 0 a Includes cardiac failure acute, cardiac failure congestive, cardiomyopathy, diastolic dysfunction, ejection fraction decreased, and left ventricular dysfunction. b Includes erythema, erythema multiforme, rash, rash generalized, rash macular, rash papular, rash pustular, skin exfoliation, and rash vesicular At 60 months, there were 26 deaths in dasatinib-treated patients (10.1%) and 26 deaths in imatinib-treated patients (10.1%); 1 death in each group was assessed by the investigator as related to study therapy.

Table 8: Adverse Reactions Reported in ≥ 10% of Adult Patients with Chronic Phase CML Resistant or Intolerant to Prior Imatinib Therapy minimum of 1 a Includes drug eruption, erythema, erythema multiforme, erythrosis, exfoliative rash, generalized erythema, genital rash, heat rash, milia, rash, rash erythematous, rash follicular, rash generalized, rash macular, rash maculopapular, rash papular, rash pruritic, rash pustular, skin exfoliation, skin irritation, urticaria vesiculosa, and rash vesicular. Cumulative rates of selected adverse reactions that were reported over time in patients treated with the 100 mg once daily recommended starting dose in a randomized dose-optimization trial of imatinib-resistant or -intolerant patients with chronic phase CML are shown in Table 9. Table 9: Selected Adverse Reactions Reported in Adult Dose Optimization Trial (Imatinib-Intolerant or -Resistant Chronic Phase CML) a a Randomized dose-optimization trial results reported in the recommended starting dose of 100 mg once daily (n=165) population.

Laboratory Abnormalities Myelosuppression was commonly reported in all patient populations. Myelosuppression was reported in patients with normal baseline laboratory values as well as in patients with pre-existing laboratory abnormalities. In patients who experienced severe myelosuppression, recovery generally occurred following dose interruption or reduction; permanent discontinuation of treatment occurred in 2% of adult patients with newly diagnosed chronic phase CML and 5% of adult patients with resistance or intolerance to prior imatinib therapy.

Grade 3 or 4 elevations of transaminases or bilirubin and Grade 3 or 4 hypocalcemia, hypokalemia, and hypophosphatemia were reported in patients with all phases of CML but were reported with an increased frequency in patients with myeloid or lymphoid blast phase CML. Elevations in transaminases or bilirubin were usually managed with dose reduction or interruption. Patients developing Grade 3 or 4 hypocalcemia during dasatinib therapy often had recovery with oral calcium supplementation.

There were no discontinuations of dasatinib therapy in this patient population due to biochemical laboratory parameters. Laboratory abnormalities reported in patients with CML resistant or intolerant to imatinib who received the recommended starting doses of dasatinib are shown by disease phase in Table 13. In the pediatric studies in CML, the rates of laboratory abnormalities were consistent with the known profile for laboratory parameters in adults.

Philadelphia Chromosome-Positive Acute Lymphoblastic Leukemia (Ph+ ALL) in Adults A total of 135 adult patients with Ph+ ALL were treated with dasatinib in clinical studies. The median duration of treatment was 3 months (range 0.03-31 months). The safety profile of patients with Ph+ ALL was similar to those with lymphoid blast phase CML.

The most frequently reported adverse reactions included fluid retention events, such as pleural effusion (24%) and superficial edema (19%), and gastrointestinal disorders, such as diarrhea ( %) were also frequently reported. Philadelphia Chromosome-Positive Acute Lymphoblastic Leukemia (Ph+ ALL) in Pediatric Patients The safety of dasatinib administered continuously in combination with multiagent chemotherapy was determined in a multicohort study of 81 pediatric patients with newly diagnosed Ph+ ALL. The median duration of therapy was 24 months (range 2 to 27 months).

Fatal adverse reactions occurred in 3 patients (4%), all of which were due to infections. Eight (10%) patients experienced adverse reactions leading to treatment discontinuation, including fungal sepsis, hepatotoxicity in the setting of graft versus host disease, thrombocytopenia, CMV infection, pneumonia, nausea, enteritis and drug hypersensitivity. The most common serious adverse reactions (incidence ≥10%) were pyrexia, febrile neutropenia, mucositis, diarrhea, sepsis, hypotension, infections (bacterial, viral and fungal), hypersensitivity, vomiting, renal insufficiency, abdominal pain, and musculoskeletal pain.

The incidence of common adverse reactions (incidence ≥20%) on study are shown in Table 14: Table 14: Adverse Reactions Reported in ≥20% of Pediatric Patients with Ph+ ALL Treated with dasatinib in Combination with Chemotherapy CA - The incidence of common adverse reactions attributed by the investigator to dasatinib (reported at a frequency of ≥10%, all grades and grade 3/4, respectively) on study (N=81), included febrile neutropenia ( %, 5%). CTCAE grade 3/4 laboratory abnormalities in pediatric patients with Ph+ ALL treated with dasatinib in combination with chemotherapy are shown in Table 15. Gastrointestinal Disorders: 1%–<10% – mucosal inflammation (including mucositis/stomatitis), dyspepsia, abdominal distension, constipation, gastritis, colitis (including neutropenic colitis), oral soft tissue disorder; 0.1%–<1% – ascites, dysphagia, anal fissure, upper gastrointestinal ulcer, esophagitis, pancreatitis, gastroesophageal reflux disease; <0.1% – protein losing gastroenteropathy, ileus, acute pancreatitis, anal fistula.

Skin and Subcutaneous Tissue Disorders: 1%–<10% – alopecia, acne, dry skin, hyperhidrosis, urticaria, dermatitis (including eczema); 0.1%–<1% – pigmentation disorder, skin ulcer, bullous conditions, photosensitivity, nail disorder, neutrophilic dermatosis, panniculitis, palmar-plantar erythrodysesthesia syndrome, hair disorder; <0.1% – leukocytoclastic vasculitis, skin fibrosis. Respiratory, Thoracic, and Mediastinal Disorders: 1%–<10% – lung infiltration, pneumonitis, cough; 0.1%–<1% – asthma, bronchospasm, dysphonia, pulmonary arterial hypertension; <0.1% – acute respiratory distress syndrome, pulmonary embolism. Nervous System Disorders: 1%–<10% – neuropathy (including peripheral neuropathy), dizziness, dysgeusia, somnolence; 0.1%–<1% – amnesia, tremor, syncope, balance disorder; <0.1% – convulsion, cerebrovascular accident, transient ischemic attack, optic neuritis, VIIth nerve paralysis, dementia, ataxia.

Blood and Lymphatic System Disorders: 0.1%–<1% – lymphadenopathy, lymphopenia; <0.1%– aplasia pure red cell. Investigations: 1%–<10% – weight increased, weight decreased; 0.1%–<1% – blood creatine phosphokinase increased, gamma-glutamyltransferase increased. Infections and Infestations: 1%–<10% – pneumonia (including bacterial, viral, and fungal), upper respiratory tract infection/inflammation, herpes virus infection, enterocolitis infection, sepsis (including fatal outcomes ).

Cardiac Disorders: 1%–<10% – arrhythmia (including tachycardia), palpitations; 0.1%–<1% – angina pectoris, cardiomegaly, pericarditis, ventricular arrhythmia (including ventricular tachycardia), electrocardiogram T-wave abnormal, troponin increased; <0.1% – cor pulmonale, myocarditis, acute coronary syndrome, cardiac arrest, electrocardiogram PR prolongation, coronary artery disease, pleuropericarditis. Eye Disorders: 1%–<10% – visual disorder (including visual disturbance, vision blurred, and visual acuity reduced), dry eye; 0.1%–<1% – conjunctivitis, visual impairment, lacrimation increased, <0.1% – photophobia. Vascular Disorders: 1%–<10% – flushing, hypertension; 0.1%–<1% – hypotension, thrombophlebitis, thrombosis; <0.1% – livedo reticularis, deep vein thrombosis, embolism.

Psychiatric Disorders: 1%–<10% – insomnia, depression; 0.1%–<1% – anxiety, affect lability, confusional state, libido decreased. Pregnancy, Puerperium, and Perinatal Conditions: <0.1% – abortion. Reproductive System and Breast Disorders: 0.1%–<1% – gynecomastia, menstrual disorder.

Injury, Poisoning, and Procedural Complications: 1%–<10% – contusion. Ear and Labyrinth Disorders: 1%–<10% – tinnitus; 0.1%–<1% – vertigo, hearing loss. Hepatobiliary Disorders: 0.1%–<1% – cholestasis, cholecystitis, hepatitis.

Renal and Urinary Disorders: 0.1%–<1% – urinary frequency, renal failure, proteinuria; <0.1%– renal impairment. Immune System Disorders: 0.1%–<1% – hypersensitivity (including erythema nodosum). Endocrine Disorders: 0.1%–<1% – hypothyroidism; <0.1% – hyperthyroidism, thyroiditis. 6.2 Postmarketing Experience The following adverse reactions have been identified during post approval use of dasatinib.

Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Infections: hepatitis B virus reactivation Cardiac disorders: atrial fibrillation/atrial flutter Respiratory, thoracic, and mediastinal disorders: interstitial lung disease, chylothorax Skin and subcutaneous tissue disorders: Stevens-Johnson syndrome Renal and urinary disorders: nephrotic syndrome Blood and lymphatic system disorders: thrombotic microangiopathy Hepatobiliary disorders: hepatotoxicity

7. DRUG INTERACTIONS Strong CYP3A4 Inhibitors: Dose reduction may be necessary. Strong CYP3A4 Inducers: Dose increase may be necessary.

Antacids: Avoid concomitant use. 7.1 Effect of Other Drugs on Dasatinib Strong CYP3A4 Inhibitors The coadministration with strong CYP3A inhibitors may increase dasatinib concentrations. Increased dasatinib concentrations may increase the risk of toxicity. Avoid concomitant use of strong CYP3A4 inhibitors.

If concomitant administration of a strong CYP3A4 inhibitor cannot be avoided, consider a dose reduction. Strong CYP3A4 Inducers The coadministration of PHYRAGO with strong CYP3A inducers may decrease dasatinib concentrations. Decreased dasatinib concentrations may reduce efficacy.

Consider alternative drugs with less enzyme induction potential. If concomitant administration of a strong CYP3A4 inducer cannot be avoided, consider a dose increase. Antacids Avoid concomitant use of PHYRAGO with antacids.

If concomitant use of an antacid cannot be avoided, administer the antacid at least 2 hours prior to or 2 hours after the dose of PHYRAGO. Concomitant use with antacids decreases dasatinib plasma concentrations, which may reduce PHYRAGO efficacy.

• Pregnancy Risk Summary Based on limited human data, PHYRAGO 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. Clinical Considerations 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. Data Human Data 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. Animal Data 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 and rabbit: 0.5 mg/kg/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.

Pediatric Use Ph+ CML in Chronic Phase The safety and effectiveness of dasatinib monotherapy have been demonstrated in pediatric patients with newly diagnosed chronic phase CML. There are no data in children under 1 year of age. Adverse reactions associated with bone growth and development were reported in 5 (5.2%) of patients.

Ph+ ALL The safety and effectiveness of dasatinib in combination with chemotherapy have been demonstrated in pediatric patients one year and over with newly diagnosed Ph+ ALL. Use of dasatinib in pediatric patients is supported by evidence from one pediatric study. One case of grade 1 osteopenia was reported.

The safety profile of dasatinib in pediatric subjects was comparable to that reported in studies in adult subjects. Monitor bone growth and development in pediatric patients. Pediatric Patients with Difficulty Swallowing Tablets Five patients with Ph+ ALL 2 to 10 years of age received at least one dose of dasatinib tablet dispersed in juice on Study CA180372.

The exposure for dispersed tablets was 36% lower as compared to intact tablets in pediatric patients. Due to unavailable clinical data, it is unclear whether dispersing PHYRAGO tablets significantly alters the safety and/or efficacy of PHYRAGO.

4. CONTRAINDICATIONS None. None.

10. OVERDOSAGE 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 ).