Label: SPRYCEL- dasatinib tablet

  • NDC Code(s): 0003-0524-11, 0003-0527-11, 0003-0528-11, 0003-0852-22, view more
    0003-0855-22, 0003-0857-22
  • Packager: E.R. Squibb & Sons, L.L.C.
  • Category: HUMAN PRESCRIPTION DRUG LABEL
  • DEA Schedule: None
  • Marketing Status: New Drug Application

Drug Label Information

Updated 08/15

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  • HIGHLIGHTS OF PRESCRIBING INFORMATION
    These highlights do not include all the information needed to use SPRYCEL safely and effectively. See full prescribing information for SPRYCEL.


    SPRYCEL ® (dasatinib) tablets, for oral use
    Initial U.S. Approval: 2006

    RECENT MAJOR CHANGES

    Indications and Usage (1)     8/2015
    Dosage and Administration (2)     8/2015
         Dose Adjustment for Adverse Reactions (2.3)     8/2015
    Warnings and Precautions (5)
         Myelosuppression (5.1)     8/2015
         Fluid Retention (5.3)     8/2015
         Severe Dermatologic Reactions (5.7)     8/2015

    INDICATIONS AND USAGE

    SPRYCEL is a kinase inhibitor indicated for the treatment of

    newly diagnosed adults with Philadelphia chromosome-positive (Ph+) chronic myeloid leukemia (CML) in chronic phase. (1, 14)
    adults with chronic, accelerated, or myeloid or lymphoid blast phase Ph+ CML with resistance or intolerance to prior therapy including imatinib. (1, 14)
    adults with Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL) with resistance or intolerance to prior therapy. (1, 14)

    DOSAGE AND ADMINISTRATION

    Chronic phase CML: 100 mg once daily. (2)
    Accelerated phase CML, myeloid or lymphoid blast phase CML, or Ph+ ALL: 140 mg once daily. (2)

    Administer orally, with or without a meal. Do not crush or cut. (2)

    DOSAGE FORMS AND STRENGTHS

    Tablets: 20 mg, 50 mg, 70 mg, 80 mg, 100 mg, and 140 mg. (3, 16)

    CONTRAINDICATIONS

    None. (4)

    WARNINGS AND PRECAUTIONS

    Myelosuppression and Bleeding Events: Severe thrombocytopenia, neutropenia, and anemia may occur. Use caution if used concomitantly with medications that inhibit platelet function or anticoagulants. Monitor complete blood counts regularly. Transfuse and interrupt SPRYCEL when indicated. (2.3, 5.1, 5.2, 6.1)
    Fluid Retention: Fluid retention, sometimes severe, including pleural effusions. Manage with supportive care measures and/or dose modification. ( 2.3, 5.3, 6.1)
    Cardiac Dysfunction: Monitor patients for signs or symptoms and treat appropriately. ( 5.4, 6.1)
    Pulmonary Arterial Hypertension (PAH): SPRYCEL may increase the risk of developing PAH which may be reversible on discontinuation. Consider baseline risk and evaluate patients for signs and symptoms of PAH during treatment. Stop SPRYCEL if PAH is confirmed. (5.5)
    QT Prolongation: Use SPRYCEL with caution in patients who have or may develop prolongation of the QT interval. (5.6)
    Severe Dermatologic Reactions: Individual cases of severe mucocutaneous dermatologic reactions have been reported. ( 5.7, 6.4)
    Tumor Lysis Syndrome: Tumor lysis syndrome has been reported. Maintain adequate hydration and correct uric acid levels prior to initiating therapy with SPRYCEL. ( 5.8)
    Embryo-Fetal Toxicity: Can cause fetal harm. Advise of potential risk to fetus and avoid pregnancy. ( 5.9, 8.1, 8.3)

    ADVERSE REACTIONS

    Most common adverse reactions (≥15%) in patients with newly diagnosed chronic phase CML included myelosuppression, fluid retention, and diarrhea. Most common adverse reactions (≥15%) in patients with resistance or intolerance to prior imatinib therapy included myelosuppression, fluid retention events, diarrhea, headache, fatigue, dyspnea, skin rash nausea, hemorrhage and musculoskeletal pain. (6)

      

    To report SUSPECTED ADVERSE REACTIONS, contact Bristol-Myers Squibb at 1-800-721-5072 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

    DRUG INTERACTIONS

    CYP3A4 Inhibitors: May increase dasatinib drug levels; dose reduction may be necessary. (2.1, 7.1)
    CYP3A4 Inducers: May decrease dasatinib drug levels, dose increase may be necessary. (2.1, 7.2)
    Antacids: May decrease dasatinib drug levels, avoid simultaneous administration. (7.2)
    H2 Antagonists/Proton Pump Inhibitors: May decrease dasatinib drug levels. (7.2)

    USE IN SPECIFIC POPULATIONS

    Lactation: Not recommended (8.2)
    Hepatic Impairment: Use SPRYCEL with caution in patients with hepatic impairment. (8.6)

    See 17 for PATIENT COUNSELING INFORMATION and FDA-approved patient labeling.

    Revised: 8/2015

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  • FULL PRESCRIBING INFORMATION: CONTENTS*

    1 INDICATIONS AND USAGE

    2 DOSAGE AND ADMINISTRATION

    2.1 Dose Modification

    2.2 Dose Escalation

    2.3 Dose Adjustment for Adverse Reactions

    3 DOSAGE FORMS AND STRENGTHS

    4 CONTRAINDICATIONS

    5 WARNINGS AND PRECAUTIONS

    5.1 Myelosuppression

    5.2 Bleeding-Related Events

    5.3 Fluid Retention

    5.4 Cardiovascular Events

    5.5 Pulmonary Arterial Hypertension

    5.6 QT Prolongation

    5.7 Severe Dermatologic Reactions

    5.8 Tumor Lysis Syndrome

    5.9 Embryo-Fetal Toxicity

    6 ADVERSE REACTIONS

    6.1 Chronic Myeloid Leukemia (CML)

    6.2 Philadelphia Chromosome-Positive Acute Lymphoblastic Leukemia (Ph+ ALL)

    6.3 Additional Pooled Data From Clinical Trials

    6.4 Postmarketing Experience

    7 DRUG INTERACTIONS

    7.1 Drugs That May Increase Dasatinib Plasma Concentrations

    7.2 Drugs That May Decrease Dasatinib Plasma Concentrations

    7.3 Drugs That May Have Their Plasma Concentration Altered By Dasatinib

    8 USE IN SPECIFIC POPULATIONS

    8.1 Pregnancy

    8.2 Lactation

    8.3 Females and Males of Reproductive Potential

    8.4 Pediatric Use

    8.5 Geriatric Use

    8.6 Hepatic Impairment

    8.7 Renal Impairment

    10 OVERDOSAGE

    11 DESCRIPTION

    12 CLINICAL PHARMACOLOGY

    12.1 Mechanism of Action

    12.3 Pharmacokinetics

    13 NONCLINICAL TOXICOLOGY

    13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

    14 CLINICAL STUDIES

    14.1 Newly Diagnosed Chronic Phase CML

    14.2 Imatinib Resistant or Intolerant CML or Ph+ ALL

    16 HOW SUPPLIED/STORAGE AND HANDLING

    16.1 How Supplied

    16.2 Storage

    16.3 Handling and Disposal

    17 PATIENT COUNSELING INFORMATION

    *
    Sections or subsections omitted from the full prescribing information are not listed.
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  • 1 INDICATIONS AND USAGE

    SPRYCEL® (dasatinib) is indicated for the treatment of adults 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.
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  • 2 DOSAGE AND ADMINISTRATION

    The recommended starting dosage of SPRYCEL for chronic phase CML is 100 mg administered orally once daily. The recommended starting dosage of SPRYCEL for accelerated phase CML, myeloid or lymphoid blast phase CML, or Ph+ ALL is 140 mg administered orally once daily. Tablets should not be crushed or cut; they should be swallowed whole. SPRYCEL can be taken with or without a meal, either in the morning or in the evening.

    In clinical studies, treatment with SPRYCEL 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) is not known.

    2.1 Dose Modification

    Concomitant Strong CYP3A4 inducers: The use of concomitant strong CYP3A4 inducers may decrease dasatinib plasma concentrations and should be avoided (e.g., dexamethasone, phenytoin, carbamazepine, rifampin, rifabutin, phenobarbital). St. John’s Wort may decrease dasatinib plasma concentrations unpredictably and should be avoided. If patients must be coadministered a strong CYP3A4 inducer, based on pharmacokinetic studies, a SPRYCEL dose increase should be considered. If the dose of SPRYCEL is increased, the patient should be monitored carefully for toxicity [see Drug Interactions (7.2)].

    Concomitant Strong CYP3A4 inhibitors: CYP3A4 inhibitors (e.g., ketoconazole, itraconazole, clarithromycin, atazanavir, indinavir, nefazodone, nelfinavir, ritonavir, saquinavir, telithromycin, and voriconazole) may increase dasatinib plasma concentrations. Grapefruit juice may also increase plasma concentrations of dasatinib and should be avoided.

    Selection of an alternate concomitant medication with no or minimal enzyme inhibition potential, if possible, is recommended. If SPRYCEL must be administered with a strong CYP3A4 inhibitor, a dose decrease should be considered. Based on pharmacokinetic studies, a dose decrease to 20 mg daily should be considered for patients taking SPRYCEL 100 mg daily. For patients taking SPRYCEL 140 mg daily, a dose decrease to 40 mg daily should be considered. These reduced doses of SPRYCEL are predicted to adjust the area under the curve (AUC) to the range observed without CYP3A4 inhibitors. However, there are no clinical data with these dose adjustments in patients receiving strong CYP3A4 inhibitors. If SPRYCEL is not tolerated after dose reduction, either the strong CYP3A4 inhibitor must be discontinued, or SPRYCEL should be stopped until treatment with the inhibitor has ceased. When the strong inhibitor is discontinued, a washout period of approximately 1 week should be allowed before the SPRYCEL dose is increased [see Drug Interactions (7.1)].

    2.2 Dose Escalation

    In clinical studies of adult CML and Ph+ ALL patients, dose escalation to 140 mg once daily (chronic phase CML) or 180 mg once daily (advanced phase CML and Ph+ ALL) was allowed in patients who did not achieve a hematologic or cytogenetic response at the recommended starting dosage.

    2.3 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 are summarized in Table 1.

    Table 1: Dose Adjustments for Neutropenia and Thrombocytopenia
    * ANC: absolute neutrophil count

    Chronic Phase CML
    (starting dose 100 mg once daily)

    ANC* <0.5 × 109/L
    or
    Platelets <50 × 109/L

    1.
    Stop SPRYCEL until ANC ≥1.0 × 10 9/L and platelets ≥50 × 10 9/L.
    2.
    Resume treatment with SPRYCEL at the original starting dose if recovery occurs in ≤7 days.
    3.
    If platelets <25 × 10 9/L or recurrence of ANC <0.5 × 10 9/L for >7 days, repeat Step 1 and resume SPRYCEL 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 SPRYCEL (for patients resistant or intolerant to prior therapy including imatinib).

    Accelerated Phase CML, Blast Phase CML and Ph+ ALL (starting dose 140 mg once daily)

    ANC* <0.5 × 109/L
    or
    Platelets <10 × 109/L

    1.
    Check if cytopenia is related to leukemia (marrow aspirate or biopsy).
    2.
    If cytopenia is unrelated to leukemia, stop SPRYCEL until ANC ≥1.0 × 10 9/L and platelets ≥20 × 10 9/L and resume at the original starting dose.
    3.
    If recurrence of cytopenia, repeat Step 1 and resume SPRYCEL at a reduced dose of 100 mg once daily (second episode) or 80 mg once daily (third episode).
    4.
    If cytopenia is related to leukemia, consider dose escalation to 180 mg once daily.

    Non-hematological adverse reactions

    If a severe non-hematological adverse reaction develops with SPRYCEL use, treatment must be withheld until the event has resolved or improved. Thereafter, treatment can be resumed as appropriate at a reduced dose depending on the severity and recurrence of the event [see Warnings and Precautions (5.1)].

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  • 3 DOSAGE FORMS AND STRENGTHS

    SPRYCEL (dasatinib) Tablets are available as 20-mg, 50-mg, 70-mg, 80-mg, 100-mg, and 140-mg white to off-white, biconvex, film-coated tablets [see How Supplied (16.1)].

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  • 4 CONTRAINDICATIONS

    None.

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  • 5 WARNINGS AND PRECAUTIONS

    5.1 Myelosuppression

    Treatment with SPRYCEL is associated with severe (NCI CTC Grade 3 or 4) thrombocytopenia, neutropenia, and anemia, which occur earlier and more frequently in patients with advanced phase CML or Ph+ ALL than in patients with chronic phase CML.

    In patients with chronic phase CML, perform complete blood counts (CBCs) every 2 weeks for 12 weeks, then every 3 months thereafter, or as clinically indicated. In patients with advanced phase CML or Ph+ ALL, perform CBCs weekly for the first 2 months and then monthly thereafter, or as clinically indicated.

    Myelosuppression is generally reversible and usually managed by withholding SPRYCEL temporarily and/or dose reduction [see Dosage and Administration (2.3) and Adverse Reactions (6.1)].

    5.2 Bleeding-Related Events

    In addition to causing thrombocytopenia in human subjects, dasatinib caused platelet dysfunction in vitro. In all CML or Ph+ ALL clinical studies, ≥grade 3 central nervous system (CNS) hemorrhages, including fatalities, occurred in <1% of patients receiving SPRYCEL. Grade 3 or greater gastrointestinal hemorrhage, including fatalities, occurred in 4% of patients and generally required treatment interruptions and transfusions. Other cases of ≥grade 3 hemorrhage occurred in 2% of patients. Most bleeding events in clinical studies were associated with severe thrombocytopenia.

    Concomitant medications that inhibit platelet function or anticoagulants may increase the risk of hemorrhage.

    5.3 Fluid Retention

    SPRYCEL may cause fluid retention. After 5 years of follow-up in the randomized newly diagnosed chronic phase CML study (n=258), grade 3 or 4 fluid retention was reported in 5% of patients, including 3% of patients with grade 3 or 4 pleural effusion. In patients with newly diagnosed or imatinib resistant or intolerant chronic phase CML, grade 3 or 4 fluid retention occurred in 6% of patients treated with SPRYCEL at the recommended dose (n=548). In patients with advanced phase CML or Ph+ ALL treated with SPRYCEL at the recommended dose (n=304), grade 3 or 4 fluid retention was reported in 8% of patients, including grade 3 or 4 pleural effusion reported in 7% of patients.

    Evaluate patients who develop symptoms of pleural effusion or other fluid retention, such as new or worsened dyspnea on exertion or at rest, pleuritic chest pain, or dry cough promptly with a chest x-ray or additional diagnostic imaging as appropriate. Fluid retention events were typically managed by supportive care measures that may include diuretics or short courses of steroids. Severe pleural effusion may require thoracentesis and oxygen therapy. Consider dose reduction or treatment interruption[see Dosage and Administration (2.3) and Adverse Reactions (6.1)].

    5.4 Cardiovascular Events

    After 5 years of follow-up in the randomized newly diagnosed chronic phase CML trial (n=258), the following cardiac adverse events occurred: cardiac ischemic events (3.9% dasatinib vs 1.6% imatinib), cardiac related fluid retention (8.5% dasatinib vs 3.9% imatinib), and conduction system abnormalities, most commonly arrhythmia and palpitations (7.0% dasatinib vs 5.0% imatinib). Two cases (0.8%) of peripheral arterial occlusive disease occurred with imatinib and 2 (0.8%) transient ischemic attacks occurred with dasatinib. Monitor patients for signs or symptoms consistent with cardiac dysfunction and treat appropriately.

    5.5 Pulmonary Arterial Hypertension

    SPRYCEL may increase the risk of developing pulmonary arterial hypertension (PAH) which may occur any time after initiation, including after more than 1 year of treatment. Manifestations include dyspnea, fatigue, hypoxia, and fluid retention. PAH may be reversible on discontinuation of SPRYCEL. Evaluate patients for signs and symptoms of underlying cardiopulmonary disease prior to initiating SPRYCEL and during treatment. If PAH is confirmed, SPRYCEL should be permanently discontinued.

    5.6 QT Prolongation

    In vitro data suggest that dasatinib has the potential to prolong cardiac ventricular repolarization (QT interval). Of 2440 patients treated with SPRYCEL at all doses tested in clinical studies, 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 SPRYCEL in five Phase 2 single-arm studies, the maximum mean changes in QTcF (90% upper bound CI) from baseline ranged from 7.0 to 13.4 ms.

    SPRYCEL may increase the risk of prolongation of QTc in patients including those with hypokalemia or hypomagnesemia, patients with congenital long QT syndrome, patients taking antiarrhythmic medicines or other medicinal products that lead to QT prolongation, and cumulative high-dose anthracycline therapy. Correct hypokalemia or hypomagnesemia prior to and during SPRYCEL administration.

    5.7 Severe Dermatologic Reactions

    Cases of severe mucocutaneous dermatologic reactions, including Stevens-Johnson syndrome and erythema multiforme, have been reported in patients treated with SPRYCEL. Discontinue permanently in patients who experience a severe mucocutaneous reaction during treatment if no other etiology can be identified.

    5.8 Tumor Lysis Syndrome

    Tumor lysis syndrome has been reported in patients with resistance to prior imatinib therapy, primarily in advanced phase disease. Due to potential for tumor lysis syndrome, maintain adequate hydration, correct uric acid levels prior to initiating therapy with SPRYCEL, and monitor electrolyte levels. Patients with advanced stage disease and/or high tumor burden may be at increased risk and should be monitored more frequently [see Adverse Reactions (6.3)].

    5.9 Embryo-Fetal Toxicity

    Based on limited human data, SPRYCEL can cause fetal harm when administered to a pregnant woman. Adverse pharmacologic effects of SPRYCEL including hydrops fetalis, fetal leukopenia and fetal thrombocytopenia have been reported with maternal exposure to SPRYCEL. Advise females of reproductive potential to avoid pregnancy, which may include the use of effective contraception, during treatment with SPRYCEL and for 30 days after the final dose [see Use in Specific Populations (8.1, 8.3)].

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  • 6 ADVERSE REACTIONS

    The following adverse reactions are discussed in greater detail in other sections of the labeling:

    Myelosuppression [see Dosage and Administration (2.3) and Warnings and Precautions (5.1)].
    Bleeding-related events [see Warnings and Precautions (5.2)].
    Fluid retention [see Warnings and Precautions (5.3)].
    Cardiovascular events [see Warnings and Precautions (5.4)].
    Pulmonary arterial hypertension [see Warnings and Precautions (5.5)].
    QT prolongation [see Warnings and Precautions (5.6) ].
    Severe dermatologic reactions [see Warnings and Precautions (5.7)].
    Tumor lysis syndrome [see Warnings and Precautions (5.8)].
    Embryo-fetal toxicity [see Warnings and Precautions (5.9)].

    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 SPRYCEL at all doses tested in clinical studies including 324 patients with newly diagnosed chronic phase CML and in 2388 patients with imatinib resistant or intolerant chronic or advanced phase CML or Ph+ ALL. The median duration of therapy in 2712 SPRYCEL-treated patients was 19.2 months (range 0–93.2 months). In a randomized trial in patients with newly diagnosed chronic phase CML, the median duration of therapy was approximately 60 months. The median duration of therapy in 1618 patients with chronic phase CML was 29 months (range 0–92.9 months).

    The median duration of therapy in 1094 patients with advanced phase CML or Ph+ ALL was 6.2 months (range 0–93.2 months).

    In the overall population of 2712 SPRYCEL-treated patients, 88% of patients experienced adverse reactions at some time and 19% experienced adverse reactions leading to treatment discontinuation.

    In the randomized trial in patients with newly diagnosed chronic phase CML, drug was discontinued for adverse reactions in 16% of SPRYCEL-treated 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 1618 SPRYCEL-treated patients with chronic phase CML, drug-related adverse events leading to discontinuation were reported in 329 (20.3%) patients; among the 1094 SPRYCEL-treated patients with advanced phase CML or Ph+ ALL, drug-related adverse events leading to discontinuation were reported in 191 (17.5%) patients.

    Adverse reactions reported in ≥10% of 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 2.

    Adverse reactions reported in ≥10% of 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 4.

    Drug-related serious adverse events (SAEs) were reported for 16.7% of SPRYCEL-treated 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 SAEs were reported for 26.1% of patients treated at the recommended dose of 100 mg once daily in the randomized dose-optimization trial of patients with chronic phase CML resistant or intolerant to prior imatinib therapy. Serious adverse reactions reported in ≥5% of patients included pleural effusion (10%).

    6.1 Chronic Myeloid Leukemia (CML)

    Adverse reactions (excluding laboratory abnormalities) that were reported in at least 10% of patients are shown in Table 2 for newly diagnosed patients with chronic phase CML and Tables 4 and 6 for CML patients with resistance or intolerance to prior imatinib therapy.

    Table 2: Adverse Reactions Reported in ≥10% of Patients with Newly Diagnosed Chronic Phase CML (minimum of 60 months follow-up)
      All Grades Grade 3/4
      SPRYCEL
    (n=258)
    Imatinib
    (n=258)
    SPRYCEL
    (n=258)
    Imatinib
    (n=258)
    Preferred Term Percent (%) of Patients
    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.

    Fluid retention

    38

    45

    5

    1

       Pleural effusion

    28

    1

    3

    0

       Superficial localized edema

    14

    38

    0

    <1

       Pulmonary hypertension

    5

    <1

    1

    0

       Generalized edema

    4

    7

    0

    0

       Pericardial effusion

    4

    1

    1

    0

       Congestive heart failure/cardiac dysfunctiona

    2

    1

    <1

    <1

       Pulmonary edema

    1

    0

    0

    0

    Diarrhea

    22

    23

    1

    1

    Musculoskeletal pain

    14

    17

    0

    <1

    Rashb

    14

    18

    0

    2

    Headache

    14

    11

    0

    0

    Abdominal pain

    11

    8

    0

    1

    Fatigue

    11

    12

    <1

    0

    Nausea

    10

    25

    0

    0

    Myalgia

    7

    12

    0

    0

    Arthralgia

    7

    10

    0

    <1

    Hemorrhagec

    8

    8

    1

    1

       Gastrointestinal bleeding

    2

    2

    1

    0

       Other bleedingd

    6

    6

    0

    <1

       CNS bleeding

    <1

    <1

    0

    <1

    Vomiting

    5

    12

    0

    0

    Muscle spasms

    5

    21

    0

    <1

    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 SPRYCEL are shown in Table 3.

    Table 3: Adverse Reactions Reported in ≥10% of Patients with Newly Diagnosed Chronic Phase CML in the SPRYCEL Treated Arm (n=258)
      Minimum of 1 Year Follow-up Minimum of 5 Years Follow-up
      All Grades Grade 3/4 All Grades Grade 3/4
    Preferred Term Percent (%) of Patients
    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.

    Fluid Retention

    19

    1

    38

    5

       Pleural effusion

    10

    0

    28

    3

       Superficial localized edema

    9

    0

    14

    0

       Pulmonary hypertension

    1

    0

    5

    1

       Generalized edema

    2

    0

    4

    0

       Pericardial effusion

    1

    <1

    4

    1

       Congestive heart failure/cardiac
       dysfunctiona

    2

    <1

    2

    <1

       Pulmonary edema

    <1

    0

    1

    0

    Diarrhea

    17

    <1

    22

    1

    Musculoskeletal pain

    11

    0

    14

    0

    Rashb

    11

    0

    14

    0

    Headache

    12

    0

    14

    0

    Abdominal pain

    7

    0

    11

    0

    Fatigue

    8

    <1

    11

    <1

    Nausea

    8

    0

    10

    0

    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 4: Adverse Reactions Reported in ≥10% of Patients with Chronic Phase CML Resistant or Intolerant to Prior Imatinib Therapy (minimum of 84 months follow-up)
      100 mg Once Daily
      Chronic
    (n=165)
    Preferred Term All Grades Grade 3/4
    Percent (%) of Patients
    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.

    Fluid retention

    48

    7

       Superficial localized edema

    22

    0

       Pleural effusion

    28

    5

       Generalized edema

    4

    0

       Pericardial effusion

    3

    1

       Pulmonary hypertension

    2

    1

    Headache

    33

    1

    Diarrhea

    28

    2

    Fatigue

    26

    4

    Dyspnea

    24

    2

    Musculoskeletal pain

    22

    2

    Nausea

    18

    1

    Skin rasha

    18

    2

    Myalgia

    13

    0

    Arthralgia

    13

    1

    Infection (including bacterial, viral, fungal, and non-specified)

    13

    1

    Abdominal pain

    12

    1

    Hemorrhage

    12

    1

       Gastrointestinal bleeding

    2

    1

    Pruritus

    12

    1

    Pain

    11

    1

    Constipation

    10

    1

    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 5.

    Table 5: Selected Adverse Reactions Reported in Dose Optimization Trial (Imatinib Intolerant or Resistant Chronic Phase CML)a
    Minimum of 2 Years Follow-up Minimum of 5 Years Follow-up Minimum of 7 Years Follow-up
    Preferred Term All Grades Grade 3/4 All Grades Grade 3/4 All Grades Grade 3/4
    Percent (%) of Patients
    a  Randomized dose-optimization trial results reported in the recommended starting dose of 100 mg once daily (n=165) population.

    Diarrhea

    27

    2

    28

    2

    28

    2

    Fluid Retention

    34

    4

    42

    6

    48

    7

       Superficial edema

    18

    0

    21

    0

    22

    0

       Pleural effusion

    18

    2

    24

    4

    28

    5

       Generalized edema

    3

    0

    4

    0

    4

    0

       Pericardial effusion

    2

    1

    2

    1

    3

    1

       Pulmonary hypertension

    0

    0

    0

    0

    2

    1

    Hemorrhage

    11

    1

    11

    1

    12

    1

       Gastrointestinal bleeding

    2

    1

    2

    1

    2

    1

    Table 6: Adverse Reactions Reported in ≥10% of Patients with Advanced Phase CML Resistant or Intolerant to Prior Imatinib Therapy
    140 mg Once Daily
    Accelerated
    (n=157)
    Myeloid Blast
    (n=74)
    Lymphoid Blast
    (n=33)
    Preferred Term All
    Grades
    Grade
    3/4
    All
    Grades
    Grade
    3/4
    All
    Grades
    Grade
    3/4
    Percent (%) of Patients
    a Includes ventricular dysfunction, cardiac failure, cardiac failure congestive, cardiomyopathy, congestive cardiomyopathy, diastolic dysfunction, ejection fraction decreased, and ventricular failure.
    b 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.

    Fluid retention

    35

    8

    34

    7

    21

    6

       Superficial localized edema

    18

    1

    14

    0

    3

    0

       Pleural effusion

    21

    7

    20

    7

    21

    6

       Generalized edema

    1

    0

    3

    0

    0

    0

       Pericardial effusion

    3

    1

    0

    0

    0

    0

       Congestive heart failure/cardiac dysfunctiona

    0

    0

    4

    0

    0

    0

       Pulmonary edema

    1

    0

    4

    3

    0

    0

    Headache

    27

    1

    18

    1

    15

    3

    Diarrhea

    31

    3

    20

    5

    18

    0

    Fatigue

    19

    2

    20

    1

    9

    3

    Dyspnea

    20

    3

    15

    3

    3

    3

    Musculoskeletal pain

    11

    0

    8

    1

    0

    0

    Nausea

    19

    1

    23

    1

    21

    3

    Skin rashb

    15

    0

    16

    1

    21

    0

    Arthralgia

    10

    0

    5

    1

    0

    0

    Infection (including bacterial, viral, fungal,
       and non-specified)

    10

    6

    14

    7

    9

    0

    Hemorrhage

    26

    8

    19

    9

    24

    9

       Gastrointestinal bleeding

    8

    6

    9

    7

    9

    3

       CNS bleeding

    1

    1

    0

    0

    3

    3

    Vomiting

    11

    1

    12

    0

    15

    0

    Pyrexia

    11

    2

    18

    3

    6

    0

    Febrile neutropenia

    4

    4

    12

    12

    12

    12

    Laboratory Abnormalities

    Myelosuppression was commonly reported in all patient populations. The frequency of Grade 3 or 4 neutropenia, thrombocytopenia, and anemia was higher in patients with advanced phase CML than in chronic phase CML (Tables 7 and 8). 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 patients in a randomized trial of patients with newly diagnosed chronic phase CML and 5% of patients with resistance or intolerance to prior imatinib therapy [see Warnings and Precautions (5.1)].

    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 the course of SPRYCEL therapy often had recovery with oral calcium supplementation.

    Laboratory abnormalities reported in patients with newly diagnosed chronic phase CML are shown in Table 7. There were no discontinuations of SPRYCEL therapy in this patient population due to biochemical laboratory parameters.

    Table 7: CTC Grade 3/4 Laboratory Abnormalities in Patients with Newly Diagnosed Chronic Phase CML (minimum of 60 months follow-up)
    SPRYCEL
    (n=258)
    Imatinib
    (n=258)
      Percent (%) of Patients
    CTC grades: neutropenia (Grade 3 ≥0.5–<1.0 × 109/L, Grade 4 <0.5 × 109/L); thrombocytopenia (Grade 3 ≥25–<50 × 109/L, Grade 4 <25 × 109/L); anemia (hemoglobin Grade 3 ≥65–<80 g/L, Grade 4 <65 g/L); elevated creatinine (Grade 3 >3–6 × upper limit of normal range (ULN), Grade 4 >6 × ULN); elevated bilirubin (Grade 3 >3–10 × ULN, Grade 4 >10 × ULN); elevated SGOT or SGPT (Grade 3 >5–20 × ULN, Grade 4 >20 × ULN); hypocalcemia (Grade 3 <7.0–6.0 mg/dL, Grade 4 <6.0 mg/dL); hypophosphatemia (Grade 3 <2.0–1.0 mg/dL, Grade 4 <1.0 mg/dL); hypokalemia (Grade 3 <3.0–2.5 mmol/L, Grade 4 <2.5 mmol/L).

    Hematology Parameters

     

     

       Neutropenia

    29

    24

       Thrombocytopenia

    22

    14

       Anemia

    13

    9

    Biochemistry Parameters

     

     

       Hypophosphatemia

    7

    31

       Hypokalemia

    0

    3

       Hypocalcemia

    4

    3

       Elevated SGPT (ALT)

    <1

    2

       Elevated SGOT (AST)

    <1

    1

       Elevated Bilirubin

    1

    0

       Elevated Creatinine

    1

    1

    Laboratory abnormalities reported in patients with CML resistant or intolerant to imatinib who received the recommended starting doses of SPRYCEL are shown by disease phase in Table 8.

    Table 8: CTC Grade 3/4 Laboratory Abnormalities in Clinical Studies of CML: Resistance or Intolerance to Prior Imatinib Therapy
    Chronic Phase CML
    100 mg Once Daily
    Advanced Phase CML
    140 mg Once Daily
    Accelerated
    Phase
    Myeloid Blast
    Phase
    Lymphoid Blast
    Phase
    (n=165) (n=157) (n=74) (n=33)
      Percent (%) of Patients
    CTC grades: neutropenia (Grade 3 ≥0.5–<1.0 × 109/L, Grade 4 <0.5 × 109/L); thrombocytopenia (Grade 3 ≥25–<50 × 109/L, Grade 4 <25 × 109/L); anemia (hemoglobin Grade 3 ≥65–<80 g/L, Grade 4 <65 g/L); elevated creatinine (Grade 3 >3–6 × upper limit of normal range (ULN), Grade 4 >6 × ULN); elevated bilirubin (Grade 3 >3–10 × ULN, Grade 4 >10 × ULN); elevated SGOT or SGPT (Grade 3 >5–20 × ULN, Grade 4 >20 × ULN); hypocalcemia (Grade 3 <7.0–6.0 mg/dL, Grade 4 <6.0 mg/dL); hypophosphatemia (Grade 3 <2.0–1.0 mg/dL, Grade 4 <1.0 mg/dL); hypokalemia (Grade 3 <3.0–2.5 mmol/L, Grade 4 <2.5 mmol/L).
    * Hematology parameters for 100 mg once-daily dosing in chronic phase CML reflects 60 month minimum follow-up.

    Hematology Parameters*

     

     

     

     

       Neutropenia

    36

    58

    77

    79

       Thrombocytopenia

    24

    63

    78

    85

       Anemia

    13

    47

    74

    52

    Biochemistry Parameters

     

     

     

     

       Hypophosphatemia

    10

    13

    12

    18

       Hypokalemia

    2

    7

    11

    15

       Hypocalcemia

    <1

    4

    9

    12

       Elevated SGPT (ALT)

    0

    2

    5

    3

       Elevated SGOT (AST)

    <1

    0

    4

    3

       Elevated Bilirubin

    <1

    1

    3

    6

       Elevated Creatinine

    0

    2

    8

    0

    Among chronic phase CML patients with resistance or intolerance to prior imatinib therapy, cumulative Grade 3 or 4 cytopenias were similar at 2 and 5 years including: neutropenia (36% vs 36%), thrombocytopenia (23% vs 24%), and anemia (13% vs 13%).

    6.2 Philadelphia Chromosome-Positive Acute Lymphoblastic Leukemia (Ph+ ALL)

    A total of 135 patients with Ph+ ALL were treated with SPRYCEL 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 (31%), nausea (24%), and vomiting (16%). Hemorrhage (19%), pyrexia (17%), rash (16%), and dyspnea (16%) were also frequently reported. Serious adverse reactions reported in ≥5% of patients included pleural effusion (11%), gastrointestinal bleeding (7%), febrile neutropenia (6%), and infection (5%).

    6.3 Additional Pooled Data From Clinical Trials

    The following additional adverse reactions were reported in patients in SPRYCEL CML and Ph+ ALL clinical studies at a frequency of ≥10%, 1%–<10%, 0.1%–<1%, or <0.1%. These events are included on the basis of clinical relevance.

    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.

    General Disorders and Administration Site-Conditions: ≥10% – peripheral edema, face edema; 1%–<10% – asthenia, chest pain, chills; 0.1%–<1% – malaise, other superficial edema; <0.1% – gait disturbance.

    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.

    Musculoskeletal and Connective Tissue Disorders: 1%–<10% – muscular weakness, musculoskeletal stiffness; 0.1%<1% – rhabdomyolysis, tendonitis, muscle inflammation, osteonecrosis, arthritis.

    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 [0.2%]).

    Metabolism and Nutrition Disorders: 1%–<10% – appetite disturbances, hyperuricemia; 0.1%–<1% – hypoalbuminemia, tumor lysis syndrome, dehydration, hypercholesterolemia; <0.1% – diabetes mellitus.

    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, photophobia, lacrimation increased.

    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.

    6.4 Postmarketing Experience

    The following additional adverse reactions have been identified during post approval use of SPRYCEL. 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.

    Cardiac disorders: atrial fibrillation/atrial flutter

    Respiratory, thoracic, and mediastinal disorders: interstitial lung disease

    Skin and subcutaneous tissue disorders: Stevens-Johnson syndrome

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  • 7 DRUG INTERACTIONS

    7.1 Drugs That May Increase Dasatinib Plasma Concentrations

    CYP3A4 Inhibitors: Dasatinib is a CYP3A4 substrate. In a trial of 18 patients with solid tumors, 20-mg SPRYCEL once daily coadministered with 200 mg of ketoconazole twice daily increased the dasatinib Cmax and AUC by four- and five-fold, respectively. Concomitant use of SPRYCEL and drugs that inhibit CYP3A4 may increase exposure to dasatinib and should be avoided. In patients receiving treatment with SPRYCEL, close monitoring for toxicity and a SPRYCEL dose reduction should be considered if systemic administration of a potent CYP3A4 inhibitor cannot be avoided [see Dosage and Administration (2.1)].

    7.2 Drugs That May Decrease Dasatinib Plasma Concentrations

    CYP3A4 Inducers: When a single morning dose of SPRYCEL was administered following 8 days of continuous evening administration of 600 mg of rifampin, a potent CYP3A4 inducer, the mean Cmax and AUC of dasatinib were decreased by 81% and 82%, respectively. Alternative agents with less enzyme induction potential should be considered. If SPRYCEL must be administered with a CYP3A4 inducer, a dose increase in SPRYCEL should be considered [see Dosage and Administration (2.1)].

    Antacids: Nonclinical data demonstrate that the solubility of dasatinib is pH dependent. In a trial of 24 healthy subjects, administration of 30 mL of aluminum hydroxide/magnesium hydroxide 2 hours prior to a single 50-mg dose of SPRYCEL was associated with no relevant change in dasatinib AUC; however, the dasatinib Cmax increased 26%. When 30 mL of aluminum hydroxide/magnesium hydroxide was administered to the same subjects concomitantly with a 50-mg dose of SPRYCEL, a 55% reduction in dasatinib AUC and a 58% reduction in Cmax were observed. Simultaneous administration of SPRYCEL with antacids should be avoided. If antacid therapy is needed, the antacid dose should be administered at least 2 hours prior to or 2 hours after the dose of SPRYCEL.

    H2 Antagonists/Proton Pump Inhibitors: Long-term suppression of gastric acid secretion by H2 antagonists or proton pump inhibitors (e.g., famotidine and omeprazole) is likely to reduce dasatinib exposure. In a trial of 24 healthy subjects, administration of a single 50-mg dose of SPRYCEL 10 hours following famotidine reduced the AUC and Cmax of dasatinib by 61% and 63%, respectively. In a trial of 14 healthy subjects, administration of a single 100-mg dose of SPRYCEL 22 hours following a 40-mg omeprazole dose at steady state reduced the AUC and Cmax of dasatinib by 43% and 42%, respectively. The concomitant use of H2 antagonists or proton pump inhibitors with SPRYCEL is not recommended. The use of antacids (at least 2 hours prior to or 2 hours after the dose of SPRYCEL) should be considered in place of H2 antagonists or proton pump inhibitors in patients receiving SPRYCEL therapy.

    7.3 Drugs That May Have Their Plasma Concentration Altered By Dasatinib

    CYP3A4 Substrates: Single-dose data from a trial of 54 healthy subjects indicate that the mean Cmax and AUC of simvastatin, a CYP3A4 substrate, were increased by 37% and 20%, respectively, when simvastatin was administered in combination with a single 100-mg dose of SPRYCEL. Therefore, CYP3A4 substrates known to have a narrow therapeutic index such as alfentanil, astemizole, terfenadine, cisapride, cyclosporine, fentanyl, pimozide, quinidine, sirolimus, tacrolimus, or ergot alkaloids (ergotamine, dihydroergotamine) should be administered with caution in patients receiving SPRYCEL.

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  • 8 USE IN SPECIFIC POPULATIONS

    8.1 Pregnancy

    Risk Summary

    Based on limited human data, SPRYCEL 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 SPRYCEL. 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 [see Data]. 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%-4% and of miscarriage is 15%-20% of clinically recognized pregnancies.

    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 [see Warnings and Precautions (5.1, 5.3)].

    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 [15 mg/m2/day] and rabbit: 0.5 mg/kg/day [6 mg/m2/day]) resulted in embryo-fetal toxicities. These doses produced maternal AUCs of 105 ng•hr/mL and 44 ng•hr/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.

    8.2 Lactation

    Risk Summary

    No data are available regarding the presence of dasatinib in human milk, the effects of the drug on the breastfed infant or the effects of the drug on milk production. However, dasatinib is present in the milk of lactating rats. Because of the potential for serious adverse reactions in nursing infants from SPRYCEL, breastfeeding is not recommended during treatment with SPRYCEL and for 2 weeks after the final dose.

    8.3 Females and Males of Reproductive Potential

    Contraception

    Females

    SPRYCEL can cause fetal harm when administered to a pregnant woman [see Use in Specific Populations (8.1)]. Advise females of reproductive potential to avoid pregnancy, which may include the use of effective contraceptive methods during treatment with SPRYCEL and for 30 days after the final dose.

    Infertility

    Based on animal data, dasatinib may result in damage to female and male reproductive tissues [see Nonclinical Toxicology (13.1)].

    8.4 Pediatric Use

    The safety and efficacy of SPRYCEL in patients less than 18 years of age have not been established.

    8.5 Geriatric Use

    No differences in confirmed Complete Cytogenetic Response (cCCyR) and MMR were observed between older and younger patients. Of the 2712 patients in clinical studies of SPRYCEL, 617 (23%) were 65 years of age and older, and 123 (5%) were 75 years of age and older. While the safety profile of SPRYCEL 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.

    8.6 Hepatic Impairment

    The effect of hepatic impairment on the pharmacokinetics of dasatinib was evaluated in healthy volunteers with normal liver function and patients with moderate (Child-Pugh class B) and severe (Child-Pugh class C) hepatic impairment. Compared to the healthy volunteers with normal hepatic function, the dose-normalized pharmacokinetic parameters were decreased in the patients with hepatic impairment.

    No dosage adjustment is necessary in patients with hepatic impairment [see Clinical Pharmacology (12.3)]. Caution is recommended when administering SPRYCEL to patients with hepatic impairment.

    8.7 Renal Impairment

    There are currently no clinical studies with SPRYCEL in patients with impaired renal function. Less than 4% of dasatinib and its metabolites are excreted via the kidney.

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  • 10 OVERDOSAGE

    Experience with overdose of SPRYCEL 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 SPRYCEL is associated with severe myelosuppression [see Warnings and Precautions (5.1) and Adverse Reactions (6.1)], 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/m2) in rodents. There was a tendency for increased systolic and diastolic blood pressure in monkeys at single doses ≥10 mg/kg (120 mg/m2).

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  • 11 DESCRIPTION

    SPRYCEL (dasatinib) is 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 C22H26ClN7O2S • H2O, 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 chemical structure

    Dasatinib is a white to off-white powder. The drug substance is insoluble in water and slightly soluble in ethanol and methanol. SPRYCEL tablets are white to off-white, biconvex, film-coated tablets containing dasatinib, with the following inactive ingredients: lactose monohydrate, microcrystalline cellulose, croscarmellose sodium, hydroxypropyl cellulose, and magnesium stearate. The tablet coating consists of hypromellose, titanium dioxide, and polyethylene glycol.

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  • 12 CLINICAL PHARMACOLOGY

    12.1 Mechanism of Action

    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 was able to 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.

    12.3 Pharmacokinetics

    Absorption

    Maximum plasma concentrations (Cmax) of dasatinib are observed between 0.5 and 6 hours (Tmax) following oral administration. Dasatinib exhibits dose proportional increases in AUC and linear elimination characteristics over the dose range of 15 to 240 mg/day. The overall mean terminal half-life of dasatinib is 3 to 5 hours.

    Data from a trial of 54 healthy subjects administered a single, 100-mg dose of dasatinib 30 minutes following consumption of a high-fat meal resulted in a 14% increase in the mean AUC of dasatinib. The observed food effects were not clinically relevant.

    Distribution

    In patients, dasatinib has an apparent volume of distribution of 2505 L, suggesting that the drug is extensively distributed in the extravascular space. Binding of dasatinib and its active metabolite to human plasma proteins in vitro was approximately 96% and 93%, respectively, with no concentration dependence over the range of 100 to 500 ng/mL.

    Metabolism

    Dasatinib is extensively metabolized in humans, primarily by the cytochrome P450 enzyme 3A4. CYP3A4 was 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 dasatinib AUC. This indicates that the active metabolite of dasatinib is unlikely to play a major role in the observed pharmacology of the drug. Dasatinib also had several other inactive oxidative metabolites.

    Dasatinib is a weak time-dependent inhibitor of CYP3A4. At clinically relevant concentrations, dasatinib does not inhibit CYP1A2, 2A6, 2B6, 2C8, 2C9, 2C19, 2D6, or 2E1. Dasatinib is not an inducer of human CYP enzymes.

    Elimination

    Elimination is primarily via the feces. Following a single oral dose of [14C]-labeled dasatinib, approximately 4% and 85% of the administered radioactivity was recovered in the urine and feces, respectively, within 10 days. Unchanged dasatinib accounted for 0.1% and 19% of the administered dose in urine and feces, respectively, with the remainder of the dose being metabolites.

    Effects of Age and Gender

    Pharmacokinetic analyses of demographic data indicate that there are no clinically relevant effects of age and gender on the pharmacokinetics of dasatinib.

    Hepatic Impairment

    Dasatinib doses of 50 mg and 20 mg were evaluated in eight patients with moderate (Child-Pugh class B) and seven patients with severe (Child-Pugh class C) hepatic impairment, respectively. Matched controls with normal hepatic function (n=15) were also evaluated and received a dasatinib dose of 70 mg. Compared to subjects with normal liver function, patients with moderate hepatic impairment had decreases in dose-normalized Cmax and AUC by 47% and 8%, respectively. Patients with severe hepatic impairment had dose-normalized Cmax decreased by 43% and AUC decreased by 28% compared to the normal controls.

    These differences in Cmax and AUC are not clinically relevant. Dose adjustment is not necessary in patients with hepatic impairment.

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  • 13 NONCLINICAL TOXICOLOGY

    13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

    In a 2-year carcinogenicity study, rats were administered oral doses of dasatinib at 0.3, 1, and 3 mg/kg/day. The highest dose resulted in a plasma drug exposure (AUC) level approximately 60% of the human exposure at 100 mg once daily. Dasatinib induced a statistically significant increase in the combined incidence of squamous cell carcinomas and papillomas in the uterus and cervix of high-dose females and prostate adenoma in low-dose males.

    Dasatinib was clastogenic when tested in vitro in Chinese hamster ovary cells, with and without metabolic activation. Dasatinib was not mutagenic when tested in an in vitro bacterial cell assay (Ames test) and was not genotoxic in an in vivo rat micronucleus study.

    Dasatinib did not affect mating or fertility in male and female rats at plasma drug exposure (AUC) similar to the human exposure at 100 mg daily; however, dasatinib induced embryo lethality. In repeat dose studies, administration of dasatinib resulted in reduced size and secretion of seminal vesicles, and immature prostate, seminal vesicle, and testis. The administration of dasatinib resulted in uterine inflammation and mineralization in monkeys, and cystic ovaries and ovarian hypertrophy in rodents.

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  • 14 CLINICAL STUDIES

    14.1 Newly Diagnosed Chronic Phase CML

    An open-label, multicenter, international, randomized trial was conducted in adult patients with newly diagnosed chronic phase CML. A total of 519 patients were randomized to receive either SPRYCEL 100 mg once daily or imatinib 400 mg once daily. Patients with a history of cardiac disease were included in this trial except those who had a myocardial infarction within 6 months, congestive heart failure within 3 months, significant arrhythmias, or QTc prolongation. The primary endpoint was the rate of confirmed complete cytogenetic response (CCyR) within 12 months. Confirmed CCyR was defined as a CCyR noted on two consecutive occasions (at least 28 days apart).

    Median age was 46 years in the SPRYCEL group and 49 years in the imatinib groups, with 10% and 11% of patients ≥65 years of age, respectively. There were slightly more male than female patients in both groups (59% vs 41%). Fifty-three percent of all patients were Caucasian and 39% were Asian. At baseline, the distribution of Hasford Scores was similar in the SPRYCEL and imatinib treatment groups (low risk: 33% and 34%; intermediate risk: 48% and 47%; high risk: 19% and 19%, respectively). With a minimum of 12 months follow-up, 85% of patients randomized to SPRYCEL and 81% of patients randomized to imatinib were still on study.

    With a minimum of 24 months follow-up, 77% of patients randomized to SPRYCEL and 75% of patients randomized to imatinib were still on study and with a minimum of 60 months follow-up, 61% and 62% of patients, respectively, were still on treatment at the time of study closure.

    Efficacy results are summarized in Table 9.

    Table 9: Efficacy Results in a Randomized Newly Diagnosed Chronic Phase CML Trial
    SPRYCEL
    (n=259)
    Imatinib
    (n=260)
    a Confirmed CCyR is defined as a CCyR noted on two consecutive occasions at least 28 days apart.
    b Major molecular response (at any time) was defined as BCR-ABL ratios ≤0.1% by RQ-PCR in peripheral blood samples standardized on the International scale. These are cumulative rates representing minimum follow up for the time frame specified.
    * Adjusted for Hasford Score and indicated statistical significance at a pre-defined nominal level of significance.
    CI = confidence interval.

    Confirmed CCyRa

       Within 12 months (95% CI)

    76.8% (71.2–81.8)

    66.2% (60.1–71.9)

       P-value

    0.007*

    Major Molecular Responseb

       12 months (95% CI)

    52.1% (45.9–58.3)

    33.8% (28.1–39.9)

       P-value

    <0.0001

       60 months (95% CI)

    76.4% (70.8–81.5)

    64.2% (58.1–70.1)

    The confirmed CCyR within 24, 36, and 60 months for SPRYCEL versus imatinib arms were 80% versus 74%, 83% versus 77%, and 83% versus 79%, respectively. The MMR at 24 and 36 months for SPRYCEL versus imatinib arms were 65% versus 50% and 69% versus 56%, respectively.

    After 60 months follow-up, median time to confirmed CCyR was 3.1 months in 215 SPRYCEL responders and 5.8 months in 204 imatinib responders. Median time to MMR after 60 months follow-up was 9.3 months in 198 SPRYCEL responders and 15.0 months in 167 imatinib responders.

    At 60 months, 8 patients (3%) on the dasatinib arm progressed to either accelerated phase or blast crisis while 15 patients (6%) on the imatinib arm progressed to either accelerated phase or blast crisis.

    The estimated 60-month survival rates for SPRYCEL- and imatinib-treated patients were 90.9% (CI: 86.6%–93.8%) and 89.6% (CI: 85.2%–92.8%), respectively. Based on data 5 years after the last patient was enrolled in the trial, 83% and 77% of patients were known to be alive in the dasatinib and imatinib treatment groups, respectively, 10% were known to have died in both treatment groups, and 7% and 13% had unknown survival status in the dasatinib and imatinib treatment groups, respectively.

    At 60 months follow-up, in the SPRYCEL arm, the rate of MMR at any time in each risk group determined by Hasford score was 90% (low risk), 71% (intermediate risk) and 67% (high risk). In the imatinib arm, the rate of MMR at any time in each risk group determined by Hasford score was 69% (low risk), 65% (intermediate risk), 54% (high risk).

    BCR-ABL sequencing was performed on blood samples from patients in the newly diagnosed trial who discontinued dasatinib or imatinib therapy. Among dasatinib-treated patients the mutations detected were T315I, F317I/L, and V299L.

    Dasatinib does not appear to be active against the T315I mutation, based on in vitro data.

    14.2 Imatinib Resistant or Intolerant CML or Ph+ ALL

    The efficacy and safety of SPRYCEL were investigated in adult patients with CML or Ph+ ALL whose disease was resistant to or who were intolerant to imatinib: 1158 patients had chronic phase CML, 858 patients had accelerated phase, myeloid blast phase, or lymphoid blast phase CML, and 130 patients had Ph+ ALL. In a clinical trial in chronic phase CML, resistance to imatinib was defined as failure to achieve a complete hematologic response (CHR; after 3 months), major cytogenetic response (MCyR; after 6 months), or complete cytogenetic response (CCyR; after 12 months); or loss of a previous molecular response (with concurrent ≥10% increase in Ph+ metaphases), cytogenetic response, or hematologic response. Imatinib intolerance was defined as inability to tolerate 400 mg or more of imatinib per day or discontinuation of imatinib because of toxicity.

    Results described below are based on a minimum of 2 years follow up after the start of SPRYCEL therapy in patients with a median time from initial diagnosis of approximately 5 years. Across all studies, 48% of patients were women, 81% were white, 15% were black or Asian, 25% were 65 years of age or older, and 5% were 75 years of age or older. Most patients had long disease histories with extensive prior treatment, including imatinib, cytotoxic chemotherapy, interferon, and stem cell transplant. Overall, 80% of patients had imatinib-resistant disease and 20% of patients were intolerant to imatinib. The maximum imatinib dose had been 400–600 mg/day in about 60% of the patients and >600 mg/day in 40% of the patients.

    The primary efficacy endpoint in chronic phase CML was MCyR, defined as elimination (CCyR) or substantial diminution (by at least 65%, partial cytogenetic response) of Ph+ hematopoietic cells. The primary efficacy endpoint in accelerated phase, myeloid blast phase, lymphoid blast phase CML, and Ph+ ALL was major hematologic response (MaHR), defined as either a CHR or no evidence of leukemia (NEL).

    Chronic Phase CML

    Dose-Optimization Trial: A randomized, open-label trial was conducted in patients with chronic phase CML to evaluate the efficacy and safety of SPRYCEL administered once daily compared with SPRYCEL administered twice daily. Patients with significant cardiac diseases, including myocardial infarction within 6 months, congestive heart failure within 3 months, significant arrhythmias, or QTc prolongation were excluded from the trial. The primary efficacy endpoint was MCyR in patients with imatinib-resistant CML. A total of 670 patients, of whom 497 had imatinib-resistant disease, were randomized to the SPRYCEL 100 mg once daily, 140 mg once daily, 50 mg twice daily, or 70 mg twice daily group. Median duration of treatment was 22 months.

    Efficacy was achieved across all SPRYCEL treatment groups with the once daily schedule demonstrating comparable efficacy (non-inferiority) to the twice daily schedule on the primary efficacy endpoint (difference in MCyR 1.9%; 95% CI [−6.8%–10.6%]); however, the 100-mg once-daily regimen demonstrated improved safety and tolerability.

    Efficacy results are presented in Tables 10, 11, and 12 for patients with chronic phase CML who received the recommended starting dose of 100 mg once daily.

    Table 10: Efficacy of SPRYCEL in Patients with Imatinib Resistant or Intolerant Chronic Phase CML (minimum of 24 months follow-up)a
    All Patients 100 mg Once Daily
    (n=167)
    a CHR (response confirmed after 4 weeks): WBC ≤ institutional ULN, platelets <450,000/mm3, no blasts or promyelocytes in peripheral blood, <5% myelocytes plus metamyelocytes in peripheral blood, basophils in peripheral blood <20%, and no extramedullary involvement.
    b MCyR combines both complete (0% Ph+ metaphases) and partial (>0%–35%) responses.

    Hematologic Response Rate % (95% CI)

       CHRa

    92% (86–95)

    Cytogenetic Response Rate % (95% CI)

       MCyRb

    63% (56–71)

       CCyR

    50% (42–58)

    Table 11: Long-Term MMR of SPRYCEL in the Dose Optimization Trial: Patients with Imatinib Resistant or Intolerant Chronic Phase CMLa
    Minimum Follow-up Period
    2 Years 5 Years 7 Years
    a  Results reported in recommended starting dose of 100 mg once daily.
    b  Major molecular response criteria: Defined as BCR-ABL/control transcripts ≤0.1% by RQ-PCR in peripheral blood samples.

    Major Molecular Responseb % (n/N)

       All Patients Randomized

    34% (57/167)

    43% (71/167)

    44% (73/167)

       Imatinib-Resistant Patients

    33% (41/124)

    40% (50/124)

    41% (51/124)

       Imatinib-Intolerant Patients

    37% (16/43)

    49% (21/43)

    51% (22/43)

    Based on data 7 years after the last patient was enrolled in the trial, 44% were known to be alive, 31% were known to have died, and 25% had an unknown survival status.

    By 7 years, transformation to either accelerated or blast phase occurred in nine patients on treatment in the 100 mg once daily treatment group.

    Advanced Phase CML and Ph+ ALL

    Dose-Optimization Trial: One randomized open-label trial was conducted in patients with advanced phase CML (accelerated phase CML, myeloid blast phase CML, or lymphoid blast phase CML) to evaluate the efficacy and safety of SPRYCEL administered once daily compared with SPRYCEL administered twice daily. The primary efficacy endpoint was MaHR. A total of 611 patients were randomized to either the SPRYCEL 140 mg once daily or 70 mg twice daily group. Median duration of treatment was approximately 6 months for both treatment groups. The once daily schedule demonstrated comparable efficacy (non-inferiority) to the twice daily schedule on the primary efficacy endpoint; however, the 140-mg once daily regimen demonstrated improved safety and tolerability.

    Response rates for patients in the 140 mg once daily group are presented in Table 12.

    Table 12: Efficacy of SPRYCEL in Imatinib Resistant or Intolerant Advanced Phase CML and Ph+ ALL (2 Year Results)
    140 mg Once Daily
    Accelerated
    (n=158)
    Myeloid Blast
    (n=75)
    Lymphoid Blast
    (n=33)
    Ph+ ALL
    (n=40)
    a    Hematologic response criteria (all responses confirmed after 4 weeks): Major hematologic response: (MaHR) = complete hematologic response (CHR) + no evidence of leukemia (NEL).
         CHR: WBC ≤ institutional ULN, ANC ≥1000/mm3, platelets ≥100,000/mm3, no blasts or promyelocytes in peripheral blood, bone marrow blasts ≤5%, <5% myelocytes plus metamyelocytes in peripheral blood, basophils in peripheral blood <20%, and no extramedullary involvement.
         NEL: same criteria as for CHR but ANC ≥500/mm3 and <1000/mm3, or platelets ≥20,000/mm3 and ≤100,000/mm3.
    b   MCyR combines both complete (0% Ph+ metaphases) and partial (>0%–35%) responses.
    CI = confidence interval     ULN = upper limit of normal range.

    MaHRa

    66%

    28%

    42%

    38%

         (95% CI)

    (59–74)

    (18–40)

    (26–61)

    (23–54)

    CHRa

    47%

    17%

    21%

    33%

         (95% CI)

    (40–56)

    (10–28)

    (9–39)

    (19–49)

    NELa

    19%

    11%

    21%

    5%

         (95% CI)

    (13–26)

    (5–20)

    (9–39)

    (1–17)

    MCyRb

    39%

    28%

    52%

    70%

         (95% CI)

    (31–47)

    (18–40)

    (34–69)

    (54–83)

    CCyR

    32%

    17%

    39%

    50%

         (95% CI)

    (25–40)

    (10–28)

    (23–58)

    (34–66)

    In the SPRYCEL 140 mg once daily group, the median time to MaHR was 1.9 months (min-max:0.7-14.5) for patients with accelerated phase CML, 1.9 months (min-max:0.9-6.2) for patients with myeloid blast phase CML, and 1.8 months (min-max:0.9-2.8) for patients with lymphoid blast phase CML.

    In patients with myeloid blast phase CML, the median duration of MaHR was 8.1 months (min-max:2.7-21.1) and 9.0 (min-max:1.8-23.1) months for the 140 mg once daily group and the 70 mg twice daily group, respectively. In patients with lymphoid blast phase CML, the median duration of MaHR was 4.7 months (min-max:3.0-9.0) and 7.9 months (min-max:1.6-22.1) for the 140 mg once daily group and the 70 mg twice daily group, respectively. In patients with Ph+ ALL who were treated with SPRYCEL 140 mg once daily, the median duration of MaHR was 4.6 months (min-max:1.4-10.2). The medians of progression-free survival for patients with Ph+ ALL treated with SPRYCEL 140 mg once daily and 70 mg twice daily were 4.0 months (min-max:0.4-11.1) and 3.1 months (min-max:0.3-20.8), respectively.

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  • 16 HOW SUPPLIED/STORAGE AND HANDLING

    16.1 How Supplied

    SPRYCEL® (dasatinib) tablets are available as described in Table 13.

    Table 13: SPRYCEL Trade Presentations

    NDC Number

    Strength

    Description

    Tablets per Bottle

    0003-0527-11

    20 mg

    white to off-white, biconvex, round, film-coated tablet with “BMS” debossed on one side and “527” on the other side

    60

    0003-0528-11

    50 mg

    white to off-white, biconvex, oval, film-coated tablet with “BMS” debossed on one side and “528” on the other side

    60

    0003-0524-11

    70 mg

    white to off-white, biconvex, round, film-coated tablet with “BMS” debossed on one side and “524” on the other side

    60

    0003-0855-22

    80 mg

    white to off-white, biconvex, triangle, film-coated tablet with “BMS” and “80” (BMS over 80) debossed on one side and “855” on the other side

    30

    0003-0852-22

    100 mg

    white to off-white, biconvex, oval, film-coated tablet with “BMS 100” debossed on one side and “852” on the other side

    30

    0003-0857-22

    140 mg

    white to off-white, biconvex, round, film-coated tablet with “BMS” and “140” (BMS over 140) debossed on one side and “857” on the other side

    30

    16.2 Storage

    SPRYCEL® 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) [see USP Controlled Room Temperature].

    16.3 Handling and Disposal

    SPRYCEL is an antineoplastic product. Follow special handling and disposal procedures.

    SPRYCEL (dasatinib) tablets consist of a core tablet (containing the active drug substance), surrounded by a film coating to prevent exposure of pharmacy and clinical personnel to the active drug substance. However, if tablets are inadvertently crushed or broken, pharmacy and clinical personnel should wear disposable chemotherapy gloves. Personnel who are pregnant should avoid exposure to crushed or broken tablets.

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  • 17 PATIENT COUNSELING INFORMATION

    Advise the patient to read the FDA-approved patient labeling (Patient Information).

    Bleeding

    Patients should be informed of the possibility of serious bleeding and to report immediately any signs or symptoms suggestive of hemorrhage (unusual bleeding or easy bruising).

    Myelosuppression

    Patients should be informed of the possibility of developing low blood cell counts; they should be instructed to report immediately should fever develop, particularly in association with any suggestion of infection.

    Fluid Retention

    Patients should be informed of the possibility of developing fluid retention (swelling, weight gain, dry cough, chest pain on respiration, or shortness of breath) and to seek medical attention promptly if those symptoms arise.

    Embryo-Fetal Toxicity

    Advise pregnant women of the potential risk to a fetus [see Warnings and Precautions (5.9) and Use in Specific Populations (8.1)].
    Advise females of reproductive potential to avoid pregnancy, which may include use of effective contraception during treatment with SPRYCEL and for 30 days after the final dose. Advise females to contact their healthcare provider if they become pregnant, or if pregnancy is suspected, while taking SPRYCEL [see Warnings and Precautions (5.9) and Use in Specific Populations (8.1, 8.3)].

    Lactation

    Advise women that breastfeeding is not recommended during treatment with SPRYCEL and for 2 weeks after the final dose [see Use in Specific Populations (8.2)].

    Gastrointestinal Complaints

    Patients should be informed that they may experience nausea, vomiting, or diarrhea with SPRYCEL. If these symptoms are bothersome or persistent, they should seek medical attention.

    Pain

    Patients should be informed that they may experience headache or musculoskeletal pain with SPRYCEL. If these symptoms are bothersome or persistent, they should seek medical attention.

    Fatigue

    Patients should be informed that they may experience fatigue with SPRYCEL. If this symptom is bothersome or persistent, they should seek medical attention.

    Rash

    Patients should be informed that they may experience skin rash with SPRYCEL. If this symptom is bothersome or persistent, they should seek medical attention.

    Lactose

    Patients should be informed that SPRYCEL contains 135 mg of lactose monohydrate in a 100-mg daily dose and 189 mg of lactose monohydrate in a 140-mg daily dose.

    Missed Dose

    If the patient misses a dose of SPRYCEL, the patient should take the next scheduled dose at its regular time. The patient should not take two doses at the same time.



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  • PATIENT INFORMATION SPRYCEL® (Spry-sell) (dasatinib) Tablets

    What is SPRYCEL?

    SPRYCEL® is a prescription medicine used to treat adults who have:

    newly diagnosed Philadelphia chromosome-positive (Ph+) chronic myeloid leukemia (CML) in chronic phase.
    Ph+ CML who no longer benefit from, or did not tolerate, other treatment, including Gleevec ® (imatinib mesylate).
    Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL) who no longer benefit from, or did not tolerate, other treatment.

    It is not known if SPRYCEL is safe and effective in children younger than 18 years old.

    Before taking SPRYCEL, tell your healthcare provider about all of your medical conditions, including if you:

    have problems with your immune system
    have liver problems
    have heart problems, including a condition called congenital long QT syndrome
    have low potassium or low magnesium levels in your blood
    are lactose (milk sugar) intolerant
    are pregnant or plan to become pregnant. SPRYCEL can harm your unborn baby. If you are able to become pregnant, you should use effective birth control during treatment and for 30 days after your final dose of SPRYCEL. Talk to your healthcare provider right away if you become pregnant during treatment with SPRYCEL.
    are breastfeeding or plan to breastfeed. It is not known if SPRYCEL passes into your breast milk. You should not breastfeed during treatment and for 2 weeks after your final dose of SPRYCEL.

    Tell your healthcare provider about all the medicines you take, including prescription and over-the-counter medicines, vitamins, antacids, and herbal supplements. If you take an antacid medicine, take it 2 hours before or 2 hours after your dose of SPRYCEL.

    How should I take SPRYCEL?

    Take SPRYCEL exactly as your healthcare provider tells you to take it.
    Your healthcare provider may change your dose of SPRYCEL or temporarily stop treatment with SPRYCEL. Do not change your dose or stop taking SPRYCEL without first talking to your healthcare provider.
    Take SPRYCEL one (1) time a day.
    Take SPRYCEL with or without food, either in the morning or in the evening.
    Swallow SPRYCEL tablets whole. Do not cut or crush the tablets.
    You should not drink grapefruit juice during treatment with SPRYCEL.
    If you miss a dose of SPRYCEL, take your next scheduled dose at your regular time. Do not take two doses at the same time.
    If you take too much SPRYCEL, call your healthcare provider or go to the nearest hospital emergency room right away.

    What are the possible side effects of SPRYCEL?

    SPRYCEL may cause serious side effects, including:

    Low Blood Cell Counts. Low blood cell counts are common with SPRYCEL and can be severe, including low red blood cell counts (anemia), low white blood cell counts (neutropenia), and low platelet counts (thrombocytopenia). Your healthcare provider will do blood tests to check your blood cell counts regularly during your treatment with SPRYCEL. Call your healthcare provider right away if you have a fever or any signs of an infection during treatment with SPRYCEL.
    Bleeding problems. SPRYCEL may cause severe bleeding that can lead to death. Call your healthcare provider right away if you have:
    o
    unusual bleeding or bruising of your skin
    o
    bright red or dark tar-like stools
    o
    decreased alertness, headache, or change in speech
    Your body may hold too much fluid (fluid retention). Fluid retention is common with SPRYCEL and can sometimes be severe. In severe cases, fluid may build up in the lining of your lungs, the sac around your heart, or your stomach cavity. Call your healthcare provider right away if you get any of these symptoms during treatment with SPRYCEL:
    o
    swelling all over your body
    o
    weight gain
    o
    shortness of breath and cough, especially if this happens with low levels of physical activity or at rest
    o
    chest pain when taking a deep breath
    Heart problems. SPRYCEL may cause an abnormal heart rate, heart problems or a heart attack. Your healthcare provider will monitor the potassium and magnesium levels in your blood, and your heart function.
    Pulmonary Arterial Hypertension (PAH). SPRYCEL may cause high blood pressure in the vessels of your lungs. PAH may happen at any time during your treatment with SPRYCEL. Your healthcare provider should check your heart and lungs before and during treatment with SPRYCEL. Call your healthcare provider right away if you have shortness of breath, tiredness, or swelling all over your body (fluid retention).
    Severe skin reactions. SPRYCEL may cause skin reactions that can sometimes be severe. Get medical help right away if you get a skin reaction with fever, sore mouth or throat, blistering or peeling of your skin or in the mouth.
    Tumor Lysis Syndrome (TLS). TLS is caused by a fast breakdown of cancer cells. TLS can cause you to have kidney failure and the need for dialysis treatment, and an abnormal heart beat. Your healthcare provider may do blood tests to check you for TLS.

    Side effects of SPRYCEL which are considered common include:

    diarrhea
    shortness of breath
    headache
    skin rash
    tiredness
    muscle pain
    nausea
    fever
    Tell your healthcare provider if you have any side effect that bothers you or that does not go away. These are not all of the possible side effects of SPRYCEL. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.

    How should I store SPRYCEL?

    Store SPRYCEL at room temperature between 68°F to 77°F (20°C to 25°C).
    Ask your healthcare provider or pharmacist about the right way to throw away outdated or unused SPRYCEL.
    Females who are pregnant should not handle crushed or broken SPRYCEL tablets.

    Keep SPRYCEL and all medicines out of the reach of children.

    General information about the safe and effective use of SPRYCEL.

    Medicines are sometimes prescribed for purposes other than those listed in a Patient Information leaflet. Do not use SPRYCEL for a condition for which it is not prescribed. Do not give SPRYCEL to other people even if they have the same symptoms you have. It may harm them. You can ask your healthcare provider or pharmacist for information about SPRYCEL that is written for health professionals.

    What are the ingredients in SPRYCEL?

    Active ingredient: dasatinib

    Inactive ingredients: lactose monohydrate, microcrystalline cellulose, croscarmellose sodium, hydroxypropyl cellulose, and magnesium stearate. The tablet coating consists of hypromellose, titanium dioxide, and polyethylene glycol.
     

    Manufactured by:
    Bristol-Myers Squibb Company, Princeton, NJ 08543 USA
    Product of Ireland

    For more information, go to www.sprycel.com or call 1-800-332-2056.

    This Patient Information has been approved by the U.S. Food and Drug Administration.


    Revised: August 2015

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  • SPRYCEL 20 mg tablets Representative Packaging

    See How Supplied section for a complete list of available packages of SPRYCEL.

    60 Tablets NDC 0003-0527-11
    SPRYCEL®
    (dasatinib)
    Tablets
    20 mg
    Rx only
    Do not crush or cut tablet
    Bristol-Myers Squibb

    SPRYCEL 20 mg Tablets
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  • SPRYCEL 50 mg tablets Representative Packaging

    60 Tablets NDC 0003-0528-11
    SPRYCEL®
    (dasatinib)
    Tablets
    50 mg
    Rx only
    Do not crush or cut tablet
    Bristol-Myers Squibb

    SPRYCEL 50 mg Tablets
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  • SPRYCEL 70 mg tablets Representative Packaging

    60 Tablets NDC 0003-0524-11
    SPRYCEL®
    (dasatinib)
    Tablets
    70 mg
    Rx only
    Do not crush or cut tablet
    Bristol-Myers Squibb

    SPRYCEL 70 mg Tablets
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  • SPRYCEL 80 mg tablets Representative Packaging

    30 Tablets NDC 0003-0855-22
    SPRYCEL®
    (dasatinib)
    Tablets
    80 mg
    Rx only
    Do not crush or cut tablet
    Bristol-Myers Squibb

    SPRYCEL 80 mg Tablets
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  • SPRYCEL 100 mg tablets Representative Packaging

    30 Tablets NDC 0003-0852-22
    SPRYCEL®
    (dasatinib)
    Tablets
    100 mg
    Rx only
    Do not crush or cut tablet
    Bristol-Myers Squibb

    SPRYCEL 100 mg Tablets
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  • SPRYCEL 140 mg tablets Representative Packaging

    30 Tablets NDC 0003-0857-22
    SPRYCEL®
    (dasatinib)
    Tablets
    140 mg
    Rx only
    Do not crush or cut tablet
    Bristol-Myers Squibb

    SPRYCEL 140 mg Tablets
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  • INGREDIENTS AND APPEARANCE
    SPRYCEL 
    dasatinib tablet
    Product Information
    Product Type HUMAN PRESCRIPTION DRUG Item Code (Source) NDC:0003-0527
    Route of Administration ORAL DEA Schedule     
    Active Ingredient/Active Moiety
    Ingredient Name Basis of Strength Strength
    dasatinib (UNII: RBZ1571X5H) (dasatinib anhydrous - UNII:X78UG0A0RN) dasatinib 20 mg
    Inactive Ingredients
    Ingredient Name Strength
    lactose monohydrate (UNII: EWQ57Q8I5X)  
    cellulose, microcrystalline (UNII: OP1R32D61U)  
    croscarmellose sodium (UNII: M28OL1HH48)  
    HYDROXYPROPYL CELLULOSE (TYPE H) (UNII: RFW2ET671P)  
    magnesium stearate (UNII: 70097M6I30)  
    hypromelloses (UNII: 3NXW29V3WO)  
    titanium dioxide (UNII: 15FIX9V2JP)  
    polyethylene glycols (UNII: 3WJQ0SDW1A)  
    Product Characteristics
    Color WHITE Score no score
    Shape ROUND (biconvex) Size 6mm
    Flavor Imprint Code BMS;527
    Contains     
    Packaging
    # Item Code Package Description Marketing Start Date Marketing End Date
    1 NDC:0003-0527-11 1 in 1 CARTON
    1 60 in 1 BOTTLE; Type 0: Not a Combination Product
    Marketing Information
    Marketing Category Application Number or Monograph Citation Marketing Start Date Marketing End Date
    NDA NDA021986 06/27/2006
    SPRYCEL 
    dasatinib tablet
    Product Information
    Product Type HUMAN PRESCRIPTION DRUG Item Code (Source) NDC:0003-0528
    Route of Administration ORAL DEA Schedule     
    Active Ingredient/Active Moiety
    Ingredient Name Basis of Strength Strength
    dasatinib (UNII: RBZ1571X5H) (dasatinib anhydrous - UNII:X78UG0A0RN) dasatinib 50 mg
    Inactive Ingredients
    Ingredient Name Strength
    lactose monohydrate (UNII: EWQ57Q8I5X)  
    cellulose, microcrystalline (UNII: OP1R32D61U)  
    croscarmellose sodium (UNII: M28OL1HH48)  
    HYDROXYPROPYL CELLULOSE (TYPE H) (UNII: RFW2ET671P)  
    magnesium stearate (UNII: 70097M6I30)  
    hypromelloses (UNII: 3NXW29V3WO)  
    titanium dioxide (UNII: 15FIX9V2JP)  
    polyethylene glycols (UNII: 3WJQ0SDW1A)  
    Product Characteristics
    Color WHITE Score no score
    Shape OVAL (biconvex) Size 11mm
    Flavor Imprint Code BMS;528
    Contains     
    Packaging
    # Item Code Package Description Marketing Start Date Marketing End Date
    1 NDC:0003-0528-11 1 in 1 CARTON
    1 60 in 1 BOTTLE; Type 0: Not a Combination Product
    Marketing Information
    Marketing Category Application Number or Monograph Citation Marketing Start Date Marketing End Date
    NDA NDA021986 06/27/2006
    SPRYCEL 
    dasatinib tablet
    Product Information
    Product Type HUMAN PRESCRIPTION DRUG Item Code (Source) NDC:0003-0524
    Route of Administration ORAL DEA Schedule     
    Active Ingredient/Active Moiety
    Ingredient Name Basis of Strength Strength
    dasatinib (UNII: RBZ1571X5H) (dasatinib anhydrous - UNII:X78UG0A0RN) dasatinib 70 mg
    Inactive Ingredients
    Ingredient Name Strength
    lactose monohydrate (UNII: EWQ57Q8I5X)  
    cellulose, microcrystalline (UNII: OP1R32D61U)  
    croscarmellose sodium (UNII: M28OL1HH48)  
    HYDROXYPROPYL CELLULOSE (TYPE H) (UNII: RFW2ET671P)  
    magnesium stearate (UNII: 70097M6I30)  
    hypromelloses (UNII: 3NXW29V3WO)  
    titanium dioxide (UNII: 15FIX9V2JP)  
    polyethylene glycols (UNII: 3WJQ0SDW1A)  
    Product Characteristics
    Color WHITE Score no score
    Shape ROUND (biconvex) Size 9mm
    Flavor Imprint Code BMS;524
    Contains     
    Packaging
    # Item Code Package Description Marketing Start Date Marketing End Date
    1 NDC:0003-0524-11 1 in 1 CARTON
    1 60 in 1 BOTTLE; Type 0: Not a Combination Product
    Marketing Information
    Marketing Category Application Number or Monograph Citation Marketing Start Date Marketing End Date
    NDA NDA021986 06/27/2006
    SPRYCEL 
    dasatinib tablet
    Product Information
    Product Type HUMAN PRESCRIPTION DRUG Item Code (Source) NDC:0003-0855
    Route of Administration ORAL DEA Schedule     
    Active Ingredient/Active Moiety
    Ingredient Name Basis of Strength Strength
    dasatinib (UNII: RBZ1571X5H) (dasatinib anhydrous - UNII:X78UG0A0RN) dasatinib 80 mg
    Inactive Ingredients
    Ingredient Name Strength
    lactose monohydrate (UNII: EWQ57Q8I5X)  
    cellulose, microcrystalline (UNII: OP1R32D61U)  
    croscarmellose sodium (UNII: M28OL1HH48)  
    HYDROXYPROPYL CELLULOSE (TYPE H) (UNII: RFW2ET671P)  
    magnesium stearate (UNII: 70097M6I30)  
    hypromelloses (UNII: 3NXW29V3WO)  
    titanium dioxide (UNII: 15FIX9V2JP)  
    polyethylene glycols (UNII: 3WJQ0SDW1A)  
    Product Characteristics
    Color WHITE Score no score
    Shape TRIANGLE (biconvex) Size 10mm
    Flavor Imprint Code BMS80;855
    Contains     
    Packaging
    # Item Code Package Description Marketing Start Date Marketing End Date
    1 NDC:0003-0855-22 1 in 1 CARTON
    1 30 in 1 BOTTLE; Type 0: Not a Combination Product
    Marketing Information
    Marketing Category Application Number or Monograph Citation Marketing Start Date Marketing End Date
    NDA NDA021986 10/28/2010
    SPRYCEL 
    dasatinib tablet
    Product Information
    Product Type HUMAN PRESCRIPTION DRUG Item Code (Source) NDC:0003-0852
    Route of Administration ORAL DEA Schedule     
    Active Ingredient/Active Moiety
    Ingredient Name Basis of Strength Strength
    dasatinib (UNII: RBZ1571X5H) (dasatinib anhydrous - UNII:X78UG0A0RN) dasatinib 100 mg
    Inactive Ingredients
    Ingredient Name Strength
    lactose monohydrate (UNII: EWQ57Q8I5X)  
    cellulose, microcrystalline (UNII: OP1R32D61U)  
    croscarmellose sodium (UNII: M28OL1HH48)  
    HYDROXYPROPYL CELLULOSE (TYPE H) (UNII: RFW2ET671P)  
    magnesium stearate (UNII: 70097M6I30)  
    hypromelloses (UNII: 3NXW29V3WO)  
    titanium dioxide (UNII: 15FIX9V2JP)  
    polyethylene glycols (UNII: 3WJQ0SDW1A)  
    Product Characteristics
    Color WHITE Score no score
    Shape OVAL (biconvex) Size 15mm
    Flavor Imprint Code BMS100;852
    Contains     
    Packaging
    # Item Code Package Description Marketing Start Date Marketing End Date
    1 NDC:0003-0852-22 1 in 1 CARTON
    1 30 in 1 BOTTLE; Type 0: Not a Combination Product
    Marketing Information
    Marketing Category Application Number or Monograph Citation Marketing Start Date Marketing End Date
    NDA NDA021986 05/30/2008
    SPRYCEL 
    dasatinib tablet
    Product Information
    Product Type HUMAN PRESCRIPTION DRUG Item Code (Source) NDC:0003-0857
    Route of Administration ORAL DEA Schedule     
    Active Ingredient/Active Moiety
    Ingredient Name Basis of Strength Strength
    dasatinib (UNII: RBZ1571X5H) (dasatinib anhydrous - UNII:X78UG0A0RN) dasatinib 140 mg
    Inactive Ingredients
    Ingredient Name Strength
    lactose monohydrate (UNII: EWQ57Q8I5X)  
    cellulose, microcrystalline (UNII: OP1R32D61U)  
    croscarmellose sodium (UNII: M28OL1HH48)  
    HYDROXYPROPYL CELLULOSE (TYPE H) (UNII: RFW2ET671P)  
    magnesium stearate (UNII: 70097M6I30)  
    hypromelloses (UNII: 3NXW29V3WO)  
    titanium dioxide (UNII: 15FIX9V2JP)  
    polyethylene glycols (UNII: 3WJQ0SDW1A)  
    Product Characteristics
    Color WHITE Score no score
    Shape ROUND (biconvex) Size 11mm
    Flavor Imprint Code BMS140;857
    Contains     
    Packaging
    # Item Code Package Description Marketing Start Date Marketing End Date
    1 NDC:0003-0857-22 1 in 1 CARTON
    1 30 in 1 BOTTLE; Type 0: Not a Combination Product
    Marketing Information
    Marketing Category Application Number or Monograph Citation Marketing Start Date Marketing End Date
    NDA NDA021986 10/28/2010
    Labeler - E.R. Squibb & Sons, L.L.C. (011550092)
    Close