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Sprycel 70 Mg 60 Film Coated Tablets

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 QT Prolongation

5.5 Congestive Heart Failure, Left Ventricular Dysfunction, and Myocardial Infarction

5.6 Pulmonary Arterial Hypertension

5.7 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 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

8.3 Nursing Mothers

8.4 Pediatric Use

8.5 Geriatric Use

8.6 Hepatic Impairment

8.7 Renal Impairment

8.8 Females of Reproductive Potential

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

17.1 Bleeding

17.2 Myelosuppression

17.3 Fluid Retention

17.4 Embryo-fetal Toxicity

17.5 Gastrointestinal Complaints

17.6 Pain

17.7 Fatigue

17.8 Rash

17.9 Lactose

17.10 Missed Dose

*Sections or subsections omitted from the full prescribing information are not listed.

FULL PRESCRIBING INFORMATION

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. The effectiveness of SPRYCEL is based on cytogenetic response and major molecular response rates [see Clinical Studies (14.1)]. The trial is ongoing and further data will be required to determine long-term outcome.

•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.

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 after the achievement of a complete cytogenetic response (CCyR) has not been investigated.

2.1 Dose Modification

Concomitant Strong CYP3A4 inducers: The use of concomitant strong CYP3A4 inducers may decrease dasatinib plasma concentrations and should be avoided (eg, 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 (eg, 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 × 109/L and platelets ≥50 × 109/L.

2.

Resume treatment with SPRYCEL at the original starting dose if recovery occurs in ≤7 days.

3.

If platelets <25 × 109/L or recurrence of ANC <0.5 × 109/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 × 109/L and platelets ≥20 × 109/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 initial severity of the event.

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)].

4 CONTRAINDICATIONS

None.

5 WARNINGS AND PRECAUTIONS

5.1 Myelosuppression

Treatment with SPRYCEL is associated with severe (NCI CTC Grade 3 or 4) thrombocytopenia, neutropenia, and anemia. Their occurrence is more frequent in patients with advanced phase CML or Ph+ ALL than in chronic phase CML. In a dose-optimization trial in patients with resistance or intolerance to prior imatinib therapy and chronic phase CML, Grade 3 or 4 myelosuppression was reported less frequently in patients treated with 100 mg once daily than in patients treated with other dosing regimens.

Perform complete blood counts weekly for the first 2 months and then monthly thereafter, or as clinically indicated. Myelosuppression was generally reversible and usually managed by withholding SPRYCEL temporarily 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 clinical studies, severe central nervous system (CNS) hemorrhages, including fatalities, occurred in 1% of patients receiving SPRYCEL. Severe gastrointestinal hemorrhage, including fatalities, occurred in 4% of patients and generally required treatment interruptions and transfusions. Other cases of severe hemorrhage occurred in 2% of patients. Most bleeding events were associated with severe thrombocytopenia.

Patients were excluded from participation in initial SPRYCEL clinical studies if they took medications that inhibit platelet function or anticoagulants. In subsequent trials, the use of anticoagulants, aspirin, and non-steroidal anti-inflammatory drugs (NSAIDs) was allowed concurrently with SPRYCEL if the platelet count was >50,000–75,000 per microliter. Exercise caution if patients are required to take medications that inhibit platelet function or anticoagulants.

5.3 Fluid Retention

SPRYCEL is associated with fluid retention. In clinical trials, severe fluid retention was reported in up to 10% of patients. Severe ascites, pulmonary edema, and generalized edema were each reported in ≤1% of patients. Patients who develop symptoms suggestive of pleural effusion, such as dyspnea or dry cough, should be evaluated by chest x-ray. Severe pleural effusion may require thoracentesis and oxygen therapy. Fluid retention events were typically managed by supportive care measures that include diuretics or short courses of steroids. In dose-optimization studies, fluid retention events were reported less frequently with once daily dosing than with other dosing regimens.

5.4 QT Prolongation

In vitro data suggest that dasatinib has the potential to prolong cardiac ventricular repolarization (QT interval). Of the 2440 patients treated with SPRYCEL 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 ms to 13.4 ms.

Administer SPRYCEL with caution to patients who have or may develop prolongation of QTc. These include patients with hypokalemia or hypomagnesemia, patients with congenital long QT syndrome, patients taking anti-arrhythmic medicines or other medicinal products that lead to QT prolongation, and cumulative high-dose anthracycline therapy. Correct hypokalemia or hypomagnesemia prior to SPRYCEL administration.

5.5 Congestive Heart Failure, Left Ventricular Dysfunction, and Myocardial Infarction

Cardiac adverse reactions were reported in 7% of 258 patients taking SPRYCEL, including, 1.6% of patients with cardiomyopathy, heart failure congestive, diastolic dysfunction, fatal myocardial infarction, and left ventricular dysfunction. Monitor patients for signs or symptoms consistent with cardiac dysfunction and treat appropriately.

5.6 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 one 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.

5.7 Embryo-fetal Toxicity

SPRYCEL can cause fetal harm when administered to a pregnant woman. Adverse fetal and infant outcomes have been reported from women who have taken SPRYCEL during pregnancy. In animal reproduction studies, embryo-fetal toxicities, including skeletal malformations, were observed in rats and rabbits at plasma concentrations below those in humans receiving therapeutic doses of dasatinib. If SPRYCEL is used during pregnancy, or if the patient becomes pregnant while taking SPRYCEL, the patient should be apprised of the potential hazard to the fetus [see Use in Specific Populations (8.1)].

Advise females of reproductive potential to avoid pregnancy, which may include the use of contraception, during treatment with SPRYCEL [see Use in Specific Populations (8.8)].

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)].

•QT prolongation [see Warnings and Precautions (5.4)].

•Congestive heart failure, left ventricular dysfunction, and myocardial infarction [see Warnings and Precautions (5.5)].

•Pulmonary Arterial Hypertension [see Warnings and Precautions (5.6)].

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 in clinical studies including 258 patients with newly diagnosed chronic phase CML and in 2182 patients with imatinib resistant or intolerant CML or Ph+ ALL.

In the newly diagnosed chronic phase CML trial with a minimum of 36 months follow up and median duration of therapy of 37 months, the median average daily dose was 99 mg.

In the imatinib resistant or intolerant CML or Ph+ ALL clinical trials, 1520 patients had a minimum of 2 years follow up and 662 patients with chronic phase CML had a minimum of 60 months follow up (starting dosage 100 mg once daily, 140 mg once daily, 50 mg twice daily, or 70 mg twice daily). Among patients with chronic phase CML and resistance or intolerance to prior imatinib therapy, the median duration of treatment with SPRYCEL 100 mg once daily was 37 months (range 1–65 months). The median duration of treatment with SPRYCEL 140 mg once daily was 15 months (range 0.03–36 months) for accelerated phase CML, 3 months (range 0.03–29 months) for myeloid blast phase CML, and 3 months (range 0.1–10 months) for lymphoid blast CML.

The majority of SPRYCEL-treated patients experienced adverse reactions at some time. In the newly diagnosed chronic phase CML trial, drug was discontinued for adverse reactions in 6% of SPRYCEL-treated patients with a minimum of 12 months follow up. After a minimum of 36 months follow up, the cumulative discontinuation rate was 9%. Among patients with resistance or intolerance to prior imatinib therapy, the rates of discontinuation for adverse reactions at 2 years were 15% in chronic phase CML for all dosages, 16% in accelerated phase CML, 15% in myeloid blast phase CML, 8% in lymphoid blast phase CML, and 8% in Ph+ ALL. In a dose-optimization trial in patients with resistance or intolerance to prior imatinib therapy and chronic phase CML with a minimum of 60 months follow up, the rate of discontinuation for adverse reactions was 18% in patients treated with 100 mg once daily.

The most frequently reported adverse reactions reported in ≥10% of patients in newly diagnosed chronic phase CML included myelosuppression, fluid retention events (pleural effusion, superficial localized edema, generalized edema), diarrhea, headache, musculoskeletal pain, rash, and nausea. Pleural effusions were reported in 50 patients (see Table 2).

The most frequently reported adverse reactions reported in ≥20% of patients with resistance or intolerance to prior imatinib therapy included myelosuppression, fluid retention events, diarrhea, headache, dyspnea, skin rash, fatigue, nausea, and hemorrhage.

The most frequently reported serious adverse reactions in patients with newly diagnosed chronic phase CML included pleural effusion (4%), hemorrhage (2%), congestive heart failure (1%), pulmonary hypertension (1%), and pyrexia (1%). The most frequently reported serious adverse reactions in patients with resistance or intolerance to prior imatinib therapy included pleural effusion (11%), gastrointestinal bleeding (4%), febrile neutropenia (4%), dyspnea (3%), pneumonia (3%), pyrexia (3%), diarrhea (3%), infection (2%), congestive heart failure/cardiac dysfunction (2%), pericardial effusion (1%), and CNS hemorrhage (1%).

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 3 and 4 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 36 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

31

44

3

1

   Pleural effusion

19

<1

2

0

   Superficial localized edema

13

37

0

<1

   Generalized edema

3

7

0

0

   Congestive heart failure/cardiac dysfunctiona

2

1

<1

<1

   Pericardial effusion

3

1

1

0

   Pulmonary hypertension

2

0

<1

0

   Pulmonary edema

1

0

0

0

Diarrhea

21

22

1

1

Headache

13

11

0

0

Musculoskeletal pain

13

17

0

<1

Rashb

13

18

0

2

Nausea

10

24

0

0

Fatigue

9

11

<1

0

Myalgia

6

12

0

0

Hemorrhagec

7

7

1

1

   Gastrointestinal bleeding

2

1

1

0

   Other bleedingd

6

5

0

1

   CNS bleeding

0

<1

0

<1

Vomiting

5

11

0

0

Muscle spasms

5

21

0

<1

The cumulative rates of the majority of adverse reactions (all grades) in newly diagnosed patients with chronic phase CML were similar after 12 and 36 months minimum follow up including congestive heart failure/cardiac dysfunction (2% vs 2%), pericardial effusion (2% vs 3%), pulmonary edema (<1% vs 1%), gastrointestinal bleeding (2% vs 2%), diarrhea (18% vs 21%), and generalized edema (3% vs 3%). Cumulative adverse reaction rates (all grades) that increased between 12 months and 36 months minimum follow up included overall fluid retention (23% vs 31%), pleural effusion (12% vs 19%), and superficial edema (10% vs 13%). A total of 9 patients (3.5%) discontinued due to pleural effusion in the trial.

At 36 months, there were 17 deaths in the dasatinib-treated patients (6.6%) and 20 deaths in the imatinib-treated patients (7.7%); 1 in each group was judged by the investigator as related to study therapy.

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Sprycel 70 Mg 60 Film Coated Tablets

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Table 3: Adverse Reactions Reported in ≥10% of Patients with Chronic Phase CML Resistant or Intolerant to Prior Imatinib Therapy (minimum of 36 months follow up)

 

100 mg Once Daily

 

Chronic 
(n=165)

Preferred Term

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

42

5

         

   Superficial localized edema

21

0

         

   Pleural effusion

24

4

         

   Generalized edema

4

0

         

   Pericardial effusion

2

1

         

   Congestive heart failure/cardiac dysfunctiona

0

0

         

   Pulmonary edema

0

0

         

Headache

33

1

         

Diarrhea

28

2

         

Fatigue

26

4

         

Dyspnea

24

2

         

Musculoskeletal pain

22

2

         

Nausea

18

1

         

Skin rashb

18

2

         

Myalgia

13

0

         

Arthralgia

12

1

         

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

13

1

         

Abdominal pain

12

1

         

Hemorrhage

11

1

         

   Gastrointestinal bleeding

2

1

         

   CNS bleeding

0

0