Sprycel

(Dasatinib)

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Dosage & Administration

In clinical studies, treatment with SPRYCEL in adults and in pediatric patients with chronic phase CML was continued until disease progression or until no longer tolerated by the patient. The effect of stopping treatment on long-term disease outcome after the achievement of a cytogenetic response (including complete cytogenetic response [CCyR]) or major molecular response (MMR and MR4.5) has not been established.

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

[see

2.2 Dosage of SPRYCEL in Pediatric Patients with CML or Ph+ ALL

The recommended starting dosage for pediatrics is based on body weight as shown in Table 1. The recommended dose should be administered orally once daily with or without food. Recalculate the dose every 3 months based on changes in body weight, or more often if necessary.

Do not crush, cut or chew tablets. Swallow tablets whole.

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

[see Use in Specific Populations (8.4)and Clinical Pharmacology (12.3)]

Table 1: Dosage of SPRYCEL for Pediatric Patients^a
Body Weight (kg)^b	Daily Dose (mg)
^aFor pediatric patients with Ph+ ALL, begin SPRYCEL therapy on or before day 15 of induction chemotherapy, when diagnosis is confirmed and continue for 2 years. ^bTablet dosing is not recommended for patients weighing less than 10 kg.
10 to less than 20	40 mg
20 to less than 30	60 mg
30 to less than 45	70 mg
at least 45	100 mg

Refer to Section 2.4for recommendations on dose escalation in adults with CML and Ph+ ALL, and pediatric patients with CML.

and

14.4 Ph+ ALL in Pediatric Patients

The efficacy of SPRYCEL in combination with chemotherapy was evaluated in a single cohort (cohort 1) of Study CA180372 (NCT01460160), a multicenter, multiple-cohort study of pediatric patients with newly diagnosed B-cell precursor Ph+ ALL. The 78 patients in cohort 1 received SPRYCEL at a daily dose of 60 mg/m²for up to 24 months, in combination with chemotherapy. The backbone chemotherapy regimen was the AIEOP-BFM ALL 2000 multi-agent chemotherapy protocol.

Patients had a median age of 10.4 years (range 2.6 to 17.9 years) and included 20 patients (25%) 2 to 6 years of age, 37 patients (46%) 7 to 12 years of age, and 24 patients (30%) 13 to 17 years of age. Eighty-two percent of patients were white, and 55% were male. Thirty-two patients (41%) had a white blood cell count (WBC) of ≥50,000 mcl at diagnosis, and 17 patients (22%) had extramedullary disease.

Efficacy was established on the basis of 3-year event-free survival (EFS), defined as the time from the start of SPRYCEL to lack of complete response at the end of the third high risk block, relapse, secondary malignancy, or death from any cause. The 3-year EFS binary rate for patients on Study CA180372 was 64.1% (95% CI: 52.4, 74.7). At the end of induction, 75 patients (96%) had a bone marrow with <5% lymphoblasts, and 76 patients (97%) achieved this by the end of consolidation.

]

SPRYCEL is a hazardous product. Follow applicable special handling and disposal procedures.¹

Sprycel Prescribing Information

SPRYCEL (dasatinib) is indicated for the treatment of adult patients with

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

SPRYCEL (dasatinib) is indicated for the treatment of pediatric patients 1 year of age and older with

•Ph+ CML in chronic phase.
•newly diagnosed Ph+ ALL in combination with chemotherapy.

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

[see

2.2 Dosage of SPRYCEL in Pediatric Patients with CML or Ph+ ALL

Do not crush, cut or chew tablets. Swallow tablets whole.

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

[see Use in Specific Populations (8.4)and Clinical Pharmacology (12.3)]

Table 1: Dosage of SPRYCEL for Pediatric Patients^a
Body Weight (kg)^b	Daily Dose (mg)
^aFor pediatric patients with Ph+ ALL, begin SPRYCEL therapy on or before day 15 of induction chemotherapy, when diagnosis is confirmed and continue for 2 years. ^bTablet dosing is not recommended for patients weighing less than 10 kg.
10 to less than 20	40 mg
20 to less than 30	60 mg
30 to less than 45	70 mg
at least 45	100 mg

Refer to Section 2.4for recommendations on dose escalation in adults with CML and Ph+ ALL, and pediatric patients with CML.

and

14.4 Ph+ ALL in Pediatric Patients

]

SPRYCEL is a hazardous product. Follow applicable special handling and disposal procedures.¹

•
Lactation:
Advise women not to breastfeed.
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 child, 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 children from SPRYCEL, breastfeeding is not recommended during treatment with SPRYCEL and for 2 weeks after the last dose.

In pediatric trials of SPRYCEL in chronic phase CML after at least 2 years of treatment, adverse reactions associated with bone growth and development were reported in 5 (5.2%) patients, one of which was severe in intensity (Growth Retardation Grade 3). These 5 cases included cases of epiphyses delayed fusion, osteopenia, growth retardation, and gynecomastia

[see

6.1 Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

The data described below reflect exposure to SPRYCEL administered as single-agent therapy at all doses tested in clinical studies (n=2809), including 324 adult patients with newly diagnosed chronic phase CML, 2388 adult patients with imatinib-resistant or -intolerant chronic or advanced phase CML or Ph+ ALL, and 97 pediatric patients with chronic phase CML. The median duration of therapy in a total of 2712 adult patients was 19.2 months (range 0 to 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 adult patients with chronic phase CML was 29 months (range 0 to 92.9 months).

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

In two non-randomized trials in 97 pediatric patients with chronic phase CML (51 patients newly diagnosed and 46 patients resistant or intolerant to previous treatment with imatinib), the median duration of therapy was 51.1 months (range 1.9 to 99.6 months).

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

In the randomized trial in adult patients with newly diagnosed chronic phase CML, drug was discontinued for adverse reactions in 16% of patients with a minimum of 60 months of follow-up. After a minimum of 60 months of follow-up, the cumulative discontinuation rate was 39%. Among the 1618 patients with chronic phase CML, drug-related adverse reactions leading to discontinuation were reported in 329 (20.3%) patients; among the 1094 patients with advanced phase CML or Ph+ ALL, drug-related adverse reactions leading to discontinuation were reported in 191 (17.5%) patients.

Among the 97 pediatric subjects, drug-related adverse reactions leading to discontinuation were reported in 1 patient (1%).

Adverse reactions reported in ≥10% of adult patients, and other adverse reactions of interest, in a randomized trial in patients with newly diagnosed chronic phase CML at a median follow-up of approximately 60 months are presented in Table 6.

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

Adverse reactions reported in ≥10% of pediatric patients at a median follow-up of approximately 51.1 months are presented in Table 11.

Drug-related serious adverse reactions (SARs) were reported for 16.7% of adult patients in the randomized trial of patients with newly diagnosed chronic phase CML. Serious adverse reactions reported in ≥5% of patients included pleural effusion (5%).

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

Drug-related SARs were reported for 14.4% of pediatric patients.

Chronic Myeloid Leukemia (CML)

Adverse reactions (excluding laboratory abnormalities) that were reported in at least 10% of adult patients are shown in Table 6 for newly diagnosed patients with chronic phase CML and Tables 8 and 10 for CML patients with resistance or intolerance to prior imatinib therapy.

Table 6: Adverse Reactions Reported in ≥10% of Adult Patients with Newly Diagnosed Chronic Phase CML (minimum of 60 months follow-up)
	All Grades		Grade 3/4
	SPRYCEL (n=258)	Imatinib (n=258)	SPRYCEL (n=258)	Imatinib (n=258)
Adverse Reaction	Percent (%) of Patients
^aIncludes cardiac failure acute, cardiac failure congestive, cardiomyopathy, diastolic dysfunction, ejection fraction decreased, and left ventricular dysfunction. ^bIncludes erythema, erythema multiforme, rash, rash generalized, rash macular, rash papular, rash pustular, skin exfoliation, and rash vesicular. ^cAdverse reaction of special interest with <10% frequency. ^dIncludes 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 dysfunction^a	2	1	<1	<1
Pulmonary edema	1	0	0	0
Diarrhea	22	23	1	1
Musculoskeletal pain	14	17	0	<1
Rash^b	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
Hemorrhage^c	8	8	1	1
Gastrointestinal bleeding	2	2	1	0
Other bleeding^d	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 7.

Table 7: Adverse Reactions Reported in ≥10% of Adult 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
Adverse Reaction	Percent (%) of Patients
^aIncludes cardiac failure acute, cardiac failure congestive, cardiomyopathy, diastolic dysfunction, ejection fraction decreased, and left ventricular dysfunction. ^bIncludes 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 dysfunction^a	2	<1	2	<1
Pulmonary edema	<1	0	1	0
Diarrhea	17	<1	22	1
Musculoskeletal pain	11	0	14	0
Rash^b	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 8: Adverse Reactions Reported in ≥10% of Adult Patients with Chronic Phase CML Resistant or Intolerant to Prior Imatinib Therapy (minimum of 84 months follow-up)
^aIncludes 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.
	100 mg Once Daily
	Chronic (n=165)
Adverse Reaction	All Grades	Grade 3/4
Adverse Reaction	Percent (%) of Patients
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 rash^a	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 9.

Table 9: Selected Adverse Reactions Reported in Adult 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
Adverse Reaction	All Grades	Grade 3/4	All Grades	Grade 3/4	All Grades	Grade 3/4
Adverse Reaction	Percent (%) of Patients
^aRandomized 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 10: Adverse Reactions Reported in ≥10% of Adult Patients with Advanced Phase CML Resistant or Intolerant to Prior Imatinib Therapy
^aIncludes ventricular dysfunction, cardiac failure, cardiac failure congestive, cardiomyopathy, congestive cardiomyopathy, diastolic dysfunction, ejection fraction decreased, and ventricular failure. ^bIncludes 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.
	140 mg Once Daily
	Accelerated (n=157)		Myeloid Blast (n=74)		Lymphoid Blast (n=33)
Adverse Reaction	All Grades	Grade 3/4	All Grades	Grade 3/4	All Grades	Grade 3/4
Adverse Reaction	Percent (%) of Patients
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 dysfunction^a	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 rash^b	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

Table 11: Adverse Reactions Reported in ≥10% of Dasatinib-Treated Pediatric Patients with Chronic Phase CML (n=97)
	All Grades	Grade 3/4
Adverse Reaction	Percent (%) of Patients
Headache	28	3
Nausea	20	0
Diarrhea	21	0
Skin rash	19	0
Vomiting	13	0
Pain in extremity	19	1
Abdominal pain	16	0
Fatigue	10	0
Arthralgia	10	1

Adverse reactions associated with bone growth and development were reported in 5 (5.2%) of pediatric patients with chronic phase CML

[see Warnings and Precautions (5.10)]

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 12 and 13). Myelosuppression was reported in patients with normal baseline laboratory values as well as in patients with pre-existing laboratory abnormalities.

In patients who experienced severe myelosuppression, recovery generally occurred following dose interruption or reduction; permanent discontinuation of treatment occurred in 2% of adult patients with newly diagnosed chronic phase CML and 5% of adult patients with resistance or intolerance to prior imatinib therapy

[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 SPRYCEL therapy often had recovery with oral calcium supplementation.

Laboratory abnormalities reported in adult patients with newly diagnosed chronic phase CML are shown in Table 12. There were no discontinuations of SPRYCEL therapy in this patient population due to biochemical laboratory parameters.

Table 12: CTC Grade 3/4 Laboratory Abnormalities in Adult 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 13.

Table 13: CTC Grade 3/4 Laboratory Abnormalities in Clinical Studies of CML in Adults: Resistance or Intolerance to Prior Imatinib Therapy
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.
	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
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 adult patients with chronic phase CML 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%).

In the pediatric studies in CML, the rates of laboratory abnormalities were consistent with the known profile for laboratory parameters in adults.

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

A total of 135 adult patients with Ph+ ALL were treated with 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%).

Philadelphia Chromosome-Positive Acute Lymphoblastic Leukemia (Ph+ ALL) in Pediatric Patients

The safety of SPRYCEL administered continuously in combination with multiagent chemotherapy was determined in a multicohort study of 81 pediatric patients with newly diagnosed Ph+ ALL.

[see Clinical Studies (14.4)]

. The median duration of therapy was 24 months (range 2 to 27 months).

Fatal adverse reactions occurred in 3 patients (4%), all of which were due to infections. Eight (10%) patients experienced adverse reactions leading to treatment discontinuation, including fungal sepsis, hepatotoxicity in the setting of graft versus host disease, thrombocytopenia, CMV infection, pneumonia, nausea, enteritis and drug hypersensitivity.

The most common serious adverse reactions (incidence ≥10%) were pyrexia, febrile neutropenia, mucositis, diarrhea, sepsis, hypotension, infections (bacterial, viral and fungal), hypersensitivity, vomiting, renal insufficiency, abdominal pain, and musculoskeletal pain.

The incidence of common adverse reactions (incidence ≥20%) on study are shown in Table 14:

Table 14: Adverse Reactions Reported in ≥20% of Pediatric Patients with Ph+ ALL Treated with SPRYCEL in Combination with Chemotherapy CA180372 (N=81)
	Percent (%) of Patients
Adverse Reaction	All Grades	Grade 3/4
Mucositis	93	60
Febrile neutropenia	86	86
Pyrexia	85	17
Diarrhea	84	31
Nausea	84	11
Vomiting	83	17
Musculoskeletal pain	83	25
Abdominal pain	78	17
Cough	78	1
Headache	77	15
Rash	68	7
Fatigue	59	3
Constipation	57	1
Arrhythmia	47	12
Hypertension	47	10
Edema	47	6
Viral infection	40	12
Hypotension	40	26
Decreased appetite	38	22
Hypersensitivity	36	20
Upper respiratory tract infection	36	10
Dyspnea	35	10
Epistaxis	31	6
Peripheral neuropathy	31	7
Sepsis (excluding fungal)	n/a	31
Altered state of consciousness	30	4
Fungal infection	30	11
Pneumonia (excluding fungal)	28	25
Pruritus	28	-
Clostridial infection (excluding sepsis)	25	14
Urinary Tract Infection	24	14
Bacteremia (excluding fungal)	22	20
Erythema	22	6
Chills	21	-
Pleural effusion	21	9
Sinusitis	21	10
Dehydration	20	9
Renal insufficiency	20	9
Visual impairment	20	-

The incidence of common adverse reactions attributed by the investigator to SPRYCEL (reported at a frequency of ≥10%, all grades and grade 3/4, respectively) on study (N=81), included febrile neutropenia (23%, 23%), nausea (21%, 4%), vomiting (19%, 4%), mucositis (17%, 6%), musculoskeletal pain (17%, 2%), abdominal pain (16%, 5%), diarrhea (16%, 7%), rash (15%, 0%), fatigue (12%, 0%), pyrexia (12%, 6%), and headache (12%, 5%).

CTCAE grade 3/4 laboratory abnormalities in pediatric patients with Ph+ ALL treated with SPRYCEL in combination with chemotherapy are shown in Table 15.

Table 15: CTCAE Grade 3/4 Laboratory Abnormalities in ≥10% of Pediatric Patients with Ph+ ALL Treated with SPRYCEL in Combination with Chemotherapy CA180372 (N=81)
	Percent (%) of Patients
Hematology Parameters
Neutropenia	96
Thrombocytopenia	88
Anemia	82
Biochemistry Parameters
Elevated SGPT (ALT)	47
Hypokalemia	40
Elevated SGOT (AST)	26
Hypocalcemia	19
Hyponatremia	19
Elevated Bilirubin	11
Hypophosphatemia	11
Toxicity grading is per CTCAE version 4.

Additional Pooled Data from Clinical Trials

The following additional adverse reactions were reported in adult and pediatric patients (n=2809) in SPRYCEL CML clinical studies and adult patients in Ph+ ALL clinical studies at a frequency of ≥10%, 1%– <10%, 0.1%– <1%, or < 0.1%. These adverse reactions are included based on 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, peripheral swelling;

<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;

<0.1%

– epiphyses delayed fusion (reported at

1%–<10%

in the pediatric studies), growth retardation (reported at

1%–<10%

in the pediatric studies).

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, lacrimation increased,

<0.1% –

photophobia.

Vascular Disorders:

1%–<10%

– flushing, hypertension;

0.1%–<1%

– hypotension, thrombophlebitis, thrombosis;

<0.1%

– livedo reticularis, deep vein thrombosis, embolism.

Psychiatric Disorders:

1%–<10%

– insomnia, depression;

0.1%–<1%

– anxiety, affect lability, confusional state, libido decreased.

Pregnancy, Puerperium, and Perinatal Conditions:

<0.1% –

abortion.

Reproductive System and Breast Disorders:

0.1%–<1%

– gynecomastia, menstrual disorder.

Injury, Poisoning, and Procedural Complications:

1%–<10%

– contusion.

Ear and Labyrinth Disorders:

1%–<10% –

tinnitus;

0.1%–<1%

– vertigo, hearing loss.

Hepatobiliary Disorders:

0.1%–<1%

– cholestasis, cholecystitis, hepatitis.

Renal and Urinary Disorders:

0.1%–<1%

– urinary frequency, renal failure, proteinuria;

<0.1% –

renal impairment.

Immune System Disorders:

0.1%–<1%

– hypersensitivity (including erythema nodosum).

Endocrine Disorders:

0.1%–<1% –

hypothyroidism;

<0.1% –

hyperthyroidism, thyroiditis.

and

8.4 Pediatric Use

Ph+ CML in Chronic Phase

The safety and effectiveness of SPRYCEL monotherapy have been demonstrated in pediatric patients with newly diagnosed chronic phase CML

[see Clinical Studies (14.3)]

. There are no data in children under 1 year of age. Adverse reactions associated with bone growth and development were reported in 5 (5.2%) of patients

[see Warnings and Precautions (5.10)]

Ph+ ALL

The safety and effectiveness of SPRYCEL in combination with chemotherapy have been demonstrated in pediatric patients one year and over with newly diagnosed Ph+ ALL. Use of SPRYCEL in pediatric patients is supported by evidence from one pediatric study. There are no data in children under 1 year of age. One case of grade 1 osteopenia was reported.

The safety profile of SPRYCEL in pediatric subjects was comparable to that reported in studies in adult subjects

[see Adverse Reactions (6.1)and Clinical Studies (14.3, 14.4)]

Monitor bone growth and development in pediatric patients

[see Warnings and Precautions (5.10)]

Pediatric Patients with Difficulty Swallowing Tablets

Five patients with Ph+ ALL 2 to 10 years of age received at least one dose of SPRYCEL tablet dispersed in juice on Study CA180372. The exposure for dispersed tablets was 36% lower as compared to intact tablets in pediatric patients

[see Clinical Pharmacology (12.3)]

. Due to the limited available clinical data, it is unclear whether dispersing SPRYCEL tablets significantly alters the safety and/or efficacy of SPRYCEL.

]

. Of these 5 cases, 1 case of osteopenia and 1 case of gynecomastia resolved during treatment.

Sprycel

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