SPRYCEL SIDE EFFECTS

SIDE EFFECTS

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

• Myelosuppression.
• Bleeding-related events.
• Fluid retention.
• Cardiovascular events.
• Pulmonary arterial hypertension.
• QT prolongation.
• Severe dermatologic reactions.
• Tumor lysis syndrome.
• Effects on growth and development in pediatric patients.

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 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 1.

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 3.

Adverse reactions reported in ≥10% of pediatric patients at a median follow-up of approximately 51.1 months are presented in Table 6.

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 1 for newly diagnosed patients with chronic phase CML and Tables 3 and 6 for CML patients with resistance or intolerance to prior imatinib therapy.

Table 1: Adverse Reactions Reported in ≥10% of Adult Patients with Newly Diagnosed Chronic Phase CML (minimum of 60 months follow-up)

Adverse Reaction	All Grades		Grade 3/4
	SPRYCEL (n=258)	Imatinib (n=258)	SPRYCEL (n=258)	Imatinib (n=258)
	Percent (%) of Patients
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 Includes cardiac failure acute, cardiac failure congestive, cardiomyopathy, diastolic dysfunction, ejection fraction decreased, and left ventricular dysfunction. b Includes erythema, erythema multiforme, rash, rash generalized, rash macular, rash papular, rash pustular, skin exfoliation, and rash vesicular. c Adverse reaction of special interest with <10% frequency. d Includes conjunctival hemorrhage, ear hemorrhage, ecchymosis, epistaxis, eye hemorrhage, gingival bleeding, hematoma, hematuria, hemoptysis, intra-abdominal hematoma, petechiae, scleral hemorrhage, uterine hemorrhage, and vaginal hemorrhage.

 

A comparison of cumulative rates of adverse reactions reported in ≥10% of patients with minimum follow-up of 1 and 5 years in a randomized trial of newly diagnosed patients with chronic phase CML treated with SPRYCEL are shown in Table 2.

Table 2: Adverse Reactions Reported in ≥10% of Adult Patients with Newly Diagnosed Chronic Phase CML in the SPRYCEL-Treated Arm (n=258)

Adverse Reaction	Minimum of 1 Year Follow-up		Minimum of 5 Years Follow-up
	All Grades	Grade 3/4	All Grades	Grade 3/4
	Percent (%) of Patients
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
a Includes cardiac failure acute, cardiac failure congestive, cardiomyopathy, diastolic dysfunction, ejection fraction decreased, and left ventricular dysfunction. b Includes erythema, erythema multiforme, rash, rash generalized, rash macular, rash papular, rash pustular, skin exfoliation, and rash vesicular.

 

At 60 months, there were 26 deaths in dasatinib-treated patients (10.1%) and 26 deaths in imatinib-treated patients (10.1%); 1 death in each group was assessed by the investigator as related to study therapy.

Table 3: 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)

Adverse Reaction	100 mg Once Daily Chronic (n=165)
	All Grades	Grade 3/4
	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 rasha	18	2
Myalgia	13	0
Arthralgia	13	1
Infection (including bacterial, viral,	13	1
fungal, and non-specified)
Abdominal pain	12	1
Hemorrhage	12	1
Gastrointestinal bleeding	2	1
Pruritus	12	1
Pain	11	1
Constipation	10	1
a Includes drug eruption, erythema, erythema multiforme, erythrosis, exfoliative rash, generalized erythema, genital rash, heat rash, milia, rash, rash erythematous, rash follicular, rash generalized, rash macular, rash maculopapular, rash papular, rash pruritic, rash pustular, skin exfoliation, skin irritation, urticaria vesiculosa, and rash vesicular.

 

Cumulative rates of selected adverse reactions that were reported over time in patients treated with the 100 mg once daily recommended starting dose in a randomized dose-optimization trial of imatinib-resistant or -intolerant patients with chronic phase CML are shown in Table 4.

Table 4: Selected Adverse Reactions Reported in Adult Dose Optimization Trial (Imatinib-Intolerant or -Resistant Chronic Phase CML)^a

Adverse Reaction	Minimum of 2 Years Follow-up		Minimum of 5 Years Follow-up		Minimum of 7 Years Follow-up
	All Grades Grade 3/4		All Grades Grade 3/4		All Grades	Grade 3/4
	Percent (%) of Patients
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
a Randomized dose-optimization trial results reported in the recommended starting dose of 100 mg once daily (n=165) population.

 

Table 5: Adverse Reactions Reported in ≥10% of Adult Patients with Advanced Phase CML Resistant or Intolerant to Prior Imatinib Therapy

Adverse Reaction	140 mg Once Daily
	Accelerated (n=157)		Myeloid Blast (n=74)		Lymphoid Blast (n=33)
	All Grades	Grade 3/4	All Grades	Grade 3/4	All Grades	Grade 3/4
	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 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
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.

 

Table 6: Adverse Reactions Reported in ≥10% of Dasatinib-Treated Pediatric Patients (n=97)

Adverse Reaction	All Grades	Grade 3/4
	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

 

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 adult patients with newly diagnosed chronic phase CML and 5% of adult patients with resistance or intolerance to prior imatinib therapy.

Grade 3 or 4 elevations of transaminases or bilirubin and Grade 3 or 4 hypocalcemia, hypokalemia, and hypophosphatemia were reported in patients with all phases of CML but were reported with an increased frequency in patients with myeloid or lymphoid blast phase CML. Elevations in transaminases or bilirubin were usually managed with dose reduction or interruption. Patients developing Grade 3 or 4 hypocalcemia during 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 7. There were no discontinuations of SPRYCEL therapy in this patient population due to biochemical laboratory parameters.

Table 7: CTC Grade ¾ 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
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
CTC grades: neutropenia (Grade 3 ≥0.5 – <1.0 x 109/L, Grade 4 <0.5 x 109/L); thrombocytopenia (Grade 3 ≥25 – <50 x 109/L, Grade 4 <25 x 109/L); anemia (hemoglobin Grade 3 ≥65 – <80 g/L, Grade 4 <65 g/L); elevated creatinine (Grade 3 >3 – 6 x upper limit of normal range (ULN), Grade 4 >6 x ULN); elevated bilirubin (Grade 3 >3 – 10 x ULN, Grade 4 >10 x ULN); elevated SGOT or SGPT (Grade 3 >5 – 20 x ULN, Grade 4 >20 x 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).

 

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 in Adults: Resistance or Intolerance to Prior Imatinib Therapy

	Chronic Phase CML 100 mg Once Daily (n=165)	Advanced Phase CML 140 mg Once Daily
		Accelerated Phase (n=157)	Myeloid Blast Phase (n=74)	Lymphoid Blast Phase (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
CTC grades: neutropenia (Grade 3 ≥0.5 – <1.0 x 109/L, Grade 4 <0.5 x 109/L); thrombocytopenia (Grade 3 ≥25 – <50 x 109/L, Grade 4 <25 x 109/L); anemia (hemoglobin Grade 3 ≥65 – <80 g/L, Grade 4 <65 g/L); elevated creatinine (Grade 3 >3 – 6 x upper limit of normal range (ULN), Grade 4 >6 x ULN); elevated bilirubin (Grade 3 >3 – 10 x ULN, Grade 4 >10 x ULN); elevated SGOT or SGPT (Grade 3 >5 – 20 x ULN, Grade 4 >20 x 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.

 

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, 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 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%).

Additional Pooled Data From Clinical Trials

The following additional adverse reactions were reported in adult and pediatric patients (n=2809) in SPRYCEL CML and 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.

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.

Infections: hepatitis B virus reactivation

Cardiac disorders: atrial fibrillation/atrial flutter

Respiratory, thoracic, and mediastinal disorders: interstitial lung disease

Skin and subcutaneous tissue disorders: Stevens-Johnson syndrome

Renal and urinary disorders: nephrotic syndrome

Blood and lymphatic system disorders: thrombotic microangiopathy