SPRYCEL (Page 2 of 9)

5.3 Fluid Retention

SPRYCEL is associated with fluid retention. In clinical trials, severe fluid retention was reported in up to 10% of patients. Ascites and generalized edema were each reported in <1% of patients. Severe pulmonary edema was 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 with CML treated with SPRYCEL in clinical studies, 15 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 5.8% 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 anytime 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 Use in Pregnancy

SPRYCEL may cause fetal harm when administered to a pregnant woman. In nonclinical studies, at plasma concentrations below those observed in humans receiving therapeutic doses of dasatinib, embryo-fetal toxicities, including skeletal malformations, were observed in rats and rabbits. There are no adequate and well-controlled studies of SPRYCEL in pregnant women. Women of childbearing potential should be advised to avoid becoming pregnant while receiving treatment with SPRYCEL [see Use in Specific Populations (8.1)].

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, the median duration of therapy was 18 months; the median average daily dose was 99 mg.

In the imatinib resistant or intolerant CML or Ph+ ALL clinical trials, patients had a minimum of 2 years 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 24 months (range 1–33 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. Among patients with resistance or intolerance to prior imatinib therapy, the rates of discontinuation for adverse reaction were 15% in chronic phase CML, 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 study in patients with resistance or intolerance to prior imatinib therapy and chronic phase CML, the rate of discontinuation for adverse reaction was lower in patients treated with 100 mg once daily than in patients treated with other dosing regimens (10% and 16%, respectively).

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, and rash. Pleural effusions were reported in 31 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 (2%), hemorrhage (2%), congestive heart failure (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 Table 3 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
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 23 43 1 1
Pleural effusion 12 0 <1 0
Superficial localized edema 10 36 0 <1
Generalized edema 3 7 0 0
Congestive heart failure/ cardiac dysfunctiona 2 1 <1 <1
Pericardial effusion 2 <1 <1 0
Pulmonary hypertension 1 0 0 0
Pulmonary edema <1 0 0 0
Diarrhea 18 19 <1 1
Headache 12 10 0 0
Musculoskeletal pain 12 16 0 <1
Rashb 11 17 0 1
Nausea 9 21 0 0
Fatigue 8 11 <1 0
Myalgia 6 12 0 0
Hemorrhagec 6 5 1 1
Gastrointestinal bleeding 2 <1 1 0
Other bleedingd 5 5 0 1
CNS bleeding 0 <1 0 <1
Vomiting 5 10 0 0
Muscle inflammation 4 19 0 <1
Table 3: Adverse Reactions Reported in ≥10% of Patients with CML Resistant or Intolerant to Prior Imatinib Therapy
100 mg Once Daily 140 mg Once Daily
Chronic(n=165) 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 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 34 4 35 8 34 7 21 6
Superficial localized edema 18 0 18 1 14 0 3 0
Pleural effusion 18 2 21 7 20 7 21 6
Generalized edema 3 0 1 0 3 0 0 0
Pericardial effusion 2 1 3 1 0 0 0 0
Congestive heart failure/ cardiac dysfunctiona 0 0 0 0 4 0 0 0
Pulmonary edema 0 0 1 0 4 3 0 0
Headache 33 1 27 1 18 1 15 3
Diarrhea 27 2 31 3 20 5 18 0
Fatigue 24 2 19 2 20 1 9 3
Dyspnea 20 2 20 3 15 3 3 3
Musculoskeletal pain 19 2 11 0 8 1 0 0
Nausea 18 1 19 1 23 1 21 3
Skin rashb 17 2 15 0 16 1 21 0
Myalgia 13 0 7 1 7 1 3 0
Arthralgia 12 1 10 0 5 1 0 0
Infection (including bacterial, viral, fungal, and non-specified) 12 1 10 6 14 7 9 0
Abdominal pain 12 1 6 0 8 3 3 0
Hemorrhage 11 1 26 8 19 9 24 9
Gastrointestinal bleeding 2 1 8 6 9 7 9 3
CNS bleeding 0 0 1 1 0 0 3 3
Vomiting 7 1 11 1 12 0 15 0
Pyrexia 5 1 11 2 18 3 6 0
Febrile neutropenia 1 1 4 4 12 12 12 12

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