Dasatinib

Dasatinib
Adult Indications & Dosage
Pediatric Indications & Dosage
Contraindications
Warnings & Precautions
Adverse Reactions
Drug Interactions
Use in Specific Populations
Administration & Monitoring
Overdosage
Pharmacology
Clinical Studies
How Supplied
Images
Patient Counseling Information
Precautions with Alcohol
Brand Names
Look-Alike Names

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Kiran Singh, M.D. [2]

Disclaimer

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Overview

Dasatinib is a tyrosine kinase inhibitor that is FDA approved for the {{{indicationType}}} of Philadelphia chromosome-positive chronic myeloid leukemia or acute lymphoblastic leukemia. Common adverse reactions include myelosuppression, fluid retention, diarrhea, headache, dyspnea, rash, fatigue, nausea, and hemorrhage.

Adult Indications and Dosage

FDA-Labeled Indications and Dosage (Adult)

Chronic Myeloid Leukemia or Acute Lymphoblastic Leukemia

• Dosing Information

• 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.

Off-Label Use and Dosage (Adult)

Guideline-Supported Use

There is limited information regarding Off-Label Guideline-Supported Use of Dasatinib in adult patients.

Non–Guideline-Supported Use

There is limited information regarding Off-Label Non–Guideline-Supported Use of Dasatinib in adult patients.

Pediatric Indications and Dosage

FDA-Labeled Indications and Dosage (Pediatric)

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

Off-Label Use and Dosage (Pediatric)

Guideline-Supported Use

There is limited information regarding Off-Label Guideline-Supported Use of Dasatinib in pediatric patients.

Non–Guideline-Supported Use

There is limited information regarding Off-Label Non–Guideline-Supported Use of Dasatinib in pediatric patients.

Contraindications

• None

Warnings

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.

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.

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.

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.

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.

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.

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.
• Advise females of reproductive potential to avoid pregnancy, which may include the use of contraception, during treatment with SPRYCEL.

Adverse Reactions

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 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%).

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.

This image is provided by the National Library of Medicine.

• 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.

This image is provided by the National Library of Medicine.

• With a minimum follow up of 60 months (see Table 3), the cumulative rates of the majority of adverse reactions (all grades) in patients with chronic phase CML treated with a starting dose of 100 mg once daily were identical with a minimum follow up of 24 and 60 months including congestive heart failure/cardiac dysfunction, pericardial effusion, pulmonary edema, and gastrointestinal bleeding or similar for diarrhea (27% vs 28%), and generalized edema (3% vs 4%). Cumulative adverse reaction rates (all grades) that increased between 24 months and 60 months minimum follow up included: overall fluid retention (34% vs 42%), pleural effusion (18% vs 24%), and superficial edema (18% vs 21%). The cumulative rate of Grade 3 or 4 pleural effusion was 2% versus 4%, respectively.

This image is provided by the National Library of Medicine.

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 5 and 6). 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 with newly diagnosed chronic phase CML and 5% of patients with resistance or intolerance to prior imatinib therapy.
• Grade 3 or 4 elevations of transaminase 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 transaminase 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 5. There were no discontinuations of SPRYCEL therapy in this patient population due to biochemical laboratory parameters.

This image is provided by the National Library of Medicine.

• 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 6.

This image is provided by the National Library of Medicine.

• 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%).

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. The most frequently reported serious adverse reactions included pleural effusion (11%), gastrointestinal bleeding (7%), febrile neutropenia (6%), infection (5%), pyrexia (4%), pneumonia (3%), diarrhea (3%), nausea (2%), vomiting (2%), and colitis (2%).

Additional Data From Clinical Trials

• The following adverse reactions were reported in patients in the SPRYCEL 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.

Body as a Whole

Cardiovascular

Digestive

Endocrine

Hematologic and Lymphatic

Metabolic and Nutritional

Musculoskeletal

Neurologic

Respiratory

Skin and Hypersensitivy Reactions

Special Senses

Urogenital

Miscellaneous

Postmarketing Experience

There is limited information regarding Postmarketing Experience of Dasatinib in the drug label.

Body as a Whole

Cardiovascular

Digestive

Endocrine

Hematologic and Lymphatic

Metabolic and Nutritional

Musculoskeletal

Neurologic

Respiratory

Skin and Hypersensitivy Reactions

Special Senses

Urogenital

Miscellaneous

Drug Interactions

• Drug

• Description

Use in Specific Populations

Pregnancy

Pregnancy Category (FDA):

• Pregnancy Category

Pregnancy Category (AUS):

• Australian Drug Evaluation Committee (ADEC) Pregnancy Category

There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Dasatinib in women who are pregnant.

Labor and Delivery

There is no FDA guidance on use of Dasatinib during labor and delivery.

Nursing Mothers

There is no FDA guidance on the use of Dasatinib with respect to nursing mothers.

Pediatric Use

There is no FDA guidance on the use of Dasatinib with respect to pediatric patients.

Geriatic Use

There is no FDA guidance on the use of Dasatinib with respect to geriatric patients.

Gender

There is no FDA guidance on the use of Dasatinib with respect to specific gender populations.

Race

There is no FDA guidance on the use of Dasatinib with respect to specific racial populations.

Renal Impairment

There is no FDA guidance on the use of Dasatinib in patients with renal impairment.

Hepatic Impairment

There is no FDA guidance on the use of Dasatinib in patients with hepatic impairment.

Females of Reproductive Potential and Males

There is no FDA guidance on the use of Dasatinib in women of reproductive potentials and males.

Immunocompromised Patients

There is no FDA guidance one the use of Dasatinib in patients who are immunocompromised.

Administration and Monitoring

Administration

• Oral

• Intravenous

Monitoring

There is limited information regarding Monitoring of Dasatinib in the drug label.

• Description

IV Compatibility

There is limited information regarding IV Compatibility of Dasatinib in the drug label.

Overdosage

Acute Overdose

Signs and Symptoms

• Description

Management

• Description

Chronic Overdose

There is limited information regarding Chronic Overdose of Dasatinib in the drug label.

Pharmacology

There is limited information regarding Dasatinib Pharmacology in the drug label.

Mechanism of Action

Structure

This image is provided by the National Library of Medicine.

Pharmacodynamics

There is limited information regarding Pharmacodynamics of Dasatinib in the drug label.

Pharmacokinetics

There is limited information regarding Pharmacokinetics of Dasatinib in the drug label.

Nonclinical Toxicology

There is limited information regarding Nonclinical Toxicology of Dasatinib in the drug label.

Clinical Studies

There is limited information regarding Clinical Studies of Dasatinib in the drug label.

How Supplied

Storage

There is limited information regarding Dasatinib Storage in the drug label.

Images

Drug Images

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Package and Label Display Panel

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Patient Counseling Information

There is limited information regarding Patient Counseling Information of Dasatinib in the drug label.

Precautions with Alcohol

• Alcohol-Dasatinib interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.

Brand Names

• Sprycel®

Look-Alike Drug Names

• A® — B®

Drug Shortage Status

Price

References

The contents of this FDA label are provided by the National Library of Medicine.

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