Dasatinib

Uses and Indications

Dasatinib is indicated for the treatment of the following conditions:

Chronic Myeloid Leukemia (CML)

• Newly diagnosed adults with Philadelphia chromosome-positive (Ph+) CML in chronic phase.

• Adults with chronic, accelerated, or myeloid or lymphoid blast phase Ph+ CML who have resistance or intolerance to prior therapy, including imatinib.

• Pediatric patients 1 year of age and older with Ph+ CML in chronic phase.

Acute Lymphoblastic Leukemia (ALL)

• Adults with Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL) who have resistance or intolerance to prior therapy.

• Pediatric patients 1 year of age and older with newly diagnosed Ph+ ALL in combination with chemotherapy.

Limitations of Use

• No specific teratogenic or nonteratogenic effects are mentioned in the provided text.

Dosage and Administration

Dasatinib is indicated for the treatment of chronic phase chronic myeloid leukemia (CML) and acute lymphoblastic leukemia (ALL) in both adults and pediatric patients.

For adults with chronic phase CML, the recommended dosage is 100 mg administered orally once daily. In cases of accelerated phase CML, myeloid or lymphoid blast phase CML, or Philadelphia chromosome-positive (Ph+) ALL, the recommended dosage is 140 mg administered orally once daily.

In pediatric patients with chronic phase CML and ALL, the starting dose should be determined based on body weight.

Dasatinib may be taken with or without food. It is important to note that the tablets should not be crushed, cut, or chewed prior to administration.

Contraindications

There are no contraindications for the use of Dasatinib in any patient population.

Warnings and Precautions

Severe thrombocytopenia, neutropenia, and anemia may occur with dasatinib. Caution is advised when used concomitantly with medications that inhibit platelet function or anticoagulants. Regular monitoring of complete blood counts is essential, and transfusions or interruptions of dasatinib should be considered when indicated.

Fluid Retention

Fluid retention, which can be severe and include pleural effusions, has been reported. Management may require supportive care measures and/or dose modification.

Cardiovascular Toxicity

Patients should be monitored for signs or symptoms of cardiovascular toxicity, and appropriate treatment should be administered as necessary.

Pulmonary Arterial Hypertension (PAH)

Dasatinib may increase the risk of developing PAH, which may be reversible upon discontinuation. Baseline risk should be considered, and patients should be evaluated for signs and symptoms of PAH during treatment. Dasatinib should be stopped if PAH is confirmed.

QT Prolongation

Caution is advised when using dasatinib in patients who have or may develop prolongation of the QT interval.

Severe Dermatologic Reactions

Individual cases of severe mucocutaneous dermatologic reactions have been reported.

Tumor Lysis Syndrome

Tumor lysis syndrome has been reported. Adequate hydration and correction of uric acid levels should be maintained prior to initiating therapy with dasatinib.

Embryo-Fetal Toxicity

Dasatinib can cause fetal harm. Patients of reproductive potential should be advised of the potential risk to the fetus and should use effective contraception.

Effects on Growth and Development in Pediatric Patients

Reports indicate delayed fusion of epiphyses, osteopenia, growth retardation, and gynecomastia in pediatric patients. Monitoring of bone growth and development is recommended.

Hepatotoxicity

Liver function should be assessed before the initiation of treatment and monitored monthly thereafter or as clinically indicated. Special attention is required when dasatinib is combined with chemotherapy known to be associated with liver dysfunction.

General Precautions

• Regular monitoring of complete blood counts is essential.

• Fluid retention should be managed with supportive care measures and/or dose modification.

• Patients should be evaluated for signs and symptoms of cardiovascular toxicity and PAH during treatment.

• Liver function should be monitored when dasatinib is combined with chemotherapy known to be associated with liver dysfunction.

Laboratory Tests

• Complete blood counts should be monitored regularly.

• Liver function should be assessed before initiation of treatment and monthly thereafter or as clinically indicated.

Emergency Medical Help

Patients should seek emergency medical help if PAH is confirmed, and dasatinib should be discontinued in such cases.

Side Effects

Patients receiving dasatinib may experience a range of adverse reactions, which can be categorized by frequency and seriousness.

Most Common Adverse Reactions

In clinical studies, the following adverse reactions were reported in ≥15% of patients receiving dasatinib as single-agent therapy:

• Myelosuppression

• Fluid retention events

• Diarrhea

• Headache

• Skin rash

• Hemorrhage

• Dyspnea

• Fatigue

• Nausea

• Musculoskeletal pain

In pediatric patients receiving dasatinib in combination with chemotherapy, the following adverse reactions were reported in ≥30% of patients:

• Mucositis

• Febrile neutropenia

• Pyrexia

• Diarrhea

• Nausea

• Vomiting

• Musculoskeletal pain

• Abdominal pain

• Cough

• Headache

• Rash

• Fatigue

• Constipation

• Arrhythmia

• Hypertension

• Edema

• Infections (bacterial, viral, and fungal)

• Hypotension

• Decreased appetite

• Hypersensitivity

• Dyspnea

• Epistaxis

• Peripheral neuropathy

• Altered state of consciousness

Serious Adverse Reactions

Myelosuppression and Bleeding Events

Severe thrombocytopenia, neutropenia, and anemia may occur. Caution is advised when dasatinib is used concomitantly with medications that inhibit platelet function or anticoagulants. Regular monitoring of complete blood counts is recommended, and transfusions or interruption of dasatinib may be necessary.

Fluid Retention

Fluid retention, which can be severe and include pleural effusions, has been reported. Management may require supportive care measures and/or dose modification.

Cardiovascular Toxicity

Patients should be monitored for signs or symptoms of cardiovascular toxicity and treated appropriately.

Pulmonary Arterial Hypertension (PAH)

Dasatinib may increase the risk of developing PAH, which may be reversible upon discontinuation. Baseline risk should be considered, and patients should be evaluated for signs and symptoms of PAH during treatment. Dasatinib should be discontinued if PAH is confirmed.

QT Prolongation

Caution is advised when using dasatinib in patients who have or may develop prolongation of the QT interval.

Severe Dermatologic Reactions

Individual cases of severe mucocutaneous dermatologic reactions have been reported.

Tumor Lysis Syndrome

Tumor lysis syndrome has been reported. Adequate hydration and correction of uric acid levels should be maintained prior to initiating therapy with dasatinib.

Embryo-Fetal Toxicity

Dasatinib can cause fetal harm. Patients of reproductive potential should be advised of the potential risk to the fetus and the need to use effective contraception.

Effects on Growth and Development in Pediatric Patients

Adverse effects on growth and development, including delayed fusion of epiphyses, osteopenia, growth retardation, and gynecomastia, have been reported. Monitoring of bone growth and development in pediatric patients is recommended.

Hepatotoxicity

Liver function should be assessed before initiation of treatment and monitored monthly thereafter or as clinically indicated, especially when dasatinib is combined with chemotherapy known to be associated with liver dysfunction.

Geriatric Use

Patients aged 65 years and older are more likely to experience commonly reported adverse reactions such as fatigue, pleural effusion, diarrhea, dyspnea, cough, lower gastrointestinal hemorrhage, and appetite disturbance. They are also more likely to experience less frequently reported adverse reactions, including abdominal distention, dizziness, pericardial effusion, congestive heart failure, hypertension, pulmonary edema, and weight decrease, and should be monitored closely.

Drug Interactions

Dasatinib, available in tablet and film-coated forms, exhibits significant interactions primarily through the CYP3A4 enzyme pathway.

Pharmacokinetic Interactions

• Strong CYP3A4 Inhibitors: Co-administration with strong CYP3A4 inhibitors may necessitate a reduction in the dose of Dasatinib to mitigate the risk of increased drug exposure and potential toxicity.

• Strong CYP3A4 Inducers: Conversely, the presence of strong CYP3A4 inducers may require an increase in the Dasatinib dose to achieve therapeutic efficacy, as these inducers can lower the plasma concentration of the drug.

Pharmacodynamic Interactions

• Antacids: The use of antacids should be avoided during the administration of Dasatinib, as they may interfere with the absorption of the drug, potentially leading to suboptimal therapeutic levels.

• H2 Antagonists and Proton Pump Inhibitors: Co-administration of H2 antagonists and proton pump inhibitors is also discouraged, as these medications can alter gastric pH and affect the absorption of Dasatinib.

In summary, careful consideration of these interactions is essential for optimizing the therapeutic regimen involving Dasatinib, ensuring both efficacy and safety for the patient.

Pediatric Use

The safety and effectiveness of dasatinib monotherapy have been demonstrated in pediatric patients with newly diagnosed chronic phase chronic myeloid leukemia (CML). There are no data available for children under 1 year of age. Adverse reactions associated with bone growth and development were reported in 5 (5.2%) of patients.

In pediatric patients aged 1 year and older, the safety and effectiveness of dasatinib in combination with chemotherapy have been established for newly diagnosed Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL). One case of grade 1 osteopenia was reported in this population. The safety profile of dasatinib in pediatric subjects was comparable to that reported in adult studies.

Monitoring of bone growth and development in pediatric patients is recommended. In a study involving five patients with Ph+ ALL aged 2 to 10 years, dasatinib tablets were administered dispersed in juice, resulting in a 36% lower exposure compared to intact tablets. Due to limited clinical data, it remains unclear whether dispersing dasatinib tablets significantly alters their safety and/or efficacy.

Geriatric Use

In clinical studies of dasatinib, 23% of the 2,712 patients were aged 65 years and older, with 5% aged 75 years and older. No significant differences in confirmed Complete Cytogenetic Response (cCCyR) and Major Molecular Response (MMR) were observed between geriatric and younger patients. However, patients aged 65 years and older are more likely to experience commonly reported adverse reactions, including fatigue, pleural effusion, diarrhea, dyspnea, cough, lower gastrointestinal hemorrhage, and appetite disturbance.

Additionally, this age group may also experience less frequently reported adverse reactions such as abdominal distention, dizziness, pericardial effusion, congestive heart failure, hypertension, pulmonary edema, and weight decrease. Due to the increased likelihood of these adverse reactions, patients aged 65 years and older should be monitored closely during treatment with dasatinib.

Pregnancy

Based on limited human data, dasatinib can cause fetal harm when administered to pregnant patients. Adverse pharmacologic effects, including hydrops fetalis, fetal leukopenia, and fetal thrombocytopenia, have been reported with maternal exposure to dasatinib. Animal reproduction studies in rats have demonstrated extensive mortality during organogenesis, the fetal period, and in neonates. Skeletal malformations were observed in a limited number of surviving rat and rabbit conceptuses, occurring at dasatinib plasma concentrations below those in humans receiving therapeutic doses.

The estimated background risk in the U.S. general population for major birth defects is 2% to 4%, and for miscarriage, it is 15% to 20% of clinically recognized pregnancies. Transplacental transfer of dasatinib has been reported, with dasatinib measured in fetal plasma and amniotic fluid at concentrations comparable to those in maternal plasma. The adverse pharmacologic effects on the fetus are similar to those observed in adult patients and may result in fetal harm or neonatal death.

Based on human experience, dasatinib is suspected to cause congenital malformations, including neural tube defects, and harmful pharmacological effects on the fetus when administered during pregnancy. In nonclinical studies, embryo-fetal toxicities were observed in rats and rabbits at plasma concentrations below those seen in humans receiving therapeutic doses. Fetal death was noted in rats, and the lowest doses tested resulted in embryo-fetal toxicities, producing maternal AUCs of 105 ng•h/mL and 44 ng•h/mL (0.1-fold the human AUC) in rats and rabbits, respectively.

Embryo-fetal toxicities included skeletal malformations at multiple sites (scapula, humerus, femur, radius, ribs, and clavicle), reduced ossification, edema, and microhepatia. In a pre- and postnatal development study in rats, administration of dasatinib from gestation day 16 through lactation day 20, gestation day 21 through lactation day 20, or lactation day 4 through lactation day 20 resulted in extensive pup mortality at maternal exposures that were below those in patients treated with dasatinib at the recommended labeling dose.

Healthcare providers are advised to inform pregnant patients of the potential risks to the fetus associated with dasatinib use.

Lactation

Dasatinib is not recommended for use during breastfeeding due to the potential for serious adverse reactions in nursing infants. Although there are no data available regarding the presence of dasatinib in human milk or its effects on breastfed children, studies in lactating rats have shown that dasatinib is present in their milk.

In animal studies, administration of dasatinib during the late stages of gestation and throughout lactation resulted in extensive pup mortality at maternal exposure levels lower than those seen in patients receiving the recommended dose. Given these findings, healthcare professionals should advise lactating mothers to avoid breastfeeding during treatment with dasatinib and for at least 2 weeks after the last dose.

Additionally, dasatinib is suspected to cause congenital malformations, including neural tube defects, when administered during pregnancy, further emphasizing the need for caution in reproductive health.

Renal Impairment

Patients with renal impairment have not been specifically addressed in the available data for Dasatinib. The information provided across multiple labels indicates that there are no dosage adjustments, special monitoring requirements, or safety considerations outlined for individuals with reduced kidney function. Consequently, healthcare professionals should exercise caution and consider the lack of specific guidance when prescribing Dasatinib to patients with renal impairment. Regular monitoring of renal function may be prudent in these cases, although no explicit recommendations are provided in the current labeling.

Hepatic Impairment

Patients with hepatic impairment should have their liver function assessed before the initiation of treatment with Dasatinib and monitored monthly thereafter, or as clinically indicated. It is essential to monitor liver function when Dasatinib is combined with chemotherapy known to be associated with liver dysfunction due to the potential for hepatotoxicity.

Overdosage

Experience with overdose of dasatinib is limited to isolated cases. The highest reported overdosage was 280 mg per day for 1 week, which resulted in severe myelosuppression and bleeding in two patients.

Patients who ingest more than the recommended dosage should be monitored closely for signs of myelosuppression, and appropriate supportive treatment should be provided.

Acute overdose in animal studies has been associated with cardiotoxicity, evidenced by ventricular necrosis and hemorrhage at single doses of ≥100 mg/kg. Additionally, there was a tendency for increased systolic and diastolic blood pressure observed in monkeys at single doses of ≥10 mg/kg.

Healthcare professionals should remain vigilant for these potential symptoms and manage them accordingly.

Nonclinical Toxicology

Teratogenic Effects

No information regarding teratogenic effects has been provided.

Non-Teratogenic Effects

Dasatinib did not affect mating or fertility in male and female rats at plasma drug exposure (AUC) levels similar to those observed in humans at a daily dose of 100 mg. In repeat-dose studies, administration of dasatinib resulted in reduced size and secretion of seminal vesicles, as well as immature prostate, seminal vesicle, and testis. Additionally, dasatinib administration led to uterine inflammation and mineralization in monkeys, along with cystic ovaries and ovarian hypertrophy in rodents.

Carcinogenesis, Mutagenesis, Impairment of Fertility

In a 2-year carcinogenicity study, rats were administered oral doses of dasatinib at 0.3, 1, and 3 mg/kg/day. The highest dose resulted in a plasma drug exposure (AUC) level approximately 60% of the human exposure at 100 mg once daily. Dasatinib induced a statistically significant increase in the combined incidence of squamous cell carcinomas and papillomas in the uterus and cervix of high-dose females, as well as prostate adenoma in low-dose males.

Dasatinib was found to be clastogenic when tested in vitro in Chinese hamster ovary cells, both with and without metabolic activation. However, it was not mutagenic when assessed in an in vitro bacterial cell assay (Ames test) and was not genotoxic in an in vivo rat micronucleus study.

Animal Pharmacology and Toxicology

No specific information regarding animal pharmacology and toxicology has been provided.

Storage and Handling

Dasatinib is supplied in tablet form, including film-coated options. The tablets should be stored at a temperature range of 20°C to 25°C (68°F to 77°F), with permissible excursions between 15°C and 30°C (59°F and 86°F) in accordance with USP Controlled Room Temperature guidelines. The packaging is designed to be child-resistant and should be dispensed in a tight container.

Special handling and disposal procedures must be followed, as Dasatinib is classified as an antineoplastic product. Personnel who are pregnant should avoid exposure to crushed or broken tablets. To minimize the risk of dermal exposure, the use of latex or nitrile gloves is recommended when handling tablets that are inadvertently crushed or broken.