Dasatinib

Description

Dasatinib tablets are a kinase inhibitor formulated for oral administration. The chemical name for dasatinib is N-(2-chloro-6-methylphenyl)-2-[[6-4-(2-hydroxyethyl)-1-piperazinyl-2-methyl-4-pyrimidinyl]amino]-5-thiazolecarboxamide, monohydrate. The molecular formula is C22H26ClN7O2S • H2O, with a formula weight of 506.02 (monohydrate) and an anhydrous free base molecular weight of 488.01.

Dasatinib appears as a white to off-white powder and is soluble in N,N-dimethylformamide, while being insoluble in acetonitrile. The tablets are white to off-white, biconvex, and film-coated, containing dasatinib along with inactive ingredients that include anhydrous lactose, lactose monohydrate, microcrystalline cellulose, croscarmellose sodium, hydroxypropyl cellulose, and magnesium stearate. The tablet coating is composed of polyvinyl alcohol, glycerol esters of fatty acids, talc, sodium lauryl sulfate, and titanium dioxide.

Uses and Indications

Dasatinib tablets are indicated for the treatment of the following conditions:

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

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

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

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

• Pediatric patients aged 1 year and older with newly diagnosed Ph+ ALL, to be administered in combination with chemotherapy.

Limitations of use have not been specified in the provided information. There are no specific teratogenic or nonteratogenic effects mentioned.

Dosage and Administration

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

In pediatric patients with chronic phase CML and acute lymphoblastic leukemia (ALL), the starting dose should be determined based on body weight, ensuring appropriate dosing for the individual patient.

The medication should be administered orally, and it can be taken with or without food. It is important to note that the tablets must not be crushed, cut, or chewed to maintain their efficacy and ensure proper absorption.

Contraindications

There are no contraindications associated with the use of this product. It is not classified as a controlled substance, and there are no identified risks of abuse, misuse, or dependence.

Warnings and Precautions

Myelosuppression and bleeding events, including severe thrombocytopenia, neutropenia, and anemia, may occur with the use of dasatinib tablets. Caution is advised when administering dasatinib concomitantly with medications that inhibit platelet function or anticoagulants. Regular monitoring of complete blood counts is essential, and transfusions should be administered as necessary. Treatment with dasatinib should be interrupted when indicated.

Fluid retention, which can be severe and may include pleural effusions, has been observed in patients. Management of fluid retention should involve supportive care measures and/or dose modifications as needed.

Patients should be monitored for signs and symptoms of cardiovascular toxicity, and appropriate treatment should be initiated as necessary. Additionally, dasatinib tablets may increase the risk of developing pulmonary arterial hypertension (PAH), which may be reversible upon discontinuation of the medication. A baseline risk assessment should be conducted, and patients should be evaluated for signs and symptoms of PAH throughout the treatment course. If PAH is confirmed, dasatinib tablets should be discontinued.

QT prolongation is another concern; therefore, dasatinib should be used with caution in patients who have or may develop a prolonged QT interval. Severe dermatologic reactions, including individual cases of mucocutaneous reactions, have been reported and warrant close monitoring.

Tumor lysis syndrome has also been documented in patients receiving dasatinib. It is crucial to maintain adequate hydration and correct uric acid levels prior to initiating therapy with dasatinib tablets.

Embryo-fetal toxicity is a significant risk associated with dasatinib. Patients of reproductive potential should be informed of the potential risk to the fetus and advised to use effective contraception during treatment. In pediatric patients, effects on growth and development, such as delayed epiphyseal fusion, osteopenia, growth retardation, and gynecomastia, have been reported. Monitoring of bone growth and development in this population is recommended.

Hepatotoxicity is another important consideration. Liver function should be assessed prior to the initiation of treatment and monitored monthly thereafter, or as clinically indicated, especially when dasatinib is combined with chemotherapy known to cause liver dysfunction.

Regular monitoring of complete blood counts and liver function tests is essential to ensure patient safety during treatment with dasatinib tablets.

Side Effects

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

Most common adverse reactions occurring in ≥15% of patients receiving dasatinib as single-agent therapy include myelosuppression, fluid retention events, diarrhea, headache, skin rash, hemorrhage, dyspnea, fatigue, nausea, and musculoskeletal pain. In pediatric patients receiving dasatinib in combination with chemotherapy, adverse reactions occurring in ≥30% of participants include 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, and altered state of consciousness.

Serious adverse reactions include severe thrombocytopenia, neutropenia, and anemia, which may necessitate caution when dasatinib is used concomitantly with medications that inhibit platelet function or anticoagulants. Regular monitoring of complete blood counts is recommended, with transfusions and interruption of dasatinib therapy as indicated. Fluid retention, which can be severe and include pleural effusions, should be managed with supportive care measures and/or dose modification.

Patients should be monitored for cardiovascular toxicity, including signs or symptoms of pulmonary arterial hypertension (PAH), which may be reversible upon discontinuation of dasatinib. If PAH is confirmed, dasatinib should be stopped. Caution is advised in patients who have or may develop QT prolongation.

Severe dermatologic reactions, including individual cases of severe mucocutaneous reactions, have been reported. Tumor lysis syndrome has also been noted, necessitating adequate hydration and correction of uric acid levels prior to initiating therapy.

Dasatinib is associated with embryo-fetal toxicity, and patients of reproductive potential should be informed of the potential risk to the fetus and advised to use effective contraception. In pediatric patients, effects on growth and development such as delayed epiphyseal fusion, osteopenia, growth retardation, and gynecomastia have been reported, warranting monitoring of bone growth and development.

Hepatotoxicity is another concern, with liver function assessments recommended before treatment initiation and monthly thereafter, or as clinically indicated, especially when combined with chemotherapy known to affect liver function.

Additionally, 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 at increased risk for 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

Strong CYP3A4 inhibitors may significantly affect the metabolism of the drug, potentially leading to increased plasma concentrations. Therefore, a dose reduction may be necessary when coadministered with these agents to mitigate the risk of adverse effects.

Conversely, strong CYP3A4 inducers can decrease the drug's plasma levels, which may necessitate a dose increase to maintain therapeutic efficacy. Careful monitoring of the patient's response and adjustment of the dosage may be required in such cases.

The concurrent use of antacids is not recommended, as they may interfere with the absorption of the drug. It is advisable to separate the administration of these medications to avoid potential interactions.

Additionally, the coadministration of H2 antagonists and proton pump inhibitors should be avoided due to the potential for reduced effectiveness of the drug. Monitoring for therapeutic outcomes is recommended if these medications are used in close temporal proximity.

Packaging & NDC

The table below lists all NDC Code configurations of Dasatinib, the U.S. brand-name prescription product. Columns show Packaging, Formulation Type, and Active Ingredient Strength.

Pediatric Use

The safety and effectiveness of dasatinib monotherapy have been established in pediatric patients with newly diagnosed chronic phase chronic myeloid leukemia (CML). In children aged one year and older, dasatinib has also demonstrated safety and efficacy when used in combination with chemotherapy for newly diagnosed Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL). However, there are no data available for children under one year of age.

In a pediatric study, five patients aged 2 to 10 years received dasatinib tablets dispersed in juice, which resulted in a 36% lower exposure compared to intact tablets. Due to the limited clinical data, it remains unclear whether this method of administration significantly affects the safety and/or efficacy of dasatinib.

Adverse reactions related to bone growth and development were reported in 5.2% of pediatric patients, including one case of grade 1 osteopenia. The safety profile of dasatinib in pediatric subjects appears comparable to that observed in adult studies. Therefore, it is recommended to monitor bone growth and development in pediatric patients receiving dasatinib.

Geriatric Use

Elderly patients, defined as those 65 years of age and older, comprised 23% of the 2712 patients in clinical studies of dasatinib, with 5% being 75 years of age and older. Clinical findings indicate that there were no significant differences in confirmed Complete Cytogenetic Response (cCCyR) and Major Molecular Response (MMR) between older and younger patients.

Despite the similarity in the overall safety profile of dasatinib between geriatric and younger populations, elderly patients are at an increased risk for several commonly reported adverse reactions. These include fatigue, pleural effusion, diarrhea, dyspnea, cough, lower gastrointestinal hemorrhage, and appetite disturbance. Additionally, they may experience less frequently reported adverse reactions such as abdominal distention, dizziness, pericardial effusion, congestive heart failure, hypertension, pulmonary edema, and weight decrease.

Given these considerations, it is essential that patients aged 65 years and older be monitored closely for these adverse effects. Healthcare providers should remain vigilant in assessing the safety and tolerability of dasatinib in this population, and appropriate dose modifications should be considered based on individual patient response and tolerability.

Pregnancy

Based on limited human data, dasatinib can cause fetal harm when administered to a pregnant woman. Adverse pharmacologic effects, including hydrops fetalis, fetal leukopenia, and fetal thrombocytopenia, have been reported with maternal exposure to dasatinib. Transplacental transfer of dasatinib has been documented, with dasatinib detected in fetal plasma and amniotic fluid at concentrations comparable to those in maternal plasma. These adverse effects on the fetus are similar to those observed in adult patients and may result in fetal harm or neonatal death.

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. 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.

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. The estimated background risk in the U.S. general population of major birth defects is 2% to 4%, and the risk of miscarriage is 15% to 20% of clinically recognized pregnancies. Healthcare providers should advise pregnant women of the potential risks to the fetus associated with dasatinib exposure.

Lactation

Administration of dasatinib during lactation has been associated with extensive pup mortality in a pre- and postnatal development study conducted in rats. This study involved administration of dasatinib from gestation day (GD) 16 through lactation day (LD) 20, GD 21 through LD 20, or LD 4 through LD 20. Notably, the maternal exposures that led to these adverse outcomes were below the exposures observed in patients treated with dasatinib at the recommended labeling dose.

Given these findings, caution is advised when considering the use of dasatinib in lactating mothers, as the potential risks to breastfed infants are not fully understood. Healthcare professionals should weigh the benefits of treatment against the potential risks to the nursing infant.

Renal Impairment

Patients with renal impairment have not been specifically addressed in the available data regarding dosage adjustments, special monitoring, or safety considerations. Therefore, healthcare professionals should exercise caution when prescribing this medication to patients with reduced kidney function, as the lack of information necessitates careful clinical judgment and monitoring.

Hepatic Impairment

Patients with hepatic impairment should undergo a thorough assessment of liver function prior to the initiation of treatment. It is recommended that liver function be monitored on a monthly basis thereafter, or more frequently as clinically indicated.

In cases where this treatment is combined with chemotherapy agents that are known to be associated with liver dysfunction, additional monitoring of liver function is advised to ensure patient safety and to manage any potential adverse effects related to hepatic impairment.

Overdosage

In clinical studies, experience with dasatinib overdose is limited to isolated cases. Notably, the highest reported dosage was 280 mg per day for one week, which resulted in severe myelosuppression and bleeding in two patients. Given the potential for serious adverse effects, it is imperative that healthcare professionals closely monitor patients who exceed the recommended dosage for signs of myelosuppression and provide appropriate supportive treatment as necessary.

In addition to hematological concerns, acute overdose in animal studies has demonstrated a risk of cardiotoxicity. Evidence of such cardiotoxicity includes findings of ventricular necrosis and valvular, ventricular, or atrial hemorrhage at single doses of 100 mg/kg (equivalent to 600 mg/m²) in rodent models. Furthermore, in primate studies, doses of 10 mg/kg (120 mg/m²) were associated with a tendency for increased systolic and diastolic blood pressure.

Healthcare professionals should remain vigilant for these potential complications and manage them accordingly in the event of an overdose.

Nonclinical Toxicology

Dasatinib did not demonstrate teratogenic effects in nonclinical studies. In terms of non-teratogenic effects, dasatinib did not affect mating or fertility in male and female rats at plasma drug exposure levels comparable to those observed in humans receiving a daily dose of 100 mg. However, 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.

In a 2-year carcinogenicity study, rats received oral doses of dasatinib at 0.3, 1, and 3 mg/kg/day. The highest dose resulted in a plasma drug exposure level approximately 60% of that seen in humans at a daily dose of 100 mg. Dasatinib induced a statistically significant increase in the combined incidence of squamous cell carcinomas and papillomas in the uterus and cervix of high-dose female rats, as well as prostate adenoma in low-dose male rats.

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

Postmarketing Experience

Postmarketing experience has identified several adverse reactions associated with the use of the product. These include myelosuppression, serious bleeding, fluid retention, cardiovascular toxicity, pulmonary arterial hypertension, tumor lysis syndrome, and bone growth abnormalities in pediatric patients.

Reports of cardiovascular toxicity encompass cardiac ischemic events, fluid retention related to cardiac issues, conduction abnormalities, and transient ischemic attacks (TIAs). Adverse reactions associated with pulmonary arterial hypertension include dyspnea, fatigue, hypoxia, and fluid retention.

Cases of tumor lysis syndrome have been documented, presenting with symptoms such as nausea, vomiting, weakness, edema, shortness of breath, muscle cramps, and seizures. Additionally, in pediatric patients, reports have indicated bone growth abnormalities, bone pain, and gynecomastia.

Patient Counseling

Healthcare providers should advise patients to read the FDA-approved patient labeling (Patient Information) to ensure they are well-informed about their treatment. It is important to inform patients about the potential risk of developing low blood cell counts and to instruct them to immediately report any fever, especially if accompanied by signs of infection.

Patients should be made aware of the risk of serious bleeding and should be instructed to report any signs or symptoms suggestive of hemorrhage, such as unusual bleeding or easy bruising, without delay. Additionally, healthcare providers should inform patients about the possibility of fluid retention, which may present as swelling, weight gain, dry cough, chest pain upon respiration, or shortness of breath. Patients should be advised to seek medical attention promptly if they experience any of these symptoms.

Healthcare providers should also discuss the risk of cardiovascular toxicity, which may include cardiac ischemic events, cardiac-related fluid retention, conduction abnormalities, and transient ischemic attacks (TIAs). Patients should be instructed to seek immediate medical attention if they experience symptoms suggestive of cardiovascular toxicity, such as chest pain, shortness of breath, palpitations, transient vision problems, or slurred speech.

It is essential to inform patients about the potential development of pulmonary arterial hypertension, characterized by dyspnea, fatigue, hypoxia, and fluid retention. Patients should be advised to seek medical attention promptly if they experience these symptoms.

Patients should be informed to report and seek medical attention immediately for any symptoms such as nausea, vomiting, weakness, edema, shortness of breath, muscle cramps, and seizures, as these may indicate tumor lysis syndrome.

For pediatric patients and their caregivers, it is important to discuss the possibility of developing bone growth abnormalities, bone pain, or gynecomastia, and to advise them to seek medical attention promptly if these symptoms arise.

Healthcare providers should counsel pregnant women about the potential risks to a fetus associated with treatment. Additionally, females of reproductive potential and males with female partners of reproductive potential should be advised to use effective contraception during treatment with dasatinib tablets and for 30 days after the last dose. Females should be instructed to contact their healthcare provider if they become pregnant or suspect they may be pregnant while taking dasatinib tablets.

Storage and Handling

Dasatinib tablets are supplied in a child-resistant package. They 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).

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

Additional Clinical Information

In patients with chronic phase chronic myeloid leukemia (CML), complete blood counts (CBCs) should be performed every 2 weeks for the first 12 weeks, followed by every 3 months or as clinically indicated. For patients with advanced phase CML or Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL), CBCs are recommended weekly for the initial 2 months, transitioning to monthly thereafter, or as clinically indicated. Pediatric patients with Ph+ ALL receiving dasatinib in combination with chemotherapy require CBCs prior to each chemotherapy block and as clinically indicated, with CBCs conducted every 2 days during consolidation chemotherapy until recovery. Additionally, transaminases should be monitored at baseline and monthly or as clinically indicated throughout treatment.

Clinicians should counsel patients, particularly females of reproductive potential and males with female partners of reproductive potential, to utilize effective contraception during dasatinib treatment and for 30 days following the last dose.

FDA Insert (PDF)

This document is the official FDA-approved prescribing information for Dasatinib as submitted by Biocon Pharma Inc.. It includes detailed information about indications, dosage, contraindications, warnings, and clinical pharmacology.

View full prescribing information (PDF)