Dasatinib

Description

Dasatinib tablets are a kinase inhibitor. 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), while the anhydrous free base has a molecular weight of 488.01. Dasatinib appears as a white to off-white powder and is soluble in N,N-dimethylformamide but insoluble in acetonitrile. The tablets are white to off-white, biconvex, film-coated, and contain dasatinib as the active ingredient. Inactive ingredients 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.

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

The medication should be administered orally and can be taken with or without food. It is important to note that the tablets must not be crushed, cut, or chewed prior to administration.

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. Therefore, the product can be used without specific restrictions related to contraindications.

Warnings and Precautions

Severe myelosuppression, including 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 if significant hematologic toxicity is observed.

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

Patients should be closely monitored for signs and symptoms of cardiovascular toxicity, and appropriate treatment should be initiated as required. Additionally, dasatinib tablets have been associated with an increased risk of pulmonary arterial hypertension (PAH). It is crucial to evaluate patients for signs and symptoms of PAH during treatment, considering their baseline risk. If PAH is confirmed, dasatinib therapy must 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 mucocutaneous reactions, have been reported in individual cases and warrant careful observation.

Tumor lysis syndrome has also been documented. To mitigate this risk, it is important to ensure adequate hydration and to correct uric acid levels prior to initiating therapy with dasatinib tablets.

Dasatinib can cause embryo-fetal toxicity, posing a risk of fetal harm. Patients of reproductive potential should be informed of this risk 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 observed. Monitoring of bone growth and development in this population is recommended.

Hepatotoxicity is a potential risk associated with dasatinib. Liver function should be assessed prior to the initiation of treatment and monitored monthly thereafter, or as clinically indicated, especially when dasatinib is used in conjunction with chemotherapy known to affect liver function.

Regular monitoring of complete blood counts and liver function is essential throughout the course of treatment. If PAH is confirmed, dasatinib therapy should be stopped immediately, and emergency medical assistance should be sought.

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 tablets 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 tablets 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.

Severe myelosuppression, including thrombocytopenia, neutropenia, and anemia, may occur. Caution is advised when dasatinib tablets are used concomitantly with medications that inhibit platelet function or anticoagulants, and regular monitoring of complete blood counts is recommended. Transfusion and interruption of dasatinib therapy may be necessary when indicated.

Fluid retention, which can be severe and include pleural effusions, has been reported. Management may require supportive care measures and/or dose modification. Patients should be monitored for signs and symptoms of cardiovascular toxicity, and appropriate treatment should be administered as needed.

Dasatinib tablets may increase the risk of pulmonary arterial hypertension (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. If PAH is confirmed, dasatinib tablets should be discontinued.

QT prolongation is a potential concern; therefore, dasatinib tablets should be used with caution in patients who have or may develop a prolonged QT interval. Individual cases of severe mucocutaneous dermatologic reactions have also been reported.

Tumor lysis syndrome has been observed, necessitating adequate hydration and correction of uric acid levels prior to initiating therapy with dasatinib tablets. Additionally, dasatinib can cause fetal harm; patients of reproductive potential should be advised of this risk and encouraged 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; liver function should be assessed before treatment initiation and monitored monthly thereafter or as clinically indicated, especially when combined with chemotherapy known to affect liver function.

Patients aged 65 years and older are at an increased risk for commonly reported adverse reactions, including fatigue, pleural effusion, diarrhea, dyspnea, cough, lower gastrointestinal hemorrhage, and appetite disturbance. They are also more likely to experience less frequently reported adverse reactions such as abdominal distention, dizziness, pericardial effusion, congestive heart failure, hypertension, pulmonary edema, and weight decrease, necessitating close monitoring.

Drug Interactions

The following drug interactions have been identified, categorized by their pharmacokinetic effects:

CYP3A4 Inhibitors and Inducers

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

• Strong CYP3A4 Inducers: When used in conjunction with strong CYP3A4 inducers, an increase in the dosage of the affected drug may be required to maintain therapeutic efficacy due to enhanced metabolism.

Gastrointestinal Agents

• Antacids: The simultaneous administration of antacids with the affected drug is not recommended, as it may interfere with absorption and reduce the drug's effectiveness.

• H2 Antagonists and Proton Pump Inhibitors: Co-administration of H2 antagonists or proton pump inhibitors should be avoided due to the potential for altered pharmacokinetics, which may lead to decreased therapeutic outcomes.

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 effectiveness 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 was found to be comparable to that observed in adult studies. 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 also 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 the emergence of these adverse reactions. Appropriate dose adjustments and careful management may be necessary to ensure the safety and efficacy of dasatinib in this population.

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 have demonstrated extensive mortality during organogenesis, the fetal period, and in neonates. In these studies, skeletal malformations were observed in a limited number of surviving rat and rabbit conceptuses, occurring at dasatinib plasma concentrations below those seen 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. Fetal death was also observed in rats.

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 below those in patients treated with dasatinib at the recommended labeling dose.

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

Lactation

Dasatinib is suspected to cause congenital malformations, including neural tube defects, and may have harmful pharmacological effects on the fetus when administered during pregnancy. In a pre- and postnatal development study in rats, administration of dasatinib from gestation day (GD) 16 through lactation day (LD) 20, GD 21 through LD 20, or LD 4 through LD 20 resulted in extensive pup mortality at maternal exposures that were below the exposures in patients treated with dasatinib at the recommended labeling dose.

Given these findings, healthcare professionals should exercise caution when considering the use of dasatinib in lactating mothers, as the potential risks to breastfed infants are not fully understood.

Renal Impairment

There is no specific information available regarding dosage adjustments, special monitoring, or safety considerations for patients with renal impairment. Healthcare professionals should exercise caution when prescribing to patients with reduced kidney function, as the absence of detailed guidance necessitates careful clinical judgment. Regular monitoring of renal function may be advisable in this patient population.

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. The highest reported dosage was 280 mg per day for one week, which resulted in severe myelosuppression and bleeding.

Healthcare professionals are advised to closely monitor patients who ingest more than the recommended dosage for signs of myelosuppression. Appropriate supportive treatment should be provided as necessary to manage these complications.

Animal studies have indicated that acute overdose may lead to cardiotoxicity, with significant findings including ventricular necrosis and hemorrhage observed at single doses of 100 mg/kg or greater. Additionally, increased systolic and diastolic blood pressure was noted in monkeys at single doses of 10 mg/kg or higher.

Given these potential risks, it is crucial for healthcare providers to remain vigilant in monitoring and managing any cases of dasatinib overdose.

Nonclinical Toxicology

Dasatinib did not affect mating or fertility in male and female rats at plasma drug exposure (AUC) 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 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 evaluated in an in vitro bacterial cell assay (Ames test) and did not demonstrate genotoxicity in an in vivo rat micronucleus study.

Postmarketing Experience

Dasatinib Tablets have been associated with a range of serious side effects reported through voluntary and surveillance programs.

Low blood cell counts, including anemia, neutropenia, and thrombocytopenia, are common and can be severe. Regular blood tests are recommended to monitor these counts, and patients should contact their healthcare provider immediately if they experience fever or signs of infection.

Bleeding problems, which can be serious and potentially fatal, have also been reported. Patients should seek medical attention for unusual bleeding or bruising, bright red or dark tar-like stools, or neurological symptoms such as decreased alertness, headache, or changes in speech.

Fluid retention is frequently observed and can be severe, potentially leading to complications such as pleural effusion, pericardial effusion, or ascites. Symptoms warranting immediate medical consultation include generalized swelling, significant weight gain, shortness of breath, dry cough, or chest pain during deep breaths.

Cardiovascular issues, including abnormal heart rate, heart attacks, and transient ischemic attacks (TIAs), have been noted. Monitoring of potassium and magnesium levels, as well as heart function, is advised. Patients should seek urgent care for symptoms such as chest pain, shortness of breath, palpitations, transient vision changes, or slurred speech.

Pulmonary arterial hypertension (PAH) may develop at any time during treatment. Patients should be monitored for symptoms like shortness of breath, fatigue, or generalized swelling.

Severe skin reactions have been reported, necessitating immediate medical attention if accompanied by fever, sore throat, or blistering.

Tumor lysis syndrome (TLS), resulting from rapid cancer cell breakdown, can lead to kidney failure and abnormal heart rhythms. Patients should be vigilant for symptoms such as nausea, shortness of breath, vomiting, muscle cramps, weakness, seizures, or swelling.

In pediatric patients, Dasatinib Tablets may affect bone growth and development, with monitoring recommended. Medical attention should be sought for any reports of bone pain.

Liver problems have been associated with Dasatinib Tablets, particularly in individuals with a history of liver issues. Monitoring of liver function is advised, and patients should report any symptoms indicative of liver dysfunction.

Patient Counseling

Patients should be advised to read the FDA-approved patient labeling (Patient Information) to understand the medication fully. It is important to inform patients about the potential for developing low blood cell counts and to encourage them to report any fever, especially if accompanied by signs of infection, immediately.

Patients should be made aware of the risk of serious bleeding and instructed to report any unusual bleeding or easy bruising without delay. Additionally, they should be informed about the possibility of fluid retention, which may present as swelling, weight gain, dry cough, chest pain during respiration, or shortness of breath. Patients experiencing these symptoms should seek medical attention promptly.

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

Patients should also be informed about the potential development of pulmonary arterial hypertension, characterized by dyspnea, fatigue, hypoxia, and fluid retention, and should be advised to seek medical attention if these symptoms arise. It is crucial to inform patients to report 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 bone growth abnormalities, bone pain, or gynecomastia, and to advise seeking medical attention if these symptoms occur. Pregnant women should be made aware of the potential risks to a fetus, and both 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 pregnancy while taking dasatinib tablets.

Breastfeeding is not recommended during treatment with dasatinib and for 2 weeks after the final dose. Patients may experience nausea, vomiting, or diarrhea, and should be advised to seek medical attention if these symptoms are bothersome or persistent. Those using antacids should be instructed to avoid taking dasatinib tablets and antacids less than 2 hours apart.

Patients may also experience headache or musculoskeletal pain, fatigue, and skin rash while on dasatinib tablets. They should be advised to seek medical attention if any of these symptoms are bothersome or persistent. It is important to inform patients that dasatinib tablets contain lactose and to be aware of the potential for hepatotoxicity, particularly in those with a history of liver diseases. Patients should seek immediate medical attention if they experience symptoms suggestive of hepatotoxicity, such as abdominal pain, jaundice, scleral icterus, anorexia, bleeding, bruising, or dark-colored urine.

Patients should be instructed on the proper dosing schedule, advising them to take the next scheduled dose at its regular time if they miss a dose, without taking two doses simultaneously. Lastly, patients should be cautioned against consuming grapefruit juice, as it may increase the concentration of dasatinib in their blood and elevate the risk of adverse reactions.

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) in accordance with USP Controlled Room Temperature guidelines.

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 that latex or nitrile gloves be used during the handling and disposal of 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 and then 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 performed every 2 days during consolidation chemotherapy until recovery. Additionally, transaminases should be monitored at baseline and monthly or as clinically indicated during treatment.

Clinicians should counsel patients, particularly females of reproductive potential and males with female partners of reproductive potential, to use 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 BluePoint Laboratories. It includes detailed information about indications, dosage, contraindications, warnings, and clinical pharmacology.

View full prescribing information (PDF)