Dasatinib

Description

Dasatinib tablets are a kinase inhibitor formulated as white to off-white, biconvex, film-coated tablets. 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 for the monohydrate and an anhydrous free base molecular weight of 488.01.

Dasatinib appears as a white to off-white powder, which is insoluble in water and slightly soluble in ethanol and methanol. Each tablet contains dasatinib along with inactive ingredients, including lactose monohydrate, microcrystalline cellulose, croscarmellose sodium, hydroxypropyl cellulose, and magnesium stearate. The tablet coating is composed of hypromellose, titanium dioxide, and polyethylene glycol.

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 orally 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 orally once daily.

For 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 taken orally, and it can be administered with or without food. It is important to note that the tablets must not be crushed, cut, or chewed prior to ingestion to maintain their efficacy.

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 closely 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 treatment. If PAH is confirmed, Dasatinib tablets 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 individual cases of mucocutaneous reactions, have been reported and warrant careful monitoring.

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

Dasatinib is associated with embryo-fetal toxicity and can cause fetal harm. Patients of reproductive potential should be informed of the potential risks to the fetus and advised to use effective contraception during treatment.

In pediatric patients, effects on growth and development have been noted, including delayed epiphyseal fusion, osteopenia, growth retardation, and gynecomastia. Monitoring of bone growth and development in this population is recommended.

Hepatotoxicity is a potential risk; therefore, liver function should be assessed prior to the initiation of treatment and monitored monthly thereafter, or as clinically indicated. This is particularly important when Dasatinib is used in conjunction 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

Adverse reactions associated with Dasatinib tablets have been observed in clinical trials and postmarketing experiences, with varying frequencies and severities among different patient populations.

Most common adverse reactions in adults (≥15%) include myelosuppression, fluid retention events, diarrhea, headache, skin rash, hemorrhage, dyspnea, fatigue, nausea, and musculoskeletal pain. In pediatric patients (≥30%), the most frequently reported adverse reactions encompass 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, necessitating caution when Dasatinib is used concomitantly with medications that inhibit platelet function or anticoagulants. Regular monitoring of complete blood counts is essential, and transfusions or interruption of Dasatinib therapy may be required. Fluid retention, which can be severe and include pleural effusions, should be managed with supportive care measures and/or dose modifications.

Patients should be monitored for cardiovascular toxicity, including signs or symptoms indicative of potential complications. Dasatinib tablets may also increase the risk of pulmonary arterial hypertension (PAH), which may be reversible upon discontinuation. It is important to evaluate patients for signs and symptoms of PAH during treatment and to discontinue Dasatinib if PAH is confirmed.

QT prolongation is another concern; thus, caution is advised in patients who have or may develop a prolonged QT interval. Severe dermatologic reactions, including individual cases of severe mucocutaneous reactions, have been reported. Additionally, tumor lysis syndrome has been documented, emphasizing the need for adequate hydration and correction of uric acid levels prior to initiating therapy.

Embryo-fetal toxicity is a significant risk, and patients of reproductive potential should be informed of the potential harm 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, necessitating monitoring of bone growth and development.

Hepatotoxicity is another important consideration; liver function should be assessed before the initiation of treatment 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 experiencing 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, warranting close monitoring in this population.

Drug Interactions

The following drug interactions have been identified, categorized by their pharmacokinetic effects and clinical implications.

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. Monitoring of clinical effects is advised. (Refer to sections 2.3 and 7.1 for further details.)

• Strong CYP3A4 Inducers: When used in conjunction with strong CYP3A4 inducers, an increase in the dosage of the affected drug may be required to achieve the desired therapeutic effect. Close monitoring of the patient's response is recommended. (Refer to sections 2.3 and 7.1 for further details.)

Gastrointestinal Agents

• Antacids: The simultaneous administration of antacids with the affected drug should be avoided, as this may interfere with the absorption and efficacy of the medication. (Refer to section 7.1 for further details.)

• H2 Antagonists and Proton Pump Inhibitors: Co-administration of H2 antagonists or proton pump inhibitors is not recommended due to potential interactions that may affect the pharmacokinetics of the affected drug. (Refer to section 7.1 for further details.)

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 tablet monotherapy have been established in pediatric patients with newly diagnosed chronic phase chronic myeloid leukemia (CML). There are no available data for children under 1 year of age. Adverse reactions related to bone growth and development were observed in 5.2% of patients.

In pediatric patients aged 1 year and older with newly diagnosed Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL), the safety and effectiveness of Dasatinib tablets in combination with chemotherapy have also been demonstrated. Again, there are no data for children under 1 year of age, and one case of grade 1 osteopenia was reported.

The safety profile of Dasatinib tablets in pediatric subjects is comparable to that observed in adult studies. It is recommended to monitor bone growth and development in pediatric patients receiving Dasatinib.

In a small cohort of five patients with Ph+ ALL aged 2 to 10 years, Dasatinib tablets were administered dispersed in juice. The exposure from dispersed tablets was found to be 36% lower compared to intact tablets. Due to the limited clinical data, the impact of dispersing Dasatinib tablets on safety and efficacy remains unclear.

Geriatric Use

Elderly patients, defined as those 65 years of age and older, comprised 23% of the 2712 patients evaluated in clinical studies of dasatinib, with 5% being 75 years of age and older. While no significant differences in confirmed Complete Cytogenetic Response (cCCyR) and Major Molecular Response (MMR) were observed between older and younger patients, it is important to note that the safety profile of dasatinib in the geriatric population was similar to that of younger patients.

However, elderly patients are more likely to experience commonly reported adverse reactions, including fatigue, pleural effusion, diarrhea, dyspnea, cough, lower gastrointestinal hemorrhage, and appetite disturbance. Additionally, they may also be at an increased risk for 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 recommended that patients aged 65 years and older be monitored closely for these adverse reactions. Healthcare providers should remain vigilant in assessing the overall health status of geriatric patients and consider potential dose adjustments as necessary to ensure safety and efficacy in this population.

Pregnancy

Dasatinib tablets can cause fetal harm when administered to pregnant patients, as evidenced by limited human data. Adverse pharmacologic effects, including hydrops fetalis, fetal leukopenia, and fetal thrombocytopenia, have been reported following maternal exposure to dasatinib. Animal reproduction studies have demonstrated significant mortality during organogenesis, the fetal period, and in neonates, with skeletal malformations observed in a limited number of surviving rat and rabbit conceptuses. Notably, these findings occurred at dasatinib plasma concentrations below those seen in humans receiving therapeutic doses.

The estimated background risk of major birth defects in the U.S. general population is 2% to 4%, while the risk of miscarriage is 15% to 20% for clinically recognized pregnancies. Transplacental transfer of dasatinib has been documented, with dasatinib detected in fetal plasma and amniotic fluid at concentrations comparable to those in maternal plasma. The adverse effects on the fetus, including hydrops fetalis, fetal leukopenia, and fetal thrombocytopenia, mirror those observed in adult patients and may lead to fetal harm or neonatal death.

Based on human experience, dasatinib is suspected to cause congenital malformations, including neural tube defects, and to exert harmful pharmacological effects on the fetus when administered during pregnancy. Nonclinical studies have revealed embryo-fetal toxicities at plasma concentrations below those observed in humans receiving therapeutic doses. These toxicities included skeletal malformations at multiple sites, 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 below those seen in patients treated with dasatinib at the recommended labeling dose.

Healthcare professionals are advised to counsel pregnant women regarding the potential risks to the fetus associated with dasatinib use and to consider alternative treatment options when necessary.

Lactation

Dasatinib is known to transfer transplacentally, with measurements indicating its presence in fetal plasma and amniotic fluid at concentrations comparable to those found in maternal plasma.

In a pre- and postnatal development study conducted in rats, administration of dasatinib during gestation and lactation resulted in significant pup mortality. This occurred at maternal exposure levels that were below those experienced by patients receiving dasatinib at the recommended labeling dose.

Given these findings, caution is advised when considering the use of dasatinib in lactating mothers, as the potential effects on breastfed infants are not fully established.

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 effectively.

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 was administered to two patients. Both individuals experienced severe myelosuppression and bleeding as a result of this overdosage.

Given the association of dasatinib tablets with severe myelosuppression, it is imperative that healthcare professionals closely monitor patients who ingest more than the recommended dosage. Appropriate supportive treatment should be provided to manage any signs of myelosuppression that may arise.

Animal studies have indicated that acute overdose can lead to cardiotoxicity. In rodents, evidence of cardiotoxicity was observed at single doses of 100 mg/kg (600 mg/m²) or greater, which included findings such as ventricular necrosis and valvular, ventricular, or atrial hemorrhage. Additionally, in primate studies, there was a noted tendency for increased systolic and diastolic blood pressure at single doses of 10 mg/kg (120 mg/m²) or higher.

In summary, healthcare professionals should remain vigilant for the potential complications associated with dasatinib overdose, particularly myelosuppression and cardiotoxicity, and should implement appropriate monitoring and management strategies for affected patients.

Nonclinical Toxicology

Dasatinib did not affect mating or fertility in male and female rats at plasma drug exposure (AUC) levels comparable to human exposure at 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 (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 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, and fluid retention. Additionally, cardiovascular toxicity has been reported, encompassing cardiac ischemic events, cardiac-related fluid retention, conduction abnormalities, and transient ischemic attacks (TIAs). Cases of pulmonary arterial hypertension and tumor lysis syndrome have also been documented.

In pediatric patients, there have been reports of bone growth abnormalities, bone pain, and gynecomastia. Furthermore, instances of embryo-fetal toxicity have been noted.

Patients are advised to report any symptoms suggestive of these conditions immediately and to seek medical attention promptly.

Patient Counseling

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

Patients should also 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, patients should be informed about the potential for fluid retention, which may present as swelling, weight gain, dry cough, chest pain upon respiration, or shortness of breath. They should be advised to seek medical attention promptly if they experience any of these symptoms.

Healthcare providers should inform patients about 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 advised 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.

Patients should also be made aware of the possibility of developing pulmonary arterial hypertension, characterized by dyspnea, fatigue, hypoxia, and fluid retention. They should be advised to seek medical attention promptly if they experience these symptoms.

It is crucial to inform patients 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 potential for bone growth abnormalities, bone pain, or gynecomastia, and to advise them to seek medical attention promptly if these symptoms arise.

Pregnant women should be advised of the potential risks to a fetus associated with the medication. Furthermore, females of reproductive potential and males with female partners of reproductive potential should be instructed to use effective contraception during treatment with Dasatinib tablets and for 30 days following the last dose. Females should be advised 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 various package configurations, with specific NDC numbers available for identification. These 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.

Due to the nature of Dasatinib as an antineoplastic product, special handling and disposal procedures must be followed. It is advised that personnel who are pregnant avoid any exposure to crushed or broken tablets. When handling tablets that are inadvertently crushed or broken, the use of latex or nitrile gloves is recommended 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 first 2 months and then monthly thereafter, or as clinically indicated. Pediatric patients with Ph+ ALL receiving Dasatinib tablets in combination with chemotherapy require CBCs prior to each chemotherapy block and as clinically indicated, with CBCs performed every 2 days during consolidation blocks until recovery. Additionally, transaminases should be monitored at baseline and monthly or as clinically indicated during treatment.

Clinicians should counsel females of reproductive potential and males with female partners of reproductive potential to use effective contraception during treatment with Dasatinib tablets 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 Prasco Laboratories. It includes detailed information about indications, dosage, contraindications, warnings, and clinical pharmacology.

View full prescribing information (PDF)