Dasatinib

Description

Dasatinib is a kinase inhibitor with the chemical name N-(2-chloro-6-methylphenyl)-2-[[6-4-(2-hydroxyethyl)-1-piperazinyl-2-methyl-4-pyrimidinyl]amino]-5-thiazolecarboxamide, monohydrate. Its 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 fine crystalline powder and is insoluble in water, with slight solubility in ethanol and methanol. Dasatinib is formulated as white to off-white, beveled edge, film-coated tablets. Each tablet contains inactive ingredients including croscarmellose sodium, hydroxypropyl cellulose, lactose monohydrate, magnesium stearate, and microcrystalline cellulose. The coating of the tablets consists of hypromellose 2910, titanium dioxide, and triacetin.

Uses and Indications

Dasatinib tablets are indicated for the treatment of newly diagnosed adults with Philadelphia chromosome-positive (Ph+) chronic myeloid leukemia (CML) in chronic phase. This drug is also indicated for adults with chronic, accelerated, or myeloid or lymphoid blast phase Ph+ CML who exhibit resistance or intolerance to prior therapy, including imatinib. Additionally, dasatinib is indicated for adults with Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL) who have resistance or intolerance to prior therapy.

In pediatric patients aged 1 year and older, dasatinib is indicated for the treatment of Ph+ CML in chronic phase. Furthermore, it is indicated for pediatric patients aged 1 year and older with newly diagnosed Ph+ ALL when used in combination with chemotherapy.

No specific teratogenic or nonteratogenic effects have been mentioned in the available data.

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, ensuring appropriate dosing tailored to the individual patient's needs.

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 to maintain their efficacy.

Contraindications

There are no contraindications associated with the use of this product.

Warnings and Precautions

Severe myelosuppression, including thrombocytopenia, neutropenia, and anemia, may occur with dasatinib therapy. Caution is advised when dasatinib is used concomitantly with medications that inhibit platelet function or anticoagulants. Regular monitoring of complete blood counts is essential, and transfusions should be administered as necessary. 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 if such symptoms arise. Additionally, dasatinib has 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 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 mucocutaneous reactions, have been reported in individual cases.

Tumor lysis syndrome has been observed in patients receiving dasatinib. To mitigate this risk, it is important to maintain adequate hydration and correct uric acid levels prior to initiating therapy.

Dasatinib poses a risk of embryo-fetal toxicity, and patients of reproductive potential should be informed of the potential risks to the fetus. Effective contraception is recommended during treatment.

In pediatric patients, dasatinib may affect growth and development, leading to delayed epiphyseal fusion, osteopenia, growth retardation, and gynecomastia. Monitoring of bone growth and development is advised in this population.

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 cause liver dysfunction.

Regular monitoring of complete blood counts and liver function tests is essential throughout the course of treatment to ensure patient safety and to manage any adverse effects promptly.

Side Effects

Patients receiving dasatinib 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 a 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, and transfusions or interruption of dasatinib may be required when 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, as dasatinib may increase the risk of pulmonary arterial hypertension (PAH), which may be reversible upon discontinuation. It is essential to evaluate patients for signs and symptoms of PAH during treatment and to discontinue dasatinib if PAH is confirmed. Caution is also advised in patients who have or may develop QT interval prolongation.

Severe dermatologic reactions, including individual cases of severe mucocutaneous reactions, have been reported. Additionally, tumor lysis syndrome has been observed; therefore, maintaining adequate hydration and correcting uric acid levels prior to initiating therapy with dasatinib is crucial.

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, necessitating monitoring of bone growth and development.

Hepatotoxicity is another concern, and 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 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

The use of this medication in conjunction with certain drug classes may lead to significant interactions that require careful management.

CYP3A4 Interactions Strong inhibitors of CYP3A4 may necessitate a reduction in the dosage of this medication to mitigate the risk of increased plasma concentrations and potential adverse effects. Conversely, strong inducers of CYP3A4 may require an increase in dosage to maintain therapeutic efficacy, as these agents can lower plasma levels of the medication.

Gastrointestinal Agents The concurrent use of antacids is not recommended, as they may interfere with the absorption of the medication. Additionally, coadministration with H2 antagonists and proton pump inhibitors should be avoided due to the potential for altered pharmacokinetics, which could affect the medication's effectiveness.

Monitoring and dosage adjustments should be considered based on the specific interactions and the clinical context of the patient.

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). However, there are no data available for children under 1 year of age. In this population, adverse reactions related to bone growth and development were reported in 5.2% of patients.

In pediatric patients aged 1 year and older with newly diagnosed Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL), dasatinib has been shown to be safe and effective when used in combination with chemotherapy. Again, there are no data for children under 1 year of age, and one case of grade 1 osteopenia was noted.

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 patients aged 2 to 10 years with Ph+ ALL, 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, it remains unclear whether this method of administration significantly affects the safety and/or efficacy of dasatinib.

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. 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 the emergence of these adverse reactions. Healthcare providers should remain vigilant in assessing the safety and efficacy of dasatinib in this population, and appropriate dose modifications should be considered based on individual patient tolerance and response.

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. The transplacental transfer of dasatinib has been documented, with dasatinib detected in fetal plasma and amniotic fluid at concentrations comparable to those in maternal plasma.

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. Specifically, embryo-fetal toxicities, including skeletal malformations at multiple sites (scapula, humerus, femur, radius, ribs, and clavicle), reduced ossification, edema, and microhepatia, were noted in both rats and rabbits at the lowest doses tested. These doses produced maternal AUCs of 105 ng•h/mL and 44 ng•h/mL (0.1-fold the human AUC) in rats and rabbits, respectively. Additionally, fetal death was observed in rats.

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 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 professionals should advise pregnant patients of the potential risk to the fetus. 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. Given the potential for serious adverse effects, dasatinib should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

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. Currently, no data are available regarding the presence of dasatinib in human milk, the effects of the drug on breastfed infants, or its impact on milk production. However, studies in lactating rats indicate that dasatinib is present in breast milk.

Due to the potential for serious adverse reactions in nursing children from dasatinib, breastfeeding is not recommended during treatment with dasatinib and for 2 weeks after the last dose.

Renal Impairment

There is no specific information regarding renal impairment, dosage adjustments, special monitoring, or safety considerations for patients with reduced kidney function. Healthcare professionals should exercise caution and consider individual patient factors when treating patients with renal impairment, as the absence of detailed guidance necessitates careful clinical judgment.

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. Additionally, when this treatment is combined with chemotherapy agents that are known to be associated with liver dysfunction, careful monitoring of liver function is essential to ensure patient safety and to mitigate the risk of hepatotoxicity.

Overdosage

In cases of dasatinib overdosage, clinical experience has primarily been derived from isolated incidents. The highest reported instance involved a dosage of 280 mg per day administered over the course of one week, which resulted in severe myelosuppression and bleeding complications.

Healthcare professionals are advised to closely monitor patients who exceed the recommended dosage for signs of myelosuppression. Appropriate supportive treatment should be provided as necessary to manage these adverse effects.

Animal studies have demonstrated that acute overdose can lead to significant cardiotoxicity, particularly at single doses of 100 mg/kg or greater. Observations from these studies included ventricular necrosis and hemorrhage. Additionally, increased systolic and diastolic blood pressure was noted in monkeys receiving single doses of 10 mg/kg or more.

In summary, vigilance in monitoring and supportive care is essential for managing dasatinib overdosage, given the potential for severe hematological and cardiovascular effects.

Nonclinical Toxicology

Dasatinib was evaluated for teratogenic effects, and no specific teratogenic effects were identified in the studies conducted.

In terms of non-teratogenic effects, dasatinib did not impact 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, dasatinib administration led to a reduction in the size and secretion of seminal vesicles, as well as the development of immature prostate, seminal vesicle, and testis. Additionally, dasatinib administration resulted in uterine inflammation and mineralization in monkeys, along with the presence of 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 achieved a plasma drug exposure level approximately 60% of that seen in humans at a daily dose of 100 mg. The study revealed 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 with dasatinib tablets has revealed several adverse events reported voluntarily or through surveillance programs.

Low blood cell counts, including anemia, neutropenia, and thrombocytopenia, are commonly observed and can be severe. Bleeding problems are also frequently reported, with some cases leading to serious outcomes, including death. Fluid retention is another common issue, which can escalate to severe conditions, such as accumulation in the lining of the lungs, the sac around the heart, or the abdominal cavity.

Cardiovascular effects associated with dasatinib tablets include abnormal heart rates, heart attacks, and transient ischemic attacks (TIAs). Additionally, pulmonary arterial hypertension has been noted as a potential complication. Skin reactions, which can be severe, have also been documented.

Tumor Lysis Syndrome (TLS) has been reported, potentially resulting in kidney failure, the need for dialysis, and abnormal heart rhythms. There have been observations of effects on bone growth and development in children, which can be severe. Liver problems have been associated with dasatinib tablets, particularly in individuals with a history of liver issues. Lastly, fertility problems in both males and females have been reported.

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 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 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 upon 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 seek medical attention if these symptoms arise. It is crucial to instruct 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, advising them to seek medical attention if these symptoms occur. Pregnant women should be informed 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 tablets and for 2 weeks after the final dose. Patients may experience nausea, vomiting, or diarrhea, and should seek medical attention if these symptoms are bothersome or persistent. Those using antacids should be advised 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 encouraged to seek medical attention if any of these symptoms become bothersome or persistent. It is important to inform patients that dasatinib tablets contain lactose monohydrate, with 131 mg in a 100 mg daily dose and 184 mg in a 140 mg daily dose.

Patients should be made aware of the risk of hepatotoxicity associated with dasatinib tablets, particularly for those with a history of liver diseases. They 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.

If a patient misses a dose of dasatinib tablets, they should take the next scheduled dose at its regular time and should not take two doses simultaneously. Lastly, patients should be advised to avoid grapefruit juice, as it may increase the concentration of dasatinib tablets in their blood, thereby elevating the risk of adverse reactions.

Storage and Handling

Dasatinib tablets are supplied in various package configurations. They should be stored at a temperature range of 20° to 25°C (68° to 77°F), with permissible excursions between 15° and 30°C (59° and 86°F).

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 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.

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 blocks 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. It is also important to monitor bone growth and development in pediatric patients.

FDA Insert (PDF)

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

View full prescribing information (PDF)