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. The molecular formula is C22H26ClN7O2S • H2O, and it has a molecular weight of 506.02 g/mol in its monohydrate form, while the anhydrous free base has a molecular weight of 488.01 g/mol. Dasatinib appears as a white to off-white powder and is characterized by its insolubility in water, with slight solubility in ethanol and methanol.

Dasatinib is available in tablet form for oral administration, with each tablet containing 20 mg, 50 mg, 70 mg, 80 mg, 100 mg, or 140 mg of dasatinib. The tablets also include inactive ingredients such as colloidal silicon dioxide, croscarmellose sodium, glyceryl monocaprylocaprate type 1, hydroxypropyl cellulose, lactose monohydrate, magnesium stearate, microcrystalline cellulose, polyvinyl alcohol-partially hydrolyzed, sodium lauryl sulfate, talc, and titanium dioxide.

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.

There are no teratogenic or nonteratogenic effects associated with dasatinib.

Dosage and Administration

For the treatment of chronic phase chronic myeloid leukemia (CML) in adults, 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) in adults, the dosage is increased to 140 mg orally once daily.

The tablets may be taken with or without food. It is important to note that the tablets should not be crushed, cut, or chewed prior to administration to ensure proper delivery of the medication.

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 are significant risks associated with dasatinib therapy. Severe thrombocytopenia, neutropenia, and anemia may occur, 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 should be administered as needed. Dasatinib should be interrupted if indicated.

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

Cardiovascular toxicity is another concern; therefore, healthcare professionals should monitor patients for any signs or symptoms and provide appropriate treatment as required.

Dasatinib has been associated with an increased risk of pulmonary arterial hypertension (PAH), which may be reversible upon discontinuation of the drug. It is crucial to consider the baseline risk for PAH and to evaluate patients for any signs or symptoms during treatment. If PAH is confirmed, dasatinib should be discontinued.

QT prolongation is a potential risk when using dasatinib. Caution is advised in patients who have or may develop a prolonged QT interval.

Severe dermatologic reactions, including individual cases of mucocutaneous reactions, have been reported. Close monitoring for these reactions is recommended.

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

Embryo-fetal toxicity is a critical consideration, as dasatinib 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, dasatinib may affect growth and development, leading to delayed epiphyseal fusion, osteopenia, growth retardation, and gynecomastia. Monitoring of bone growth and development in this population is essential.

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

In summary, regular monitoring of complete blood counts and liver function is imperative throughout the course of dasatinib therapy. Healthcare professionals should remain vigilant for signs of cardiovascular toxicity, PAH, and severe dermatologic reactions, and manage fluid retention appropriately. If PAH is confirmed, dasatinib must be discontinued immediately.

Side Effects

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

Most commonly reported adverse reactions (≥ 15%) include myelosuppression, fluid retention events, diarrhea, headache, skin rash, hemorrhage, dyspnea, fatigue, nausea, and musculoskeletal pain. Among these, myelosuppression can manifest as severe thrombocytopenia, neutropenia, and anemia. Caution is advised when dasatinib is 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 may include pleural effusions, requires management through supportive care measures and/or dose modification. Patients should be monitored for cardiovascular toxicity, with appropriate treatment initiated for any signs or symptoms that arise.

Dasatinib has been associated with an increased risk of pulmonary arterial hypertension (PAH), which may be reversible upon discontinuation of the drug. It is important to evaluate patients for signs and symptoms of PAH during treatment, and dasatinib should be stopped if PAH is confirmed. Additionally, caution is warranted in patients who have or may develop QT interval prolongation.

Severe dermatologic reactions, including individual cases of mucocutaneous reactions, have been reported. Tumor lysis syndrome has also been observed; therefore, maintaining adequate hydration and correcting uric acid levels prior to initiating therapy is essential.

Embryo-fetal toxicity is a significant concern, as dasatinib can cause fetal harm. Patients of reproductive potential should be informed of this risk 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 dasatinib is 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, and should be monitored closely for these effects.

Drug Interactions

The use of this medication may be affected by various drug interactions, which can be categorized into pharmacokinetic interactions based on their effects on metabolic pathways and absorption.

CYP3A4 Interactions

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

• Strong CYP3A4 Inducers: When used alongside strong CYP3A4 inducers, an increase in the medication dosage may be required to maintain therapeutic efficacy due to enhanced metabolism and reduced plasma levels.

Gastrointestinal Agents

• Antacids: It is advised to avoid simultaneous administration of antacids, as they may interfere with the absorption of the medication, potentially leading to suboptimal therapeutic outcomes.

• H2 Antagonists and Proton Pump Inhibitors: Co-administration with H2 antagonists and proton pump inhibitors should be avoided due to the potential for altered absorption and reduced effectiveness of the medication.

Monitoring and dosage adjustments should be considered in the presence of these interactions to ensure optimal therapeutic outcomes and minimize adverse effects.

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

Pediatric patients require careful monitoring of bone growth and development during treatment with Sprycel (dasatinib) tablets. Although pediatric use information has been approved, the product is not labeled with this information due to Bristol-Myers Squibb Company's marketing exclusivity rights. Healthcare professionals should remain vigilant in assessing the impact of dasatinib on pediatric patients' growth and development.

Geriatric Use

In clinical studies involving dasatinib, 23% of the 2,712 patients evaluated were aged 65 years and older, with 5% being 75 years of age and older. The efficacy outcomes, specifically confirmed Complete Cytogenetic Response (cCCyR) and Major Molecular Response (MMR), did not demonstrate significant differences between older and younger patients.

While the overall safety profile of dasatinib in geriatric patients appears comparable to that of younger individuals, it is important to note that patients aged 65 years and older 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, this age group may also experience less frequently reported adverse reactions such as abdominal distention, dizziness, pericardial effusion, congestive heart failure, hypertension, pulmonary edema, and weight decrease.

Given these considerations, it is recommended 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.

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. The lowest doses tested in both rats and rabbits resulted in embryo-fetal toxicities, with maternal AUCs of 105 ng•h/mL and 44 ng•h/mL (0.1-fold the human AUC), respectively. These toxicities included skeletal malformations at multiple sites, reduced ossification, edema, and microhepatia. Additionally, fetal death was observed in rats.

Based on human experience, dasatinib is suspected to cause congenital malformations, including neural tube defects, and may exert 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 below those seen in patients treated with dasatinib at the recommended labeling dose.

Healthcare professionals should advise pregnant women of the potential risks to the fetus associated with dasatinib use.

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

Renal Impairment

Patients with renal impairment may not have specific information regarding dosage adjustments, special monitoring, or safety considerations outlined in the prescribing information. Therefore, healthcare professionals should exercise caution when prescribing to patients with reduced kidney function, as the absence of detailed guidance necessitates careful clinical judgment and individualized patient assessment. Regular monitoring of renal function is advisable to ensure patient safety and therapeutic efficacy.

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. Notably, the highest reported dosage was 280 mg per day for one week, which occurred in two patients. Both individuals experienced severe myelosuppression and bleeding as a result of this overdose.

Given the association of dasatinib with severe myelosuppression, it is imperative that healthcare professionals closely monitor patients who exceed the recommended dosage. Vigilant observation for signs of myelosuppression is essential, and appropriate supportive treatment should be administered as necessary.

Additionally, animal studies have indicated that acute overdose may lead to cardiotoxicity. Evidence of such cardiotoxicity includes ventricular necrosis and hemorrhage in the valvular, ventricular, and atrial regions, observed at single doses of 100 mg/kg (600 mg/m²) in rodent models. Furthermore, a tendency for increased systolic and diastolic blood pressure was noted in monkeys at single doses of 10 mg/kg (120 mg/m²).

In summary, healthcare professionals should be aware of the potential severe effects of dasatinib overdose, including 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 mg/kg/day, 1 mg/kg/day, and 3 mg/kg/day. The highest dose resulted in a plasma drug exposure (AUC) level approximately 60% of the human exposure 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 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, fluid retention, and cardiovascular toxicity, which encompasses cardiac ischemic events, cardiac-related fluid retention, conduction abnormalities, and transient ischemic attacks (TIAs). Additionally, pulmonary arterial hypertension and tumor lysis syndrome have been reported. In pediatric patients, there have been observations of bone growth abnormalities, bone pain, and gynecomastia.

Patients are encouraged to report any symptoms that may arise, including fever, unusual bleeding, swelling, weight gain, dry cough, chest pain on respiration, shortness of breath, chest pain, palpitations, transient vision problems, slurred speech, dyspnea, fatigue, hypoxia, nausea, vomiting, weakness, edema, muscle cramps, seizures, and any signs of pregnancy.

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 during respiration, or shortness of breath. Patients should be advised to seek medical attention promptly if they experience any of these symptoms.

It is crucial to inform patients about the potential for 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.

Patients should also be made aware of the risk 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 any of these symptoms.

Healthcare providers should 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, advising them to seek medical attention promptly if these symptoms arise.

Pregnant women should be advised of the potential risks to a fetus associated with treatment. Additionally, healthcare providers should counsel females of reproductive potential and males with female partners of reproductive potential to use effective contraception during treatment with dasatinib and for 30 days following 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.

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 (68ºF to 77ºF), with permissible excursions between 15°C to 30°C (59°F to 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 strictly 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 monitoring 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. Additionally, transaminases should be monitored at baseline and monthly during treatment or as clinically indicated.

Clinicians should counsel patients, particularly females of reproductive potential and males with female partners of reproductive potential, to utilize effective contraception during treatment with dasatinib 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 Zydus Pharmaceuticals USA Inc.. It includes detailed information about indications, dosage, contraindications, warnings, and clinical pharmacology.

View full prescribing information (PDF)