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 formula weight of 506.02 (monohydrate). Dasatinib appears as a white to off-white powder and is sparingly soluble in dimethyl sulfoxide and N,N-dimethylformamide, while being practically insoluble in water.

Dasatinib is formulated as white to off-white, biconvex, film-coated tablets. Each tablet contains dasatinib along with inactive ingredients, which include croscarmellose sodium, hydroxypropyl cellulose, lactose monohydrate, magnesium stearate, and microcrystalline cellulose. The tablet coating is composed of hypromellose, titanium dioxide, and polyethylene glycol.

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 specific teratogenic or nonteratogenic effects mentioned in the provided data.

Dosage and Administration

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

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

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

Severe myelosuppression, including thrombocytopenia, neutropenia, and anemia, may occur with dasatinib. 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. 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 may require supportive care measures and/or dose modifications.

Patients should be closely monitored for signs and symptoms of cardiovascular toxicity, and appropriate treatment should be initiated as needed. Additionally, dasatinib has been associated with an increased risk of pulmonary arterial hypertension (PAH), which may be reversible upon discontinuation of the drug. A baseline risk assessment is recommended, and patients should be evaluated for signs and symptoms of PAH throughout treatment. Dasatinib should be discontinued if PAH is confirmed.

QT prolongation is another concern; therefore, dasatinib should be used with caution in patients with a known risk of QT interval prolongation.

Severe dermatologic reactions, including mucocutaneous reactions, have been reported in individual cases. Tumor lysis syndrome is also a potential risk; thus, maintaining adequate hydration and correcting uric acid levels prior to initiating therapy with dasatinib is crucial.

Dasatinib poses a risk of embryo-fetal toxicity, and 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, 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 concern with dasatinib; therefore, 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 tests is essential to ensure patient safety during dasatinib therapy.

Side Effects

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

The most common adverse reactions, occurring in 15% or more of patients, include myelosuppression, fluid retention events, diarrhea, headache, skin rash, hemorrhage, dyspnea, fatigue, nausea, and musculoskeletal pain. Myelosuppression may manifest as 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 recommended, with transfusions and interruption of dasatinib therapy indicated as necessary.

Fluid retention, which can be severe and may include pleural effusions, should be managed with supportive care measures and/or dose modifications. Patients should be monitored for cardiovascular toxicity, and appropriate treatment should be administered for any signs or symptoms that arise. Additionally, 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 to discontinue dasatinib if PAH is confirmed.

QT prolongation is another concern; dasatinib should be used with caution in patients who have or may develop a prolonged QT interval. Severe dermatologic reactions, including individual cases of severe mucocutaneous reactions, have also been reported. Tumor lysis syndrome has been observed, highlighting the need for adequate hydration and correction of uric acid levels prior to initiating therapy.

Dasatinib poses a risk of embryo-fetal toxicity, and patients of reproductive potential should be advised of the potential risk to the fetus and the necessity of using 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 significant 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 affect liver function.

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

Drug Interactions

The use of strong CYP3A4 inhibitors may necessitate a dose reduction of the affected medication due to the potential for increased plasma concentrations and enhanced pharmacological effects. Conversely, when strong CYP3A4 inducers are coadministered, a dose increase may be required to achieve the desired therapeutic effect, as these inducers can lower plasma levels of the medication.

Coadministration of antacids is not recommended, as simultaneous administration may interfere with the absorption and efficacy of the medication. Additionally, the use of H2 antagonists and proton pump inhibitors should be avoided in conjunction with this medication, as they may also impact its absorption and overall effectiveness. Monitoring and adjustments should be considered based on the clinical scenario and patient response.

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 regarding the potential impact of dasatinib on pediatric patients' growth and development.

Geriatric Use

In clinical studies involving dasatinib, 23% of the 2712 patients were aged 65 years and older, with 5% being 75 years and older. The efficacy of dasatinib, as measured by confirmed Complete Cytogenetic Response (cCCyR) and Major Molecular Response (MMR), did not differ significantly between elderly patients and their younger counterparts.

While the overall safety profile of dasatinib in geriatric patients appears comparable to that of younger patients, 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 pregnant patients. 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, including skeletal malformations at multiple sites (scapula, humerus, femur, radius, ribs, and clavicle), reduced ossification, edema, and microhepatia. Fetal death was also observed in rats at maternal exposures below those in patients treated with dasatinib at the recommended labeling dose.

Based on human experience, dasatinib is suspected to cause congenital malformations, including neural tube defects, and may result in 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.

Healthcare professionals are advised to inform pregnant patients of the potential risks to the fetus associated with dasatinib use.

Lactation

Dasatinib can cause fetal harm when administered to a pregnant woman. Animal studies indicate that administration of dasatinib during specific periods of gestation and lactation (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 exposure levels that were below those observed in patients treated with dasatinib at the recommended labeling dose.

Given these findings, the use of dasatinib in lactating mothers is not recommended due to the potential risks to breastfed infants. Healthcare professionals should carefully consider the benefits and risks of treatment in lactating mothers and discuss alternative options with them.

Renal Impairment

Patients with renal impairment have not been specifically addressed in the available prescribing information. There are no dosage adjustments, special monitoring requirements, or safety considerations outlined for individuals with reduced kidney function. Healthcare professionals should exercise caution and consider the lack of data when prescribing to 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. Notably, the highest reported dosage was 280 mg per day for one week, which resulted in severe myelosuppression and bleeding in two patients. Given the potential for severe myelosuppression associated with dasatinib, it is imperative that healthcare professionals closely monitor patients who exceed the recommended dosage. Appropriate supportive treatment should be administered as necessary.

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. Additionally, 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 remain vigilant for signs of myelosuppression and cardiotoxicity in patients who have ingested dosages of dasatinib beyond the recommended levels, ensuring that appropriate monitoring and supportive care are provided.

Nonclinical Toxicology

Dasatinib did not demonstrate teratogenic effects in nonclinical studies. 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 cystic ovaries and ovarian hypertrophy in rodents.

In a two-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. Conversely, dasatinib did not exhibit mutagenic properties in an in vitro bacterial cell assay (Ames test) and was not genotoxic 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). Other noted adverse reactions include pulmonary arterial hypertension and tumor lysis syndrome. In pediatric patients, there have been reports of bone growth abnormalities, bone pain, and gynecomastia.

Patients are advised to report any symptoms suggestive of these conditions immediately.

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

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

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

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

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

Pregnant women should be advised of the potential risks to a fetus associated with treatment. Furthermore, 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° to 25°C (68° to 77°F), with permissible excursions between 15° to 30°C (59° 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 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 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 Aurobindo Pharma Limited. It includes detailed information about indications, dosage, contraindications, warnings, and clinical pharmacology.

View full prescribing information (PDF)