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 S-1,2-Propanediol. The molecular formula is C22H26ClN7O2S • C3H8O2, and it has a formula weight of 564.11 g/mol for (S)-propylene glycol, while the free base has a molecular weight of 488.01 g/mol.

Dasatinib (S)-propylene glycol appears as a white to brown colored powder and is freely soluble in dimethyl formamide and N-methyl-2-pyrrolidone, but is practically insoluble in dichloromethane, methanol, ethanol, acetone, n-heptane, n-hexane, tetrahydrofuran, toluene, ethyl acetate, petroleum ether, (S)-propylene glycol, and water.

Dasatinib is formulated as white to off-white, round/oval, film-coated tablets containing dasatinib (S)-propylene glycol. The tablets include inactive ingredients such as anhydrous lactose, colloidal silicon dioxide, croscarmellose sodium, hydrogenated castor oil, magnesium stearate, and microcrystalline cellulose. The tablet coating is composed of hypromellose, titanium dioxide, and triacetin.

Uses and Indications

Dasatinib is indicated for the treatment of newly diagnosed adults with Philadelphia chromosome-positive (Ph+) chronic myeloid leukemia (CML) in chronic phase. It 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, as well as for newly diagnosed Ph+ ALL in combination with chemotherapy.

No teratogenic or nonteratogenic effects are specified in the provided information.

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

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 the use of dasatinib tablets. Caution is advised when administering dasatinib concomitantly with medications that inhibit platelet function or anticoagulants. Regular monitoring of complete blood counts is essential, and transfusions should be administered as necessary. Treatment with dasatinib should be interrupted if significant hematologic toxicity is observed.

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

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

QT prolongation is another concern; therefore, dasatinib tablets 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 also been documented. To mitigate this risk, it is important to ensure adequate hydration and to correct uric acid levels prior to initiating therapy with dasatinib tablets.

Dasatinib can cause embryo-fetal toxicity, and healthcare providers should inform patients of reproductive potential about the risks to the fetus. Effective contraception is recommended for patients of reproductive age.

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 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 recommended to ensure patient safety throughout the treatment course.

Side Effects

Adverse reactions associated with dasatinib tablets have been observed in clinical trials and postmarketing experiences, with varying degrees of severity and frequency.

Most common adverse reactions 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, and transfusions or interruption of dasatinib therapy should be considered 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 signs of cardiovascular toxicity, and appropriate treatment should be administered as necessary. Additionally, dasatinib tablets 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 dasatinib should be discontinued if PAH is confirmed.

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 severe mucocutaneous reactions, have also been reported.

Tumor lysis syndrome has been documented, emphasizing the importance of maintaining adequate hydration and correcting uric acid levels prior to initiating therapy with dasatinib. Furthermore, dasatinib can cause embryo-fetal toxicity, posing potential risks to the fetus; patients of reproductive potential should be advised to use effective contraception.

In pediatric patients, common adverse reactions 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. Notably, effects on growth and development have been observed, including delayed fusion of epiphyses, osteopenia, growth retardation, and gynecomastia, necessitating monitoring of bone growth and development in this population.

Lastly, hepatotoxicity is a concern, and 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.

Drug Interactions

The use of this medication may result in significant drug interactions, which are categorized as follows:

Pharmacokinetic 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 adverse effects.

Strong CYP3A4 Inducers Conversely, the presence of strong CYP3A4 inducers may require an increase in the medication dosage to achieve the desired therapeutic effect, as these inducers can lower plasma concentrations.

Pharmacodynamic Interactions

Antacids It is advised to avoid simultaneous administration of antacids with this medication, as this may interfere with its absorption and efficacy.

H2 Antagonists and Proton Pump Inhibitors Co-administration of H2 antagonists and proton pump inhibitors should also be avoided due to potential interactions that could affect the medication's therapeutic outcomes.

Monitoring and dosage adjustments should be considered based on the specific clinical scenario and the presence of these interacting agents.

Packaging & NDC

The table below lists all NDC Code configurations of Dasatinib, the U.S. brand-name prescription product. Columns show Packaging, Formulation Type, and Active Ingredient Strength.

Pediatric Use

The safety and effectiveness of dasatinib monotherapy have been established in pediatric patients with newly diagnosed chronic phase chronic myeloid leukemia (CML). In children aged one year and older, dasatinib has also demonstrated safety and effectiveness in combination with chemotherapy for newly diagnosed Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL). However, there are no data available for children under one year of age.

In a pediatric study, five patients aged 2 to 10 years received dasatinib tablets dispersed in juice, which resulted in a 36% lower exposure compared to intact tablets. Due to the limited clinical data, it remains unclear whether this method of administration significantly affects the safety and/or efficacy of dasatinib.

Adverse reactions related to bone growth and development were reported in 5.2% of pediatric patients, including one case of grade 1 osteopenia. Therefore, it is recommended to monitor bone growth and development in pediatric patients receiving dasatinib. The safety profile observed in pediatric subjects is comparable to that reported in adult studies.

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.

Despite the comparable safety profile of dasatinib in geriatric patients relative to younger populations, elderly patients, particularly those 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 imperative that patients aged 65 years and older are monitored closely for the emergence of these adverse effects. Healthcare providers should remain vigilant in assessing the overall health status and response to treatment in geriatric patients to ensure optimal management and safety.

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. 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.

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 observed in patients treated with dasatinib at the recommended labeling dose.

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

Due to the potential risks associated with dasatinib, lactating mothers are advised to exercise caution. The effects of dasatinib on breastfed infants have not been established, and the drug's presence in human breast milk is not well characterized. Therefore, healthcare professionals should weigh the benefits of breastfeeding against the potential risks to the infant when considering the use of dasatinib in lactating mothers.

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 these patients to ensure safety and 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. 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

Experience with dasatinib overdose in clinical studies is limited to isolated cases. Notably, the highest reported overdose involved a dosage of 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 have ingested more than the recommended dosage. Appropriate supportive treatment should be administered as necessary to manage any arising complications.

In addition to hematological concerns, acute overdose in animal studies has demonstrated potential cardiotoxicity. Evidence of this cardiotoxicity includes findings of ventricular necrosis and valvular, ventricular, and atrial hemorrhage at single doses of 100 mg/kg (600 mg/m²) or greater in rodent models. Furthermore, 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 signs of myelosuppression and cardiotoxicity in patients who may have overdosed on dasatinib, ensuring that appropriate monitoring and supportive care are provided.

Nonclinical Toxicology

Dasatinib did not affect mating or fertility in male and female rats at plasma drug exposure (AUC) levels comparable to those observed in humans receiving a daily dose of 100 mg. However, in repeat dose studies, administration of dasatinib resulted in reduced size and secretion of seminal vesicles, as well as immature prostate, seminal vesicle, and testis. Additionally, dasatinib administration led to uterine inflammation and mineralization in monkeys, along with cystic ovaries and ovarian hypertrophy in rodents.

In a 2-year carcinogenicity study, rats were administered oral doses of dasatinib at 0.3, 1, and 3 mg/kg/day. The highest dose resulted in a plasma drug exposure (AUC) level approximately 60% of the human exposure at 100 mg once daily. Dasatinib induced a statistically significant increase in the combined incidence of squamous cell carcinomas and papillomas in the uterus and cervix of high-dose females, as well as prostate adenoma in low-dose males.

Dasatinib was found to be clastogenic when tested in vitro in Chinese hamster ovary cells, both with and without metabolic activation. However, it was not mutagenic when evaluated in an in vitro bacterial cell assay (Ames test) and did not exhibit genotoxicity in an in vivo rat micronucleus study.

Postmarketing Experience

No specific postmarketing experience details are available. As such, there are no additional adverse events or rare case reports to summarize at this time.

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 encourage them to report any fever, especially if accompanied by signs of infection, immediately.

Patients should also be made aware of the risk of serious bleeding. They 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 seek medical attention promptly if they experience any of these symptoms.

Healthcare providers should discuss the risk of cardiovascular toxicity with patients, 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 informed about the possibility of developing pulmonary arterial hypertension, characterized by dyspnea, fatigue, hypoxia, and fluid retention. They should be encouraged to seek medical attention promptly if they experience these symptoms.

It is crucial to inform patients to report and seek medical attention 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 made aware 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 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.

Storage and Handling

Dasatinib tablets are supplied in various package configurations. They should be stored at a temperature range of 20°C to 25°C (68°F to 77°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 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 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 throughout treatment.

Clinicians should counsel females of reproductive potential to avoid pregnancy during treatment with dasatinib tablets and for 30 days following the final dose, emphasizing the importance of effective contraception.

FDA Insert (PDF)

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

View full prescribing information (PDF)