Dasatinib

Description

Dasatinib is a kinase inhibitor. The chemical name for dasatinib is N-(2-chloro-6-methylphenyl)-2-[[6-4-(2-hydroxyethyl)-1-piperazinyl-2-methyl-4-pyrimidinyl]amino]-5-thiazolecarboxamide. The molecular formula is C22H26ClN7O2S, with a molecular weight of 488.01 g/mol. Dasatinib appears as a white to off-white powder and is insoluble in water, with slight solubility in ethanol and methanol. Dasatinib tablets are white to off-white, film-coated tablets containing dasatinib. The inactive ingredients in dasatinib tablets include croscarmellose sodium, hydroxypropyl cellulose, lactose monohydrate, methacrylic acid copolymer, microcrystalline cellulose, magnesium stearate, and talc. The tablet coating consists of hypromellose, medium chain triglycerides, and titanium dioxide.

Uses and Indications

Dasatinib tablets are indicated for the treatment of the following conditions:

• Newly diagnosed adults with Philadelphia chromosome-positive (Ph+) chronic myeloid leukemia (CML) in chronic phase.

• Adults with chronic, accelerated, or myeloid or lymphoid blast phase Ph+ CML who exhibit resistance or intolerance to prior therapy, including imatinib.

• Adults with Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL) who demonstrate resistance or intolerance to prior therapy.

• Pediatric patients aged 1 year and older with Ph+ CML in chronic phase.

• Pediatric patients aged 1 year and older with newly diagnosed Ph+ ALL, to be administered in combination with chemotherapy.

Limitations of use have not been specified in the provided information. There are no specific teratogenic or nonteratogenic effects mentioned.

Dosage and Administration

For adults with chronic phase chronic myeloid leukemia (CML), the recommended dosage is 100 mg administered orally once daily. In cases of accelerated phase CML, myeloid or lymphoid blast phase CML, or Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL), the dosage increases to 140 mg orally once daily.

In pediatric patients with chronic phase CML and Ph+ ALL, the starting dose should be determined based on body weight.

The medication 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.

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. Therefore, the product can be used without specific restrictions related to contraindications.

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 when 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 needed.

Patients should be closely monitored for signs and symptoms of cardiovascular toxicity, and appropriate treatment should be initiated as necessary. 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 a potential risk associated with dasatinib. Therefore, it 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 is another serious risk; thus, maintaining adequate hydration and correcting uric acid levels prior to initiating dasatinib therapy 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. Effective contraception is advised during treatment. In pediatric patients, effects on growth and development, such as delayed epiphyseal fusion, osteopenia, growth retardation, and gynecomastia, have been reported. Monitoring of bone growth and development in this population is essential.

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

Regular monitoring of complete blood counts and liver function tests is recommended 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.

Among the most common adverse reactions occurring in ≥15% of patients receiving dasatinib as a single-agent therapy are 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 necessitate caution when dasatinib is used concomitantly with medications that inhibit platelet function or anticoagulants. Regular monitoring of complete blood counts is recommended, and dasatinib should be interrupted or transfusions administered as indicated. Fluid retention, which can be severe and include pleural effusions, may also occur and 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 could 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 advised in patients who have or may develop QT prolongation.

Severe dermatologic reactions, including individual cases of mucocutaneous reactions, have been reported. Additionally, tumor lysis syndrome has been observed, necessitating adequate hydration and correction of uric acid levels prior to initiating therapy with dasatinib.

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, warranting 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 cause liver dysfunction.

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.

Drug Interactions

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

CYP3A4 Inhibitors and Inducers Co-administration with strong CYP3A4 inhibitors may necessitate a reduction in dosage to mitigate the risk of increased drug exposure and potential adverse effects. Conversely, when used alongside strong CYP3A4 inducers, an increase in dosage may be required to maintain therapeutic efficacy due to enhanced metabolism of the medication.

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

H2 Antagonists and Proton Pump Inhibitors The coadministration of H2 antagonists and proton pump inhibitors is not recommended, as these agents may alter the pharmacokinetics of the medication, potentially leading to reduced therapeutic outcomes.

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 tablets 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 a pediatric study, dasatinib tablets demonstrated safety and efficacy in combination with chemotherapy for pediatric patients aged 1 year and older with newly diagnosed Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL).

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

In a subset of patients aged 2 to 10 years with Ph+ ALL, dasatinib tablets were administered dispersed in juice, resulting in a 36% lower exposure compared to intact tablets. Due to the limited clinical data, it remains unclear whether dispersing dasatinib tablets significantly affects their safety and/or efficacy in pediatric patients.

Geriatric Use

In clinical studies involving dasatinib tablets, 23% of the 2712 patients were aged 65 years and older, with 5% being 75 years of age and older. The efficacy outcomes, including 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 tablets in geriatric patients appears comparable to that of younger patients, it is important to note that 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 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 therapy in this population.

Pregnancy

Based on limited human data, dasatinib tablets 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.

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 risks to the fetus associated with dasatinib use. Given the evidence of fetal harm and the potential for congenital malformations, dasatinib should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

Lactation

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

In a pre- and postnatal development study conducted in rats, administration of dasatinib during gestation 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. Notably, the maternal exposures associated with this outcome were below those observed 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 effects on breastfed infants are not fully established.

Renal Impairment

Patients with renal impairment have not been specifically addressed in terms of dosage adjustments, special monitoring, or safety considerations. Therefore, healthcare professionals should exercise caution when prescribing this medication to individuals with reduced kidney function, as the absence of detailed guidance necessitates careful clinical judgment. Regular monitoring of renal function may be prudent 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

In cases of overdosage, the highest reported intake of 280 mg per day for one week resulted in severe myelosuppression and bleeding in two patients. Healthcare professionals are advised to closely monitor patients who exceed the recommended dosage for signs of myelosuppression and to administer appropriate supportive treatment as necessary.

Animal studies have indicated that acute overdose can lead to significant cardiotoxicity, characterized by ventricular necrosis and hemorrhage, particularly at single doses of 100 mg/kg or greater. Additionally, increased systolic and diastolic blood pressure has been observed in primate models at doses starting from 10 mg/kg.

Given these findings, it is imperative for healthcare providers to remain vigilant in monitoring and managing potential complications associated with overdosage, ensuring that patients receive timely and effective care.

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

Dasatinib tablets have been associated with a range of serious side effects reported through voluntary and surveillance programs.

Low blood cell counts, including anemia, neutropenia, and thrombocytopenia, are common and can be severe. Regular blood tests are recommended to monitor these counts, and patients should contact their healthcare provider immediately if they experience fever or signs of infection.

Bleeding problems, which can be serious and potentially fatal, have also been reported. Patients should seek medical attention for unusual bleeding or bruising, bright red or dark tar-like stools, or neurological symptoms such as decreased alertness or changes in speech.

Fluid retention is frequently observed and may become severe, leading to complications such as pulmonary edema or pericardial effusion. Symptoms warranting immediate medical consultation include generalized swelling, significant weight gain, shortness of breath, dry cough, and chest pain during deep breaths.

Cardiovascular issues, including abnormal heart rates, heart attacks, and transient ischemic attacks (TIAs), have been noted. Monitoring of potassium and magnesium levels, as well as heart function, is advised. Patients should seek urgent care for symptoms such as chest pain, shortness of breath, palpitations, vision changes, or slurred speech.

Pulmonary arterial hypertension (PAH) may develop at any time during treatment. Patients should be monitored for symptoms like shortness of breath, fatigue, and generalized swelling.

Severe skin reactions have been reported, necessitating immediate medical attention if accompanied by fever, sore throat, or skin blistering or peeling.

Tumor lysis syndrome (TLS), resulting from rapid cancer cell breakdown, can lead to kidney failure and abnormal heart rhythms. Patients should be vigilant for symptoms such as nausea, vomiting, weakness, swelling, shortness of breath, muscle cramps, or seizures.

In pediatric patients, dasatinib may affect growth and development, with healthcare providers advised to monitor bone growth closely. Immediate medical attention is recommended for any reports of bone pain.

Liver problems have been associated with dasatinib, particularly in individuals with a history of liver issues. Monitoring of liver function is essential, and patients should seek medical help for symptoms such as abdominal pain, jaundice, loss of appetite, bleeding, bruising, or dark urine.

Patient Counseling

Healthcare providers should advise patients to read the FDA-approved patient labeling (Patient Information) thoroughly to understand the medication's use and potential risks.

Patients should be informed about the possibility of developing low blood cell counts and instructed to immediately report any fever, especially if accompanied by signs of infection. It is crucial to communicate the risk of serious bleeding; patients must be advised to report any unusual bleeding or easy bruising without delay.

Additionally, patients should be made aware of the potential for fluid retention, which may manifest as swelling, weight gain, dry cough, chest pain during respiration, or shortness of breath. They should be encouraged to seek medical attention promptly if they experience any of these symptoms.

Healthcare providers should also inform patients about the risk of cardiovascular toxicity, which may include cardiac ischemic events, fluid retention related to cardiac issues, conduction abnormalities, and transient ischemic attacks (TIAs). Patients must 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.

Furthermore, patients should be informed about 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 notice any of these symptoms.

It is important for 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, necessitating immediate medical attention.

Healthcare providers should counsel pregnant women about the potential risks to a fetus associated with the medication. Additionally, females of reproductive potential and males with female partners of reproductive potential should be advised to use effective contraception to prevent unintended pregnancy during treatment.

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), with permissible excursions between 15°C and 30°C (59°F 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 any exposure to crushed or broken tablets. When handling tablets that are inadvertently crushed or broken, the use of latex or nitrile gloves is recommended to minimize the risk of dermal exposure.

Additional Clinical Information

In patients with chronic phase chronic myeloid leukemia (CML), complete blood counts (CBCs) should be performed every 2 weeks for the first 12 weeks, followed by every 3 months or as clinically indicated. For patients with advanced phase CML or Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL), CBCs are recommended weekly for the first 2 months and then monthly thereafter, or as clinically indicated. Pediatric patients with Ph+ ALL receiving dasatinib tablets in combination with chemotherapy require CBCs prior to each chemotherapy block and as clinically indicated, with CBCs performed every 2 days during consolidation blocks until recovery. Additionally, transaminases should be monitored at baseline and monthly or as clinically indicated during treatment.

Clinicians should counsel patients, particularly females of reproductive potential and males with female partners of reproductive potential, to use effective contraception during treatment with dasatinib tablets and for 30 days following the last dose. 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 Lupin Pharmaceuticals, Inc.. It includes detailed information about indications, dosage, contraindications, warnings, and clinical pharmacology.

View full prescribing information (PDF)