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, monohydrate. The molecular formula is C22H26ClN7O2S • H2O, with a formula weight of 506.02 (monohydrate). The anhydrous free base has a molecular weight of 488.01. Dasatinib appears as a white to off-white fine crystalline powder and is insoluble in water, while being slightly soluble in ethanol and methanol. Dasatinib is formulated as white to off-white, beveled edge, film-coated tablets. The tablets contain inactive ingredients including croscarmellose sodium, hydroxypropyl cellulose, lactose monohydrate, magnesium stearate, and microcrystalline cellulose. The coating of the tablets consists of hypromellose 2910, titanium dioxide, and triacetin.

Uses and Indications

Dasatinib tablets are indicated for the treatment of 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 in combination with chemotherapy.

Limitations of use have not been specified in the provided information. There are no 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.

For pediatric patients with chronic phase CML and 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.

Warnings and Precautions

Myelosuppression and Bleeding Events Severe 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. In cases of significant myelosuppression, transfusion may be necessary, and dasatinib should be interrupted as indicated.

Fluid Retention Patients may experience fluid retention, which can be severe and may include pleural effusions. Management should involve supportive care measures and/or dose modification as needed.

Cardiovascular Toxicity Healthcare professionals should monitor patients for any signs or symptoms indicative of cardiovascular toxicity and provide appropriate treatment as necessary.

Pulmonary Arterial Hypertension (PAH) Dasatinib has been associated with an increased risk of developing PAH, which may be reversible upon discontinuation of the drug. It is important to consider baseline risk factors and to evaluate patients for signs and symptoms of PAH throughout the course of treatment. Dasatinib should be discontinued if PAH is confirmed.

QT Prolongation Caution is warranted when administering dasatinib to patients who have or may develop prolongation of the QT interval. Continuous monitoring is recommended.

Severe Dermatologic Reactions Reports of severe mucocutaneous dermatologic reactions have been documented. Healthcare providers should remain vigilant for these reactions.

Tumor Lysis Syndrome Tumor lysis syndrome has been reported in patients receiving dasatinib. Adequate hydration and correction of uric acid levels should be ensured prior to initiating therapy.

Embryo-Fetal Toxicity 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.

Effects on Growth and Development in Pediatric Patients In pediatric patients, dasatinib may lead to delayed epiphyseal fusion, osteopenia, growth retardation, and gynecomastia. Monitoring of bone growth and development is recommended in this population.

Hepatotoxicity Prior to initiating treatment with dasatinib, liver function should be assessed. Monthly monitoring of liver function is advised thereafter, or more frequently if clinically indicated, especially when dasatinib is used in conjunction with chemotherapy known to affect liver function.

General Precautions Regular monitoring of complete blood counts is essential throughout treatment. Fluid retention should be managed with supportive care measures and/or dose adjustments. Continuous evaluation for cardiovascular toxicity and signs of PAH is necessary. Caution should be exercised in patients with a risk of QT interval prolongation. Pediatric patients require careful monitoring of bone growth and development. Liver function assessments should be conducted before treatment initiation and monthly thereafter, or as clinically indicated.

Side Effects

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

Most common adverse reactions occurring in ≥15% of patients receiving dasatinib as a single-agent therapy include myelosuppression, fluid retention events, diarrhea, headache, skin rash, hemorrhage, dyspnea, fatigue, nausea, and musculoskeletal pain. In pediatric patients receiving dasatinib in combination with chemotherapy, adverse reactions occurring in ≥30% of participants include mucositis, febrile neutropenia, pyrexia, diarrhea, nausea, vomiting, musculoskeletal pain, abdominal pain, cough, headache, rash, fatigue, constipation, arrhythmia, hypertension, edema, infections (bacterial, viral, and fungal), hypotension, decreased appetite, hypersensitivity, dyspnea, epistaxis, peripheral neuropathy, and altered state of consciousness.

Serious adverse reactions include severe thrombocytopenia, neutropenia, and anemia, which may necessitate caution when dasatinib is used concomitantly with medications that inhibit platelet function or anticoagulants. Regular monitoring of complete blood counts is recommended, with transfusions and interruption of dasatinib as indicated. Fluid retention, which can be severe and include pleural effusions, should be managed with supportive care measures and/or dose modification.

Patients should be monitored for cardiovascular toxicity, including signs or symptoms of pulmonary arterial hypertension (PAH), which may be reversible upon discontinuation of dasatinib. If PAH is confirmed, dasatinib should be stopped. Caution is also advised in patients who have or may develop QT prolongation.

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

Dasatinib is associated with embryo-fetal toxicity, and patients of reproductive potential should be informed of the potential risk to the fetus and advised to use effective contraception. In pediatric patients, effects on growth and development such as delayed epiphyseal fusion, osteopenia, growth retardation, and gynecomastia have been reported, necessitating monitoring of bone growth and development.

Hepatotoxicity is another concern, with liver function assessments recommended before initiation of treatment and monthly thereafter, or as clinically indicated, especially when combined with chemotherapy known to affect liver function.

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

Drug Interactions

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

Pharmacokinetic Interactions

CYP3A4 Inhibitors Co-administration with strong CYP3A4 inhibitors may necessitate a reduction in the dosage of this medication to mitigate the risk of increased plasma concentrations and potential adverse effects.

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

Pharmacodynamic Interactions

Antacids It is advised to avoid the 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 is not recommended, as these agents may alter the pharmacokinetics of this medication, potentially leading to reduced effectiveness.

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

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

The safety profile of dasatinib tablets in pediatric subjects is comparable to that observed in adult studies. It is recommended to monitor bone growth and development in pediatric patients receiving dasatinib.

In a small cohort of five patients with Ph+ ALL aged 2 to 10 years, dasatinib tablets were administered dispersed in juice. The exposure from dispersed tablets was found to be 36% lower compared to intact tablets. Due to the limited clinical data, it remains unclear whether this method of administration significantly affects the safety and/or efficacy of dasatinib.

Geriatric Use

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, 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, elderly patients 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 essential that patients aged 65 years and older be monitored closely for the emergence of these adverse reactions. Appropriate dose adjustments and vigilant clinical oversight may be warranted 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. The transplacental transfer of dasatinib has been documented, with dasatinib detected in fetal plasma and amniotic fluid at concentrations comparable to those in maternal plasma.

Animal reproduction studies have demonstrated extensive mortality during organogenesis, the fetal period, and in neonates. In these studies, skeletal malformations were observed in a limited number of surviving rat and rabbit conceptuses, occurring at dasatinib plasma concentrations below those seen in humans receiving therapeutic doses. Specifically, embryo-fetal toxicities, including skeletal malformations at multiple sites (scapula, humerus, femur, radius, ribs, and clavicle), reduced ossification, edema, and microhepatia, were noted in both rats and rabbits at the lowest doses tested. These doses produced maternal AUCs of 105 ng•h/mL and 44 ng•h/mL (0.1-fold the human AUC) in rats and rabbits, respectively.

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 providers should advise pregnant patients of the potential risk to a fetus. The estimated background risk in the U.S. general population of major birth defects is 2% to 4%, and the risk of miscarriage is 15% to 20% of clinically recognized pregnancies. Given the potential for serious adverse effects, dasatinib should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

Lactation

Dasatinib is suspected to cause congenital malformations, including neural tube defects, and may have harmful pharmacological effects on the fetus when administered during pregnancy. Currently, there are no data available regarding the presence of dasatinib in human milk, the effects of the drug on breastfed infants, or its impact on milk production. However, studies in lactating rats indicate that dasatinib is present in breast milk.

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

Renal Impairment

Patients with renal impairment may not have specific dosage adjustments, special monitoring, or safety considerations outlined in the available data. Therefore, healthcare professionals should exercise caution when prescribing to this population, as the lack of information necessitates careful clinical judgment regarding the use of the medication in individuals with reduced kidney function. 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. 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

Patients who exceed the recommended dosage of dasatinib should be closely monitored for signs of myelosuppression, as significant adverse effects have been documented. In clinical experience, the highest reported overdose involved a dosage of 280 mg per day for one week, which resulted in severe myelosuppression and bleeding complications.

In the event of an overdose, it is imperative to provide appropriate supportive treatment tailored to the patient's clinical presentation. Continuous monitoring for myelosuppression is essential, as this condition can lead to serious hematological complications.

Animal studies have demonstrated that acute overdoses can lead to cardiotoxicity, with evidence of ventricular necrosis and hemorrhage observed at single doses of 100 mg/kg or greater. Additionally, increased systolic and diastolic blood pressure has been noted in primate models at doses starting from 10 mg/kg. These findings underscore the importance of vigilance in managing patients who may have ingested dosages exceeding the recommended levels.

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, 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 in an in vitro bacterial cell assay (Ames test) and did not demonstrate 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 chest pain, shortness of breath, palpitations, transient vision changes, or slurred speech.

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

Severe skin reactions, including those accompanied by fever, sore throat, or blistering, have been reported. Immediate medical assistance is recommended for these reactions.

Tumor lysis syndrome (TLS), characterized by rapid breakdown of cancer cells, can lead to kidney failure and abnormal heart rhythms. Symptoms such as nausea, vomiting, shortness of breath, weakness, muscle cramps, swelling, and seizures require urgent medical attention.

In pediatric patients, dasatinib may affect growth and development, necessitating monitoring of bone growth. Medical help should be sought if bone pain occurs.

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

Fertility issues in both males and females have also been noted, and patients are encouraged to discuss any concerns with their healthcare provider.

Patient Counseling

Patients should be advised to read the FDA-approved patient labeling (Patient Information) thoroughly. It is important to inform them about the potential for developing low blood cell counts and to encourage them to report any fever, especially if accompanied by signs of infection, immediately.

Patients should be made aware of the risk of serious bleeding and instructed to report any unusual bleeding or easy bruising without delay. Additionally, they should be informed about the possibility of fluid retention, which may present as swelling, weight gain, dry cough, chest pain during respiration, or shortness of breath. Patients experiencing these symptoms should seek medical attention promptly.

Healthcare providers should discuss the risk of cardiovascular toxicity with patients, which may include cardiac ischemic events, fluid retention related to cardiac issues, conduction abnormalities, and transient ischemic attacks (TIAs). Patients should be advised to seek immediate medical attention if they experience symptoms 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 potential development of pulmonary arterial hypertension, characterized by dyspnea, fatigue, hypoxia, and fluid retention, and should be advised to seek medical attention if these symptoms arise. It is crucial to inform patients to report any symptoms such as nausea, vomiting, weakness, edema, shortness of breath, muscle cramps, and seizures, as these may indicate tumor lysis syndrome.

For pediatric patients and their caregivers, it is important to discuss the possibility of bone growth abnormalities, bone pain, or gynecomastia, and to advise them to seek medical attention promptly if these symptoms occur. Pregnant women should be made aware of the potential risks to a fetus.

Healthcare providers should counsel 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. Females should be advised to contact their healthcare provider if they become pregnant or suspect they may be pregnant while taking dasatinib tablets. Additionally, breastfeeding is not recommended during treatment with dasatinib tablets and for 2 weeks after the final dose.

Patients may experience nausea, vomiting, or diarrhea while taking dasatinib tablets, and they should be advised to seek medical attention if these symptoms are bothersome or persistent. Those using antacids should be instructed to avoid taking dasatinib tablets and antacids less than 2 hours apart.

Patients should be informed that headache or musculoskeletal pain may occur with dasatinib tablets, and they should seek medical attention if these symptoms are bothersome or persistent. Fatigue and skin rash are also potential side effects, and patients should be advised to report these symptoms if they become bothersome.

It is important to inform patients that dasatinib tablets contain lactose monohydrate, with 131 mg in a 100 mg daily dose and 184 mg in a 140 mg daily dose. Patients should be made aware of the risk of hepatotoxicity associated with dasatinib tablets, particularly for those with a history of liver diseases. They should seek immediate medical attention if they experience symptoms suggestive of hepatotoxicity, such as abdominal pain, jaundice, scleral icterus, anorexia, bleeding, bruising, or dark-colored urine.

Patients should be advised on the proper dosing schedule, specifically that if they miss a dose of dasatinib tablets, they should take the next scheduled dose at its regular time and not take two doses simultaneously. Lastly, patients should be cautioned against consuming grapefruit juice, as it may increase the concentration of dasatinib tablets in their blood, thereby elevating the risk of adverse reactions.

Storage and Handling

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

Due to the nature of dasatinib as an antineoplastic product, special handling and disposal procedures must be followed. It is advised that personnel who are pregnant avoid 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 and then monthly thereafter, or as clinically indicated. Pediatric patients with Ph+ ALL receiving dasatinib in combination with chemotherapy require CBCs prior to each chemotherapy block and as clinically indicated, with CBCs performed every 2 days during consolidation chemotherapy until recovery. Additionally, transaminases should be monitored at baseline and monthly or as clinically indicated throughout treatment.

Clinicians should counsel patients, particularly females of reproductive potential and males with female partners of reproductive potential, to utilize effective contraception during dasatinib treatment and for 30 days following the last dose.

FDA Insert (PDF)

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

View full prescribing information (PDF)