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. Its molecular formula is C22H26ClN7O2S•H2O, and it has 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 powder and is insoluble in water. It is slightly soluble in ethanol, methanol, polyethylene glycol 400, and propylene glycol, very slightly soluble in acetone and acetonitrile, and practically insoluble in corn oil.

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

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 specific teratogenic or nonteratogenic effects have been mentioned in the provided data.

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; however, 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.

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 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 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 should be conducted, 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 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. It is crucial to maintain adequate hydration and correct uric acid levels prior to initiating therapy with dasatinib.

Dasatinib poses a risk of embryo-fetal toxicity, and patients of reproductive potential should be informed of the potential risk 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 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 combined with chemotherapy known to cause liver dysfunction.

Regular monitoring of complete blood counts and liver function is essential throughout the course of treatment to ensure patient safety and manage any adverse effects effectively.

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 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 developing pulmonary arterial hypertension (PAH), which may be reversible upon discontinuation. It is important 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 interval 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 with dasatinib 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, 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 affect liver function.

Geriatric patients, particularly those 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, 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 Interactions Strong inhibitors of CYP3A4 may necessitate a reduction in the dosage of this medication to mitigate the risk of increased plasma concentrations and potential adverse effects. Conversely, strong inducers of CYP3A4 may require an increase in dosage to maintain therapeutic efficacy, as they can lead to decreased plasma levels of the medication.

Gastrointestinal Agents The concurrent use of antacids is not recommended, as they may interfere with the absorption of the medication. Additionally, coadministration with H2 antagonists and proton pump inhibitors should be avoided due to the potential for altered pharmacokinetics, which could affect the medication's effectiveness.

Monitoring and dosage adjustments should be considered based on the specific interactions and the clinical context of the patient.

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 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 tablets have demonstrated safety and effectiveness when used in combination with chemotherapy. Again, there are no data for children under 1 year of age, and one case of grade 1 osteopenia was noted.

The safety profile of dasatinib 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 tablets.

Geriatric Use

In clinical studies involving dasatinib, 23% of the 2,712 patients 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 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 vigilant clinical oversight may be necessary to ensure the safety and efficacy of dasatinib in this population.

Pregnancy

Based on limited human data, dasatinib can cause fetal harm when administered to a pregnant woman. Adverse pharmacologic effects, including hydrops fetalis, fetal leukopenia, and fetal thrombocytopenia, have been reported with maternal exposure to dasatinib. 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, which are 0.1-fold the human AUC.

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

Healthcare providers should advise pregnant patients of the potential risk to the fetus. The estimated background risk in the U.S. general population for 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 can cause fetal harm when administered to a pregnant woman. There is no available data on the excretion of dasatinib in human breast milk or its effects on breastfed infants. Due to the potential risks associated with dasatinib, lactating mothers are advised to use effective contraception during treatment and for 30 days after the last dose. Additionally, based on animal data, dasatinib may result in damage to female and male reproductive tissues, which may have implications for nursing infants. Therefore, the use of dasatinib in lactating mothers should be approached with caution, and the potential risks and benefits should be carefully considered.

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. 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 clinical studies, experience with dasatinib overdose is limited to isolated cases. The highest reported overdosage involved a patient taking 280 mg per day for one week, which resulted in severe myelosuppression and bleeding.

Healthcare professionals are advised to closely monitor patients who ingest more than the recommended dosage for signs of myelosuppression. Appropriate supportive treatment should be provided as necessary to manage these complications.

Animal studies have indicated that acute overdose can lead to significant cardiotoxicity. Specifically, doses of dasatinib at or above 100 mg/kg were associated with ventricular necrosis and hemorrhage. Additionally, increased systolic and diastolic blood pressure was observed in monkeys at single doses of 10 mg/kg or greater.

Given these findings, it is crucial for healthcare providers to remain vigilant in monitoring and managing potential overdose situations to mitigate serious adverse effects.

Nonclinical Toxicology

Dasatinib did not demonstrate teratogenic effects in nonclinical studies. In terms of non-teratogenic effects, dasatinib did not adversely affect 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 reduced size and secretion of seminal vesicles, as well as immature development of the prostate, seminal vesicles, and testes. 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

Dasatinib tablets have been associated with a range of serious side effects reported in postmarketing experience, including:

Low blood cell counts, which are common and can be severe, manifesting as anemia, neutropenia, and thrombocytopenia. 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 are frequently reported and can be serious, potentially leading to fatal outcomes. Patients should seek immediate medical attention for unusual bleeding or bruising, bright red or dark tar-like stools, decreased alertness, headache, or changes in speech.

Fluid retention is another common side effect, which can become severe. Symptoms may include widespread swelling, weight gain, shortness of breath, dry cough, and chest pain during deep breaths. Patients are advised to report these symptoms to their healthcare provider promptly.

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 essential. Patients should seek urgent medical help if they experience chest pain, shortness of breath, palpitations, vision changes, or slurred speech.

Pulmonary arterial hypertension (PAH) may occur at any time during treatment. Patients should be monitored for symptoms such as shortness of breath, fatigue, and fluid retention, and should contact their healthcare provider if these arise.

Severe skin reactions have been reported, which may include fever, sore mouth or throat, and blistering or peeling skin. Immediate medical assistance is recommended for these reactions.

Tumor lysis syndrome (TLS) can result from rapid cancer cell breakdown, leading to kidney failure and abnormal heart rhythms. Symptoms such as nausea, shortness of breath, vomiting, muscle cramps, weakness, seizures, and swelling warrant urgent medical attention.

In pediatric patients, dasatinib tablets may affect bone growth and development, necessitating monitoring by healthcare providers. Parents should seek medical help if their child experiences bone pain.

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

Patient Counseling

Patients should be advised to read the FDA-approved patient labeling (Patient Information) to understand the medication fully. It is important to inform patients 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 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 seeking medical attention if these symptoms occur. Pregnant women should be made aware of the potential risks to a fetus, and both females of reproductive potential and males with female partners of reproductive potential should be advised to use effective contraception during treatment with dasatinib 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.

Breastfeeding is not recommended during treatment with dasatinib and for 2 weeks after the final dose, and patients should be informed of this. Patients may experience nausea, vomiting, or diarrhea while on dasatinib, and they should seek medical attention if these symptoms are bothersome or persistent. Those using antacids should be advised to avoid taking dasatinib and antacids less than 2 hours apart.

Patients may also experience headache or musculoskeletal pain, fatigue, and skin rash while taking dasatinib. They should be encouraged to seek medical attention if any of these symptoms become bothersome or persistent. It is important to inform patients that dasatinib contains lactose monohydrate, with 135 mg in a 100-mg daily dose and 189 mg in a 140-mg daily dose.

Patients should be made aware that dasatinib can cause hepatotoxicity, particularly in those with a history of liver diseases, and 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. If a patient misses a dose of dasatinib, they should take the next scheduled dose at its regular time and should not take two doses simultaneously. Lastly, patients should be advised to avoid grapefruit juice, as it may increase the concentration of dasatinib in their blood, thereby increasing the risk of adverse reactions.

Storage and Handling

The product is supplied in a tight container, adhering to USP guidelines. It 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 to 86°F) as defined by USP Controlled Room Temperature.

Due to the nature of Dasatinib as an antineoplastic agent, special handling and disposal procedures must be followed. Personnel who are pregnant should avoid any exposure to crushed or broken tablets. When handling inadvertently crushed or broken tablets, it is recommended to use latex or nitrile gloves 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 advise 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. 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 Apotex Corp.. It includes detailed information about indications, dosage, contraindications, warnings, and clinical pharmacology.

View full prescribing information (PDF)