Dasatinib

Description

Dasatinib is chemically identified as 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, with a formula weight of 506.02 for the monohydrate form and a molecular weight of 488.01 for the anhydrous free base. The drug appears as an off-white to yellowish powder and is characterized by its practical insolubility in water, slight to very slight solubility in methanol, and free solubility in dimethyl sulfoxide and N,N-dimethyl formamide.

Dasatinib is formulated as white to off-white, biconvex, film-coated tablets. The inactive ingredients in these tablets include croscarmellose sodium, hydroxypropyl cellulose, lactose anhydrous, magnesium stearate, and microcrystalline cellulose. The tablet coating is composed of hypromellose, polyethylene glycol, 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.

There are no teratogenic or nonteratogenic effects associated with dasatinib.

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, the starting dose should be determined based on body weight, ensuring appropriate dosing adjustments are made according to individual patient needs.

The medication should be taken orally, and it can be administered with or without food. It is important to note that the tablets must not be crushed, cut, or chewed prior to ingestion to maintain their efficacy.

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. Additionally, there are no specific instructions advising against its use in any particular conditions or situations.

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 if such symptoms arise. Additionally, dasatinib has 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 should be discontinued.

QT prolongation is another concern with dasatinib. Caution is warranted in patients who have or may develop a prolonged QT interval.

Severe dermatologic reactions, including mucocutaneous reactions, have been reported in individual cases. Clinicians should remain vigilant for these adverse effects.

Tumor lysis syndrome has been documented in patients receiving dasatinib. To mitigate this risk, it is important to maintain adequate hydration and correct uric acid levels prior to initiating therapy.

Dasatinib poses a risk of embryo-fetal toxicity, and healthcare providers should inform patients of reproductive potential about the potential 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 is advised in this population.

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 essential throughout the course of treatment to ensure patient safety and to manage any emerging complications effectively.

Side Effects

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

Most commonly reported adverse reactions (≥15%) include myelosuppression, fluid retention events, diarrhea, headache, skin rash, hemorrhage, dyspnea, fatigue, nausea, and musculoskeletal pain. Among these, myelosuppression can manifest as severe thrombocytopenia, neutropenia, and anemia, necessitating careful monitoring and management.

Fluid retention, which can be severe and may include pleural effusions, is another significant concern. Patients should be monitored for signs of cardiovascular toxicity, and appropriate treatment should be initiated as needed. Additionally, there is an increased risk of developing pulmonary arterial hypertension (PAH), which may be reversible upon discontinuation of the treatment.

QT prolongation is a potential risk, and caution is advised in patients with a history of or predisposition to this condition. Severe dermatologic reactions, including individual cases of mucocutaneous reactions, have been reported and warrant attention.

Tumor lysis syndrome has also been documented in patients undergoing treatment. Furthermore, the drug has been associated with embryo-fetal toxicity, which can result in fetal harm, including hydrops fetalis, fetal leukopenia, and fetal thrombocytopenia.

In pediatric patients, there are notable effects on growth and development, including delayed fusion of epiphyses, osteopenia, growth retardation, and gynecomastia.

Hepatotoxicity is another critical consideration; liver function should be assessed prior to treatment initiation and monitored monthly thereafter, or as clinically indicated.

Patients aged 65 years and older are particularly susceptible to adverse reactions. Commonly reported reactions in this demographic include fatigue, pleural effusion, diarrhea, dyspnea, cough, lower gastrointestinal hemorrhage, and appetite disturbance. Less frequently reported reactions include abdominal distention, dizziness, pericardial effusion, congestive heart failure, hypertension, pulmonary edema, and weight decrease.

Overall, careful monitoring and management of these adverse reactions are essential to ensure patient safety and treatment efficacy.

Drug Interactions

The use of this medication may result in significant drug interactions that require careful consideration and management.

CYP3A4 Interactions Strong inhibitors of CYP3A4 may necessitate a reduction in dosage to mitigate the risk of increased drug exposure 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 drug levels.

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

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

Dasatinib monotherapy has demonstrated safety and effectiveness in pediatric patients with newly diagnosed chronic phase chronic myeloid leukemia (CML). However, there are no available data regarding its use in children under 1 year of age.

In clinical observations, adverse reactions related to bone growth and development were reported in 5 (5.2%) of pediatric patients. Therefore, it is recommended to monitor bone growth and development in this population.

While additional pediatric use information is approved for Bristol-Myers Squibb Company’s Sprycel (dasatinib) tablets, the drug product is not labeled with that pediatric information due to the company's marketing exclusivity rights.

Geriatric Use

Elderly patients, defined as those 65 years of age and older, comprised 23% of the 2712 patients in clinical studies of dasatinib, with 5% being 75 years of age and older. Clinical findings indicate that there were no significant differences in confirmed Complete Cytogenetic Response (cCCyR) and Major Molecular Response (MMR) between older and younger patients.

Despite the similarity in the overall safety profile of dasatinib between geriatric and younger populations, elderly patients 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, they may 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 these adverse reactions. Healthcare providers should remain vigilant in assessing the safety and efficacy of dasatinib in this population, and appropriate dose adjustments should be made as necessary to mitigate risks.

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. Animal reproduction studies in rats have demonstrated extensive mortality during organogenesis, the fetal period, and in neonates, with skeletal malformations observed in a limited number of surviving rat and rabbit conceptuses. These findings occurred at dasatinib plasma concentrations below those in humans receiving therapeutic doses.

Dasatinib is suspected to cause congenital malformations, including neural tube defects, and harmful pharmacological effects on the fetus when administered during pregnancy. Transplacental transfer of dasatinib has been reported, with dasatinib measured in fetal plasma and amniotic fluid at concentrations comparable to those in maternal plasma. The adverse pharmacologic effects on the fetus are similar to those observed in adult patients and may result in fetal harm or neonatal death.

In nonclinical studies, embryo-fetal toxicities were observed in rats and rabbits at plasma concentrations below those observed in humans receiving therapeutic doses. Fetal death was noted in rats, and the lowest doses of dasatinib tested resulted in embryo-fetal toxicities, producing maternal AUCs of 105 ng•h/mL and 44 ng•h/mL (0.1-fold the human AUC) in rats and rabbits, respectively. These toxicities included skeletal malformations at multiple sites, reduced ossification, edema, and microhepatia.

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 risk to a fetus associated with dasatinib use.

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

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 this patient population.

Hepatic Impairment

Patients with hepatic impairment should undergo a thorough assessment of liver function prior to the initiation of treatment. It is recommended that liver function be monitored on a monthly basis thereafter, or more frequently as clinically indicated.

In cases where this treatment is combined with chemotherapy agents that are known to be associated with liver dysfunction, additional monitoring of liver function is advised to ensure patient safety and to manage any potential adverse effects effectively.

Overdosage

In clinical studies, experience with dasatinib overdose is limited to isolated cases. Notably, the highest reported overdosage involved two patients who ingested 280 mg per day for one week, resulting in severe myelosuppression and bleeding complications.

Healthcare professionals are advised to closely monitor patients who exceed the recommended dosage for signs of myelosuppression. Appropriate supportive treatment should be provided as necessary to manage these adverse effects.

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

In summary, vigilance in monitoring and supportive care is crucial for patients experiencing dasatinib overdose, particularly in light of the potential for severe hematological and cardiovascular complications.

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 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 vigilant for symptoms such as shortness of breath, fatigue, or generalized swelling and report these to their healthcare provider.

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

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

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

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 to their healthcare provider promptly.

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, advising them to seek 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 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.

Breastfeeding is not recommended during treatment with dasatinib tablets and for 2 weeks after the final dose. Patients may experience nausea, vomiting, or diarrhea, 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 may also experience headache or musculoskeletal pain, fatigue, and skin rash while on dasatinib tablets. They should be advised to seek medical attention if any of these symptoms are bothersome or persistent. It is important to inform patients that dasatinib tablets contain lactose anhydrous, with 173 mg in a 100-mg daily dose and 242 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.

If a patient misses a dose of dasatinib tablets, they should take the next scheduled dose at its regular time and should not take two doses at the same time. Lastly, patients should be advised to avoid grapefruit juice, as it may increase the concentration of dasatinib tablets in their blood, thereby increasing the risk of adverse reactions.

Storage and Handling

Dasatinib tablets are supplied in various package configurations. They should be stored at a controlled room temperature of 25°C (77°F), with permissible excursions between 15° to 30°C (59° to 86°F) as per USP guidelines.

Due to the nature of Dasatinib as an antineoplastic product, special handling and disposal procedures must be strictly followed. It is advised that personnel who are pregnant avoid any exposure to crushed or broken tablets. When handling tablets that have been inadvertently crushed or broken, the use of latex or nitrile gloves is recommended to minimize the risk of dermal exposure.

Additional Clinical Information

In patients with chronic phase chronic myeloid leukemia (CML), complete blood counts (CBCs) should be performed every 2 weeks for the first 12 weeks, followed by every 3 months or as clinically indicated. For patients with advanced phase CML or Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL), CBCs are recommended weekly for the initial 2 months, transitioning to monthly thereafter, or as clinically indicated. Additionally, transaminases should be monitored at baseline and monthly during treatment or as clinically indicated.

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

FDA Insert (PDF)

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

View full prescribing information (PDF)