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. The molecular formula is C22H26ClN7O2S • H2O, with a formula weight of 506.02 for the monohydrate and 488.01 for the anhydrous free base. Dasatinib appears as a white to off-white powder and is characterized by its insolubility in water, slight solubility in ethanol, methanol, polyethylene glycol 400, and propylene glycol, very slight solubility in acetone and acetonitrile, and practical insolubility 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, including 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 teratogenic or nonteratogenic effects have been reported.

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 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. Caution is advised when administering dasatinib concomitantly with medications that inhibit platelet function or anticoagulants. Regular monitoring of complete blood counts is essential, and transfusions should be administered as necessary. 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 may require supportive care measures and/or dose modifications.

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 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 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 therapy with dasatinib is critical.

Dasatinib poses a risk of embryo-fetal toxicity, and patients of reproductive potential should be informed of the potential risks to the fetus and advised to use effective contraception. In pediatric patients, dasatinib may affect growth and development, leading to delayed epiphyseal fusion, osteopenia, growth retardation, and gynecomastia. Monitoring of bone growth and development in this population is recommended.

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 used in conjunction with chemotherapy known to cause liver dysfunction.

Regular monitoring of complete blood counts and liver function is essential throughout the treatment course.

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.

Severe myelosuppression, including thrombocytopenia, neutropenia, and anemia, may occur. Caution is advised when dasatinib is used concomitantly with medications that inhibit platelet function or anticoagulants, and regular monitoring of complete blood counts is recommended. Transfusion and interruption of dasatinib therapy may be necessary when 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 signs and symptoms of cardiovascular toxicity, and appropriate treatment should be administered as needed.

Dasatinib may increase the risk of developing pulmonary arterial hypertension (PAH), which may be reversible upon discontinuation of the drug. Baseline risk should be considered, and patients should be evaluated for signs and symptoms of PAH during treatment. Dasatinib should be discontinued if PAH is confirmed. Caution is also advised in patients who have or may develop prolongation of the QT interval.

Severe mucocutaneous dermatologic reactions have been reported in individual cases. 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 can cause fetal harm; thus, patients of reproductive potential should be advised of the potential risk to the fetus and the necessity of using effective contraception. In pediatric patients, effects on growth and development, such as delayed fusion of epiphyses, osteopenia, growth retardation, and gynecomastia, have been reported, necessitating monitoring of bone growth and development.

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

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 more likely to experience 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 may be affected by various drug interactions, which can be categorized into pharmacokinetic interactions based on the involvement of cytochrome P450 enzymes and other drug classes.

CYP3A4 Interactions

• Strong CYP3A4 Inhibitors: Co-administration with strong CYP3A4 inhibitors may necessitate a dose reduction of the medication to mitigate the risk of increased plasma concentrations and potential adverse effects.

• Strong CYP3A4 Inducers: When used in conjunction with strong CYP3A4 inducers, an increase in the medication dosage may be required to achieve the desired therapeutic effect, as these inducers can lower plasma levels of the drug.

Gastrointestinal Agents

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

• H2 Antagonists and Proton Pump Inhibitors: Co-administration of H2 antagonists and proton pump inhibitors should be avoided due to the potential for altered pharmacokinetics, which may affect the therapeutic outcomes of the medication.

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 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. Adverse reactions related to bone growth and development were observed 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, no data exist for children under 1 year of age, and one case of grade 1 osteopenia was reported in this population.

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, the impact of dispersing dasatinib tablets on safety and efficacy remains unclear.

Geriatric Use

In clinical studies involving dasatinib, 23% of the 2,712 patients evaluated were aged 65 years and older, with 5% being 75 years and older. The efficacy of dasatinib, as measured by confirmed Complete Cytogenetic Response (cCCyR) and Major Molecular Response (MMR), did not differ significantly between older and younger patients.

However, the safety profile of dasatinib in geriatric patients warrants careful consideration. Patients aged 65 years and older are more likely to experience commonly reported adverse reactions, including fatigue, pleural effusion, diarrhea, dyspnea, cough, lower gastrointestinal hemorrhage, and appetite disturbance. Additionally, they may also be at increased risk for less frequently reported adverse reactions such as abdominal distention, dizziness, pericardial effusion, congestive heart failure, hypertension, pulmonary edema, and weight decrease.

Given these findings, it is essential that elderly patients receiving dasatinib are monitored closely for these adverse effects. Healthcare providers should consider appropriate dose modifications and implement vigilant monitoring strategies to ensure the safety and well-being of geriatric patients during treatment.

Pregnancy

Dasatinib is associated with potential fetal harm when administered to pregnant patients. Limited human data indicate that dasatinib can cause adverse pharmacologic effects, including hydrops fetalis, fetal leukopenia, and fetal thrombocytopenia, following maternal exposure. These effects are similar to those observed in adult patients and may lead to significant fetal harm or neonatal death.

Animal reproduction studies have demonstrated extensive mortality during organogenesis, the fetal period, and in neonates. In these studies, skeletal malformations were noted in a limited number of surviving rat and rabbit conceptuses, occurring at dasatinib plasma concentrations below those observed in humans receiving therapeutic doses. Furthermore, embryo-fetal toxicities, including fetal death, reduced ossification, edema, and microhepatia, were observed in both rats and rabbits at doses that produced maternal AUCs significantly lower than those seen in humans.

Dasatinib has been shown to cross the placenta, with measurable concentrations found in fetal plasma and amniotic fluid that are comparable to maternal plasma levels. Based on human experience, dasatinib is suspected to cause congenital malformations, including neural tube defects, when administered during pregnancy.

Healthcare professionals should advise pregnant women of the potential risks to the fetus associated with dasatinib use. 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.

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. Notably, the highest reported overdose involved a dosage of 280 mg per day for one week, which occurred in two patients. Both individuals experienced severe myelosuppression and bleeding as a result of this overdose.

Given the association of dasatinib with severe myelosuppression, it is imperative that healthcare professionals closely monitor patients who exceed the recommended dosage. Appropriate supportive treatment should be administered as necessary to manage any signs of myelosuppression.

Additionally, animal studies have indicated that acute overdose may lead to cardiotoxicity. Evidence of such cardiotoxicity includes ventricular necrosis and hemorrhage in the valvular, ventricular, and atrial regions, observed at single doses of 100 mg/kg (600 mg/m²) in rodent models. Furthermore, a tendency for increased systolic and diastolic blood pressure has been noted in monkeys at single doses of 10 mg/kg (120 mg/m²).

In summary, healthcare professionals should remain vigilant for symptoms of myelosuppression and cardiotoxicity in patients who have ingested dasatinib in excess of the recommended dosage, ensuring that appropriate monitoring and supportive care are provided.

Nonclinical Toxicology

Dasatinib did not demonstrate teratogenic effects in nonclinical studies. In terms of non-teratogenic effects, dasatinib did not impact 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 a reduction in the size and secretion of seminal vesicles, as well as the presence of immature prostate, seminal vesicle, and testis. 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

Postmarketing experience has identified several adverse reactions associated with dasatinib, reported voluntarily or through surveillance programs. These include myelosuppression, serious bleeding, fluid retention, and cardiovascular toxicity, which encompasses cardiac ischemic events, cardiac-related fluid retention, conduction abnormalities, and transient ischemic attacks (TIAs). Additionally, pulmonary arterial hypertension, tumor lysis syndrome, and bone growth abnormalities, including bone pain and gynecomastia in pediatric patients, have been noted. There is also a potential for embryo-fetal toxicity.

Patients are advised to report any symptoms indicative of these conditions promptly. Symptoms to monitor include fever, particularly when associated with signs of infection; unusual bleeding or easy bruising; swelling, weight gain, dry cough, chest pain upon respiration, or shortness of breath; chest pain, shortness of breath, palpitations, transient vision problems, or slurred speech; dyspnea, fatigue, hypoxia, and fluid retention; as well as nausea, vomiting, weakness, edema, muscle cramps, and seizures. Pediatric patients should be monitored for bone growth abnormalities, bone pain, or gynecomastia.

Pregnant women are cautioned about the potential risks to a fetus and are advised to contact their healthcare provider if they become pregnant or suspect pregnancy while undergoing treatment with dasatinib. Effective contraception is recommended for females of reproductive potential during treatment and for 30 days following the last dose, as well as for males with female partners of reproductive potential.

Patient Counseling

Healthcare providers should advise patients to read the FDA-approved patient labeling (Patient Information) to ensure they are well-informed about their treatment. It is important to inform patients about the potential risk of developing low blood cell counts and to instruct them to immediately report any fever, especially if accompanied by signs of infection.

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

Healthcare providers should also discuss the risk of cardiovascular toxicity, which may include cardiac ischemic events, cardiac-related fluid retention, conduction abnormalities, and transient ischemic attacks (TIAs). Patients should be instructed 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 potential development of pulmonary arterial hypertension, characterized by dyspnea, fatigue, hypoxia, and fluid retention. They should be advised to seek medical attention promptly if they experience these symptoms.

It is crucial to inform patients to report and seek medical attention immediately for any symptoms such as nausea, vomiting, weakness, edema, shortness of breath, muscle cramps, and seizures, as these may indicate tumor lysis syndrome.

For pediatric patients and their caregivers, healthcare providers should discuss the possibility of bone growth abnormalities, bone pain, or gynecomastia, advising them to seek medical attention promptly if these symptoms arise.

Pregnant women should be advised of the potential risks to a fetus associated with treatment. Additionally, healthcare providers should counsel females of reproductive potential and males with female partners of reproductive potential 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 they may be pregnant while taking dasatinib.

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.

Special handling and disposal procedures must be followed for Dasatinib, an antineoplastic agent. 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 initial 2 months, transitioning to 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 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 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 Apotex Corp.. It includes detailed information about indications, dosage, contraindications, warnings, and clinical pharmacology.

View full prescribing information (PDF)