Sprycel

Description

SPRYCEL (dasatinib) is a kinase inhibitor indicated for the treatment of certain types of cancer. 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. Its molecular formula is C22H26ClN7O2S • H2O, with a formula weight of 506.02 for the monohydrate form and an anhydrous free base molecular weight of 488.01.

Dasatinib appears as a white to off-white powder and is characterized by its insolubility in water, with slight solubility in ethanol and methanol. SPRYCEL is formulated as white to off-white, biconvex, film-coated tablets containing dasatinib. The inactive ingredients in the tablet formulation include lactose monohydrate, microcrystalline cellulose, croscarmellose sodium, hydroxypropyl cellulose, and magnesium stearate. The tablet coating is composed of hypromellose, titanium dioxide, and polyethylene glycol.

Uses and Indications

SPRYCEL 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, SPRYCEL 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, SPRYCEL 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 or Ph+ ALL, the starting dose should be determined based on body weight.

The medication may be taken with or without food. It is important to note that the tablets should not be crushed, cut, or chewed prior to administration.

Contraindications

There are no contraindications associated with the use of this product. It is not classified as a controlled substance, and there are no identified risks of abuse, misuse, or dependence.

Warnings and Precautions

Myelosuppression and bleeding events are significant risks associated with the use of SPRYCEL. Severe thrombocytopenia, neutropenia, and anemia may occur, necessitating caution when administering SPRYCEL alongside medications that inhibit platelet function or anticoagulants. Regular monitoring of complete blood counts is essential, and transfusions should be administered as needed. Treatment with SPRYCEL should be interrupted if indicated.

Fluid retention, which can be severe and may include pleural effusions, has been observed in patients receiving SPRYCEL. Management of fluid retention should involve supportive care measures and/or dose modifications as necessary.

Patients should be closely monitored for signs or symptoms of cardiovascular toxicity, and appropriate treatment should be initiated as required. Additionally, there is an increased risk of developing pulmonary arterial hypertension (PAH) with SPRYCEL use. It is crucial to consider baseline risk factors and evaluate patients for signs and symptoms of PAH throughout the treatment course. If PAH is confirmed, SPRYCEL should be discontinued.

QT prolongation is another concern; therefore, SPRYCEL should be used with caution in patients who have or may develop a prolonged QT interval. Severe dermatologic reactions, including individual cases of mucocutaneous reactions, have been reported and warrant careful monitoring.

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

Embryo-fetal toxicity is a potential risk associated with SPRYCEL, and healthcare providers should advise patients of reproductive potential regarding the risk to the fetus. Effective contraception should be utilized.

In pediatric patients, effects on growth and development have been noted, including delayed epiphyseal fusion, osteopenia, growth retardation, and gynecomastia. Monitoring of bone growth and development in this population is recommended.

Hepatotoxicity is another critical consideration; liver function should be assessed before the initiation of treatment and monitored monthly thereafter, or as clinically indicated. This is particularly important when SPRYCEL 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 treatment with SPRYCEL to ensure patient safety and manage potential adverse effects effectively.

Side Effects

Adverse reactions associated with SPRYCEL include a range of common and serious events.

Most commonly reported adverse reactions in adult patients include myelosuppression, fluid retention events, diarrhea, headache, skin rash, hemorrhage, dyspnea, fatigue, nausea, and musculoskeletal pain. Myelosuppression may manifest as severe thrombocytopenia, neutropenia, and anemia, necessitating caution when used with medications that inhibit platelet function or anticoagulants. Regular monitoring of complete blood counts is recommended, with transfusions and interruption of SPRYCEL indicated as necessary.

Fluid retention, which can be severe and include pleural effusions, should be managed with supportive care measures and/or dose modifications. Patients should be monitored for cardiovascular toxicity, and appropriate treatment should be administered as needed. Additionally, SPRYCEL may increase the risk of 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 SPRYCEL if PAH is confirmed. Caution is also advised in patients who have or may develop QT interval prolongation.

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

In pediatric patients, the most common adverse reactions include mucositis, febrile neutropenia, pyrexia, diarrhea, nausea, vomiting, musculoskeletal pain, abdominal pain, cough, headache, rash, fatigue, constipation, arrhythmia, hypertension, edema, and various infections. Additional concerns include hypotension, decreased appetite, hypersensitivity, dyspnea, epistaxis, peripheral neuropathy, and altered states of consciousness. Notably, 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 in this population.

Hepatotoxicity is another important consideration; liver function should be assessed before treatment initiation and monitored monthly thereafter or as clinically indicated, especially when combined with chemotherapy known to affect liver function.

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

Lastly, SPRYCEL has been associated with embryo-fetal toxicity, and patients of reproductive potential should be advised of the potential risk to the fetus and the necessity of using effective contraception during treatment.

Drug Interactions

The use of this medication may result in significant drug interactions, which are categorized as follows:

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, due to the potential for reduced plasma concentrations.

Gastrointestinal Agents

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

• H2 Antagonists and Proton Pump Inhibitors: Co-administration with H2 antagonists or proton pump inhibitors should be avoided to prevent potential interactions that could compromise the medication's effectiveness.

Monitoring and dosage adjustments should be considered based on the specific clinical scenario and the presence of any interacting agents.

Packaging & NDC

The table below lists all NDC Code configurations of Sprycel (dasatinib), the U.S. brand-name prescription product. Columns show Packaging, Formulation Type, and Active Ingredient Strength.

Pediatric Use

The safety and effectiveness of SPRYCEL 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), the safety and effectiveness of SPRYCEL in combination with chemotherapy have also been demonstrated. Again, there are no data for children under 1 year of age, and one case of grade 1 osteopenia was reported in this population.

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

In a small cohort of five patients with Ph+ ALL aged 2 to 10 years, SPRYCEL 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 SPRYCEL.

Geriatric Use

In clinical studies of SPRYCEL, 23% of the 2712 patients enrolled 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 older and younger patients.

While the overall safety profile of SPRYCEL in geriatric patients appears comparable to that of younger patients, it is important to note that elderly patients, particularly those aged 65 years and older, are at an increased risk for several commonly reported adverse reactions. These include fatigue, pleural effusion, diarrhea, dyspnea, cough, lower gastrointestinal hemorrhage, and appetite disturbance. Additionally, they may also experience less frequently reported adverse reactions such as abdominal distention, dizziness, pericardial effusion, congestive heart failure, hypertension, pulmonary edema, and weight decrease.

Given these considerations, it is recommended that patients aged 65 years and older be monitored closely for the emergence of these adverse reactions. Appropriate dose adjustments and careful management may be necessary to ensure the safety and efficacy of treatment in this population.

Pregnancy

Based on limited human data, SPRYCEL (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 SPRYCEL. Animal reproduction studies in rats have demonstrated extensive mortality during organogenesis, the fetal period, and in neonates. Skeletal malformations were observed in a limited number of surviving rat and rabbit conceptuses, occurring at dasatinib plasma concentrations below those in humans receiving therapeutic doses. Therefore, it is essential to advise pregnant patients of the potential risk to a 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. 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, such as hydrops fetalis, fetal leukopenia, and fetal thrombocytopenia, are similar to those observed in adult patients and may result in fetal harm or neonatal death.

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 nonclinical studies, embryo-fetal toxicities were observed in rats and rabbits at plasma concentrations below those seen in humans receiving therapeutic doses. Fetal death was noted in rats, and the lowest doses 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 below those in patients treated with dasatinib at the recommended labeling dose. Given these findings, healthcare professionals should carefully consider the risks and benefits of dasatinib therapy in pregnant patients and those of childbearing potential.

Lactation

Administration of dasatinib from gestation day (GD) 16 through lactation day (LD) 20, GD 21 through LD 20, or LD 4 through LD 20 resulted in extensive pup mortality at maternal exposures that were below the exposures in patients treated with dasatinib at the recommended labeling dose.

Given the potential for serious adverse effects, lactating mothers are advised to avoid the use of dasatinib while breastfeeding. The risks to breastfed infants are not fully characterized, but the observed pup mortality in animal studies raises significant concerns regarding the safety of dasatinib during lactation.

Renal Impairment

Patients with renal impairment have not been specifically addressed in the available data regarding dosage adjustments, special monitoring, or safety considerations. Therefore, healthcare professionals should exercise caution when prescribing this medication to patients with reduced kidney function, as the lack of information necessitates careful clinical judgment and monitoring.

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 overdose of SPRYCEL has been limited to isolated cases. Notably, the highest reported overdosage involved two patients who ingested 280 mg per day for one week. Both individuals developed severe myelosuppression and experienced bleeding complications.

Given the association of SPRYCEL 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 arising complications.

Animal studies have indicated that acute overdose may lead to cardiotoxicity. Evidence of such cardiotoxicity includes findings of ventricular necrosis and hemorrhage in the valvular, ventricular, and atrial regions at single doses of 100 mg/kg (600 mg/m²) or higher in rodent models. Additionally, in primate studies, there was a noted tendency for increased systolic and diastolic blood pressure at doses of 10 mg/kg (120 mg/m²) or greater.

In summary, healthcare professionals should remain vigilant for signs of myelosuppression and cardiotoxicity in patients who have overdosed on SPRYCEL, ensuring that appropriate monitoring and supportive care are provided.

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

Postmarketing experience has identified several adverse events reported voluntarily or through surveillance programs.

Myelosuppression has been noted, with recommendations for patients to be informed about the potential for low blood cell counts. Patients should be advised to report any fever, particularly in conjunction with signs of infection.

Bleeding events have also been reported, and patients are encouraged to be aware of the possibility of serious bleeding. They should seek immediate medical attention for any signs or symptoms suggestive of hemorrhage, such as unusual bleeding or easy bruising.

Fluid retention is another concern, with patients advised to be vigilant for symptoms including swelling, weight gain, dry cough, chest pain on respiration, or shortness of breath. Prompt medical attention is recommended if these symptoms occur.

Cardiovascular toxicity has been associated with the use of the product, including cardiac ischemic events, cardiac-related fluid retention, conduction abnormalities, and transient ischemic attacks (TIAs). Patients should be informed of the potential for these events and advised to seek immediate medical attention for symptoms such as chest pain, shortness of breath, palpitations, transient vision problems, or slurred speech.

The development of pulmonary arterial hypertension has been reported, with symptoms including dyspnea, fatigue, hypoxia, and fluid retention. Patients should be instructed to seek medical attention promptly if they experience these symptoms.

Tumor lysis syndrome has been identified as a potential risk, and patients should be informed to report any symptoms such as nausea, vomiting, weakness, edema, shortness of breath, muscle cramps, and seizures, which may indicate this condition.

In pediatric patients, there is a possibility of growth and development issues, including bone growth abnormalities, bone pain, or gynecomastia. Caregivers should be advised to seek medical attention promptly if these symptoms arise.

Patient Counseling

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

Patients should also be made aware of the risk of serious bleeding. They should be instructed to report any signs or symptoms suggestive of hemorrhage, such as unusual bleeding or easy bruising, without delay. Additionally, patients need to be informed about the potential for 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 discuss the risk of cardiovascular toxicity with patients, 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.

Patients should also be informed about the possibility of developing pulmonary arterial hypertension, characterized by dyspnea, fatigue, hypoxia, and fluid retention. They should be advised to seek medical attention promptly if they experience any of these symptoms.

Furthermore, patients must be informed 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, it is essential to communicate the risk of developing bone growth abnormalities, bone pain, or gynecomastia. They should be advised to seek medical attention promptly if any of these symptoms arise.

Storage and Handling

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

Due to the nature of SPRYCEL 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 inadvertently crushed or broken tablets, 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. Pediatric patients with Ph+ ALL receiving SPRYCEL in combination with chemotherapy require CBCs prior to each chemotherapy block and as clinically indicated, with CBCs conducted 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 SPRYCEL and for 30 days following the last dose.

FDA Insert (PDF)

This document is the official FDA-approved prescribing information for Sprycel as submitted by E. R. Squibb & Sons, L. L. C.. It includes detailed information about indications, dosage, contraindications, warnings, and clinical pharmacology.

View full prescribing information (PDF)