Phyrago

Description

PHYRAGO (dasatinib) is a kinase inhibitor. The chemical name for dasatinib (anhydrous) is N-(2-chloro-6-methylphenyl)-2-[[6-4-(2-hydroxyethyl)-1-piperazinyl-2-methyl-4-pyrimidinyl]amino]-5-thiazolecarboxamide. The molecular formula is C22H26ClN7O2S, with a formula weight of 488.01. Dasatinib (anhydrous) appears as a white to light yellow powder and is insoluble in water, with slight solubility in ethanol and methanol. PHYRAGO is supplied as white to light yellow, biconvex, immediate release tablets for oral use, containing dasatinib (anhydrous). Inactive ingredients include croscarmellose sodium, dibasic calcium phosphate, magnesium stearate, methacrylic acid-ethyl acrylate copolymer, microcrystalline cellulose, propyl gallate, and silica dimethyl silylate.

Uses and Indications

PHYRAGO 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, PHYRAGO 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, PHYRAGO 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 diagnosed with chronic phase CML or 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. Therefore, the product can be used without specific restrictions related to contraindications.

Warnings and Precautions

Severe myelosuppression, including thrombocytopenia, neutropenia, and anemia, may occur with the use of PHYRAGO. Caution is advised when administering this medication concomitantly with agents that inhibit platelet function or anticoagulants. Regular monitoring of complete blood counts is essential, and transfusions should be administered as necessary. Interrupting PHYRAGO therapy may be required based on clinical judgment.

Fluid retention, which can be severe and may include pleural effusions, has been observed in patients. Management of this condition should involve supportive care measures and, if necessary, dose modifications.

Patients should be closely monitored for signs and symptoms of cardiovascular toxicity, and appropriate treatment should be initiated as needed. Additionally, PHYRAGO has the potential to increase the risk of developing pulmonary arterial hypertension (PAH). It is crucial to evaluate patients for baseline risk factors and to monitor for any signs or symptoms of PAH throughout the treatment course. If PAH is confirmed, PHYRAGO should be discontinued.

QT prolongation is another concern associated with PHYRAGO. 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 also been documented. To mitigate this risk, it is important to ensure adequate hydration and to correct uric acid levels prior to initiating therapy with PHYRAGO.

Embryo-fetal toxicity is a significant risk associated with PHYRAGO. Healthcare providers should inform patients of reproductive potential about the potential risks to the fetus and recommend the use of effective contraception during treatment.

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 is essential in this population.

Hepatotoxicity is a potential risk, necessitating assessment of liver function prior to the initiation of treatment and monthly thereafter, or as clinically indicated. This monitoring is particularly important when PHYRAGO is used in conjunction with chemotherapy agents known to cause liver dysfunction.

Regular monitoring of complete blood counts and liver function tests is recommended to ensure patient safety throughout the treatment process.

Side Effects

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

Common adverse reactions include myelosuppression, fluid retention events, diarrhea, headache, skin rash, hemorrhage, dyspnea, fatigue, nausea, and musculoskeletal pain. In pediatric patients, the most frequently reported adverse reactions also include mucositis, febrile neutropenia, pyrexia, vomiting, abdominal pain, cough, constipation, arrhythmia, hypertension, edema, infections (bacterial, viral, and fungal), hypotension, decreased appetite, hypersensitivity, epistaxis, peripheral neuropathy, and altered state of consciousness.

Serious adverse reactions may include severe thrombocytopenia, neutropenia, and anemia, necessitating caution when PHYRAGO is used concomitantly with medications that inhibit platelet function or anticoagulants. Regular monitoring of complete blood counts is recommended, and transfusions or interruption of therapy may be required when indicated. 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 signs of cardiovascular toxicity, and PHYRAGO may increase the risk of developing pulmonary arterial hypertension (PAH), which may be reversible upon discontinuation. It is essential to evaluate patients for signs and symptoms of PAH during treatment and to discontinue PHYRAGO if PAH is confirmed. Caution is advised in patients with or at risk for QT prolongation.

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

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

Hepatotoxicity is another concern, with liver function assessments recommended before treatment initiation and 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 may also be more susceptible to less frequently reported adverse reactions, including abdominal distention, dizziness, pericardial effusion, congestive heart failure, hypertension, pulmonary edema, and weight decrease.

In cases of overdose, severe myelosuppression and bleeding have been reported, and patients who ingest more than the recommended dosage should be closely monitored for these effects and provided with appropriate supportive treatment. Acute overdose in animal studies has been associated with cardiotoxicity, evidenced by ventricular necrosis and valvular/ventricular/atrial hemorrhage.

Drug Interactions

Concomitant use of strong CYP3A4 inhibitors may necessitate a dose reduction of the affected medication due to the potential for increased plasma concentrations and enhanced pharmacological effects.

Conversely, the presence of strong CYP3A4 inducers may require a dose increase to achieve the desired therapeutic effect, as these agents can lead to decreased plasma levels of the affected medication.

Additionally, the use of antacids alongside the affected medication is not recommended. This combination may interfere with the absorption and efficacy of the medication, potentially leading to suboptimal therapeutic outcomes. Monitoring for clinical effects is advised when these interactions are a concern.

Packaging & NDC

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

Pediatric Use

The safety and effectiveness of dasatinib monotherapy have been established in pediatric patients with newly diagnosed chronic phase chronic myeloid leukemia (CML). However, there are no data available for children under 1 year of age. In this population, adverse reactions related to bone growth and development were reported in 5.2% of patients.

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

The safety profile of dasatinib 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 lack of clinical data, it remains unclear whether the dispersion of PHYRAGO tablets significantly affects their safety and/or efficacy.

Geriatric Use

In clinical studies involving dasatinib, 23% of the 2712 patients were aged 65 years and older, with 5% being 75 years and older. The efficacy of dasatinib, as measured by confirmed Complete Cytogenetic Response (cCCyR) and Major Molecular Response (MMR), did not differ significantly between elderly patients and their younger counterparts.

While the overall safety profile of dasatinib in geriatric patients appears comparable to that of younger patients, those aged 65 years and older are at an increased risk for several commonly reported adverse reactions. These include fatigue, pleural effusion, diarrhea, dyspnea, cough, lower gastrointestinal hemorrhage, and appetite disturbance. Additionally, elderly patients may 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 are monitored closely for these adverse effects during treatment with dasatinib. Healthcare providers should remain vigilant in assessing the safety and tolerability of the medication in this population, and appropriate dose modifications should be considered based on individual patient response and tolerability.

Pregnancy

Based on limited human data, PHYRAGO 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. Transplacental transfer of dasatinib has been documented, with dasatinib detected in fetal plasma and amniotic fluid at concentrations comparable to those in maternal plasma. These adverse effects on the fetus are similar to those observed in adult patients and may result in fetal harm or neonatal death.

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. In nonclinical studies, embryo-fetal toxicities were observed in rats and rabbits at plasma concentrations below those seen in humans treated with dasatinib. These toxicities included fetal death in rats and skeletal malformations, reduced ossification, edema, and microhepatia in both species. In a pre- and postnatal development study in rats, administration of dasatinib during gestation and lactation resulted in extensive pup mortality at maternal exposures below those in patients treated with dasatinib at the recommended labeling dose.

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. 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. Healthcare providers should advise pregnant women of the potential risks to the fetus associated with dasatinib exposure.

Lactation

No data are available regarding the presence of dasatinib in human milk, the effects of the drug on the breastfed child, or the effects of the drug on milk production. However, dasatinib is present in the milk of lactating rats. Due to the potential for serious adverse reactions in nursing children from dasatinib, breastfeeding is not recommended during treatment with PHYRAGO and for 2 weeks after the last dose.

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.

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 related to hepatic impairment.

Overdosage

In cases of dasatinib overdosage, clinical experience has primarily been derived from isolated incidents. The highest reported instance involved a dosage of 280 mg per day administered over the course of one week, which resulted 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, characterized by ventricular necrosis and hemorrhage at doses of 100 mg/kg or greater. Additionally, increased systolic and diastolic blood pressure has been documented in primate models following single doses of 10 mg/kg or more.

In summary, vigilance in monitoring and supportive care is crucial for managing dasatinib overdosage, particularly in relation to hematologic and cardiovascular effects.

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

During post-approval use of dasatinib, the following adverse reactions have been identified. These reactions were reported voluntarily from a population of uncertain size, making it challenging to reliably estimate their frequency or establish a causal relationship to drug exposure.

Infections, including hepatitis B virus reactivation, have been noted. Cardiac disorders such as atrial fibrillation and atrial flutter have also been reported. Respiratory, thoracic, and mediastinal disorders include interstitial lung disease and chylothorax. Skin and subcutaneous tissue disorders have been associated with Stevens-Johnson syndrome. Additionally, renal and urinary disorders, specifically nephrotic syndrome, have been observed. Blood and lymphatic system disorders, including thrombotic microangiopathy, have been documented. Lastly, hepatobiliary disorders, particularly hepatotoxicity, have been reported.

Patient Counseling

Healthcare providers should advise patients to read the FDA-approved patient labeling (Patient Information) thoroughly to understand the medication's use and potential risks.

Patients should be informed about the possibility of developing low blood cell counts. They must be instructed to immediately report any fever, especially if accompanied by signs of infection.

It is essential to inform patients about the risk of serious bleeding. They should be advised to report any signs or symptoms suggestive of hemorrhage, such as unusual bleeding or easy bruising, without delay.

Patients should also be made aware of the potential for fluid retention, which may manifest as swelling, weight gain, dry cough, chest pain upon respiration, or shortness of breath. They should be encouraged to seek medical attention promptly if they experience any of these symptoms.

Additionally, healthcare providers should inform patients about the risk of cardiovascular toxicity, which may include cardiac ischemic events, fluid retention related to cardiac issues, conduction abnormalities, and transient ischemic attacks (TIAs). Patients should be advised to seek immediate medical attention if they experience symptoms suggestive of cardiovascular toxicity, such as chest pain, shortness of breath, palpitations, transient vision problems, or slurred speech.

Patients should also be informed about the possibility of developing pulmonary arterial hypertension, characterized by symptoms such as 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 instructed 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 important to communicate the potential risk of developing bone growth abnormalities and bone pain, ensuring they are aware of the need for monitoring and reporting any related concerns.

Storage and Handling

PHYRAGO is supplied in a configuration that includes specific packaging details, which are essential for proper handling and storage. 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 and 86°F).

As PHYRAGO is classified as a hazardous drug, it is imperative to adhere to special handling and disposal procedures. Personnel who are pregnant should avoid any exposure to the tablets. To minimize the risk of dermal exposure to the active substance, it is recommended that healthcare professionals utilize latex or nitrile gloves during the handling and disposal of the tablets.

Additional Clinical Information

No further data are available.

FDA Insert (PDF)

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

View full prescribing information (PDF)