Chronic Myelogenous Leukemia (CML) Treatments
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Generic Name
Dasatinib
Brand Names
Phyrago, Sprycel
FDA approval date: June 27, 2006
Classification: Kinase Inhibitor
Form: Tablet
What is Phyrago (Dasatinib)?
PHYRAGO is indicated for the treatment of adult patients with newly diagnosed Philadelphia chromosome-positive chronic myeloid leukemia in chronic phase. chronic, accelerated, or myeloid or lymphoid blast phase Ph+ CML with resistance or intolerance to prior therapy including imatinib. Philadelphia chromosome-positive acute lymphoblastic leukemia with resistance or intolerance to prior therapy. PHYRAGO is indicated for the treatment of pediatric patients 1 year of age and older with Ph+ CML in chronic phase. newly diagnosed Ph+ ALL in combination with chemotherapy. PHYRAGO TM is a kinase inhibitor indicated for the treatment of newly diagnosed adults with Philadelphia chromosome-positive chronic myeloid leukemia in chronic phase. adults with chronic, accelerated, or myeloid or lymphoid blast phase Ph+ CML with resistance or intolerance to prior therapy including imatinib. adults with Philadelphia chromosome-positive acute lymphoblastic leukemia with resistance or intolerance to prior therapy. pediatric patients 1 year of age and older with Ph+ CML in chronic phase. pediatric patients 1 year of age and older with newly diagnosed Ph+ ALL in combination with chemotherapy.
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Brand Information
1INDICATIONS AND USAGE
PHYRAGO is indicated for the treatment of adult patients with
- newly diagnosed Philadelphia chromosome-positive (Ph+) chronic myeloid leukemia (CML) in chronic phase.
- chronic, accelerated, or myeloid or lymphoid blast phase Ph+ CML with resistance or intolerance to prior therapy including imatinib.
- Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL) with resistance or intolerance to prior therapy.
PHYRAGO is indicated for the treatment of pediatric patients 1 year of age and older with
- Ph+ CML in chronic phase.
- newly diagnosed Ph+ ALL in combination with chemotherapy.
2DOSAGE FORMS AND STRENGTHS
PHYRAGO is available as 20 mg, 50 mg, 70 mg, 80 mg, 100 mg, and 140 mg white to light yellow, biconvex, immediate release tablets.
3CONTRAINDICATIONS
None.
4ADVERSE REACTIONS
The following clinically significant adverse reactions are discussed in greater detail in other sections of the labeling:
- Myelosuppression
- Bleeding-related events
- Fluid retention
- Cardiovascular toxicity
- Pulmonary arterial hypertension
- QT prolongation
- Severe dermatologic reactions
- Tumor lysis syndrome
- Effects on growth and development in pediatric patients
- Hepatotoxicity
4.1Clinical Trials Experience
Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.
The data described below reflect exposure to dasatinib administered as single-agent therapy at all doses tested in clinical studies (n = 2809), including 324 adult patients with newly diagnosed chronic phase CML and 2388 adult patients with imatinib-resistant or -intolerant chronic or advanced phase CML or Ph+ ALL, and 97 pediatric patients with chronic phase CML. The median duration of therapy in a total of 2712 adult patients was 19.2 months (range 0 to 93.2 months). In a randomized trial in patients with newly diagnosed chronic phase CML, the median duration of therapy was approximately 60 months. The median duration of therapy in 1618 adult patients with chronic phase CML was 29 months (range 0 to 92.9 months).
In two non-randomized trials in 97 pediatric patients with chronic phase CML (51 patients newly diagnosed and 46 patients resistant or intolerant to previous treatment with imatinib), the median duration of therapy was 51.1 months (range 1.9 to 99.6 months).
In the overall population of 2712 adult patients, 88% of patients experienced adverse reactions at some time and 19% experienced adverse reactions leading to treatment discontinuation.
In the randomized trial in adult patients with newly diagnosed chronic phase CML, drug was discontinued for adverse reactions in 16% of patients with a minimum of 60 months of follow- up. After a minimum of 60 months of follow-up, the cumulative discontinuation rate was 39%. Among the 1618 patients with chronic phase CML, drug-related adverse reactions leading to discontinuation were reported in 329 (20.3%) patients; among the 1094 patients with advanced phase CML or Ph+ ALL, drug-related adverse reactions leading to discontinuation were reported in 191 (17.5%) patients.
Among the 97 pediatric subjects, drug-related adverse reactions leading to discontinuation were reported in 1 patient (1%).
Adverse reactions reported in ≥ 10% of adult patients, and other adverse reactions of interest, in a randomized trial in patients with newly diagnosed chronic phase CML at a median follow-up of approximately 60 months are presented in Table 6.
Adverse reactions reported in ≥ 10% of adult patients treated at the recommended dose of 100 mg once daily (n=165), and other adverse reactions of interest, in a randomized dose-optimization trial of patients with chronic phase CML resistant or intolerant to prior imatinib therapy at a median follow-up of approximately 84 months are presented in Table 8.
Adverse reactions reported in ≥10% of pediatric patients at a median follow-up of approximately 51.1 months are presented in Table 11.
Drug-related serious adverse reactions (SARs) were reported for 16.7% of adult patients in the randomized trial of patients with newly diagnosed chronic phase CML. Serious adverse reactions reported in 5% of patients included pleural effusion (5%).
Drug-related SARs were reported for 26.1% of patients treated at the recommended dose of 100 mg once daily in the randomized dose-optimization trial of adult patients with chronic phase CML resistant or intolerant to prior imatinib therapy. Serious adverse reactions reported in ≥ 5% of patients included pleural effusion (10%).
Drug-related SARs were reported for 14.4% of pediatric patients.
Chronic Myeloid Leukemia (CML)
Adverse reactions (excluding laboratory abnormalities) that were reported in at least 10% of adult patients are shown in Table 6 for newly diagnosed patients with chronic phase CML and Tables 8 and 10 for CML patients with resistance or intolerance to prior imatinib therapy.
a Includes cardiac failure acute, cardiac failure congestive, cardiomyopathy, diastolic dysfunction, ejection fraction decreased, and left ventricular dysfunction.
b Includes erythema, erythema multiforme, rash, rash generalized, rash macular, rash papular, rash pustular, skin exfoliation, and rash vesicular.
c Adverse reaction of special interest with <10% frequency.
d Includes conjunctival hemorrhage, ear hemorrhage, ecchymosis, epistaxis, eye hemorrhage, gingival bleeding, hematoma, hematuria, hemoptysis, intra-abdominal hematoma, petechiae, scleral hemorrhage, uterine hemorrhage, and vaginal hemorrhage
b Includes erythema, erythema multiforme, rash, rash generalized, rash macular, rash papular, rash pustular, skin exfoliation, and rash vesicular.
c Adverse reaction of special interest with <10% frequency.
d Includes conjunctival hemorrhage, ear hemorrhage, ecchymosis, epistaxis, eye hemorrhage, gingival bleeding, hematoma, hematuria, hemoptysis, intra-abdominal hematoma, petechiae, scleral hemorrhage, uterine hemorrhage, and vaginal hemorrhage
A comparison of cumulative rates of adverse reactions reported in ≥ 10% of patients with minimum follow-up of 1 and 5 years in a randomized trial of newly diagnosed patients with chronic phase CML treated with dasatinib are shown in Table 7.
a Includes cardiac failure acute, cardiac failure congestive, cardiomyopathy, diastolic dysfunction, ejection fraction decreased, and left ventricular dysfunction.
bIncludes erythema, erythema multiforme, rash, rash generalized, rash macular, rash papular, rash pustular, skin exfoliation, and rash vesicular
bIncludes erythema, erythema multiforme, rash, rash generalized, rash macular, rash papular, rash pustular, skin exfoliation, and rash vesicular
At 60 months, there were 26 deaths in dasatinib-treated patients (10.1%) and 26 deaths in imatinib-treated patients (10.1%); 1 death in each group was assessed by the investigator as related to study therapy.
a Includes drug eruption, erythema, erythema multiforme, erythrosis, exfoliative rash, generalized erythema, genital rash, heat rash, milia, rash, rash erythematous, rash follicular, rash generalized, rash macular, rash maculopapular, rash papular, rash pruritic, rash pustular, skin exfoliation, skin irritation, urticaria vesiculosa, and rash vesicular.
Cumulative rates of selected adverse reactions that were reported over time in patients treated with the 100 mg once daily recommended starting dose in a randomized dose-optimization trial of imatinib-resistant or -intolerant patients with chronic phase CML are shown in Table 9.
a Randomized dose-optimization trial results reported in the recommended starting dose of 100 mg once daily (n=165) population.
4.2Postmarketing Experience
The following adverse reactions have been identified during post approval use of dasatinib. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.
Infections: hepatitis B virus reactivation
Cardiac disorders: atrial fibrillation/atrial flutter
Respiratory, thoracic, and mediastinal disorders: interstitial lung disease, chylothorax
Skin and subcutaneous tissue disorders: Stevens-Johnson syndrome
Renal and urinary disorders: nephrotic syndrome
Blood and lymphatic system disorders: thrombotic microangiopathy
Hepatobiliary disorders: hepatotoxicity
5OVERDOSAGE
Experience with overdose of dasatinib in clinical studies is limited to isolated cases. The highest overdosage of 280 mg per day for 1 week was reported in two patients and both developed severe myelosuppression and bleeding. Since dasatinib is associated with severe myelosuppression [see Warnings and Precautions (5.1) and Adverse Reactions (6.1)], monitor patients who ingest more than the recommended dosage closely for myelosuppression and give appropriate supportive treatment. Acute overdose in animals was associated with cardiotoxicity. Evidence of cardiotoxicity included ventricular necrosis and valvular/ventricular/atrial hemorrhage at single doses ≥100 mg/kg (600 mg/m
6DESCRIPTION
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 C
Dasatinib (anhydrous) is a white to light yellow powder. The drug substance is insoluble in water and slightly soluble in ethanol and methanol.
PHYRAGO is supplied as white to light yellow, biconvex, immediate release tablets for oral use containing dasatinib (anhydrous), with the following inactive ingredients: croscarmellose sodium, dibasic calcium phosphate, magnesium stearate, methacrylic acid-ethyl acrylate copolymer, microcrystalline cellulose, propyl gallate, and silica dimethyl silylate.
7REFERENCES
1. http://www.osha.gov/SLTC/hazardousdrugs/index.html
8HOW SUPPLIED/STORAGE AND HANDLING
How Supplied
PHYRAGO (dasatinib) tablets are available in bottles with a child-resistant closure and desiccant container(s) as described in Table 21. The desiccant container(s) should remain within the bottle after opening and should not be swallowed or eaten.
Storage
PHYRAGO should be stored at 20°C to 25°C (68°F to 77°F); excursions permitted between 15°C and 30°C (59°F and 86°F) [see USP Controlled Room Temperature].
Handling and Disposal
PHYRAGO is a hazardous drug. Follow special handling and disposal procedures.
Personnel who are pregnant should avoid exposure to tablets.
To prevent exposure of healthcare professionals to the active substance, the use of latex or nitrile gloves for appropriate disposal when handling tablets is recommended, to minimize the risk of dermal exposure.
9PATIENT COUNSELING INFORMATION
Advise the patient to read the FDA-approved patient labeling (Patient Information).
Myelosuppression
Inform patients of the possibility of developing low blood cell counts. Advise patients to immediately report fever particularly in association with any suggestion of infection
Bleeding
Inform patients of the possibility of serious bleeding and to report immediately any signs or symptoms suggestive of hemorrhage (unusual bleeding or easy bruising)
Fluid Retention
Inform patients of the possibility of developing fluid retention (swelling, weight gain, dry cough, chest pain on respiration, or shortness of breath) and advise them to seek medical attention promptly if those symptoms arise
Cardiovascular Toxicity
Inform patients of the possibility of developing cardiovascular toxicity, including cardiac ischemic events, cardiac-related fluid retention, conduction abnormalities, and TIAs. Advise patients to seek immediate medical attention if symptoms suggestive of cardiovascular toxicity occur, such as chest pain, shortness of breath, palpitations, transient vision problems, or slurred speech
Pulmonary Arterial Hypertension
Inform patients of the possibility of developing pulmonary arterial hypertension (dyspnea, fatigue, hypoxia, and fluid retention) and advise them to seek medical attention promptly if those symptoms arise
Tumor Lysis Syndrome
Inform patients to immediately report and seek medical attention for any symptoms such as nausea, vomiting, weakness, edema, shortness of breath, muscle cramps, and seizures, which may indicate tumor lysis syndrome
Growth and Development in Pediatric Patients
Inform pediatric patients and their caregivers of the possibility of developing bone growth abnormalities, bone pain, or gynecomastia and advise them to seek medical attention promptly if those symptoms arise
Embryo-Fetal Toxicity
- Advise pregnant women of the potential risk to a fetus
- Advise females of reproductive potential and males with female partners of reproductive potential to use effective contraception during treatment with PHYRAGO and for 30 days after the last dose. Advise females to contact their healthcare provider if they become pregnant, or if pregnancy is suspected, while taking PHYRAGO
Lactation
- Advise women not to breastfeed during treatment with PHYRAGO and for 2 weeks after the last dose
Gastrointestinal Complaints
Inform patients that they may experience nausea, vomiting, or diarrhea with PHYRAGO. Advise patients to seek medical attention if these symptoms are bothersome or persistent.
Advise patients using antacids to avoid taking PHYRAGO and antacids less than 2 hours apart
Pain
Inform patients that they may experience headache or musculoskeletal pain with PHYRAGO. Advise patients to seek medical attention if these symptoms are bothersome or persistent.
Fatigue
Inform patients that they may experience fatigue with PHYRAGO. Advise patients to seek medical attention if this symptom is bothersome or persistent.
Rash
Inform patients that they may experience skin rash with PHYRAGO. Advise patients to seek medical attention if this symptom is bothersome or persistent.
Lactose
PHYRAGO does not contain lactose.
Hepatotoxicity
Advise patients that PHYRAGO can cause hepatotoxicity and that patients with previous history of liver diseases may be at risk. Advise patients to seek immediate medical attention if any symptoms suggestive of hepatotoxicity occur, such as abdominal pain, jaundice and scleral icterus, anorexia, bleeding, bruising, and dark-colored urine
Instructions for Taking PHYRAGO
- Missed Dose
Advise patients that if they miss a dose of PHYRAGO they should take the next scheduled dose at its regular time. The patient should not take two doses at the same time.
- Grapefruit Juice
Advise patients not to drink grapefruit juice as it may increase the amount of dasatinib in their blood and therefore increase their risk of adverse reactions.
Manufactured by:
Bora Pharmaceutical Services Inc.
Mississauga, Ontario, L5N 6L4,
Canada
Bora Pharmaceutical Services Inc.
Mississauga, Ontario, L5N 6L4,
Canada
Marketed by:
Cycle Pharmaceuticals Ltd
Cambridge, CB3 0FA
United Kingdom
PHYRAGO™ is a trademark of Handa Therapeutics, LLC
For patent information, please refer to www.phyrago.com/patents
10Dasatinib Oral Tablets 20 mg
11Dasatinib Oral Tablets 50 mg
12Dasatinib Oral Tablets 70 mg
13Dasatinib Oral Tablets 80 mg
14Dasatinib Oral Tablets 100 mg
15Dasatinib Oral Tablets 140 mg
