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Generic Name: Dasatinib
Class: Antineoplastic Agents
VA Class: AN900
Chemical Name: N - (2 - Chloro - 6 - methylphenyl) - 2 - [[6 - [4 - (2 - hydroxyethyl) - 1 - piperazinyl] - 2 - methyl - 4 - pyrimidinyl]amino] - 5 - thiazolecarboxamide, monohydrate
Molecular Formula: C22H26C1N7O2S • H2O
CAS Number: 863127-77-9

Introduction

Antineoplastic agent; a kinase inhibitor.1 2 3

Uses for Sprycel

Chronic Myelogenous Leukemia (CML)

Treatment of newly diagnosed Philadelphia chromosome-positive (Ph+) CML in adults who are in the chronic phase of the disease.1 19

Treatment of Ph+ CML in adults who are in myeloid or lymphoid blast crisis, in the accelerated phase, or in the chronic phase of the disease, after failure (secondary to resistance or intolerance) of prior therapy including imatinib.1 2 11 12 13 14 16 17

Slideshow: View Frightful (But Dead Serious) Drug Side Effects

Designated an orphan drug by FDA for use in the treatment of CML.4

Acute Lymphocytic (Lymphoblastic) Leukemia (ALL)

Treatment of Philadelphia chromosome-positive (Ph+) ALL in adults following failure (secondary to resistance or intolerance) of prior therapy (designated an orphan drug by FDA for this use).1 2 4 15

Sprycel Dosage and Administration

General

  • Use under supervision of a qualified clinician.1

  • Optimal duration of therapy has not been clearly established.1 Effect of discontinuance of treatment after achievement of a complete cytogenetic response has not been established.1

Administration

Oral Administration

Administer orally once daily (morning or evening) without regard to meals.1

Administer at the same time each day.1

Swallow tablets whole; do not cut, chew, or crush.1 10

Dosage

Adjustments may be necessary when used in conjunction with CYP3A4 inhibitors or inducers.1 (See Drugs Affecting Hepatic Microsomal Enzymes under Interactions.)

Adults

CML
Chronic Phase
Oral

100 mg once daily.1 If hematologic or cytogenetic response is not achieved, increase dosage to 140 mg once daily.1

Continue treatment until evidence of disease progression or until no longer tolerated by the patient.1

Accelerated Phase or Blast Crisis
Oral

140 mg once daily.1 If hematologic or cytogenetic response is not achieved, increase dosage to 180 mg once daily.1

Continue treatment until evidence of disease progression or until no longer tolerated by the patient.1

ALL
Oral

140 mg once daily.1 If hematologic or cytogenetic response is not achieved, increase dosage to 180 mg once daily.1

Continue treatment until evidence of disease progression or until no longer tolerated by the patient.1

Dosage Modification for Toxicity
Nonhematologic Adverse Effects

If a severe nonhematologic adverse reaction occurs, withhold dasatinib until the event has resolved or improved.1 Thereafter, resume therapy, as appropriate, at a reduced dosage depending on the initial severity of the event.1

Adverse Hematologic Effects

Temporary interruption, dosage reduction, or discontinuance is indicated in patients experiencing severe neutropenia and/or thrombocytopenia.1 10 Hematopoietic growth factor has been used in patients with resistant myelosuppression.1

Dosage Adjustments for Neutropenia and Thrombocytopenia: Chronic Phase CML

Initial Dosage

Episode of Neutropenia or Thrombocytopenia (Hematologic Measurements)

Dosage Adjustment

100 mg once daily1

First episode (ANC <500/mm3 or platelets <50,000/mm3)1

Withhold dasatinib; may resume at original dosage (100 mg once daily) if ANC reaches ≥1000/mm3 and platelets reach ≥50,000/mm3 within 7 days1

 

Second episode (ANC <500/mm3 lasting >7 days or platelets <25,000/mm3)1

Withhold dasatinib; may resume at reduced dosage of 80 mg once daily when ANC reaches ≥1000/mm3 and platelets reach ≥50,000/mm31

 

Third episode (ANC <500/mm3 lasting >7 days or platelets <25,000/mm3)1

Patients receiving dasatinib for newly diagnosed disease: Withhold dasatinib; may resume at reduced dosage of 50 mg once daily when ANC reaches ≥1000/mm3 and platelets reach ≥50,000/mm31

 

 

Patients receiving dasatinib following failure of prior therapy: Discontinue drug1

Dosage Adjustments for Neutropenia and Thrombocytopenia: Accelerated Phase or Blast Phase CML and Ph+ ALL

Initial Dosage

Hematologic Measurements

Dosage Adjustment

140 mg once daily1

ANC <500/mm3 or platelets <10,000/mm3

1. If cytopenia is unrelated to leukemia (as determined by marrow aspirate or biopsy), discontinue dasatinib until ANC ≥1000/mm3 and platelets ≥20,000/mm31

 

 

2. Resume treatment at original dosage (140 mg once daily)1

 

 

3. If recurrence of ANC <500/mm3 or platelets <10,000/mm3 occurs, repeat step 1 and resume therapy at a reduced dosage of 100 mg once daily (following a second episode) or 80 mg once daily (following a third episode)1

 

 

4. If cytopenia is related to leukemia (as determined by marrow aspirate or biopsy), consider increasing dosage to 180 mg once daily1

Special Populations

Hepatic Impairment

Dosage adjustment not necessary.1 (See Hepatic Impairment under Cautions.)

Renal Impairment

No special dosage recommendations at this time.1 (See Renal Impairment under Cautions.)

Geriatric Patients

No special dosage recommendations at this time.1 (See Geriatric Use under Cautions.)

Cautions for Sprycel

Contraindications

  • No known contraindications.1

Warnings/Precautions

Fetal/Neonatal Morbidity and Mortality

May cause fetal harm; teratogenicity and embryolethality demonstrated in animals.1 Avoid pregnancy during therapy.1 If used during pregnancy or if patient becomes pregnant, apprise of potential fetal hazard.1

Use adequate forms of contraception during therapy.1

Women who are pregnant should not handle crushed or broken dasatinib tablets.1

Hematologic Effects

Myelosuppression (principally severe neutropenia, anemia, and thrombocytopenia) occurs commonly and is usually reversible;1 more frequent in patients in the accelerated or blast phase of CML and in those with Ph+ ALL than in patients in the chronic phase of CML.1

Temporary suspension of therapy or dosage reduction may be required if hematologic toxicity occurs.1 (See Dosage Modification for Toxicity under Dosage and Administration.)

Perform CBCs weekly during the first 2 months of therapy and monthly (or as clinically indicated) thereafter.1

Hemorrhage

Risk of severe hemorrhage, including potentially fatal CNS or GI hemorrhage; usually associated with severe thrombocytopenia.1

Severe GI hemorrhage may require treatment interruption and transfusions.1

Use with caution in patients receiving anticoagulants or drugs that inhibit platelet function.1 (See Specific Drugs under Interactions.)

Fluid Retention

Risk of potentially severe fluid retention (i.e., pleural effusion, pericardial effusion, pulmonary edema, ascites, generalized edema).1

Fluid retention generally managed with supportive care (e.g., diuretics, short course of corticosteroids).1

Evaluate symptoms suggestive of pleural effusion (e.g., dyspnea, dry cough) by chest radiograph.1 Severe pleural effusion may require thoracentesis and oxygen therapy.1

Hepatic Effects

Grade 3 or 4 elevations of serum bilirubin, AST, and/or ALT reported; more frequent in patients in myeloid or lymphoid blast phase of CML and in those with Ph+ ALL.1

Electrolyte Disturbances

Grade 3 or 4 hypophosphatemia and hypocalcemia reported; more frequent in patients in myeloid or lymphoid blast phase of CML and in those with Ph+ ALL.1

Hypocalcemia generally managed with oral calcium supplementation.1

Prolongation of QT Interval

May cause prolongation of the QT interval.1 Use with caution in patients who have or may develop prolongation of the QT interval (e.g., hypokalemia, hypomagnesemia, congenital long QT syndrome, use of drugs known to prolong QT interval, cumulative high-dose anthracycline therapy).1

Correct hypokalemia or hypomagnesemia prior to administration of dasatinib.1

Left Ventricular Dysfunction, CHF, and MI

Cardiomyopathy, CHF, diastolic dysfunction, fatal MI, and left ventricular dysfunction reported; monitor patient for manifestations of cardiac dysfunction and provide appropriate treatment if they occur.1

Pulmonary Arterial Hypertension (PAH)

May increase risk for development of PAH.1 21 May occur at any time after initiation of therapy (e.g., 8–60 months);1 21 22 23 24 25 reported most often in patients with comorbidities or receiving other drugs concomitantly.21 May be reversible upon discontinuance of dasatinib.1 21 22 23 24

Evaluate patient for manifestations of cardiopulmonary disease before and during dasatinib therapy.1 21 Consider PAH in any patient with dyspnea, fatigue, hypoxia, and fluid retention; however, exclude other etiologies of dyspnea prior to initiating invasive diagnostic procedures for PAH.1 21

Interruption of therapy accompanied by monitoring for improvement may be considered if PAH is suspected.21 If PAH is confirmed (e.g., by cardiac catheterization), permanently discontinue the drug.1 21

Lactose-intolerant Patients

140-mg daily dosage contains 189 mg of lactose monohydrate; 100-mg daily dosage contains 135 mg of lactose monohydrate.1

Specific Populations

Pregnancy

Category D.1 (See Fetal/Neonatal Morbidity and Mortality under Cautions.)

Lactation

Not known whether dasatinib is distributed into milk.1 Discontinue nursing because of potential risk to nursing infants.1 10

Pediatric Use

Safety and efficacy not established in patients <18 years of age.1

Geriatric Use

No substantial difference in efficacy relative to younger adults, but patients ≥65 years of age are more likely to experience toxicity.1

Hepatic Impairment

Not studied in patients with hepatic impairment (ALT and/or AST >2.5 times ULN10 and/or total bilirubin >2 times ULN); however the drug is metabolized extensively in the liver.1 10 Use with caution.1

Renal Impairment

Not studied in patients with renal impairment (Scr >1.5 times ULN); however, renal impairment not expected to decrease dasatinib clearance.1 (See Special Populations under Pharmacokinetics.)

Common Adverse Effects

Patients receiving dasatinib as first-line therapy: Neutropenia,1 thrombocytopenia,1 anemia,1 fluid retention (e.g., pleural effusion or superficial localized edema),1 diarrhea,1 headache,1 musculoskeletal pain,1 rash.1

Patients receiving dasatinib following failure of prior therapy: Fluid retention (e.g., superficial and/or localized edema, generalized edema, pleural effusion, pericardial effusion, CHF or cardiac dysfunction, pulmonary edema),1 2 neutropenia,1 2 thrombocytopenia,1 2 anemia,1 hemorrhage (e.g., GI or CNS hemorrhage),1 diarrhea,1 2 vomiting,1 2 abdominal pain,1 nausea,1 2 headache,1 2 fatigue,1 2 pyrexia,1 musculoskeletal pain,1 myalgia,1 arthralgia,1 rash,1 2 dyspnea,1 hypophosphatemia,1 hypokalemia,1 hypocalcemia,1 febrile neutropenia,1 infection (e.g., bacterial, viral, fungal).1 2

Interactions for Sprycel

Metabolized principally by CYP3A4; weak inhibitor of CYP3A4.1

Does not inhibit CYP isoenzymes 1A2, 2A6, 2B6, 2C8, 2C9, 2C19, 2D6, or 2E1; does not induce human CYP isoenzymes.1

Drugs Affecting Hepatic Microsomal Enzymes

Inhibitors of CYP3A4: Potential pharmacokinetic interaction (increased plasma dasatinib concentrations). 1 Consider alternative drugs with no or less enzyme inhibition potential.1 If concomitant use with a potent CYP3A4 inhibitor cannot be avoided, consider reducing dasatinib dosage to 20 mg daily (if current dosage is 100 mg daily) or to 40 mg daily (if current dosage is 140 mg daily) based on pharmacokinetic considerations (no clinical data with these dosage adjustments available).1 If dasatinib is not tolerated following dosage reduction, discontinue the CYP3A4 inhibitor or interrupt dasatinib therapy until treatment with the CYP3A4 inhibitor is completed.1 Upon discontinuance of a potent CYP3A4 inhibitor, allow approximately 1 week to elapse before increasing dasatinib dosage.1

Inducers of CYP3A4: Potential pharmacokinetic interaction (decreased plasma dasatinib concentrations).1 Avoid concomitant use of potent CYP3A4 inducers; consider alternative drugs with no or less enzyme induction potential.1 If concomitant therapy cannot be avoided, consider increase in dasatinib dosage and closely monitor patient for toxicity.1

Drugs Affecting Coagulation

Potential for bleeding; use anticoagulants and drugs that inhibit platelet function concomitantly with caution.1 Initial clinical trials of dasatinib excluded patients receiving such drugs; subsequent trials permitted use of anticoagulants, aspirin, and NSAIAs if patient's platelet count exceeded 50,000–75,000/mm3.1

Drugs Metabolized by Hepatic Microsomal Enzymes

Substrates of CYP3A4: Potential pharmacokinetic interaction (increased plasma substrate concentrations).1 10

Specific Drugs and Foods

Drug or Food

Interaction

Comments

Alfentanil

Possible increased plasma concentrations and AUC of alfentanil1

Use concomitantly with caution1

Antacids (e.g., calcium carbonate, aluminum and magnesium hydroxides)

Possible decreased plasma dasatinib concentrations, secondary to apparent pH-dependence of dasatinib solubility1 26 Dasatinib AUC unchanged when administered 2 hours after antacid (aluminum and magnesium hydroxides) but decreased 55% when administered concomitantly with antacid1 26

Administer antacids ≥2 hours before or ≥2 hours after a dose of dasatinib1 26

Anticoagulants (e.g., warfarin)

Possible increased risk of hemorrhage1

Use concomitantly with caution1

Anticonvulsants (carbamazepine, phenobarbital, phenytoin)

Possible decreased plasma dasatinib concentrations1

Avoid concomitant use if possible; if concomitant therapy necessary, consider increasing dasatinib dosage and closely monitor for toxicity1

Antifungals, azoles (i.e., itraconazole, ketoconazole, voriconazole)

Possible increased plasma dasatinib concentrations and increased exposure to dasatinib1 Ketoconazole: Increased dasatinib AUC by fivefold and peak concentration by fourfold1

Avoid concomitant use if possible; if concomitant therapy necessary, closely monitor for toxicity and consider reducing dasatinib dosage to 20 mg daily (if current dosage is 100 mg daily) or 40 mg daily (if current dosage is 140 mg daily)1 (see Drugs Affecting Hepatic Microsomal Enzymes under Interactions)

Antihistamines (terfenadine and astemizole [no longer commercially available])

Possible increased plasma concentrations of terfenadine and astemizole1 10

 

Cisapride

Possible increased plasma concentrations of cisapride1 10

Use concomitantly with caution1

Dexamethasone

Possible decreased plasma dasatinib concentrations1

Avoid concomitant use if possible; if concomitant therapy necessary, consider increasing dasatinib dosage and closely monitor for toxicity1

Ergot alkaloids (dihydroergotamine, ergotamine)

Possible increased plasma concentrations of ergot alkaloids1 10

Use concomitantly with caution1

Fentanyl

Possible increased plasma concentrations of fentanyl1 10

Use concomitantly with caution1

Grapefruit juice

Possible increased plasma dasatinib concentrations1

Avoid concomitant use1

Histamine H2-receptor antagonists (e.g., cimetidine, famotidine, ranitidine)

Possible decreased plasma dasatinib concentrations, secondary to apparent pH-dependence of dasatinib solubility1 Famotidine: Decreased dasatinib AUC and peak concentration by 61–63% when given 10 hours before dasatinib1 26

Concomitant use not recommended1

HIV protease inhibitors (e.g., atazanavir, indinavir, nelfinavir, ritonavir, saquinavir)

Possible increased plasma dasatinib concentrations and increased exposure to dasatinib1

Avoid concomitant use if possible; if concomitant therapy necessary, closely monitor for toxicity and consider reducing dasatinib dosage to 20 mg daily (if current dosage is 100 mg daily) or 40 mg daily (if current dosage is 140 mg daily)1 (see Drugs Affecting Hepatic Microsomal Enzymes under Interactions)

Immunosuppressive agents (cyclosporine, sirolimus, tacrolimus)

Possible increased plasma concentrations of immunosuppressive agents1 10

Use concomitantly with caution1

Macrolide antibiotics (i.e., clarithromycin, erythromycin, telithromycin)

Possible increased plasma dasatinib concentrations and increased exposure to dasatinib1

Avoid concomitant use if possible; if concomitant therapy necessary, closely monitor for toxicity and consider reducing dasatinib dosage to 20 mg daily (if current dosage is 100 mg daily) or 40 mg daily (if current dosage is 140 mg daily)1 (see Drugs Affecting Hepatic Microsomal Enzymes under Interactions)

Nefazodone

Possible increased plasma dasatinib concentrations and increased exposure to dasatinib1

Avoid concomitant use if possible; if concomitant therapy necessary, closely monitor for toxicity and consider reducing dasatinib dosage to 20 mg daily (if current dosage is 100 mg daily) or 40 mg daily (if current dosage is 140 mg daily)1 (see Drugs Affecting Hepatic Microsomal Enzymes under Interactions)

NSAIAs (e.g., aspirin)

Possible increased risk of hemorrhage1

Use concomitantly with caution1

Pimozide

Possible increased plasma concentrations of pimozide1 10

Use concomitantly with caution1

Proton-pump inhibitors (e.g., esomeprazole, lansoprazole, omeprazole, pantoprazole, rabeprazole)

Possible decreased plasma dasatinib concentrations, secondary to apparent pH-dependence of dasatinib solubility1 Omeprazole: Decreased dasatinib AUC and peak concentration by 42–43% when given 22 hours before dasatinib1

Concomitant use not recommended1

Quinidine

Possible increased plasma concentrations of quinidine1 10

Use concomitantly with caution1

Rifamycins (rifabutin, rifampin)

Possible decreased plasma dasatinib concentrations and AUC of dasatinib1 Rifampin: Decreased dasatinib AUC and peak concentration by 81–82%1

Avoid concomitant use if possible; if concomitant therapy necessary, consider increasing dasatinib dosage and closely monitor for toxicity1

St. John’s wort (Hypericum perforatum)

Potential for unpredictable decreases in plasma dasatinib concentrations1

Concomitant use not recommended1

Simvastatin

Possible increased plasma concentrations and AUC of simvastatin1

Use concomitantly with caution1

Sprycel Pharmacokinetics

Absorption

Onset

Following oral administration, peak plasma concentrations are attained within 0.5–6 hours.1

Special Populations

In patients with moderate or severe hepatic impairment (Child-Pugh class B or C), peak plasma concentrations and AUC (normalized for differences in administered doses) are lower than in healthy individuals; differences not considered clinically important.1

Distribution

Extent

Extensively distributed into the extravascular space.1

Plasma Protein Binding

Approximately 96 and 93% for dasatinib and active metabolite, respectively.1

Elimination

Metabolism

Metabolized in the liver, principally by CYP3A4, to an active metabolite and several inactive metabolites.1

Elimination Route

Eliminated principally in feces (85%) mainly as metabolites and to a lesser extent in urine (4%). 1

Half-life

3–5 hours.1

Special Populations

No clinically relevant effects of age and gender on pharmacokinetics.1

Stability

Storage

Oral

Tablets

20–25°C (may be exposed to 15–30°C).1

Actions

  • Inhibits multiple tyrosine kinases including Bcr-Abl, the Src family (Src, Lck, Yes, Fyn), c-Kit, EphA-2, and platelet-derived growth factor (PDGFR)-β; predicted to bind to multiple conformations of the Abl kinase.1

  • Inhibits Bcr-Abl tyrosine kinase, an abnormal protein created by the Philadelphia chromosome abnormality in CML and Ph+ ALL that exhibits enhanced tyrosine kinase activity (i.e., increased phosphorylation of tyrosine residues).5 6 7 8 9

  • Overcomes imatinib resistance resulting from Bcr-Abl kinase domain mutations, activation of alternate signaling pathways involving the Src family kinases (Lyn, Hck), and multidrug-resistance gene overexpression.1

Advice to Patients

  • Importance of taking only as prescribed.1 Take at about the same time each day; do not discontinue therapy without first consulting clinician.1

  • Importance of advising patients to swallow dasatinib tablets whole with water and not to break, chew, cut, or crush the tablets.1 Importance of not drinking grapefruit juice while taking the drug.1

  • Risk of severe fluid retention, bleeding, and cytopenia.1 Importance of immediately informing clinician if fever, any bleeding or bruising, swelling, weight gain, or increasing shortness of breath occurs.1

  • Importance of close medical supervision in patients receiving dasatinib.1

  • Importance of informing clinicians if patient is lactose intolerant.1

  • Importance of women informing their clinician if they are or plan to become pregnant or plan to breast-feed; necessity for clinicians to advise women to avoid pregnancy during therapy, advise pregnant women of risk to the fetus, and advise women to utilize effective contraception during therapy.1 Importance of advising patients that pregnant women should not handle crushed or broken dasatinib tablets.1

  • Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs and herbal supplements, as well as any concomitant illnesses.1

  • Importance of informing patients of other important precautionary information.1 (See Cautions.)

Preparations

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Dasatinib

Routes

Dosage Forms

Strengths

Brand Names

Manufacturer

Oral

Tablets, film-coated

20 mg

Sprycel

Bristol Myers-Squibb

50 mg

Sprycel

Bristol Myers-Squibb

70 mg

Sprycel

Bristol Myers-Squibb

80 mg

Sprycel

Bristol Myers-Squibb

100 mg

Sprycel

Bristol Myers-Squibb

140 mg

Sprycel

Bristol Myers Squibb

Comparative Pricing

This pricing information is subject to change at the sole discretion of DS Pharmacy. This pricing information was updated 02/2014. Actual costs to patients will vary depending on the use of specific retail or mail-order locations and health insurance copays.

Sprycel 20MG Tablets (B-M SQUIBB U.S. (PRIMARY CARE)): 30/$2,304.00 or 90/$6,777.22

AHFS DI Essentials. © Copyright, 2004-2014, Selected Revisions April 19, 2012. American Society of Health-System Pharmacists, Inc., 7272 Wisconsin Avenue, Bethesda, Maryland 20814.

References

1. Bristol Myers-Squibb Company. Sprycel (dasatinib) tablets prescribing information and patient information. Princeton, NJ; 2011 Oct.

2. Talpaz M, Shah NP, Kantarjian H et al. Dasatinib in imatinib-resistant Philadelphia chromosome-positive leukemias. N Engl J Med. 2006; 354:2531-41. [PubMed 16775234]

3. Shah NP. Loss of response to imatinib: mechanisms and management. Hematology Am Soc Hematol Educ Program. 2005; :183-7. [PubMed 16304378]

4. Food and Drug Administration. Orphan designations pursuant to Section 526 of the Federal Food and Cosmetic Act as amended by the Orphan Drug Act (P.L. 97-414). Rockville, MD; 2006 Mar 21. From FDA website. Accessed 2011 Oct 31.

5. Druker BJ, Lydon NB. Lessons learned from the development of an Abl tyrosine kinase inhibitor for chronic myelogenous leukemia. J Clin Investig. 2000; 105:3-7. [PubMed 10619854]

6. McGuire TR, Kazakoff PW. Chronic leukemias. In: DiPiro JT, Talbert RL, Yee GC et al., eds. Pharmacotherapy: a pathophysiologic approach. 4th ed. Stamford: Appleton and Lange; 1999:2169-80.

7. Druker BJ, Talpaz M, Resta DJ et al. Efficacy and safety of a specific inhibitor of the Bcr-Abl tyrosine kinase in chronic myeloid leukemia. N Engl J Med. 2001; 344:1031-7. [IDIS 461596] [PubMed 11287972]

8. Anon. Gleevec (STI-571) for chronic myeloid leukemia. Med Lett Drugs Ther. 2001; 43:49-50. [PubMed 11402258]

9. Weisberg E, Griffin J. Mechanisms of resistance imatinib (STI-571) in preclinical models and in leukemia patients. Drug Resistance Updates. 2001; 4:22-8. [PubMed 11512149]

10. Bristol-Myers Squibb, Plainsboro, NJ: Personal communication.

11. Shah NP, Kantarjian HM, Kim DW et al. Intermittent target inhibition with dasatinib 100 mg once daily preserves efficacy and improves tolerability in imatinib-resistant and -intolerant chronic-phase chronic myeloid leukemia. J Clin Oncol. 2008; 26:3204-12. [PubMed 18541900]

12. Kantarjian H, Cortes J, Kim DW et al. Phase 3 study of dasatinib 140 mg once daily versus 70 mg twice daily in patients with chronic myeloid leukemia in accelerated phase resistant or intolerant to imatinib: 15-month median follow-up. Blood. 2009; 113:6322-9. [PubMed 19369231]

13. Kantarjian H, Pasquini R, Hamerschlak N et al. Dasatinib or high-dose imatinib for chronic-phase chronic myeloid leukemia after failure of first-line imatinib: a randomized phase 2 trial. Blood. 2007; 109:5143-50. [PubMed 17317857]

14. Hochhaus A, Baccarani M, Deininger M et al. Dasatinib induces durable cytogenetic responses in patients with chcronic myelogenous leukemia in chronic phase with resistance or intolerance to imatinib. Leukemia. 2008; 22:1200-6. [PubMed 18401416]

15. Ottmann O, Dombret H, Martinelli G et al. Dasatinib induces rapid hematologic and cytogenetic responses in adult patients with Philadelphia chromosome positive acute lymphoblastic leukemia with resistance or intolerance to imatinib: interim results of a phase 2 study. Blood. 2007; 110:2309-15. [PubMed 17496201]

16. Cortes J, Kim DW, Raffoux E et al. Efficacy and safety of dasatinib in imatinib-resistant or -intolerant patients with chronic myeloid leukemia in blast phase. Leukemia. 2008; 22:2176-83. [PubMed 18754032]

17. Guilhot F, Apperley J, Kim DW et al. Dasatinib induces significant hematologic and cytogenetic responses in patients with imatinib-resistant or -intolerant chronic myeloid leukemia in accelerated phase. Blood. 2007; 109:4143-50. [PubMed 17264298]

18. Food and Drug Administration. Center for Drug Evaluation and Research: Application number 21-986 and 22-072: Medical Review(s). From FDA website.

19. Kantarjian H, Shah NP, Hochhaus A et al. Dasatinib versus imatinib in newly diagnosed chronic-phase chronic myeloid leukemia. N Engl J Med. 2010; 362:2260-70. [PubMed 20525995]

20. Hasford J, Pfirrmann M, Hehlmann R et al. A new prognostic score for survival of patients with chronic myeloid leukemia treated with interferon alfa. Writing Committee for the Collaborative CML Prognostic Factors Project Group. J Natl Cancer Inst. 1998; 90:850-8. [PubMed 9625174]

21. Food and Drug Administration. Drug safety communication: Sprycel (dasatinib) and risk of pulmonary arterial hypertension [Oct 2011]. From FDA web site.

22. Mattei D, Feola M, Orzan F et al. Reversible dasatinib-induced pulmonary arterial hypertension and right ventricle failure in a previously allografted CML patient. Bone Marrow Transplant. 2009; 43:967-8. [PubMed 19104491]

23. Dumitrescu D, Seck C, ten Freyhaus H et al. Fully reversible pulmonary arterial hypertension associated with dasatinib treatment for chronic myeloid leukaemia. Eur Respir J. 2011; 38:218-20. [PubMed 21719499]

24. Orlandi EM, Rocca B, Pazzano AS et al. Reversible pulmonary arterial hypertension likely related to long-term, low-dose dasatinib treatment for chronic myeloid leukaemia. Leuk Res. 2011; :. [PubMed 21890201]

25. . Dasatinib: pulmonary arterial hypertension. French data. Prescrire Int. 2011; 20:241.

26. Eley T, Luo FR, Agrawal S et al. Phase I study of the effect of gastric acid pH modulators on the bioavailability of oral dasatinib in healthy subjects. J Clin Pharmacol. 2009; 49:700-9. [PubMed 19395585]

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