SPRYCEL^®
(dasatinib) Tablets

SPRYCEL^® (dasatinib) is an inhibitor of multiple tyrosine kinases. 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. The molecular formula is C₂₂H₂₆ClN₇O₂S • H₂O, which corresponds to a formula weight of 506.02 (monohydrate). The anhydrous free base has a molecular weight of 488.01. Dasatinib has the following chemical structure:

Dasatinib is a white to off-white powder and has a melting point of 280°–286° C. The drug substance is insoluble in water and slightly soluble in ethanol and methanol.

SPRYCEL tablets are white to off-white, biconvex, film-coated tablets containing dasatinib, with the following inactive ingredients: lactose monohydrate, microcrystalline cellulose, croscarmellose sodium, hydroxypropyl cellulose, and magnesium stearate. The tablet coating consists of hypromellose, titanium dioxide, and polyethylene glycol.

Dasatinib, at nanomolar concentrations, inhibits the following kinases: BCR-ABL, SRC family (SRC, LCK, YES, FYN), c-KIT, EPHA2, and PDGFRβ. Based on modeling studies, dasatinib is predicted to bind to multiple conformations of the ABL kinase.

In vitro, dasatinib was active in leukemic cell lines representing variants of imatinib mesylate sensitive and resistant disease. Dasatinib inhibited the growth of chronic myeloid leukemia (CML) and acute lymphoblastic leukemia (ALL) cell lines overexpressing BCR-ABL. Under the conditions of the assays, dasatinib was able to overcome imatinib resistance resulting from BCR-ABL kinase domain mutations, activation of alternate signaling pathways involving the SRC family kinases (LYN, HCK), and multi-drug resistance gene overexpression.

The pharmacokinetics of dasatinib have been evaluated in 229 healthy subjects and in 137 patients with leukemia.

Pharmacokinetic analyses of demographic data indicate that there are no clinically relevant effects of age and gender on the pharmacokinetics of SPRYCEL.

The pharmacokinetics of SPRYCEL have not been evaluated in pediatric patients.

SPRYCEL is not an inducer of human CYP enzymes. SPRYCEL is a time-dependent inhibitor of CYP3A4 and may decrease the metabolic clearance of drugs that are primarily metabolized by CYP3A4. (See PRECAUTIONS.) At clinically relevant concentrations, dasatinib does not inhibit CYP 1A2, 2A6, 2B6, 2C8, 2C9, 2C19, 2D6, or 2E1.

Four single-arm multicenter studies were conducted to determine the efficacy and safety of SPRYCEL in patients with CML or Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL) resistant to or intolerant of treatment with imatinib. Resistance to imatinib included failure to achieve a complete hematologic response (within 3–6 months) or major cytogenetic response (by month 12) or progression of disease after a previous cytogenetic or hematologic response. Imatinib intolerance included inability to tolerate 400 mg or more of imatinib per day or discontinuation of imatinib because of toxicity. The chronic phase CML study enrolled 186 patients, the accelerated phase CML study 107 patients, the myeloid blast phase study 74 patients, and the lymphoid blast phase CML/Ph+ ALL study 78 patients. The studies are ongoing. The results are based on a minimum of 6 months follow-up after the start of dasatinib therapy. Across all studies, 49% of patients were women, 89% were white, 10% were black or Asian, 23% were over the age of 65 years, and 3% were over the age of 75 years. Most patients had long disease histories with extensive prior treatment, including imatinib, cytotoxic chemotherapy, interferon, and stem cell transplant (Table 1). The maximum imatinib dose had been 400–600 mg/day in about one-half of the patients and >600 mg/day in the other half.

All patients were treated with dasatinib 70 mg BID on a continuous basis. The median durations of treatment are shown in Table 2.

The primary efficacy endpoint in chronic phase CML was major cytogenetic response (MCyR), defined as elimination (complete cytogenetic response, CCyR) or substantial diminution (by at least 65%, partial cytogenetic response) of Ph+ hematopoietic cells. The primary endpoint in accelerated phase, myeloid blast phase, and lymphoid blast phase CML, and Ph+ ALL was major hematologic response (MaHR), defined as either a complete hematologic response or no evidence of leukemia (defined in Table 3).

Dasatinib treatment resulted in cytogenetic and hematologic responses in patients with all phases of CML and with Ph+ ALL. The response rates for the single-arm studies are reported in Table 3. In chronic phase CML patients, the MCyR rate was 45% with a complete response (0% Ph+ cells) rate of 33%. The MaHR rate was 59% in accelerated phase patients, 32% in myeloid phase patients, 31% in lymphoid blast phase patients, and 42% in Ph+ ALL patients.

Most cytogenetic responses occurred after 12 weeks of treatment, when the first cytogenetic analyses were performed. Hematologic and cytogenetic responses were stable during the 6-month follow-up of patients with chronic phase, accelerated phase, and myeloid blast phase CML. The median durations of major hematologic response were 3.7 months in lymphoid blast CML and 4.8 months in Ph+ ALL.

There were no age- or gender-related response differences.

SPRYCEL (dasatinib) is indicated for the treatment of adults with chronic, accelerated, or myeloid or lymphoid blast phase chronic myeloid leukemia with resistance or intolerance to prior therapy including imatinib. The effectiveness of SPRYCEL is based on hematologic and cytogenetic response rates (see CLINICAL STUDIES). There are no controlled trials demonstrating a clinical benefit, such as improvement in disease-related symptoms or increased survival.

SPRYCEL is also indicated for the treatment of adults with Philadelphia chromosome-positive acute lymphoblastic leukemia with resistance or intolerance to prior therapy.

None known.

Dasatinib may cause fetal harm when administered to a pregnant woman. In nonclinical studies, at plasma concentrations below those observed in humans receiving therapeutic doses of SPRYCEL, fetal toxicity was observed in rats and rabbits. Fetal death was observed in rats. In both rats and rabbits, the lowest doses of dasatinib tested (rat: 2.5 mg/kg/day [15 mg/m²/day] and rabbit: 0.5 mg/kg/day [6 mg/m²/day]) resulted in embryo-fetal toxicities. These doses produced maternal AUCs of 105 ng•hr/mL (0.3-fold the human AUC in females at the recommended dose of 70 mg BID) and 44 ng•hr/mL (0.1-fold the human AUC) in rats and rabbits, respectively. Embryo-fetal toxicities included skeletal malformations at multiple sites (scapula, humerus, femur, radius, ribs, clavicle), reduced ossification (sternum; thoracic, lumbar, and sacral vertebrae; forepaw phalanges; pelvis; and hyoid body), edema, and microhepatia.

SPRYCEL is not recommended for use in women who are pregnant or contemplating pregnancy. If SPRYCEL is used during pregnancy, or if the patient becomes pregnant while taking SPRYCEL, the patient should be apprised of the potential hazard to the fetus.

The potential effects of SPRYCEL on sperm counts, function, and fertility have not been studied (see PRECAUTIONS: Carcinogenesis, Mutagenesis, Impairment of Fertility: Impairment of Fertility). Sexually active male or female patients taking SPRYCEL should use adequate contraception.

There are currently no clinical studies with SPRYCEL in patients with impaired liver function (clinical studies have excluded patients with ALT and/or AST >2.5 times the upper limit of the normal range and/or total bilirubin >2 times the upper limit of the normal range). Metabolism of dasatinib is mainly hepatic. Caution is recommended in patients with hepatic impairment.

There are currently no clinical studies with SPRYCEL in patients with impaired renal function (clinical studies have excluded patients with serum creatinine concentration >1.5 times the upper limit of the normal range). Dasatinib and its metabolites are minimally excreted via the kidney. Since the renal excretion of unchanged dasatinib and its metabolites is <4%, a decrease in total body clearance is not expected in patients with renal insufficiency.

It is unknown whether SPRYCEL is excreted in human milk. Women who are taking SPRYCEL should not breast-feed.

The safety and efficacy of SPRYCEL in patients <18 years of age have not been established.

Of the 511 patients in clinical studies of SPRYCEL (dasatinib), 119 (23%) were over 65 years of age, while 13 (3%) were over 75 years of age. No overall differences in safety or efficacy were observed between these patients and younger patients. However, greater sensitivity of some older individuals cannot be ruled out.

The data described below reflect exposure to SPRYCEL in 911 patients with leukemia from 1 Phase I and 5 Phase II clinical studies. The median duration of therapy was 6 months (range 0–19 months).

The majority of SPRYCEL-treated patients experienced adverse drug reactions at some time. Drug was discontinued for adverse drug reactions in 6% of patients in chronic phase CML, 5% in accelerated phase CML, 11% in myeloid blast phase CML, and 6% in lymphoid blast phase CML or Ph+ ALL.

The most frequently reported adverse events included fluid retention events such as pleural effusion; gastrointestinal events including diarrhea, nausea, abdominal pain and vomiting; and bleeding events.

The most frequently reported serious adverse events (SAEs) included pyrexia (9%), pleural effusion (8%), febrile neutropenia (7%), gastrointestinal bleeding (6%), pneumonia (6%), thrombocytopenia (5%), dyspnea (4%), anemia (3%), cardiac failure (3%), and diarrhea (2%).

All treatment-emergent adverse events (excluding laboratory abnormalities), regardless of relationship to study drug, that were reported in at least 10% of the patients in SPRYCEL clinical studies are shown in Table 4.

Myelosuppression was commonly reported in all patient populations. The frequency of Grade 3 or 4 neutropenia, thrombocytopenia, and anemia was higher in patients with advanced CML or Ph+ ALL than in chronic phase CML. Myelosuppression was reported in patients with normal baseline laboratory values as well as in patients with pre-existing laboratory abnormalities.

In patients who experienced severe myelosuppression, recovery generally occurred following dose interruption and/or reduction; permanent discontinuation of treatment occurred in 1% of patients.

Grade 3 or 4 elevations of transaminases or bilirubin and Grade 3 or 4 hypocalcemia and hypophosphatemia were reported in patients with all phases of CML but were reported with an increased frequency in patients with myeloid or lymphoid blast CML and Ph+ ALL. Elevations in transaminases or bilirubin were usually managed with dose reduction or interruption. Patients developing Grade 3 or 4 hypocalcemia during the course of SPRYCEL therapy often had recovery with oral calcium supplementation.

A single-dose overdose of SPRYCEL 200 mg in a patient with accelerated phase CML was reported with no associated symptoms or change in laboratory parameters. In the event of overdosage, the patient should be observed and appropriate supportive treatment given. (See PRECAUTIONS.)

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/m²) in rodents. There was a tendency for increased systolic and diastolic blood pressure in monkeys at single doses ≥10 mg/kg (120 mg/m²).

The recommended dosage of SPRYCEL (dasatinib) is 140 mg/day administered orally in two divided doses (70 mg twice daily [BID]), one in the morning and one in the evening with or without a meal. Tablets should not be crushed or cut; they should be swallowed whole.

In clinical studies, treatment with SPRYCEL was continued until disease progression or until no longer tolerated by the patient. The effect of stopping treatment after the achievement of a complete cytogenetic response has not been investigated.

Dose increase or reduction of 20-mg increments per dose is recommended based on individual safety and tolerability.

CYP3A4 inducers such as rifampin may decrease SPRYCEL plasma concentrations. Coadministration of SPRYCEL with rifampin resulted in a decrease in the mean C_max and AUC of dasatinib by 81% and 82%, respectively (a 5-fold decrease in SPRYCEL plasma concentrations). Selection of an alternate concomitant medication with no or minimal enzyme induction potential is recommended. If SPRYCEL must be administered with a CYP3A4 inducer, a dose increase should be considered.

If the dose of SPRYCEL is increased, the patient should be monitored carefully for toxicity (see CLINICAL PHARMACOLOGY and PRECAUTIONS: Drug Interactions). St. John's wort may decrease SPRYCEL plasma concentrations unpredictably. Patients receiving SPRYCEL should not take St. John's wort concomitantly.

CYP3A4 inhibitors such as ketoconazole may increase SPRYCEL plasma concentrations. Selection of an alternate concomitant medication with no or minimal enzyme inhibition potential is recommended. If SPRYCEL must be administered with a strong CYP3A4 inhibitor, a dose decrease to 20–40 mg daily should be considered (see CLINICAL PHARMACOLOGY and PRECAUTIONS: Drug Interactions).

In clinical studies of adult CML and Ph+ ALL patients, dose escalation to 90 mg BID (chronic phase CML) or 100 mg BID (advanced phase CML and Ph+ ALL) was allowed in patients who did not achieve a hematologic or cytogenetic response at the recommended dosage.

SPRYCEL^® (dasatinib) tablets are available as described in Table 7.

SPRYCEL (dasatinib) tablets should be stored at 25° C (77° F); excursions permitted between 15°–30° C (59°–86° F) [see USP Controlled Room Temperature].

Procedures for proper handling and disposal of anticancer drugs should be considered. Several guidelines on this subject have been published.^1-9 There is no general agreement that all of the procedures recommended in the guidelines are necessary or appropriate.

SPRYCEL (dasatinib) tablets consist of a core tablet (containing the active drug substance), surrounded by a film coating to prevent exposure of pharmacy and clinical personnel to the active drug substance. However, if tablets are crushed or broken, pharmacy and clinical personnel should wear disposable chemotherapy gloves. Personnel who are pregnant should avoid exposure to crushed and/or broken tablets.

• ONS Clinical Practice Committee. Cancer Chemotherapy Guidelines and Recommendations for Practice. Pittsburgh, PA: Oncology Nursing Society; 1999:32-41.
• Recommendations for the Safe Handling of Parenteral Antineoplastic Drugs. Washington, DC: Division of Safety, Clinical Center Pharmacy Department and Cancer Nursing Services, National Institutes of Health; 1992. US Dept of Health and Human Services, Public Health Service Publication NIH 92-2621.
• AMA Council on Scientific Affairs. Guidelines for Handling Parenteral Antineoplastics. JAMA. 1985; 253:1590-1592.
• National Study Commission on Cytotoxic Exposure. Recommendations for Handling Cytotoxic Agents. 1987. Available from Louis P. Jeffrey, Sc.D., Chairman, National Study Commission on Cytotoxic Exposure. Massachusetts College of Pharmacy and Allied Health Sciences, 179 Longwood Avenue, Boston, MA 02115.
• Clinical Oncological Society of Australia. Guidelines and Recommendations for Safe Handling of Antineoplastic Agents. Med J Australia. 1983; 1:426-428.
• Jones RB, Prank R, Mass T. Safe Handling of Chemotherapeutic Agents: A Report from the Mount Sinai Medical Center. CA-A Cancer J for Clin. 1983; 33:258-263.
• American Society of Hospital Pharmacists. ASHP Technical Assistance Bulletin on Handling Cytotoxic and Hazardous Drugs. Am J Hosp Pharm. 1990; 47:1033-1049.
• Controlling Occupational Exposure to Hazardous Drugs (OSHA Work-Practice Guidelines). Am J Health-Syst Pharm. 1996; 53:1669-1685.
• NIOSH Alert: Preventing Occupational Exposures to Antineoplastic and Other Hazardous Drugs in Health Care Settings. Department of Health and Human Services, Centers for Disease Control and Prevention, National Institute for Occupational Safety and Health, Publication number 2004-165. September, 2004.