dasatinib 70 MG Oral Tablet [Sprycel]

DRUG INTERACTIONS

7 CYP3A4 Inhibitors: May increase dasatinib drug levels and should be avoided.

If coadministration cannot be avoided, monitor closely and consider reducing SPRYCEL dose.

(2.1, 7.1) CYP3A4 Inducers: May decrease dasatinib drug levels.

If coadministration cannot be avoided, consider increasing SPRYCEL dose.

(2.1, 7.2) Antacids: May decrease dasatinib drug levels.

Avoid simultaneous administration.

If needed, administer the antacid at least 2 hours prior to or 2 hours after the dose of SPRYCEL.

(7.2) H2 Antagonists/Proton Pump Inhibitors: May decrease dasatinib drug levels.

Consider antacids in place of H2 antagonists or proton pump inhibitors.

(7.2) 7.1 Drugs That May Increase Dasatinib Plasma Concentrations CYP3A4 Inhibitors: Dasatinib is a CYP3A4 substrate.

In a study of 18 patients with solid tumors, 20-mg SPRYCEL once daily coadministered with 200 mg of ketoconazole twice daily increased the dasatinib Cmax and AUC by four- and five-fold, respectively.

Concomitant use of SPRYCEL and drugs that inhibit CYP3A4 may increase exposure to dasatinib and should be avoided.

In patients receiving treatment with SPRYCEL, close monitoring for toxicity and a SPRYCEL dose reduction should be considered if systemic administration of a potent CYP3A4 inhibitor cannot be avoided [see Dosage and Administration (2.1)].

7.2 Drugs That May Decrease Dasatinib Plasma Concentrations CYP3A4 Inducers: When a single morning dose of SPRYCEL was administered following 8 days of continuous evening administration of 600 mg of rifampin, a potent CYP3A4 inducer, the mean Cmax and AUC of dasatinib were decreased by 81% and 82%, respectively.

Alternative agents with less enzyme induction potential should be considered.

If SPRYCEL must be administered with a CYP3A4 inducer, a dose increase in SPRYCEL should be considered [see Dosage and Administration (2.1)].

Antacids: Nonclinical data demonstrate that the solubility of dasatinib is pH dependent.

In a study of 24 healthy subjects, administration of 30 mL of aluminum hydroxide/magnesium hydroxide 2 hours prior to a single 50-mg dose of SPRYCEL was associated with no relevant change in dasatinib AUC; however, the dasatinib Cmax increased 26%.

When 30 mL of aluminum hydroxide/magnesium hydroxide was administered to the same subjects concomitantly with a 50-mg dose of SPRYCEL, a 55% reduction in dasatinib AUC and a 58% reduction in Cmax were observed.

Simultaneous administration of SPRYCEL with antacids should be avoided.

If antacid therapy is needed, the antacid dose should be administered at least 2 hours prior to or 2 hours after the dose of SPRYCEL.

H2 Antagonists/Proton Pump Inhibitors: Long-term suppression of gastric acid secretion by H2 antagonists or proton pump inhibitors (eg, famotidine and omeprazole) is likely to reduce dasatinib exposure.

In a study of 24 healthy subjects, administration of a single 50-mg dose of SPRYCEL 10 hours following famotidine reduced the AUC and Cmax of dasatinib by 61% and 63%, respectively.

In a study of 14 healthy subjects, administration of a single 100-mg dose of SPRYCEL 22 hours following a 40-mg omeprazole dose at steady state reduced the AUC and Cmax of dasatinib by 43% and 42%, respectively.

The concomitant use of H2 antagonists or proton pump inhibitors with SPRYCEL is not recommended.

The use of antacids (at least 2 hours prior to or 2 hours after the dose of SPRYCEL) should be considered in place of H2 antagonists or proton pump inhibitors in patients receiving SPRYCEL therapy.

7.3 Drugs That May Have Their Plasma Concentration Altered By Dasatinib CYP3A4 Substrates: Single-dose data from a study of 54 healthy subjects indicate that the mean Cmax and AUC of simvastatin, a CYP3A4 substrate, were increased by 37% and 20%, respectively, when simvastatin was administered in combination with a single 100-mg dose of SPRYCEL.

Therefore, CYP3A4 substrates known to have a narrow therapeutic index such as alfentanil, astemizole, terfenadine, cisapride, cyclosporine, fentanyl, pimozide, quinidine, sirolimus, tacrolimus, or ergot alkaloids (ergotamine, dihydroergotamine) should be administered with caution in patients receiving SPRYCEL.

OVERDOSAGE

10 Experience with overdose of SPRYCEL in clinical studies is limited to isolated cases.

Overdosage of 280 mg per day for 1 week was reported in two patients and both developed severe myelosuppression and bleeding.

Since SPRYCEL is associated with severe myelosuppression [see Warnings and Precautions (5.1) and Adverse Reactions (6.1)], patients who ingested more than the recommended dosage should be closely monitored for myelosuppression and given 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/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).

DESCRIPTION

11 SPRYCEL (dasatinib) is a kinase inhibitor.

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.

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.

Chemical Structure

CLINICAL STUDIES

14 14.1 Newly Diagnosed Chronic Phase CML An open-label, multicenter, international, randomized trial was conducted in adult patients with newly diagnosed chronic phase CML.

A total of 519 patients were randomized to receive either SPRYCEL 100 mg once daily or imatinib 400 mg once daily.

The primary endpoint was the rate of confirmed complete cytogenetic response (CCyR) within 12 months.

Confirmed CCyR was defined as a CCyR noted on two consecutive occasions (at least 28 days apart).

Median age was 46 years in the SPRYCEL group and 49 years in the imatinib groups, with 10% and 11% of patients ≥65 years of age.

There were slightly more male than female patients in both groups (59% vs 41%).

Fifty-three percent of all patients were Caucasian, and 39% were Asian.

At baseline, the distribution of Hasford Scores was similar in the SPRYCEL and imatinib treatment groups (low risk: 33% and 34%; intermediate risk: 48% and 47%; high risk: 19% and 19%, respectively).

The median duration of treatment was 14 months for SPRYCEL and 14 months for imatinib.

With a minimum of 12 months follow-up, 85% of patients randomized to SPRYCEL and 81% of patients randomized to imatinib were still on study.

Efficacy results are summarized in Table 6.

Table 6: Efficacy Results in Newly Diagnosed Patients with Chronic Phase CML SPRYCEL (n=259) Imatinib (n=260) p-value Response rate (95% CI) a Confirmed CCyR is defined as a CCyR noted on two consecutive occasions at least 28 days apart.

b Major molecular response (at any time) was defined as BCR-ABL ratios ≤0.1% by RQ-PCR in peripheral blood samples standardized on the International scale.

*Adjusted for Hasford Score and indicated statistical significance at a pre-defined nominal level of significance.

CI = confidence interval.

Confirmed CCyR within 12 months a 76.8% (71.2–81.8) 66.2% (60.1–71.9) p=0.007* Major Molecular Response b 52.1% (45.9–58.3) 33.8% (28.1–39.9) p<0.0001* Median time to confirmed CCyR was 3.1 months in 199 SPRYCEL responders and 5.6 months in 177 imatinib responders.

Median time to MMR was 6.3 months in 135 SPRYCEL responders and 9.2 months in 88 imatinib responders.

Five patients on the dasatinib arm progressed to either accelerated phase or blast crisis while nine patients on the imatinib arm progressed to either accelerated phase or blast crisis.

14.2 Imatinib Resistant or Intolerant CML or Ph+ ALL The efficacy and safety of SPRYCEL were investigated in adult patients with CML or Ph+ ALL whose disease was resistant to or who were intolerant to imatinib: 1158 patients had chronic phase CML, 858 patients had accelerated phase, myeloid blast phase, or lymphoid blast phase CML, and 130 patients had Ph+ ALL.

In a clinical study in chronic phase CML, resistance to imatinib was defined as failure to achieve a complete hematologic response (CHR; after 3 months), major cytogenetic response (MCyR; after 6 months), or complete cytogenetic response (CCyR; after 12 months); or loss of a previous molecular response (with concurrent ≥10% increase in Ph+ metaphases), cytogenetic response, or hematologic response.

Imatinib intolerance was defined as inability to tolerate 400 mg or more of imatinib per day or discontinuation of imatinib because of toxicity.

Results described below are based on a minimum of 2 years follow-up after the start of SPRYCEL therapy in patients with a median time from initial diagnosis of approximately 5 years.

Across all studies, 48% of patients were women, 81% were white, 15% were black or Asian, 25% were 65 years of age or older, and 5% were 75 years of age or older.

Most patients had long disease histories with extensive prior treatment, including imatinib, cytotoxic chemotherapy, interferon, and stem cell transplant.

Overall, 80% of patients had imatinib-resistant disease and 20% of patients were intolerant to imatinib.

The maximum imatinib dose had been 400–600 mg/day in about 60% of the patients and >600 mg/day in 40% of the patients.

The primary efficacy endpoint in chronic phase CML was MCyR, defined as elimination (CCyR) or substantial diminution (by at least 65%, partial cytogenetic response) of Ph+ hematopoietic cells.

The primary efficacy endpoint in accelerated phase, myeloid blast phase, lymphoid blast phase CML, and Ph+ ALL was major hematologic response (MaHR), defined as either a CHR or no evidence of leukemia (NEL).

Chronic Phase CML Dose-Optimization Study: A randomized, open-label study was conducted in patients with chronic phase CML to evaluate the efficacy and safety of SPRYCEL administered once daily compared with SPRYCEL administered twice daily.

Patients with significant cardiac diseases, including myocardial infarction within 6 months, congestive heart failure within 3 months, significant arrhythmias, or QTc prolongation were excluded from the study.

The primary efficacy endpoint was MCyR in patients with imatinib-resistant CML.

A total of 670 patients, of whom 497 had imatinib-resistant disease, were randomized to the SPRYCEL 100 mg once daily, 140 mg once daily, 50 mg twice daily, or 70 mg twice daily group.

Median duration of treatment was 22 months.

Efficacy was achieved across all SPRYCEL treatment groups with the once daily schedule demonstrating comparable efficacy (non-inferiority) to the twice daily schedule on the primary efficacy endpoint (difference in MCyR 1.9%; 95% CI [-6.8%–10.6%]).

Efficacy results are presented in Table 7 for patients with chronic phase CML who received the recommended starting dose of 100 mg once daily.

Additional efficacy results in this patient population are described after the table.

Results for all patients with chronic phase CML, regardless of dosage (a starting dosage of 100 mg once daily, 140 mg once daily, 50 mg twice daily, or 70 mg twice daily), were consistent with those for patients treated with 100 mg once daily.

Table 7: Efficacy of SPRYCEL in Imatinib Resistant or Intolerant Chronic Phase CML 100 mg Once Daily (n=167) a CHR (response confirmed after 4 weeks): WBC ≤ institutional ULN, platelets <450,000/mm3, no blasts or promyelocytes in peripheral blood, <5% myelocytes plus metamyelocytes in peripheral blood, basophils in peripheral blood <20%, and no extramedullary involvement.

b MCyR combines both complete (0% Ph+ metaphases) and partial (>0%–35%) responses.

CHRa% (95% CI) 92% (86–95) MCyRb% (95% CI) 63% (56–71) CCyR% (95% CI) 50% (42–58) In the SPRYCEL 100 mg once daily group, median time to MCyR was 2.9 months (95% CI: [2.8–3.0]).

Based on the Kaplan-Meier estimates, 93% (95% CI: [88%–98%]) of patients who had achieved an MCyR maintained that response for 18 months.

The estimated rate of progression-free survival and overall survival in all patients treated with 100 mg once daily was 80% (95% CI: [73%–87%]) and 91% (95% CI: [86%–96%]), respectively, at 2 years.

Advanced Phase CML and Ph+ ALL Dose-Optimization Study: One randomized open-label study was conducted in patients with advanced phase CML (accelerated phase CML, myeloid blast phase CML, or lymphoid blast phase CML) to evaluate the efficacy and safety of SPRYCEL administered once daily compared with SPRYCEL administered twice daily.

The primary efficacy endpoint was MaHR.

A total of 611 patients were randomized to either the SPRYCEL 140 mg once daily or 70 mg twice daily group.

Median duration of treatment was approximately 6 months for both treatment groups.

The once daily schedule demonstrated comparable efficacy (non-inferiority) to the twice daily schedule on the primary efficacy endpoint.

The efficacy and safety of SPRYCEL were also investigated in patients with Ph+ ALL in one randomized study (starting dosage 140 mg once daily or 70 mg twice daily) and one single-arm study (starting dosage 70 mg twice daily).

The primary efficacy endpoint was MaHR.

A total of 130 patients were enrolled in these studies.

The median duration of therapy was 3 months.

Response rates are presented in Table 8.

Table 8: Efficacy of SPRYCEL in Imatinib Resistant or Intolerant Advanced Phase CML and Ph+ ALL 140 mg Once Daily Accelerated (n=158) Myeloid Blast (n=75) Lymphoid Blast (n=33) Ph+ ALL (n=40) a Hematologic response criteria (all responses confirmed after 4 weeks): Major hematologic response: (MaHR) = complete hematologic response (CHR) + no evidence of leukemia (NEL).

CHR: WBC ≤ institutional ULN, ANC ≥1000/mm3, platelets ≥100,000/mm3, no blasts or promyelocytes in peripheral blood, bone marrow blasts ≤5%, <5% myelocytes plus metamyelocytes in peripheral blood, basophils in peripheral blood <20%, and no extramedullary involvement.

NEL: same criteria as for CHR but ANC ≥500/mm3 and <1000/mm3, or platelets ≥20,000/mm3 and ≤100,000/mm3.

b MCyR combines both complete (0% Ph+ metaphases) and partial (>0%–35%) responses.

CI = confidence interval ULN = upper limit of normal range.

MaHR a 66% 28% 42% 38% (95% CI) (59–74) (18–40) (26–61) (23–54) CHRa 47% 17% 21% 33% (95% CI) (40–56) (10–28) (9–39) (19–49) NELa 19% 11% 21% 5% (95% CI) (13–26) (5–20) (9–39) (1–17) MCyR b 39% 28% 52% 70% (95% CI) (31–47) (18–40) (34–69) (54–83) CCyR 32% 17% 39% 50% (95% CI) (25–40) (10–28) (23–58) (34–66) In the SPRYCEL 140 mg once daily group, the median time to MaHR was 1.9 months for patients with accelerated phase CML, 1.9 months for patients with myeloid blast phase CML, and 1.8 months for patients with lymphoid blast phase CML.

In patients with myeloid blast phase CML, the median duration of MaHR was 8 months and 9 months for the 140 mg once daily group and the 70 mg twice daily group, respectively.

In patients with lymphoid blast phase CML, the median duration of MaHR was 5 months and 8 months for the 140 mg once daily group and the 70 mg twice daily group, respectively.

In patients with Ph+ ALL who were treated with SPRYCEL 140 mg once daily, the median duration of MaHR was 4.6 months.

The medians of progression-free survival for patients with Ph+ ALL treated with SPRYCEL 140 mg once daily and 70 mg twice daily were 4.0 months and 3.5 months, respectively.

HOW SUPPLIED

16 /STORAGE AND HANDLING 16.1 How Supplied SPRYCEL® (dasatinib) tablets are available as described in Table 9.

Table 9: SPRYCEL Trade Presentations NDC Number Strength Description Tablets per Bottle 54868-5759-0 70 mg white to off-white, biconvex, round, film-coated tablet with “BMS” debossed on one side and “524” on the other side 60 16.2 Storage SPRYCEL® tablets should be stored at 20° to 25°C (68° to 77°F); excursions permitted between 15°–30°C (59°–86°F) [see USP Controlled Room Temperature].

16.3 Handling and Disposal Procedures for proper handling and disposal of anticancer drugs should be considered.

Several guidelines on this subject have been published [see References (15)].

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 inadvertently crushed or broken, pharmacy and clinical personnel should wear disposable chemotherapy gloves.

Personnel who are pregnant should avoid exposure to crushed or broken tablets.

RECENT MAJOR CHANGES

Warnings and Precautions, Pulmonary Arterial Hypertension (5.6) 10/2011

GERIATRIC USE

8.5 Geriatric Use In the newly diagnosed chronic phase CML study, 25 patients (10%) were 65 years of age and over and 7 patients (3%) were 75 years of age and over.

Of the 2182 patients in clinical studies of SPRYCEL with resistance or intolerance to imatinib therapy, 547 (25%) were 65 years of age and over and 105 (5%) were 75 years of age and over.

No differences in efficacy were observed between older and younger patients.

Compared to patients under age 65 years, patients aged 65 years and older are more likely to experience toxicity.

DOSAGE FORMS AND STRENGTHS

3 SPRYCEL (dasatinib) Tablets are available as 20-mg, 50-mg, 70-mg, 80-mg, 100-mg, and 140-mg white to off-white, biconvex, film-coated tablets.

[See How Supplied (16.1).] Tablets: 20 mg, 50 mg, 70 mg, 80 mg, 100 mg, and 140 mg.

(3, 16)

MECHANISM OF ACTION

12.1 Mechanism of Action 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.

INDICATIONS AND USAGE

1 SPRYCEL® (dasatinib) is indicated for the treatment of adults with newly diagnosed Philadelphia chromosome-positive (Ph+) chronic myeloid leukemia (CML) in chronic phase.

The effectiveness of SPRYCEL is based on cytogenetic response and major molecular response rates [see Clinical Studies (14.1)].

The trial is ongoing and further data will be required to determine long-term outcome.

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.

SPRYCEL is a kinase inhibitor indicated for the treatment of newly diagnosed adults with Philadelphia chromosome-positive (Ph+) chronic myeloid leukemia (CML) in chronic phase.

The trial is ongoing and further data will be required to determine long-term outcome.

(1, 14) adults with chronic, accelerated, or myeloid or lymphoid blast phase Ph+ CML with resistance or intolerance to prior therapy including imatinib.

(1, 14) adults with Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL) with resistance or intolerance to prior therapy.

(1, 14)

PEDIATRIC USE

8.4 Pediatric Use The safety and efficacy of SPRYCEL in patients less than 18 years of age have not been established.

PREGNANCY

8.1 Pregnancy Pregnancy Category D SPRYCEL may cause fetal harm when administered to a pregnant woman.

There are no adequate and well-controlled studies of SPRYCEL in pregnant women.

Women of childbearing potential should be advised of the potential hazard to the fetus and to avoid becoming pregnant.

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.

In nonclinical studies, at plasma concentrations below those observed in humans receiving therapeutic doses of dasatinib, embryo-fetal toxicities were 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 a dose of 70 mg twice daily) 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, and clavicle), reduced ossification (sternum; thoracic, lumbar, and sacral vertebrae; forepaw phalanges; pelvis; and hyoid body), edema, and microhepatia.

NUSRING MOTHERS

8.3 Nursing Mothers It is unknown whether SPRYCEL is excreted in human milk.

Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from SPRYCEL, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.

WARNING AND CAUTIONS

5 WARNINGS AND PRECAUTIONS Myelosuppression: Severe thrombocytopenia, neutropenia, and anemia may occur and require dose interruption or reduction.

Monitor complete blood counts regularly.

(2.3, 5.1, 6.1) Bleeding Related Events (mostly associated with severe thrombocytopenia): CNS and gastrointestinal hemorrhages, including fatalities, have occurred.

Severe hemorrhage may require treatment interruptions and transfusions.

Use SPRYCEL with caution in patients requiring medications that inhibit platelet function or anticoagulants.

(5.2, 6.1) Fluid Retention: SPRYCEL is associated with fluid retention, sometimes severe, including ascites, edema, and pleural and pericardial effusions.

Manage with appropriate supportive care measures.

(5.3, 6.1) QT Prolongation: Use SPRYCEL with caution in patients who have or may develop prolongation of the QT interval.

(5.4) Congestive Heart Failure, Left Ventricular Dysfunction and Myocardial Infarction: Monitor patients for signs and symptoms consistent with cardiac dysfunction and treat appropriately.

(5.5, 6.1) Pulmonary Arterial Hypertension (PAH): SPRYCEL may increase the risk of developing PAH which may be reversible on discontinuation.

Evaluate patients for signs and symptoms of underlying cardiopulmonary disease prior to initiating SPRYCEL and during treatment.

(5.6) Use in Pregnancy: Fetal harm may occur when administered to a pregnant woman.

Women should be advised of the potential hazard to the fetus and to avoid becoming pregnant.

(5.7, 8.1) 5.1 Myelosuppression Treatment with SPRYCEL is associated with severe (NCI CTC Grade 3 or 4) thrombocytopenia, neutropenia, and anemia.

Their occurrence is more frequent in patients with advanced phase CML or Ph+ ALL than in chronic phase CML.

In a dose-optimization study in patients with resistance or intolerance to prior imatinib therapy and chronic phase CML, Grade 3 or 4 myelosuppression was reported less frequently in patients treated with 100 mg once daily than in patients treated with other dosing regimens.

Perform complete blood counts weekly for the first 2 months and then monthly thereafter, or as clinically indicated.

Myelosuppression was generally reversible and usually managed by withholding SPRYCEL temporarily or dose reduction [see Dosage and Administration (2.3) and Adverse Reactions (6.1)].

5.2 Bleeding Related Events In addition to causing thrombocytopenia in human subjects, dasatinib caused platelet dysfunction in vitro.

In all clinical studies, severe central nervous system (CNS) hemorrhages, including fatalities, occurred in 1% of patients receiving SPRYCEL.

Severe gastrointestinal hemorrhage, including fatalities, occurred in 4% of patients and generally required treatment interruptions and transfusions.

Other cases of severe hemorrhage occurred in 2% of patients.

Most bleeding events were associated with severe thrombocytopenia.

Patients were excluded from participation in initial SPRYCEL clinical studies if they took medications that inhibit platelet function or anticoagulants.

In subsequent trials, the use of anticoagulants, aspirin, and non-steroidal anti-inflammatory drugs (NSAIDs) was allowed concurrently with SPRYCEL if the platelet count was >50,000–75,000 per microliter.

Exercise caution if patients are required to take medications that inhibit platelet function or anticoagulants.

5.3 Fluid Retention SPRYCEL is associated with fluid retention.

In clinical trials, severe fluid retention was reported in up to 10% of patients.

Ascites and generalized edema were each reported in <1% of patients.

Severe pulmonary edema was reported in 1% of patients.

Patients who develop symptoms suggestive of pleural effusion, such as dyspnea or dry cough, should be evaluated by chest X-ray.

Severe pleural effusion may require thoracentesis and oxygen therapy.

Fluid retention events were typically managed by supportive care measures that include diuretics or short courses of steroids.

In dose-optimization studies, fluid retention events were reported less frequently with once daily dosing than with other dosing regimens.

5.4 QT Prolongation In vitro data suggest that dasatinib has the potential to prolong cardiac ventricular repolarization (QT interval).

Of the 2440 patients with CML treated with SPRYCEL in clinical studies, 15 patients (<1%) had QTc prolongation reported as an adverse reaction.

Twenty-two patients (1%) experienced a QTcF >500 ms.

In 865 patients with leukemia treated with SPRYCEL in five Phase 2 single-arm studies, the maximum mean changes in QTcF (90% upper bound CI) from baseline ranged from 7.0 ms to 13.4 ms.

Administer SPRYCEL with caution to patients who have or may develop prolongation of QTc.

These include patients with hypokalemia or hypomagnesemia, patients with congenital long QT syndrome, patients taking anti-arrhythmic medicines or other medicinal products that lead to QT prolongation, and cumulative high-dose anthracycline therapy.

Correct hypokalemia or hypomagnesemia prior to SPRYCEL administration.

5.5 Congestive Heart Failure, Left Ventricular Dysfunction, and Myocardial Infarction Cardiac adverse reactions were reported in 5.8% of 258 patients taking SPRYCEL, including 1.6% of patients with cardiomyopathy, heart failure congestive, diastolic dysfunction, fatal myocardial infarction, and left ventricular dysfunction.

Monitor patients for signs or symptoms consistent with cardiac dysfunction and treat appropriately.

5.6 Pulmonary Arterial Hypertension SPRYCEL may increase the risk of developing pulmonary arterial hypertension (PAH) which may occur anytime after initiation, including after more than one year of treatment.

Manifestations include dyspnea, fatigue, hypoxia, and fluid retention.

PAH may be reversible on discontinuation of SPRYCEL.

Evaluate patients for signs and symptoms of underlying cardiopulmonary disease prior to initiating SPRYCEL and during treatment.

If PAH is confirmed, SPRYCEL should be permanently discontinued.

5.7 Use in Pregnancy SPRYCEL 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 dasatinib, embryo-fetal toxicities, including skeletal malformations, were observed in rats and rabbits.

There are no adequate and well-controlled studies of SPRYCEL in pregnant women.

Women of childbearing potential should be advised to avoid becoming pregnant while receiving treatment with SPRYCEL [see Use in Specific Populations (8.1)].

INFORMATION FOR PATIENTS

17 PATIENT COUNSELING INFORMATION See FDA-Approved Patient Labeling.

17.1 Bleeding Patients should be informed of the possibility of serious bleeding and to report immediately any signs or symptoms suggestive of hemorrhage (unusual bleeding or easy bruising).

17.2 Myelosuppression Patients should be informed of the possibility of developing low blood cell counts; they should be instructed to report immediately should fever develop, particularly in association with any suggestion of infection.

17.3 Fluid Retention Patients should be informed of the possibility of developing fluid retention (swelling, weight gain, or shortness of breath) and to seek medical attention if those symptoms arise.

17.4 Pregnancy Patients should be informed that dasatinib may cause fetal harm when administered to a pregnant woman.

Women should be advised of the potential hazard to the fetus and to avoid becoming pregnant.

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 [see Warnings and Precautions (5.7)].

17.5 Gastrointestinal Complaints Patients should be informed that they may experience nausea, vomiting, or diarrhea with SPRYCEL.

If these symptoms are significant, they should seek medical attention.

17.6 Pain Patients should be informed that they may experience headache or musculoskeletal pain with SPRYCEL.

If these symptoms are significant, they should seek medical attention.

17.7 Fatigue Patients should be informed that they may experience fatigue with SPRYCEL.

If this symptom is significant, they should seek medical attention.

17.8 Rash Patients should be informed that they may experience skin rash with SPRYCEL.

If this symptom is significant, they should seek medical attention.

17.9 Lactose Patients should be informed that SPRYCEL contains 135 mg of lactose monohydrate in a 100-mg daily dose and 189 mg of lactose monohydrate in a 140-mg daily dose.

17.10 Missed Dose If the patient misses a dose of SPRYCEL, the patient should take the next scheduled dose at its regular time.

The patient should not take two doses at the same time.

DOSAGE AND ADMINISTRATION

2 The recommended starting dosage of SPRYCEL for chronic phase CML is 100 mg administered orally once daily.

The recommended starting dosage of SPRYCEL for accelerated phase CML, myeloid or lymphoid blast phase CML, or Ph+ ALL is 140 mg administered orally once daily.

Tablets should not be crushed or cut; they should be swallowed whole.

SPRYCEL can be taken with or without a meal, either in the morning or in the evening.

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 (CCyR) has not been investigated.

Chronic phase CML: 100 mg once daily.

(2) Accelerated phase CML, myeloid or lymphoid blast phase CML, or Ph+ ALL: 140 mg once daily.

(2) Administered orally, with or without a meal.

Tablets should not be crushed or cut.

(2) 2.1 Dose Modification Concomitant Strong CYP3A4 inducers: The use of concomitant strong CYP3A4 inducers may decrease dasatinib plasma concentrations and should be avoided (eg, dexamethasone, phenytoin, carbamazepine, rifampin, rifabutin, phenobarbital).

St.

John’s Wort may decrease dasatinib plasma concentrations unpredictably and should be avoided.

If patients must be coadministered a strong CYP3A4 inducer, based on pharmacokinetic studies, a SPRYCEL dose increase should be considered.

If the dose of SPRYCEL is increased, the patient should be monitored carefully for toxicity [see Drug Interactions (7.2)].

Concomitant Strong CYP3A4 inhibitors: CYP3A4 inhibitors (eg, ketoconazole, itraconazole, clarithromycin, atazanavir, indinavir, nefazodone, nelfinavir, ritonavir, saquinavir, telithromycin, and voriconazole) may increase dasatinib plasma concentrations.

Grapefruit juice may also increase plasma concentrations of dasatinib and should be avoided.

Selection of an alternate concomitant medication with no or minimal enzyme inhibition potential, if possible, is recommended.

If SPRYCEL must be administered with a strong CYP3A4 inhibitor, a dose decrease should be considered.

Based on pharmacokinetic studies, a dose decrease to 20 mg daily should be considered for patients taking SPRYCEL 100 mg daily.

For patients taking SPRYCEL 140 mg daily, a dose decrease to 40 mg daily should be considered.

These reduced doses of SPRYCEL are predicted to adjust the area under the curve (AUC) to the range observed without CYP3A4 inhibitors.

However, there are no clinical data with these dose adjustments in patients receiving strong CYP3A4 inhibitors.

If SPRYCEL is not tolerated after dose reduction, either the strong CYP3A4 inhibitor must be discontinued, or SPRYCEL should be stopped until treatment with the inhibitor has ceased.

When the strong inhibitor is discontinued, a washout period of approximately 1 week should be allowed before the SPRYCEL dose is increased.

[See Drug Interactions (7.1).] 2.2 Dose Escalation In clinical studies of adult CML and Ph+ ALL patients, dose escalation to 140 mg once daily (chronic phase CML) or 180 mg once daily (advanced phase CML and Ph+ ALL) was allowed in patients who did not achieve a hematologic or cytogenetic response at the recommended starting dosage.

2.3 Dose Adjustment for Adverse Reactions Myelosuppression In clinical studies, myelosuppression was managed by dose interruption, dose reduction, or discontinuation of study therapy.

Hematopoietic growth factor has been used in patients with resistant myelosuppression.

Guidelines for dose modifications are summarized in Table 1.

Table 1: Dose Adjustments for Neutropenia and Thrombocytopenia * ANC: absolute neutrophil count Chronic Phase CML (starting dose 100 mg once daily) ANC* <0.5 × 109/L or Platelets <50 × 109/L 1.

Stop SPRYCEL until ANC ≥1.0 × 109/L and platelets ≥50 × 109/L.

2.

Resume treatment with SPRYCEL at the original starting dose if recovery occurs in ≤7 days.

3.

If platelets <25 × 109/L or recurrence of ANC 7 days, repeat Step 1 and resume SPRYCEL at a reduced dose of 80 mg once daily for second episode.

For third episode, further reduce dose to 50 mg once daily (for newly diagnosed patients) or discontinue SPRYCEL (for patients resistant or intolerant to prior therapy including imatinib).

Accelerated Phase CML, Blast Phase CML and Ph+ ALL (starting dose 140 mg once daily) ANC* <0.5 × 109/L or Platelets <10 × 109/L 1.

Check if cytopenia is related to leukemia (marrow aspirate or biopsy).

2.

If cytopenia is unrelated to leukemia, stop SPRYCEL until ANC ≥1.0 × 109/L and platelets ≥20 × 109/L and resume at the original starting dose.

3.

If recurrence of cytopenia, repeat Step 1 and resume SPRYCEL at a reduced dose of 100 mg once daily (second episode) or 80 mg once daily (third episode).

4.

If cytopenia is related to leukemia, consider dose escalation to 180 mg once daily.

Non-hematological adverse reactions If a severe non-hematological adverse reaction develops with SPRYCEL use, treatment must be withheld until the event has resolved or improved.

Thereafter, treatment can be resumed as appropriate at a reduced dose depending on the initial severity of the event.