The following adverse reactions are discussed in greater detail in other sections of the labeling.

• Myelosuppression [see DOSAGE AND ADMINISTRATION and Warnings and PRECAUTIONS].
• Bleeding related events [see Warnings and PRECAUTIONS].
• Fluid retention [see Warnings and PRECAUTIONS].
• QT prolongation [see Warnings and PRECAUTIONS].

Clinical Studies Experience

The data described below reflect exposure to SPRYCEL (dasatinib) in 2182 patients with leukemia in clinical studies (starting dosage 100 mg once daily, 140 mg once daily, 50 mg twice daily, or 70 mg twice daily). The median duration of therapy was 11 months (range 0.03–26 months).

The majority of SPRYCEL-treated patients experienced adverse reactions at some time. Drug was discontinued for adverse reactions in 9% of patients in chronic phase CML, 10% in accelerated phase CML, 15% in myeloid blast phase CML, and 8% in lymphoid blast phase CML or Ph+ ALL. In a Phase 3 dose-optimization study in patients with chronic phase CML, the rate of discontinuation for adverse reaction was lower in patients treated with 100 mg once daily than in patients treated with 70 mg twice daily (4% and 12%, respectively).

The most frequently reported adverse reactions (reported in ≥ 20% of patients) included fluid retention events, diarrhea, headache, skin rash, nausea, hemorrhage, fatigue, and dyspnea.

The most frequently reported serious adverse reactions included pleural effusion (9%), pyrexia (3%), pneumonia (3%), infection (2%), febrile neutropenia (4%), gastrointestinal bleeding (4%), dyspnea (3%), sepsis (1%), diarrhea (2%), congestive heart failure (2%), and pericardial effusion (1%).

All adverse reactions (excluding laboratory abnormalities) that were reported in at least 10% of the patients in SPRYCEL clinical studies are shown in Table 2.

Table 2: Adverse Reactions Reported in ≥ 10% of All Patients (All Grades) in Clinical Studies

In a Phase 2 randomized study of chronic phase CML, 101 patients received SPRYCEL (dasatinib) (starting dosage 70 mg twice daily) and 49 patients received imatinib (starting dosage 800 mg daily [400 mg twice daily]). Crossover to the alternate therapy was permitted in this study. The median duration of therapy prior to crossover was longer for SPRYCEL (19 months) than for imatinib (3 months). Selected adverse reactions are presented in Table 3.

Table 3: Selected Adverse Reactions in Phase 2 Randomized Study (Chronic Phase CML)

In the Phase 3 dose-optimization study in patients with chronic phase CML, the median duration of therapy was approximately 12 months (range < 1–20 months). Selected adverse reactions are shown by dose regimen in Table 4.

Table 4: Selected Adverse Reactions Reported in Phase 3 Dose-Optimization Study (Chronic Phase CML)

Laboratory Abnormalities

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 phase CML or Ph+ ALL than in chronic phase CML (Table 5). 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 or reduction; permanent discontinuation of treatment occurred in 1% of patients [see Warnings and PRECAUTIONS].

Grade 3 or 4 elevations of transaminase 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 phase CML and Ph+ ALL. Elevations in transaminase 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.

In the Phase 2 randomized study, the frequency of Grade 3 or 4 neutropenia, thrombo- cytopenia, and anemia was 63%, 56%, and 19%, respectively, in the SPRYCEL (dasatinib) group and 39%, 14%, and 8%, respectively, in the imatinib group. The frequency of Grade 3 or 4 hypocalcemia was 4% in the SPRYCEL group and 0% in the imatinib group. Laboratory abnormalities reported in the Phase 3 dose-optimization study in patients with chronic phase CML are shown in Table 6.

Table 5: CTC Grades 3/4 Laboratory Abnormalities in Clinical Studies

Table 6: CTC Grades 3/4 Laboratory Abnormalities in Phase 3 Dose- Optimization Study (Chronic Phase CML)

Additional Data From Clinical Trials

The following adverse reactions were reported in patients in the SPRYCEL clinical studies at a frequency of < 10% (1%– < 10%, 0.1%– < 1%, or < 0.1%).These events are included on the basis of clinical relevance.

Gastrointestinal Disorders: 1%– < 10% – mucosal inflammation (including mucositis/stomatitis), dyspepsia, abdominal distension, constipation, gastritis, oral soft tissue disorder, colitis (including neutropenic colitis); 0.1%– < 1% – dysphagia, anal fissure, upper gastrointestinal ulcer, pancreatitis; < 0.1% – esophagitis.

General Disorders and Administration Site Conditions: 1%– < 10% – asthenia, pain, chest pain, chills; 0.1%– < 1%– malaise; < 0.1%– temperature intolerance.

Skin and Subcutaneous Tissue Disorders: 1%– < 10% – pruritus, acne, alopecia, dry skin, hyperhidrosis, urticaria, dermatitis (including eczema); 0.1%– < 1%– skin ulcer, bullous conditions, pigmentation disorder, nail disorder, photosensitivity, acute febrile neutrophilic dermatosis, panniculitis; < 0.1% – palmar-plantar erythrodysesthesia syndrome.

Respiratory, Thoracic, and Mediastinal Disorders: 1%– < 10% – cough, lung infiltration, pneumonitis; 0.1%– < 1% – asthma, bronchospasm; < 0.1% – acute respiratory distress syndrome.

Nervous System Disorders: 1%– < 10% – neuropathy (including peripheral neuropathy), dizziness, dysgeusia, somnolence; 0.1%– < 1% – tremor, syncope, amnesia; < 0.1%– convulsion, cerebrovascular accident, transient ischemic attack.

Blood and Lymphatic System Disorders: 1%– < 10% – febrile neutropenia, pancytopenia; < 0.1%– aplasia pure red cell.

Musculoskeletal and Connective Tissue Disorders: 1%– < 10% – arthralgia, myalgia, muscle inflammation, muscular weakness; 0.1%– < 1% – musculoskeletal stiffness, rhabdomyolysis; < 0.1%– tendonitis.

Investigations: 1%– < 10% – weight decreased, weight increased; 0.1%– < 1% – blood creatine phosphokinase increased.

Infections and Infestations: 1%– < 10% – infections (including bacterial, viral, fungal, non-specified), pneumonia (including bacterial, viral, and fungal), upper respiratory tract infection/inflammation, herpes virus infection, enterocolitis infection; 0.1%– < 1%– sepsis (including fatal outcomes).

Metabolism and Nutrition Disorders: 1%– < 10%– anorexia, appetite disturbances; 0.1%– < 1% – hyperuricemia.

Cardiac Disorders: 1%– < 10% – arrhythmia (including tachycardia), palpitations; 0.1%– < 1% – angina pectoris, cardiomegaly, pericarditis, ventricular arrhythmia (including ventricular tachycardia), myocardial infarction; < 0.1%– myocarditis, acute coronary syndrome.

Eye Disorders: 1%– < 10%– visual disorder, dry eye; 0.1%– < 1%– conjunctivitis.

Vascular Disorders:1%– < 10%– flushing, hypertension; 0.1%– < 1% – hypotension, thrombophlebitis; < 0.1%– livedo reticularis.

Psychiatric Disorders: 1%– < 10% – insomnia, depression; 0.1%– < 1% – anxiety, affect lability, confusional state, libido decreased.

Reproductive System and Breast Disorders: 0.1%– < 1% – gynecomastia, menstruation irregular.

Injury, Poisoning, and Procedural Complications: 1%– < 10%– contusion.

Ear and Labyrinth Disorders: 0.1%– < 1%– tinnitus, vertigo.

Hepatobiliary Disorders: 0.1%– < 1%– cholecystitis, hepatitis; < 0.1% – cholestasis.

Renal and Urinary Disorders: 0.1%– < 1% – renal failure, urinary frequency, proteinuria.

Neoplasms Benign, Malignant, and Unspecified: 0.1%– < 1% – tumor lysis syndrome.

Immune System Disorders: 0.1%– < 1% – hypersensitivity (including erythema nodosum).

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 (dasatinib) 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].

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].

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. The concomitant use of H₂ antagonists or proton pump inhibitors with SPRYCEL is not recommended. The use of antacids should be considered in place of H₂ antagonists or proton pump inhibitors in patients receiving SPRYCEL therapy.

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.

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