WARNINGS
Pregnancy (Category D)
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.
PRECAUTIONS
General
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 CML or Ph+ ALL than in chronic phase CML. Complete blood counts should be performed 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 and ADVERSE REACTIONS: Laboratory Abnormalities).
Bleeding Related Events
In addition to causing thrombocytopenia in human subjects, dasatinib caused platelet dysfunction in vitro. Severe CNS hemorrhages, including fatalities, occurred in 1% of patients receiving SPRYCEL. Severe gastrointestinal hemorrhage occurred in 7% of patients and generally required treatment interruptions and transfusions. Other cases of severe hemorrhage occurred in 4% of patients. Most bleeding events were associated with severe thrombocytopenia.
Patients were excluded from participation in SPRYCEL (dasatinib) clinical studies if they took medications that inhibit platelet function or anticoagulants. Caution should be exercised if patients are required to take medications that inhibit platelet function or anticoagulants.
Fluid Retention
SPRYCEL is associated with fluid retention, which was severe in 9% of patients, including pleural and pericardial effusion reported in 5% and 1% of patients, respectively. Severe ascites and generalized edema were each reported in 1%. 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.
QT Prolongation
In vitro data suggest that dasatinib has the potential to prolong cardiac ventricular repolarization (QT interval). In single-arm clinical studies in patients with leukemia treated with SPRYCEL, the mean QTc interval changes from baseline using Fridericia’s method (QTcF) were 3–6 msec; the upper 95% confidence intervals for all mean changes from baseline were <8 msec. Nine patients had QTc prolongation reported as an adverse event. Three patients (<1%) experienced a QTcF >500 msec.
SPRYCEL (dasatinib) should be administered 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. Hypokalemia or hypomagnesemia should be corrected prior to SPRYCEL administration.
Information for Patients (see Patient Information Leaflet)
Lactose Content
SPRYCEL contains 189 mg of lactose monohydrate in a 140-mg daily dose.
Drug Interactions
Drugs that may increase dasatinib plasma concentrations
CYP3A4 Inhibitors: Dasatinib is a CYP3A4 substrate. Concomitant use of SPRYCEL and drugs that inhibit CYP3A4 (eg, ketoconazole, itraconazole, erythromycin, clarithromycin, ritonavir, atazanavir, indinavir, nefazodone, nelfinavir, saquinavir, telithromycin) 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 CLINICAL PHARMACOLOGY and DOSAGE AND ADMINISTRATION.)
Drugs that may decrease dasatinib plasma concentrations
CYP3A4 Inducers: Drugs that induce CYP3A4 activity may decrease dasatinib plasma concentrations. In patients in whom CYP3A4 inducers (eg, dexamethasone, phenytoin, carbamazepine, rifampicin, phenobarbital) are indicated, alternative agents with less enzyme induction potential should be used. If SPRYCEL must be administered with a CYP3A4 inducer, a dose increase in SPRYCEL should be considered.
St. John's wort (Hypericum perforatum) may decrease SPRYCEL plasma concentrations unpredictably. Patients receiving SPRYCEL should not take St. John's wort. (See CLINICAL PHARMACOLOGY and DOSAGE AND ADMINISTRATION.)
Antacids: Nonclinical data demonstrate that the solubility of dasatinib is pH dependent. 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. (See CLINICAL PHARMACOLOGY.)
H2 Blockers/Proton Pump Inhibitors: Long-term suppression of gastric acid secretion by H2 blockers or proton pump inhibitors (eg, famotidine and omeprazole) is likely to reduce dasatinib exposure. The concomitant use of H2 blockers or proton pump inhibitors with SPRYCEL is not recommended. The use of antacids should be considered in place of H2 blockers or proton pump inhibitors in patients receiving SPRYCEL therapy. (See CLINICAL PHARMACOLOGY.)
Drugs that may have their plasma concentration altered by dasatinib
CYP3A4 Substrates: Dasatinib is a time-dependent inhibitor of CYP3A4. 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. (See CLINICAL PHARMACOLOGY.)
Hepatic Impairment
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.
Renal 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.
Carcinogenesis, Mutagenesis, Impairment of Fertility
Carcinogenesis
Carcinogenicity studies were not performed with dasatinib.
Mutagenesis
Dasatinib was clastogenic when tested in vitro in Chinese hamster ovary cells, with and without metabolic activation. Dasatinib was not mutagenic when tested in an in vitro bacterial cell assay (Ames test) and was not genotoxic in an in vivo rat micronucleus study.
Impairment of Fertility
The effects of dasatinib on male and female fertility have not been studied. However, results of repeat-dose toxicity studies in multiple species indicate the potential for dasatinib to impair reproductive function and fertility. Effects evident in male animals included reduced size and secretion of seminal vesicles, and immature prostate, seminal vesicle, and testis. The administration of dasatinib resulted in uterine inflammation and mineralization in monkeys, and cystic ovaries and ovarian hypertrophy in rodents.
Pregnancy
Pregnancy Category D (See WARNINGS)
Nursing Mothers
It is unknown whether SPRYCEL is excreted in human milk. Women who are taking SPRYCEL should not breast-feed.
Pediatric Use
The safety and efficacy of SPRYCEL in patients <18 years of age have not been established.
Geriatric Use
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.
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