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Carcinogenesis and Mutagenesis: In a 2-year carcinogenicity study in rats at doses up to 3 mg/kg/day (approximately equal to the human clinical exposure), a statistically significant increase in the combined incidence of squamous cell carcinomas and papillomas in the uterus and cervix in females and of prostate adenoma in males was noted. The relevance of the findings from the rat carcinogenicity study for humans is not known.
Dasatinib was clastogenic in vitro to dividing Chinese hamster ovary cells with and without metabolic activation at concentrations ranging from 5 to 60 mcg/mL. Dasatinib was not mutagenic when tested in in vitro bacterial cell assays (Ames test) and was not genotoxic in an in vivo rat micronucleus study.
Cardiovascular: The Phase III clinical study in patients with newly diagnosed CML in chronic phase excluded patients with uncontrolled or significant cardiovascular disease. The dasatinib arm (n=258) included 1.6% of patients with prior cardiac disease and 24% with baseline cardiovascular risk factors. Cardiac adverse reactions of congestive heart failure/cardiac dysfunction, pericardial effusion, arrhythmias, palpitations, QT prolongation, and myocardial infarction (including fatal) were reported in patients taking dasatinib (see Adverse Reactions). Severe pericardial effusion (1.2%) and arrhythmia (0.4%) were also reported in patients. Adverse cardiac events were more frequent in patients with cardiovascular risk factors or a previous medical history of cardiac disease (see Adverse Reactions). Patients with risk factors or a history of cardiac disease should be evaluated at baseline and monitored carefully for clinical signs or symptoms consistent with cardiac dysfunction (such as chest pain, shortness of breath, and diaphoresis) during routine follow up.
In the Phase III clinical trials in patients with resistance or intolerance to prior imatinib therapy, patients were excluded from enrolment for a broad range of cardiac events or conditions. A significantly abnormal ECG at screening was also an exclusion criterion. No prospective evaluation of cardiac function was carried out.
In all clinical trials with patients resistant or intolerant to prior imatinib therapy, congestive heart failure/cardiac dysfunction was reported in 96 (4%) of subjects, of which 49 (2%) were considered to be severe. In some cases, the event was triggered by an acute volume load, including transfusion of blood products.
QT Prolongation: In vitro data suggest that dasatinib and its N-dealkylated metabolite, BMS-582691 have the potential to prolong cardiac ventricular repolarization (QT interval).
In 865 patients with leukemia treated with dasatinib in Phase II clinical studies, the mean changes from baseline in QTcF interval were 4 to 6 msec; the upper 95% confidence intervals for all mean changes from baseline were <7 msec. Of the 2182 patients with resistance or intolerance to prior imatinib therapy who received dasatinib in clinical studies, 21 patients (<1%) experienced a QTcF >500 msec.
In the Phase III clinical study in patients with newly diagnosed CML in chronic phase, patients with baseline QTcF interval >450 msec were excluded. After 5 years of follow-up, QTc prolongation was reported in one patient (<1%) who experienced a QTcF >500 msec and discontinued dasatinib treatment. APO-DASATINIB should be administered with caution in patients who have or may develop prolongation of QTc. These include patients with hypokalemia or hypomagnesemia, patients with congenital long QT syndrome, patients taking antiarrhythmic medicines or other medicinal products that lead to QT prolongation, and cumulative high-dose anthracycline therapy.
Hypokalemia or hypomagnesemia should be corrected prior to administration of APO-DASATINIB. (See Drug-Drug Interactions as follows, Interactions, and Pharmacology: Pharmacodynamics under Actions.)
Drug-Drug Interactions: CYP3A4 inhibitors: Concomitant use of dasatinib and medicinal products that potently inhibit CYP3A4 (e.g. ketoconazole, itraconazole, erythromycin, clarithromycin, ritonavir, atazanavir, lopinavir, grapefruit juice) may increase exposure to dasatinib. Therefore, in patients receiving APO-DASATINIB, co-administration of a potent CYP3A4 inhibitor is not recommended. Selection of an alternate concomitant medication with no or minimal CYP3A4 inhibition potential is recommended. If systemic administration of a potent CYP3A4 inhibitor cannot be avoided, close monitoring for toxicity and an APO-DASATINIB dose reduction to 20 or 40 mg daily should be considered (see Interactions and Dosage & Administration).
CYP3A4 inducers: Concomitant use of dasatinib and medicinal products that induce CYP3A4 (e.g. dexamethasone, phenytoin, carbamazepine, rifampicin, phenobarbital or Hypericum perforatum, also known as St. John's Wort) may substantially reduce exposure to dasatinib, potentially increasing the risk of therapeutic failure. In addition, more healthy male subjects experienced increases in QTcF of >30 msec from the baseline ECG recordings when dasatinib and rifampicin were administered 12 hours apart compared to when dasatinib was administered alone (25% vs. 10%). No subject experienced QTcF >450 msec or a change from baseline >60 msec. (See Interactions.) Therefore, concomitant use of potent CYP3A4 inducers with dasatinib is not recommended. In patients in whom rifampicin or other CYP3A4 inducers are indicated, alternative agents with less enzyme induction potential should be used.
CYP3A4 substrates: Concomitant use of dasatinib and a CYP3A4 substrate may increase exposure to the CYP3A4 substrate. In addition, three healthy subjects (n=48) experienced increases in QTcF of >30 msec from the baseline ECG recordings following concomitant use of a single dose of dasatinib and simvastatin. No subject experienced QTcF >450 msec or a change from baseline >60 msec (see Interactions). Therefore, caution is warranted when APO-DASATINIB is co-administered with a drug that potentially alters CYP3A4 activity, a QTc prolonger, or CYP3A4 substrates of narrow therapeutic index such as cyclosporine, macrolide antibiotics, benzodiazepine, pimozide, or ergot alkaloids (ergotamine, dihydroergotamine). The effect of a CYP3A4 substrate on the pharmacokinetic parameters of dasatinib has not been studied.
H2 antagonists or proton pump inhibitors: Long-term suppression of gastric acid secretion by H2 antagonists or proton pump inhibitors (e.g. cimetidine, ranitidine, famotidine and omeprazole) is likely to reduce dasatinib exposure (see Interactions). The use of antacids should be considered in place of H2 antagonists or proton pump inhibitors in patients receiving APO-DASATINIB therapy.
Antacids: Concomitant use of dasatinib and aluminum hydroxide/magnesium hydroxide may reduce exposure to dasatinib. However, aluminum hydroxide/magnesium hydroxide products may be administered up to 2 hours prior to, or 2 hours following the administration of dasatinib (see Interactions).
Antiemetics: No information is available on the safety of concomitant use of dasatinib with antiemetics (prochlorperazine, metoclopramide, 5-HT3 inhibitors).
Lactose: APO-DASATINIB tablets 20 mg, 50 mg and 70 mg contain lactose monohydrate in proportional amounts of 29.68 mg, 74.2 mg and 103.88 mg, respectively. Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take dasatinib.
Fluid Retention: Dasatinib is associated with fluid retention. Patients with pre-existing pleural effusion were excluded from Phase III studies.
In the Phase III dose-optimization studies in patients with resistance or intolerance to prior imatinib therapy, severe fluid retention was reported in 11% of patients, including severe pleural and pericardial effusion reported in 7% and 2% of patients, respectively. Severe ascites and generalized edema were each reported in <1% of patients. Other manifestations of fluid retention in these studies included pulmonary edema (3%), congestive heart failure/cardiac dysfunction (4%), and pericardial effusion (5%). Nineteen patients had severe pulmonary edema. In patients with chronic phase CML with resistance or intolerance to prior imatinib therapy, Grade 3 or 4 fluid retention events were reported less frequently in patients treated with 100 mg once daily (5%) than in patients treated with 140 mg once daily (9%) (see Adverse Reactions). In these studies, fluid retention events were typically managed by supportive care measures that include diuretics or short courses of steroids. Pleural effusion required oxygen in some cases and at least one thoracentesis in 64 (3%) patients.
In the Phase III study conducted with newly diagnosed chronic phase CML patients, grades 1 to 4 fluid retention and pleural effusion were reported in 22% and 10%, respectively, by 12 months of treatment (see Adverse Reactions). The median time to onset of pleural effusion was 28 weeks (range 4 to 88 weeks). With appropriate medical care, 23 patients (88% of those with pleural effusion) were able to continue on dasatinib. After 5 years follow-up, fluid retention and pleural effusion were reported in 43% and 29% of patients, respectively. The median time to first grade 1-2 pleural effusion was 114 weeks and to first grade 3-4 pleural effusions was 175 weeks. Dasatinib treatment was discontinued due to pleural effusion in 5.8% of all dasatinib-treated patients. Out of patients with a pleural effusion, dasatinib treatment was interrupted in 62% and dose reduced in 41%, and was also managed through the use of diuretics or other appropriate supportive care measures.
In all patients with newly diagnosed or imatinib resistant or intolerant patients with chronic phase CML (n=548), severe fluid retention occurred in 36 (7%) patients receiving dasatinib at the recommended dose. In patients with advanced phase CML or Ph+ ALL treated with dasatinib at the recommended dose (n=304), severe fluid retention was reported in 11% of patients, including severe pleural effusion reported in 8% of patients.
Patients who develop symptoms suggestive of pleural effusion or other fluid retention such as new or worsened dyspnea on exertion or at rest, pleuritic chest pain, or dry cough should be evaluated promptly with chest X-ray or additional diagnostic imaging as appropriate (see Dosage & Administration and Adverse Reactions). Consider treatment interruption, dose reduction, or treatment discontinuation.
Hemorrhage: Nonclinical studies have shown that dasatinib inhibits platelet aggregation in vitro and in vivo and increases bleeding time in vivo. Patients with a history of significant bleeding disorder unrelated to CML were excluded in dasatinib clinical studies. Patients taking concomitant medications that inhibit platelet function or anticoagulants were excluded in initial imatinib-resistant dasatinib clinical studies. In subsequent trials, the use of anticoagulants, aspirin, and non-steroidal anti-inflammatory drugs (NSAIDs) was allowed concurrently with dasatinib if the platelet count was >50,000 per microliter. Caution should be exercised when dasatinib is to be concurrently administered with anticoagulants (see Interactions).
In clinical studies in 2,712 CML or Ph+ ALL patients with a median duration of therapy of 19.2 months (range 0 - 93.2 months), 272 (10%) patients experienced Grade 3 to 4 bleeding. Fifty-six (2%) patients experienced fatal bleeding. In 23 (1%) of these patients, fatal bleeding occurred more than 30 days after dasatinib discontinuation.
Intracranial hemorrhage occurred in 66 (2.4%) of 2,712 CML or Ph+ ALL patients, of which 27 (1%) cases were considered related to dasatinib. Intracranial hemorrhage was fatal in 25 (0.9%) of these patients, of which ten (0.4%) cases were considered related to dasatinib.
Gastrointestinal hemorrhage regardless of relationship to dasatinib occurred in 15% of 2,712 CML or Ph+ ALL patients. The bleeding was severe in 6% of these patients and generally required treatment interruptions and packed cell transfusions. Other episodes of severe bleeding occurred in 3% of patients.
Grade 3 to 4 hemorrhages were reported in 2.3% of 258 patients with newly diagnosed chronic phase CML (see Adverse Reactions).
Hepatic Impairment: The effect of hepatic impairment on the single-dose pharmacokinetics of dasatinib was assessed in 8 moderately hepatic impaired subjects who received a 50-mg dose and 5 severely hepatic impaired subjects who received a 20-mg dose compared to matched healthy subjects who received a 70-mg dose of dasatinib. Hepatic impairment did not result in clinically meaningful change in dasatinib exposure at the doses studied. However no pharmacokinetic information is available from patients with hepatic impairment treated with a 70 to 100 mg dose of dasatinib (see Pharmacology: Pharmacokinetics under Actions). Due to the limitations of this clinical study, caution is recommended in patients with hepatic impairment.
In nonclinical studies, increased liver weight and foci of hepatocellular alteration were observed in rats, and hepatocellular vacuolation was observed in monkeys following repeat dose administration of dasatinib (6 to 9 months). Increased ALT was observed in monkeys, and increased AST and/or decreased albumin were observed in rats and monkeys.
In clinical studies with 2,712 patients, 4 cases of hepatotoxicity, 4 cases of hepatocellular injury, 4 cases of hepatic steatosis, 2 cases of jaundice, 2 cases of liver disorder, 1 case of toxic hepatitis, 1 case of hepatic failure, 2 cases of abnormal hepatic function and 1 case of hepatitis were observed.
Immune: Hepatitis B virus reactivation: Reactivation of hepatitis B virus (HBV) has occurred in patients who are chronic carriers of this virus after receiving a BCR-ABL tyrosine kinase inhibitor (TKI), including dasatinib. Some cases resulted in acute hepatic failure or fulminant hepatitis leading to liver transplantation or death. Patients should be tested for HBV infection before initiating treatment with dasatinib. Patients currently on dasatinib should have baseline testing for HBV infection in order to identify chronic carriers of the virus. Experts in liver disease and in the treatment of hepatitis B should be consulted before treatment is initiated in patients with positive HBV serology (including those with active disease) and for patients who test positive for HBV infection during treatment. Carriers of HBV who require treatment with dasatinib should be closely monitored for signs and symptoms of active HBV infection throughout therapy and for several months following termination of therapy.
Myelosuppression: Treatment with dasatinib is associated with thrombocytopenia, neutropenia, and anemia which occur earlier and more frequently in patients with advanced phase CML or Ph+ ALL than in patients with chronic phase CML. In a Phase III dose-optimization study in patients with chronic phase CML with resistance or intolerance to prior imatinib therapy with a minimum follow-up of 24 months, Grade 3 or 4 myelosuppression was reported less frequently in patients treated with 100 mg once daily (neutropenia 35%, thrombocytopenia 23% and anemia 13%) than in patients treated with 70 mg twice daily (neutropenia 45%, thrombocytopenia 38% and anemia 18%). Severe febrile neutropenia (including fatal outcomes) was reported in 2% of chronic phase patients and 14% of advanced phase CML patients.
In patients with advanced phase CML or Ph+ ALL treated with dasatinib complete blood counts (CBCs) should be performed weekly for the first 2 months and then monthly thereafter, or as clinically indicated.
In patients with chronic phase CML, CBCs should be performed every 2 weeks for 12 weeks, then every 3 months thereafter or as clinically indicated.
Myelosuppression was generally reversible and usually managed by withholding dasatinib temporarily or dose reduction (see Dosage & Administration and Adverse Reactions). In clinical studies in patients with resistance or intolerance to prior imatinib therapy, severe (CTC Grade 3 or 4) cases of anemia were managed with blood transfusions. Packed red blood cells were transfused in 30% of chronic phase CML patients and 79% of myeloid blast phase CML patients. Platelet transfusions were required in 17% of chronic phase CML patients and 66% of myeloid blast phase CML patients.
Monitoring and Laboratory Tests: In patients with chronic phase CML, complete blood counts (CBCs) should be performed every two weeks for 12 weeks, then every 3 months thereafter, or as clinically indicated. In patients with advanced phase CML or Ph+ ALL, CBC should be performed weekly for the first 2 months and then monthly thereafter, or as clinically indicated (see Myelosuppression as previously mentioned).
Hepatic function tests (AST, ALT and bilirubin), CK and renal function tests should be performed every two weeks for the first 2 months and then monthly thereafter or as clinically indicated (see Hepatic Impairment as previously mentioned and Rhabdomyolysis as follows).
Pulmonary arterial hypertension: PAH (pre-capillary pulmonary arterial hypertension confirmed by right heart catheterization) has been reported in association with dasatinib treatment in post-marketing reports. In these cases, PAH was reported after initiation of dasatinib therapy, including after more than one year of treatment. Patients should be evaluated for signs and symptoms of underlying cardiopulmonary disease prior to initiation dasatinib therapy. An echocardiography should be performed at treatment initiation in every patient presenting symptoms of cardiac disease and considered in patients with risk factors for cardiac or pulmonary disease. Patients who develop dyspnoea and fatigue after initiation of therapy should be evaluated for common etiologies including pleural effusion, pulmonary oedema, anaemia, or lung infiltration. In accordance with recommendations for management of non-haematologic adverse reactions the dose of dasatinib should be reduced or therapy interrupted during this evaluation. If no explanation is found, or if there is no improvement with dose reduction or interruption, the diagnosis of PAH should be considered. The diagnostic approach should follow standard practice guidelines. If PAH is confirmed, dasatinib should be permanently discontinued. Follow up should be performed according to standard practice guidelines. Improvements in haemodynamic and clinical parameters have been observed in dasatinib-treated patients with PAH following cessation of dasatinib therapy.
Renal Impairment: There are currently no clinical studies with dasatinib in patients with impaired renal function. The study in patients with newly diagnosed chronic phase CML excluded patients with serum creatinine concentration >3 times the upper limit of the normal range, and studies in patients with chronic phase CML with resistance or intolerance to prior imatinib therapy 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. The effect of dialysis on dasatinib pharmacokinetics has not been studied.
Rhabdomyolysis: Cases of rhabdomyolysis with acute renal failure have been reported. Patients with muscle symptoms (muscle aches/pains) should be investigated to rule out rhabdomyolysis (elevated creatine kinase, elevated serum creatinine, hyperkalemia, hyperphosphatemia, brown urine, elevated ALT and AST).
Sexual Health: Reproduction: Dasatinib can cause fetal harm when administered to pregnant women. Knowledge of the potential effects of dasatinib on the sperm of male patients, and the level of maternal or fetal exposure from the semen of male dasatinib patients, is limited. Sexually active male patients or female patients of child bearing potential taking APO-DASATINIB should use highly effective contraception.
Fertility: The effects of dasatinib on male and female fertility in humans are not known. Based on animal studies, dasatinib may impair fertility in females of reproductive potential.
Skin - Severe dermatologic reactions: Individual cases of severe mucocutaneous dermatologic reactions, including Stevens-Johnson syndrome and erythema multiforme, have been reported with the use of dasatinib. APO-DASATINIB should be permanently discontinued in patients who experience a severe mucocutaneous reaction during treatment if no other etiology can be identified.
Use in Pregnancy: See Pregnant Women under Use in Pregnancy & Lactation.
Use in Lactation: See Nursing Women under Use in Pregnancy & Lactation.
Use in Children: The safety and efficacy of dasatinib in patients <18 years of age have not been established. Based on findings from the rat study (see Nursing Women under Use in Pregnancy & Lactation), APO-DASATINIB should not be used in children under two years of age.
Use in the Elderly: In the newly diagnosed chronic phase CML study, 25 patients (10%) were 65 years of age and older and 7 patients (3%) were 75 years of age and older. Patients of 65 years and over had more serious adverse events reported (any or drug-related) compared to those under 65 years (40.7% vs. 29.7%, 16.7% vs. 12.1%, respectively). Of the 2,712 patients in clinical studies of dasatinib, 617 (23%) were 65 years of age and older and 123 (5%) were 75 years of age and older. While the safety profile of dasatinib in the geriatric population was similar to that in the younger population, patients aged 65 years and older are more likely to experience the commonly reported adverse reactions diarrhea, fatigue, cough, pleural effusion, dyspnea, dizziness, peripheral edema, pneumonia, hypertension, arrhythmia, congestive heart failure, pericardial effusion, lower gastrointestinal hemorrhage, abdominal distension and more likely to experience the less frequently reported events pulmonary edema, lung infiltration, arthritis, and urinary frequency and should be monitored closely. No differences in cCCyR and MMR were observed between older and younger patients. However, in the two randomized studies in patients with imatinib resistant or intolerant chronic phase CML, the rates of major cytogenetic response (MCyR) at 2 years were lower among patients aged 65 years and older (42% MCyR in patients ≥65 years versus 56% MCyR in the rest of the study population and 47% MCyR in patients ≥65 years versus 68% MCyR in the rest of the study population in studies CA180017 and CA180034, respectively).
