Apo-Dasatinib

Dasatinib.

APO-DASATINIB 20 mg tablet is white to off-white, round, biconvex coated tablet, engraved "APO" on one side, "DA" over "20" on the other side.
APO-DASATINIB 50 mg tablet is white to off-white, oval, bevelled-edged, biconvex coated tablet, engraved "APO" on one side, "DAS50" on the other side.
APO-DASATINIB 70 mg tablet is white to off-white, round, biconvex coated tablet, engraved "APO" on one side, "DA" over "70" on the other side.
APO-DASATINIB film-coated tablets are available for oral administration in strengths 20 mg, 50 mg, 70 mg dasatinib.
Excipients/Inactive Ingredients: The tablet core contains the following non-medicinal ingredients: colloidal silicon dioxide, croscarmellose sodium, ethylcellulose, lactose monohydrate, magnesium stearate and microcrystalline cellulose.
The film-coating contains the following inactive ingredients: hydroxypropyl cellulose, hydroxypropyl methylcellulose, titanium dioxide and triethyl citrate.

Pharmacology: Mechanism of Action: Dasatinib inhibits the activity of the BCR-ABL kinase and SRC family kinases (LYN, HCK), along with a number of other kinases including c-KIT, ephrin (EPH) receptor kinases, and PDGFβ receptor. Dasatinib is a potent inhibitor of the BCR-ABL and SRC family kinases with potency at sub-nanomolar concentrations. It binds not only to the inactive but also to the active conformation of the enzyme.
Pharmacodynamics: In vitro, dasatinib is active in leukemic cell lines representing variants of imatinib sensitive and resistant disease. These nonclinical studies show that dasatinib can overcome imatinib resistance resulting from BCR-ABL overexpression, BCR-ABL kinase domain mutations (14/15 mutations with exception of T315I), activation of alternate signaling pathways involving the SRC family kinases (LYN, HCK), and multidrug resistance gene, MDR1, overexpression.
In vivo, in separate experiments using murine models of CML, dasatinib prevented the progression of chronic CML to blast phase and prolonged the survival of mice bearing patient-derived CML cell lines.
Electrocardiogram: In five Phase II clinical studies in patients with leukemia, repeated baseline and on-treatment ECGs were obtained at pre-specified time points and read centrally for 865 patients receiving dasatinib 70 mg BID. QT interval was corrected for heart rate by Fridericia's method. At all post-dose time points on day 8, the mean changes from baseline in QTcF interval were 4 to 6 msec, with associated upper 95% confidence intervals <7 msec. Of the 2182 patients who received dasatinib in clinical trials, 21 patients (<1%) experienced a QTcF >500 msec. (See Precautions.)
Pharmacokinetics: The pharmacokinetics of dasatinib were evaluated in 229 healthy subjects and in 84 patients with leukemia.
Absorption: Dasatinib is rapidly absorbed in patients following oral administration. Peak concentrations were observed between 0.25 to 6 hours. The overall mean terminal half-life of dasatinib is approximately 3 to 5 hours.
Distribution: In patients, dasatinib has a large apparent volume of distribution (2505 L) suggesting that the drug is extensively distributed in the extravascular space.
Metabolism: Dasatinib is extensively metabolized in humans. In a study of 8 healthy subjects administered 100 mg of [¹⁴C]-labeled dasatinib, unchanged dasatinib represented 29% of circulating radioactivity in plasma. Plasma concentration and measured in vitro activity indicate that metabolites of dasatinib are unlikely to play a major role in the observed pharmacology of the drug. CYP3A4 is a major enzyme responsible for the metabolism of dasatinib.
Excretion: Elimination is predominantly in the feces, mostly as metabolites. Following a single oral dose of [¹⁴C]-labeled dasatinib, approximately 89% of the dose was eliminated within 10 days, with 4% and 85% of the administered radioactivity recovered in the urine and feces, respectively. Unchanged dasatinib accounted for 0.1% and 19% of the administered dose in urine and feces, respectively, with the remainder of the dose being metabolites.
Special Populations and Conditions: Pediatrics: No clinical studies were conducted with dasatinib in pediatric populations.
Hepatic Insufficiency: 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. The mean C_max and AUC of dasatinib adjusted for the 70-mg dose was decreased by 47% and 8%, respectively, in moderate hepatic impairment compared to subjects with normal hepatic function. In severe hepatic impaired subjects, the mean C_max and AUC adjusted for the 70-mg dose was decreased by 43% and 28%, respectively, compared to subjects with normal hepatic function. 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. Due to limitations of this clinical study, caution is recommended in patients with hepatic impairment (see Precautions and Dosage & Administration).
Renal Insufficiency: No clinical studies were conducted with dasatinib in patients with decreased renal function. Less than 4% of dasatinib and its metabolites are excreted via the kidney. (See Precautions.)
Drug-Drug Interactions: See Interactions.
Drug-Food Interactions: Data from a study of 54 healthy subjects administered a single, 100-mg dose of dasatinib 30 minutes following consumption of a high-fat meal indicated a 14% increase in the mean AUC of dasatinib. Consumption of a low-fat meal 30 minutes prior to dasatinib resulted in a 21% increase in the mean AUC of dasatinib. The observed food effects do not represent clinically relevant changes in exposure.

APO-DASATINIB is indicated for the treatment of adults with newly diagnosed Philadelphia chromosome positive (Ph+) chronic myeloid leukemia (CML) in chronic phase. Clinical effectiveness of dasatinib treatment in patients with newly diagnosed Ph+ CML in chronic phase is based on confirmed complete cytogenetic response rate (cCCyR) within 12 months. As of the 60 month cut-off date, overall survival, prevention of progression to advanced stage CML, or time-in cCCyR benefits have not been demonstrated.
APO-DASATINIB is indicated for the treatment of adults with Ph+ chronic, accelerated, or blast phase chronic myeloid leukemia (CML) with resistance or intolerance to prior therapy including imatinib mesylate. Clinical effectiveness of dasatinib in CML is based on the rates of hematologic and cytogenetic responses in clinical trials with a minimum of 24 months of follow-up.
APO-DASATINIB is indicated for the treatment of adults with Ph+ acute lymphoblastic leukemia (ALL) with resistance or intolerance to prior therapy. Clinical effectiveness in Ph+ ALL is based on the rates of hematologic and cytogenetic responses in clinical trials with a minimum of 24 months of follow-up.
APO-DASATINIB should only be prescribed by a qualified physician who is experienced in the use of antineoplastic therapy.
Geriatrics (≥65 years of age): 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 events 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).
Pediatrics (<18 years of age): The safety and efficacy of dasatinib in patients <18 years of age have not been established. Nonclinical studies demonstrated greater toxicity in rat pups (see Use in Children under Precautions).

Recommended Starting Dose: The recommended starting dosage of APO-DASATINIB for chronic phase CML is 100 mg administered orally once daily (OD), either in the morning or in the evening.
The recommended starting dosage of APO-DASATINIB for accelerated phase CML, or myeloid or lymphoid blast CML, is 140 mg/day administered orally once daily (140 mg QD) either in the morning or in the evening.
The recommended starting dosage of APO-DASATINIB for Ph+ ALL is 140 mg administered orally once daily (140 mg QD) either in the morning or in the evening.
Dosing recommendations in patients with imatinib resistant or intolerant CML and Ph+ ALL are based on the results of two randomized Phase III dose-optimization studies.
APO-DASATINIB can be taken with or without food. Tablets should not be crushed or cut; they should be swallowed whole.
In clinical studies, treatment with dasatinib was continued until disease progression or until no longer tolerated by the patient. The effect of stopping treatment on long-term disease outcome after the achievement of a complete cytogenetic response (CCyR) or major molecular response (MMR) has not been investigated.
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 dosage.
Dose reduction for concomitant use of strong CYP3A4 inhibitors: The concomitant use of strong CYP3A4 inhibitors and grapefruit juice with APO-DASATINIB should be avoided (see Interactions). CYP3A4 inhibitors such as ketoconazole may increase dasatinib plasma concentrations. If possible, an alternative concomitant medication with no or minimal enzyme inhibition potential should be selected. If APO-DASATINIB must be administered with a strong CYP3A4 inhibitor, consider a dose decrease to: 40 mg daily for patients taking APO-DASATINIB 140 mg daily; 20 mg daily for patients taking APO-DASATINIB 100 mg daily; 20 mg daily for patients taking APO-DASATINIB 70 mg daily.
For patients taking APO-DASATINIB 60 mg or 40 mg daily, consider interrupting APO-DASATINIB until the inhibitor is discontinued. Allow a washout period of approximately 1 week after the inhibitor is stopped before reinitiating APO-DASATINIB.
The reduced doses of dasatinib are predicted to adjust the area under the curve (AUC) to the range observed without CYP3A4 inhibitors; however, clinical data are not available with these dose adjustments in patients receiving strong CYP3A4 inhibitors. If APO-DASATINIB is not tolerated after dose reduction, either discontinue the strong CYP3A4 inhibitor or stop APO-DASATINIB until the inhibitor is discontinued. Allow a washout period of approximately 1 week after the inhibitor is stopped before the APO-DASATINIB dose is increased.
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. (See Table 1.)

Click on icon to see table/diagram/image

Non-hematological adverse reactions: If a moderate (Grade 2) non-hematological adverse reaction develops with APO-DASATINIB, treatment should be interrupted until the adverse reaction has resolved or returned to baseline. The same dose should be resumed if this is the first occurrence and the dose should be reduced if this is a recurrent adverse reaction.
If a severe (Grade 3 or 4) non-hematological adverse reaction develops with APO-DASATINIB 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. However, in patients diagnosed with pulmonary arterial hypertension (PAH), APO-DASATINIB should be permanently discontinued.
Patients with chronic CML who received 100 mg once daily, dose reduction to 80 mg once daily with further reduction from 80 mg once daily to 50 mg once daily, if needed, is recommended. For adult patients with advanced phase CML or Ph+ ALL who received 140 mg once daily, dose reduction to 100 mg once daily with further reduction from 100 mg once daily to 80 mg once daily, if needed, is recommended.
Pediatrics (<18 years of age): APO-DASATINIB is not recommended for use in children below 18 years of age due to a lack of data on safety and efficacy.
Hepatic impairment: No clinical pharmacokinetic trials were conducted with a 70 to 100 mg dose of dasatinib in patients with decreased liver function. APO-DASATINIB should be used with caution in patients with moderate to severe hepatic impairment (see Precautions).
Renal impairment: No clinical trials were conducted with dasatinib in patients with decreased renal function (trials excluded patients with serum creatinine concentration >1.5 times the upper limit of the normal range). Since the renal clearance of dasatinib and its metabolites is <4%, a decrease in total body clearance is not expected in patients with renal insufficiency.

Experience with overdose of dasatinib in clinical studies is limited to isolated cases. The highest reported dosage ingested was 280 mg per day for 1 week in two patients and both developed a significant decrease in platelet counts. Since dasatinib is associated with severe myelosuppression (see Precautions and Adverse Reactions), patients who ingested more than the recommended dosage should be closely monitored for myelosuppression and appropriate supportive treatment given.

Use of APO-DASATINIB is contraindicated in patients with hypersensitivity to dasatinib or to any other component of APO-DASATINIB.
Breastfeeding is contraindicated in women taking dasatinib.

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).

Pregnant Women: Dasatinib can cause fetal harm when administered to pregnant women. There have been post-marketing reports of spontaneous abortion and fetal and infant anomalies from women who have taken dasatinib during pregnancy (see Adverse Reactions). Studies in animals have shown that at concentrations which are readily achievable in humans receiving therapeutic doses of dasatinib, fetal toxicity (embryofetal lethality, skeletal abnormalities including malformations) was observed in both pregnant rats and rabbits. Fetal death was observed in rats.
APO-DASATINIB therefore should not be used in women who are pregnant or contemplating pregnancy. Women of child bearing potential must be advised to use highly effective contraception (i.e. a method of birth control that results in a failure rate less than 1% per year when used consistently and correctly) during APO-DASATINIB treatment. If APO-DASATINIB is used during pregnancy, or if the patient becomes pregnant while taking APO-DASATINIB, the patient should be apprised of the potential hazard to the fetus.
Nursing Women: It is unknown whether dasatinib is excreted in human milk. In an exploratory pre- and post-natal development study in rats, postnatal exposure to dasatinib through lactation resulted in pleural effusion and mortality in pups before postnatal age of 20 days at an exposure of 0.27 times the adult clinical dose. Women who are taking APO-DASATINIB must not breastfeed (see Contraindications).

Adverse Drug Reaction Overview: The data described as follows reflect exposure to dasatinib at all doses studied from clinical studies in 2,712 patients, including 324 patients with newly diagnosed chronic phase CML and 2388 patients with imatinib intolerant or resistant chronic or advanced phase CML or Ph+ ALL. The median duration of therapy in 2,712 dasatinib treated patients was 19.2 months (range 0 to 93.2 months).
The majority of dasatinib-treated patients experienced adverse events at some time. Most events were mild to moderate. In the overall population of 2,712 dasatinib-treated subjects, 798 (29.4%) experienced adverse events leading to treatment discontinuation. Among the 258 patients in the Phase III newly diagnosed chronic phase CML study with follow up over a minimum of 60 months, serious adverse events, regardless of relationship to dasatinib, were reported in 35% of patients treated with dasatinib. A total of 69% of patients had dose interruption and 37% had dose reduction.
Dasatinib was discontinued due to study drug toxicity in 14% of dasatinib-treated patients with a minimum of 60 months follow-up. The reasons for discontinuation were thrombocytopenia, leukopenia, pleural effusion, colitis, creatinine kinase increased, pericardial effusion, prolonged QTc interval, chest pain, optic neuritis, pulmonary hypertension, dyspnea, pleurisy, pneumothorax, acute myocardial infarction, abdominal discomfort, abdominal pain, colitis, diarrhea, peripheral edema, and acute renal failure.
Among the 1,618 dasatinib-treated subjects with chronic phase CML, adverse reactions leading to discontinuation were reported in 329 (20.3%) subjects, and among the 1,094 dasatinib-treated subjects with advanced phase disease (including Ph+ ALL), adverse reactions leading to discontinuation were reported in 191 (17.5%) subjects.
In a Phase III dose-optimization study in chronic phase CML patients resistant or intolerant to prior imatinib therapy with a minimum of 84 months follow-up, the rate of discontinuation for adverse reactions was 21% in patients treated with 100 mg once daily.
The median time to onset for Grade 1 or 2 pleural effusion events was 114 weeks (range 4-299 weeks). Fewer than 3% of pleural effusion events were Grade 3 or 4. With appropriate medical care, 58 patients (80% of those with pleural effusion) were able to continue on dasatinib (see Precautions).
With a minimum of 60 months of follow up, the most frequently adverse events reported in dasatinib-treated patients with newly diagnosed chronic phase CML were fluid retention (including pleural effusion, superficial edema, pulmonary hypertension, generalized edema, pericardial effusion, congestive heart failure/cardiac dysfunction, pulmonary edema), diarrhea, infection (including bacterial, viral, fungal and non-specified), upper respiratory tract infection/inflammation, musculoskeletal pain, headache, cough, rash, pyrexia, and abdominal pain.
With a minimum of 84 months of follow up, in 165 patients with chronic phase CML resistant or intolerant to prior imatinib therapy treated with the recommended dose of 100 mg once daily, the most frequently reported adverse events, regardless of causality or severity, were diarrhea, fluid retention, headache, musculoskeletal pain, hemorrhage, pyrexia, fatigue, infection, skin rash, nausea, dyspnea, cough, upper respiratory tract infection/inflammation, vomiting, pain, abdominal pain, arthralgia, myalgia, pruritus and constipation.
Clinical Trial Adverse Drug Reactions in Patients Treated with Dasatinib: Newly diagnosed patients with chronic phase CML: In the Phase III study in patients with newly diagnosed chronic phase CML the median duration of therapy was 60 months for both groups (range: <1 to 73 months for the dasatinib group and <1 month to 75 months in the imatinib group); the median average daily dose was 99 mg and 400 mg, respectively.
All treatment-emergent adverse events (excluding laboratory abnormalities), regardless of relationship to study drug, that were reported in at least 5% of the patients are shown in Table 2. (See Table 2.)
A total of 26 (10%) dasatinib-treated patients died (11 of infections and 2 of myocardial infarction) and a total of 26 patients (10%) in the imatinib arm died (including 1 of myocardial infarction, 1 of pneumonia, 1 of fatal bleeding at time of disease progression and 2 of unknown cause/clinical deterioration and decrease in performance status).

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Patients with imatinib intolerant or resistant CML or Ph+ ALL: All treatment-emergent adverse events (excluding laboratory abnormalities), regardless of relationship to study drug, that were reported in at least 5% of the patients treated with dasatinib at the recommended dose of 100 mg once daily in a Phase III clinical study of imatinib intolerant or resistant chronic phase CML are shown in Table 3. (See Table 3.)
In the Phase III dose-optimization study in patients with imatinib intolerant or resistant chronic phase CML, the median overall duration of therapy with 100 mg once daily was 30 months (range 1 to 93 months).

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With a minimum follow-up of 84 months, long-term cumulative safety data are available for the 100 mg once daily dose. Due to the allowance of switching to the 100 mg once daily dosing in the other three arms of the trial, safety results of these treatment groups are similar to the 100 mg once daily dose. Adverse events (all grades) that continued to occur in patients treated on the 100 mg once daily schedule at 2 and 7 years included: overall fluid retention (34% vs. 48%), pleural effusion (18% vs. 28%), and superficial edema (18% vs. 22%). Grade 3 or 4 pleural effusion among patients treated with 100 mg once daily at 2 and 7 years was 2% vs. 5%, respectively.
In the Phase III dose-optimization study exploring the once daily schedule of dasatinib (140 mg once daily) in patients with imatinib intolerant or resistant advanced diseases, the median duration of therapy was 13.62 months (range .03 to 31.15 months) for accelerated phase CML, 3.19 months (range .03 to 27.73 months) for myeloid blast CML, 3.55 months (range .10 to 22.08 months) for lymphoid blast CML, and 2.99 months (range .16 to 23.46 months) for Ph+ ALL. (See Table 4.)

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Less Common Clinical Trial Adverse Drug Reactions (<5% all grades) Reported in Clinical Trials in Patients Treated with Dasatinib: The following additional adverse reactions, regardless of relationship to therapy or dosing regimen, were reported in patients in the dasatinib clinical studies (n=2,712) at a frequency of <5%, unless otherwise noted. These reactions are presented by frequency category. Frequent reactions are those occurring in ≥1% of patients, infrequent reactions are those occurring in 0.1% to <1% of patients and rare reactions are those occurring in <0.1% of patients. These events are included based on clinical relevance.
Blood and Lymphatic System Disorders: Frequent: myelosuppression (including anemia, neutropenia, thrombocytopenia).
Infrequent: coagulopathy, lymphadenopathy, lymphopenia.
Rare: aplasia pure red cell, splenic calcification.
Cardiac Disorders: Frequent: angina pectoris, cardiomegaly, myocardial infarction (including fatal outcomes).
Infrequent: electrocardiogram QT prolonged, pericarditis, ventricular arrhythmia (including ventricular tachycardia), acute coronary syndrome, cor pulmonale myocarditis, electrocardiogram T wave abnormal, troponin increased, cardiac arrest, coronary artery disease.
Rare: arteriosclerosis coronary artery, restrictive cardiomyopathy, electrocardiogram PR prolongation, pleuropericarditis.
Congenital, Familial and Genetic Disorders: Rare: porokeratosis.
Ear and Labyrinth Disorders: Frequent: tinnitus, vertigo, hearing loss.
Endocrine Disorders: Frequent: hypothyroidism.
Infrequent: hyperthyroidism, thyroiditis.
Eye Disorders: Frequent: conjunctivitis, dry eye, visual disorder.
Infrequent: visual impairment, lacrimation increased.
Rare: pterygium, retinal vascular disorder, photophobia.
Gastrointestinal Disorders: Frequent: dysphagia, gastroesophageal reflux disease, colitis (including neutropenic colitis), oral soft tissue disorder.
Infrequent: anal fissure, esophagitis, anal fistula, upper gastrointestinal ulcer, pancreatitis, ileus.
Rare: protein-losing gastroenteropathy, volvulus, pancreatitis acute.
General Disorders and Administration Site Conditions: Frequent: malaise, face edema (>5%), other superficial edema.
Rare: gait disturbance.
Hepatobiliary Disorders: Infrequent: cholecystitis, cholestasis, hepatitis.
Rare: acquired dilatation intrahepatic duct.
Immune System Disorders: Rare: anaphylactic reaction.
Infections and Infestations: Rare: sialoadenitis.
Injury, Poisoning and Procedural Complications: Rare: epicondylitis.
Investigations: Infrequent: blood creatine phosphokinase increased, gamma-glutamyltransferase increased.
Rare: clostridum test positive, coxsackle virus test positive, hepatitis C RNA increased, platelet aggregation abnormal, blood chloride increased.
Metabolism and Nutrition Disorders: Frequent: dehydration.
Infrequent: hypoalbuminemia, diabetes mellitus, tumour lysis syndrome, hypercholesterolemia.
Musculoskeletal and Connective Tissue Disorders: Frequent: muscular weakness, musculoskeletal stiffness.
Infrequent: tendonitis, rhabdomyolysis, muscle inflammation, osteonecrosis.
Rare: chondrocalcinosis, osteochondrosis, gouty tophus.
Neoplasms Benign, Malignant and Unspecified: Rare: oral papilloma.
Nervous System Disorders: Frequent: dysgeusia, syncope, amnesia, tremor, convulsion, somnolence.
Infrequent: cerebrovascular accident, transient ischemic attack, balance disorder, ataxia.
Rare: VIIth nerve paralysis, cerebellar infarction, dementia, reversible posterior encephalopathy syndrome, optic neuritis, carotid artery stenosis.
Pregnancy, Puerperium and Perinatal Conditions: Rare: abortion.
Psychiatric Disorders: Frequent: confusional state, affect lability.
Infrequent: libido decreased.
Rare: hypomania, seasonal affective disorder.
Renal and Urinary Disorders: Infrequent: proteinuria, renal impairment.
Rare: nephrocalcinosis, bladder diverticulum, glomerulonephritis.
Reproductive System and Breast Disorders: Frequent: gynecomastia.
Infrequent: menstrual disorder.
Rare: orchitis non-infective, vaginal prolapse.
Respiratory, Thoracic, and Mediastinal Disorders: Frequent: asthma, lung infiltration, dysphonia, pneumonitis.
Infrequent: bronchospasm, acute respiratory distress syndrome (including fatal outcomes), pulmonary embolism, oropharyngeal discomfort.
Rare: pulmonary arterial hypertension, nasal septum deviation, rhinitis hypertrophic, reflux laryngitis, nasal septum perforation.
Skin and Subcutaneous Tissue Disorders: Frequent: urticaria, skin ulcer, photosensitivity.
Infrequent: bullous conditions, nail disorder, neutrophilic dermatosis, palmar-plantar erythrodysaesthesia syndrome, panniculitis, hair disorder.
Rare: asteatosis, leukocytoclastic vasculitis, skin fibrosis.
Vascular Disorders: Frequent: thrombophlebitis.
Infrequent: deep vein thrombosis, thrombosis, atherosclerosis.
Rare: livedo reticularis, peripheral arterial occlusive disease, arterial occlusive disease, embolism, cerebral arteriosclerosis.
Abnormal Hematologic and Clinical Chemistry Findings: Myelosuppression was commonly reported in all studies. However, 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. Most patients continued treatment without further progressive myelosuppression.
Newly diagnosed patients with chronic phase CML: Laboratory abnormalities reported in patients treated with dasatinib in the Phase III clinical study in patients with newly diagnosed CML are shown in Table 5. (See Table 5.)
Myelosuppression was less frequently reported in newly diagnosed chronic phase CML, than in chronic phase CML patients with resistance or intolerance to prior imatinib therapy. In dasatinib-treated patients who experienced grade 3 or 4 myelosuppression, recovery generally occurred following brief dose interruptions and/or reductions and permanent discontinuation of treatment occurred in 2.3% of patients due to drug-related hematologic toxicities.

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Patients with imatinib intolerant or resistant CML or Ph+ ALL: Laboratory abnormalities that were reported in patients treated with dasatinib in clinical studies are shown in Table 6 for imatinib intolerant or resistant chronic or advanced phase CML and Ph+ ALL. (See Table 6.)
In patients who experienced severe myelosuppression, recovery generally occurred following brief dose interruptions and/or reductions. Occasionally permanent discontinuation of treatment was required.
Elevations of transaminases or bilirubin were reported in all disease phases, but were more common in patients with advanced disease. The numbers of patients who developed three or more simultaneous significant elevations of transaminases or bilirubin suggestive of hepatic toxicity were as follows: Chronic phase, 4; accelerated, 13; myeloid blast, 13; lymphoid blast, 7. Most events were managed with dose reduction or interruption. One patient required discontinuation of treatment due to abnormalities of liver function tests. Although causality has not been established, the occurrence of abnormal liver function tests on treatment should be followed closely and consideration given to discontinuing dasatinib.
Hypocalcemia: Between 48% and 76% of patients experienced hypocalcemia at least once during this period. Grade 3 or 4 abnormalities were reported in 2, 7, 16, 13 and 9% of the patients in the chronic phase CML (n=1150), accelerated phase CML (n=502), myeloid blast phase CML (n=280), lymphoid blast phase CML (n=115) and Ph+ ALL (n=135), respectively. The percentage of patients with hypocalcemia who were treated with calcium supplements is 7% for chronic phase CML, 16% for accelerated phase CML, 28% for myeloid blast CML, 20% for lymphoid blast CML and 20% for Ph+ ALL.
Hypophosphatemia: Between 41% and 50% of patients experienced hypophosphatemia at least once during this period. Grade 3 or 4 abnormalities were reported in 10, 13, 20, 19 and 21% of the patients in the chronic phase CML (n=1150), accelerated phase CML (n=502), myeloid blast phase CML (n=280), lymphoid blast phase CML (n=115) and Ph+ ALL (n=135), respectively.
In the Phase II randomized study, the frequency of Grade 3 or 4 neutropenia, thrombocytopenia, and anemia was 63%, 57%, and 20%, respectively, in the dasatinib group and 39%, 14%, and 8%, respectively, in the imatinib group. The frequency of Grade 3 or 4 hypocalcemia was 5% in the dasatinib group and 0% in the imatinib group.

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Post-Market Adverse Drug Reactions: The following additional adverse reactions have been identified during post approval use of dasatinib. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. (See Table 7.)

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Overview: Dasatinib is an inhibitor of CYP3A4 and may decrease the metabolic clearance of drugs that are primarily metabolized by CYP3A4. At clinically relevant concentrations, dasatinib does not inhibit CYP 1A2, 2A6, 2B6, 2C8, 2C9, 2C19, 2D6, or 2E1. Dasatinib is not an inducer of CYP enzymes.
Drug-Drug Interactions: Drugs that may increase dasatinib plasma concentrations: CYP3A4 Inhibitors: In vitro studies indicate that dasatinib is a CYP3A4 substrate. In a study of 18 patients with solid tumors, 20-mg dasatinib once daily co-administered with 200 mg of ketoconazole BID increased the dasatinib C_max and AUC by four- and five-fold, respectively. Substances that inhibit CYP3A4 activity (eg, ketoconazole, itraconazole, erythromycin, clarithromycin, grapefruit juice) may decrease metabolism and increase concentrations of dasatinib and should be avoided. 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, a dose reduction should be considered and the patient should be closely monitored for toxicity (see Drug-Food Interactions as follows, Precautions, and Dosage & Administration).
Drugs that may decrease dasatinib plasma concentrations: CYP3A4 Inducers: Data from a study of 20 healthy subjects indicate that when a single morning dose of dasatinib was administered following 8 days of continuous evening administration of 600 mg of rifampicin, a potent CYP3A4 inducer, the mean C_max and AUC of dasatinib were decreased by 81% and 82%, respectively. In addition, more healthy male subjects experienced increases in QTcF of >30 msec from the baseline recordings when a single dose of dasatinib was administered 12 hours following rifampicin compared to when dasatinib was given alone (25% vs. 10%, n=20). No subject experienced QTcF >450 msec or a change from baseline ≥60 msec (see Precautions).
Antacids: Nonclinical data indicate that dasatinib has pH dependent solubility. 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 dasatinib was associated with no relevant change in dasatinib AUC or C_max. On the contrary, when 30 mL of aluminum hydroxide/magnesium hydroxide was administered to the same subjects concomitantly with a 50 mg dose of dasatinib, a 55% reduction in dasatinib AUC and a 58% reduction in C_max were observed (see Precautions).
Famotidine: In a study of 24 healthy subjects, administration of a single 50 mg dose of dasatinib 10 hours following famotidine reduced the AUC and C_max of dasatinib by 61% and 63%, respectively (see Precautions).
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 C_max and AUC of simvastatin, a prototypical CYP3A4 substrate, were increased by 37% and 20%, respectively, when simvastatin (80 mg) was administered in combination with a single 100 mg dose of dasatinib. In addition, three healthy subjects (n=48) experienced QTcF of >30 msec from the baseline ECG recordings following the concomitant use of a single dose of simvastatin and dasatinib. No subject experienced QTcF >450 msec or a change from baseline >60 msec. The effect of CYP3A4 substrates on the pharmacokinetics of dasatinib has not been studied (see Precautions).
Drugs that prolong QTc interval or induce torsades de pointes: The concomitant use of dasatinib with medicinal products known to prolong QTc interval or medicinal products able to induce torsades de pointes should be avoided if possible. Medicinal products that are generally accepted to carry the risk of QT prolongation and torsades de pointes include but are not limited to the examples that follow: Class IA (e.g. disopyramide, procainamide), Class III (e.g. amiodarone, sotalol, ibutilide), or Class IC (e.g. flecainide) antiarrhythmic medicinal products, antipsychotics (e.g. chlorpromazine, haloperidol, pimozide), opioids (e.g. methadone), macrolide antibiotics (e.g. erythromycin, clarithromycin), quinolone antibiotics (e.g. moxifloxacin), antimalarials (e.g. chloroquine), GI stimulants or others (e.g. domperidone).
Drug-Food Interactions: APO-DASATINIB should not be taken with grapefruit or grapefruit juice.
Drug-Herb Interactions: Concomitant use of dasatinib and St John's Wort (Hypericum perforatum) may substantially reduce exposure to dasatinib.

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

APO-DASATINIB tablets should be stored below 25°C.

Targeted Cancer Therapy

L01EA02 - dasatinib ; Belongs to the class of BCR-ABL tyrosine kinase inhibitors. Used in the treatment of cancer.

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