Dasatinib-vista
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INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT DASATINIB-VISTA (DASATINIB-VISTA)
Composition:
Active substance: dasatinib;
1 tablet contains 20 mg, 50 mg, 70 mg, or 140 mg of anhydrous dasatinib;
Excipients: lactose monohydrate; microcrystalline cellulose;
hydroxypropylcellulose; sodium croscarmellose; magnesium stearate;
film-coating "Opadry II white": hypromellose; lactose monohydrate; titanium dioxide (E 171); triacetin.
Pharmaceutical form. Film-coated tablets.
Main physicochemical properties:
20 mg: white or almost white, biconvex, round, film-coated tablets; engraved with "D7SB" on one side and "20" on the other;
50 mg: white or almost white, biconvex, oval, film-coated tablets; engraved with "D7SB" on one side and "50" on the other;
70 mg: white or almost white, biconvex, round, film-coated tablets; engraved with "D7SB" on one side and "70" on the other;
140 mg: white or almost white, biconvex, round, film-coated tablets; engraved with "D7SB" on one side and "140" on the other.
Pharmacotherapeutic group. Antineoplastic agents. Protein kinase inhibitors. ATC code L01XE06.
Pharmacological Properties.
Pharmacodynamics.
Dasatinib reduces the activity of BCR-ABL kinase and SRC family kinases, along with other selected oncogenic kinases, including receptor tyrosine kinases, ephrin (EPH) receptor kinases, and PDGFβ receptor. Dasatinib is a potent, subnanomolar inhibitor of BCR-ABL kinase, exerting its effect at a concentration of 0.6–0.8 nmol. It binds to both inactive and active conformations of the BCR-ABL enzyme.
In vitro, dasatinib demonstrated activity in leukemic cell lines, both imatinib-sensitive and imatinib-resistant. These preclinical studies indicate that dasatinib may overcome imatinib resistance due to BCR-ABL overexpression, mutations in the BCR-ABL kinase domain, activation of alternative signaling pathways involving SRC family kinases (LYN, HCK), and overexpression of the multidrug resistance gene. Additionally, dasatinib inhibits SRC family kinases at subnanomolar concentrations.
In vivo, in individual experiments using experimental mice with CML, dasatinib prevented the progression from chronic-phase CML to blast phase and prolonged survival in mice implanted with CML cell lines derived from patients, grown in various sites, including the central nervous system (CNS).
Clinical Efficacy and Safety
In phase I studies, hematologic and cytogenetic responses were observed across all phases of CML and Ph-positive ALL in the first 84 treated patients, with responses lasting up to 27 months. Responses were durable across all phases of CML and Ph-positive ALL. Four single-arm, uncontrolled, open-label phase II clinical trials were conducted to evaluate the safety and efficacy of dasatinib in patients with chronic-phase, accelerated-phase, or myeloid blast-phase CML who were resistant or intolerant to imatinib. One single-arm, non-comparative study was conducted in patients with chronic-phase disease who had failed prior therapy with 400 mg or 600 mg of imatinib. The initial dose of dasatinib was 70 mg twice daily. Dose adjustments were permitted to optimize efficacy or manage toxicity. Two single-arm, open-label phase III trials were conducted to evaluate the efficacy of dasatinib administered once daily versus twice daily. Additionally, one open-label, randomized, comparative phase III trial was conducted in adult patients with newly diagnosed chronic-phase CML. The efficacy of dasatinib is based on hematologic and cytogenetic response rates. Durability of response and estimated survival rates further support the clinical benefits of dasatinib. A total of 2712 patients were enrolled in clinical trials, of whom 23% were aged ≥65 years and 5% were aged ≥75 years.
Pharmacokinetics.
The pharmacokinetics of dasatinib were evaluated in 229 healthy adult volunteers and 84 patients.
Absorption.
Dasatinib is rapidly absorbed in patients following oral administration, with peak plasma concentrations (Cmax) observed within 0.5–3 hours.
After oral administration, the increase in mean exposure (AUC) is approximately dose-proportional over doses ranging from 25 mg to 120 mg twice daily. The overall mean elimination half-life of dasatinib is approximately 5–6 hours. Data obtained after administration of a single 100 mg dose of dasatinib to healthy volunteers 30 minutes after a high-fat meal indicated a 14% increase in mean AUC of dasatinib. Administration with a low-calorie meal taken 30 minutes before dasatinib resulted in a 21% increase in mean AUC. The observed food effects do not represent clinically significant changes in exposure.
Distribution.
In patients, dasatinib has a large apparent volume of distribution (2,505 L), indicating extensive distribution into the extravascular space. At clinically relevant concentrations, dasatinib is approximately 96% bound to plasma proteins, as determined by in vitro experiments.
Metabolism.
The CYP3A4 isoenzyme is the primary enzyme responsible for dasatinib metabolism. In healthy volunteers administered a single 100 mg dose of [14C]-labeled dasatinib, unchanged dasatinib accounted for 29% of circulating radioactivity in plasma. Plasma concentration and in vitro activity data suggest that dasatinib metabolites are unlikely to play a major role in the drug's pharmacological activity.
Elimination.
The drug is primarily excreted in feces. After a single oral dose of [14C]-dasatinib, approximately 4% and 85% of the administered radioactivity was excreted in urine and feces, respectively, over 10 days. Unchanged dasatinib accounted for 0.1% and 19% of the dose excreted in urine and feces, respectively, with the remainder of the dose consisting of metabolites.
Hepatic and Renal Impairment.
The pharmacokinetics of dasatinib were studied in 8 patients with moderate hepatic impairment after a single 50 mg dose and in 5 patients with severe hepatic impairment after a single 20 mg dose, compared to pharmacokinetic data after a 70 mg dose. The Cmax and AUC values for dasatinib were 47% and 8% lower, respectively, in patients with moderate hepatic impairment compared to healthy volunteers. In patients with severe hepatic impairment, the Cmax and AUC reductions were 43% and 28%, respectively. The pharmacokinetics of dasatinib are not altered in patients with renal impairment.
Pediatrics.
The pharmacokinetics of dasatinib were evaluated in 104 pediatric patients with leukemia or solid tumors (72 receiving the drug in tablet form and 32 receiving powder for oral suspension). In a pediatric pharmacokinetic study, dasatinib exposure (Cavg, Cmin, and Cmax), normalized by dose, was similar between 21 patients with chronic-phase CML and 16 patients with Ph+ ALL. The pharmacokinetics of dasatinib tablets were evaluated in 72 children with relapsed or refractory leukemia or solid tumors receiving oral doses ranging from 60 mg/m² to 120 mg/m² once daily and from 50 mg/m² to 110 mg/m² twice daily. Data were pooled from two studies and showed that dasatinib is rapidly absorbed. The median Tmax ranged between 0.5 and 6 hours, and the mean elimination half-life ranged from 2 to 5 hours across all dose levels and age groups.
Clinical characteristics.
Indications.
The medicinal product Dasatinib-Vista is indicated for the treatment of adult patients with:
- newly diagnosed chronic myeloid leukemia (CML) positive for the Philadelphia chromosome (Ph+) in the chronic phase;
- CML in chronic phase, accelerated phase, or blast phase with resistance or intolerance to prior therapy including imatinib mesylate;
- Ph-positive acute lymphoblastic leukemia (ALL) and lymphoid blast CML with resistance or intolerance to prior therapy.
The medicinal product Dasatinib-Vista is indicated for the treatment of children with:
- newly diagnosed Ph+ CML in chronic phase (Ph+CML-CP) or Ph+CML-CP with resistance or intolerance to prior therapy including imatinib mesylate;
- newly diagnosed Ph+ acute lymphoblastic leukemia (ALL) in combination with chemotherapy.
Contraindications.
Hypersensitivity to the active substance or to any of the excipients of the product.
Interaction with other medicinal products and other forms of interaction.
Medicinal substances that may increase dasatinib plasma concentrations In vitro studies have shown that dasatinib is a substrate of CYP3A4. Concomitant administration of dasatinib with medicinal products or substances that strongly inhibit CYP3A4 (e.g., ketoconazole, itraconazole, erythromycin, clarithromycin, ritonavir, telithromycin, grapefruit juice) may increase dasatinib plasma concentrations. Therefore, patients taking dasatinib should not systematically receive medicinal products that are potent inhibitors of CYP3A4 (see section "Special warnings and precautions for use").
In vitro experimental data indicate that approximately 96% of dasatinib is protein-bound in plasma at clinically relevant concentrations. Studies on the interaction of dasatinib with other medicinal products that bind to plasma proteins have not been conducted. The potential for displacement and its clinical significance are unknown.
Medicinal substances that may reduce dasatinib plasma concentrations. When dasatinib was administered after eight daily evening doses of 600 mg rifampicin, a potent CYP3A4 inducer, dasatinib AUC decreased by 82%. Other medicinal products that induce CYP3A4 activity (e.g., dexamethasone, phenytoin, carbamazepine, phenobarbital, or herbal preparations containing St. John's wort [Hypericum perforatum]) may also increase dasatinib metabolism and reduce its plasma concentration. Therefore, concomitant use of potent CYP3A4 inducers with dasatinib is not recommended. For patients requiring rifampicin or other CYP3A4 inducers, alternative medicinal products with less enzyme-inducing activity should be used. Concomitant use of dexamethasone, a weak CYP3A4 inducer, with dasatinib is permitted. A reduction in dasatinib AUC of approximately 25% is expected when dexamethasone is used concomitantly, which is unlikely to be clinically significant.
H2-receptor antagonists and proton pump inhibitors.
Prolonged suppression of hydrochloric acid secretion by H2-receptor antagonists or proton pump inhibitors (e.g., famotidine, omeprazole) may reduce dasatinib concentrations. In a single-dose study in healthy volunteers, administration of famotidine 10 hours before a single dose of dasatinib reduced dasatinib exposure by 61%. In a single-dose (100 mg) study involving 14 patients, a 43% reduction in AUC and a 42% reduction in Cmax of dasatinib were observed 22 hours after a 4-day regimen of 40 mg omeprazole.
Alternative use of antacids instead of H2-receptor antagonists or proton pump inhibitors should be considered for patients undergoing treatment with Dasatinib-Vista (see section "Special warnings and precautions for use").
Antacids.
Non-clinical data indicate that dasatinib solubility is pH-dependent. In healthy volunteers, concomitant administration of antacids (aluminum hydroxide/magnesium hydroxide) with dasatinib reduced the AUC of a single dose of dasatinib by 55% and Cmax in plasma by 58%. However, when antacids were administered 2 hours before a single dose of dasatinib, no significant changes in dasatinib concentration or effect were observed. Therefore, antacids may be taken either 2 hours before or 2 hours after dasatinib administration (see section "Special warnings and precautions for use").
Medicinal substances whose plasma concentrations may be altered by dasatinib. Concomitant administration of dasatinib with a CYP3A4 substrate may increase the effect of the CYP3A4 substrate. In a study in healthy volunteers, a single 100 mg dose of dasatinib increased the AUC and Cmax of simvastatin, a known CYP3A4 substrate, by 20% and 37%, respectively. A greater effect cannot be excluded after multiple doses of dasatinib. Therefore, CYP3A4 substrates with a narrow therapeutic index (e.g., astemizole, terfenadine, cisapride, pimozide, quinidine, bepridil, or ergot alkaloids [ergotamine, dihydroergotamine]) should be used with caution in patients receiving dasatinib (see section "Special warnings and precautions for use"). In vitro studies suggest a potential risk of interaction with CYP2C8 substrates, such as glitazones.
Children.
Drug interaction studies with dasatinib have been conducted only in adult patients.
Special precautions for use.
Clinically significant interactions.
Dasatinib is a substrate and inhibitor of cytochrome P450 (CYP) 3A4. Therefore, there is a potential for interactions with other medicinal products administered concomitantly that are primarily metabolized by or inhibit CYP3A4 activity (see section "Interaction with other medicinal products and other forms of interaction"). Concomitant administration of dasatinib with medicinal products or substances that strongly inhibit CYP3A4 (e.g., ketoconazole, itraconazole, erythromycin, clarithromycin, ritonavir, telithromycin, grapefruit juice) may increase dasatinib plasma concentrations. Therefore, concomitant use of potent CYP3A4 inhibitors is not recommended in patients receiving dasatinib (see section "Interaction with other medicinal products and other forms of interaction").
Concomitant administration of dasatinib with medicinal products that induce CYP3A4 (e.g., dexamethasone, phenytoin, carbamazepine, rifampicin, phenobarbital, or herbal preparations containing St. John’s wort) may significantly reduce dasatinib plasma concentrations, potentially increasing the risk of treatment failure. Therefore, in patients receiving dasatinib, alternative medicinal products with less effect on CYP3A4 induction should be considered (see section "Interaction with other medicinal products and other forms of interaction").
Concomitant administration of dasatinib and a CYP3A4 substrate may enhance the effect of the CYP3A4 substrate. Therefore, caution is required when dasatinib is administered concomitantly with CYP3A4 substrates that have a narrow therapeutic range, such as astemizole, terfenadine, cisapride, pimozide, quinidine, bepridil, or ergot alkaloids (ergotamine, dihydroergotamine) (see section "Interaction with other medicinal products and other forms of interaction").
Concomitant administration of dasatinib with H2-receptor blockers (e.g., famotidine), proton pump inhibitors (e.g., omeprazole), or aluminium hydroxide/magnesium hydroxide may reduce the effect of dasatinib. Therefore, H2-receptor blockers and proton pump inhibitors are not recommended, and medicinal products containing aluminium hydroxide/magnesium hydroxide should be administered 2 hours before or 2 hours after dasatinib administration (see section "Interaction with other medicinal products and other forms of interaction").
Special patient groups.
Based on results from a single-dose pharmacokinetic study, patients with mild, moderate, or severe hepatic impairment may receive the recommended initial dose of the medicinal product (see sections "Pharmacokinetics" and "Posology and method of administration"). Due to limitations of this clinical study, dasatinib should be used with caution in patients with hepatic impairment (see section "Posology and method of administration").
Important adverse reactions.
Myelosuppression.
Treatment with dasatinib may cause anemia, neutropenia, and thrombocytopenia. These reactions occur earlier and more frequently in patients with advanced-phase CML or Ph-positive ALL than in patients with chronic-phase CML.
Adult patients with advanced-phase CML or Ph-positive ALL receiving dasatinib as monotherapy should have complete blood counts performed weekly for the first 2 months, then monthly, or as clinically indicated. Adult and pediatric patients with chronic-phase CML should have complete blood counts performed every 2 weeks for 12 weeks, then every 3 months, or as clinically indicated. Pediatric patients with Ph-positive ALL receiving dasatinib in combination with chemotherapy should have complete blood counts performed before the start of each chemotherapy cycle and as clinically indicated. During consolidation chemotherapy cycles, complete blood counts should be performed every 2 days until recovery (see sections "Posology and method of administration" and "Adverse reactions").
Myelosuppression is usually reversible and can be managed by temporary interruption of dasatinib or dose reduction.
Bleeding.
Among patients with chronic-phase CML (n = 548), 5 patients (1%) receiving dasatinib experienced grade 3 or 4 bleeding. In clinical trials of patients with advanced-phase CML receiving the recommended dose of dasatinib (n = 304), grade 3 or 4 CNS hemorrhage occurred in 1% of patients. One case was fatal and associated with grade 4 thrombocytopenia according to Common Toxicity Criteria (CTC). Gastrointestinal bleeding of grade 3 or 4 occurred in 6% of patients with advanced-phase CML, requiring treatment interruption and blood transfusion. Other grade 3 or 4 bleeding events occurred in 2% of patients with advanced-phase CML. Most bleeding adverse reactions in these patients were primarily associated with grade 3 or 4 thrombocytopenia (see section "Adverse reactions"). In addition, in vitro and in vivo platelet function analyses indicate that dasatinib treatment reversibly affects platelet activation. Caution is required when administering medicinal products that impair platelet function or anticoagulants to patients.
Fluid retention.
Dasatinib may cause fluid retention. In a phase III clinical trial of patients with newly diagnosed chronic-phase CML, fluid retention of grade 3 or 4 was observed in 13 patients (5%) in the dasatinib group and in 2 patients (1%) in the imatinib group, with at least 60 months of follow-up (see section "Adverse reactions"). Among all patients with chronic-phase CML treated with dasatinib, grade 3 or 4 fluid retention occurred in 32 patients (6%) receiving dasatinib at the recommended dose (n = 548). In clinical trials of patients with advanced-phase CML receiving dasatinib at the recommended dose (n = 304), grade 3 or 4 fluid retention was observed in 8% of patients, including pleural and pericardial effusions of grade 3 or 4 in 7% and 1% of patients, respectively. Among these patients, pulmonary edema and pulmonary hypertension of grade 3 or 4 were each observed in 1%.
Patients with symptoms suggestive of pleural effusion, such as dyspnea or dry cough, should undergo chest X-ray. Grade 3 or 4 pleural effusion may require thoracentesis and oxygen therapy. Fluid retention adverse reactions are usually managed with additional therapeutic measures, including diuretics and short-term corticosteroid courses (see sections "Posology and method of administration" and "Adverse reactions"). Elderly patients (aged 65 years or older) may more frequently develop pleural effusion, dyspnea, cough, pericardial effusion, and chronic heart failure than younger patients and therefore require special monitoring. Cases of chylothorax have also been reported in patients with pleural effusion (see section "Adverse reactions").
Pulmonary arterial hypertension (PAH).
Pulmonary arterial hypertension (PAH), confirmed by right heart catheterization, may occur during dasatinib treatment (see section "Adverse reactions"). In these cases, PAH developed after initiation of dasatinib treatment, including after more than 1 year of treatment.
Patients should be evaluated for signs and symptoms of cardiac and pulmonary disease before starting dasatinib treatment. Echocardiography should be performed at the start of treatment for each patient with cardiac symptoms and considered for patients with risk factors for cardiac and pulmonary disease. Patients who develop dyspnea and fatigue after starting treatment should be evaluated for common causes of disease, including pleural effusion, pulmonary edema, anemia, or lung infiltration. According to recommendations for managing non-hematologic adverse reactions (see section "Posology and method of administration"), dasatinib dose should be reduced or treatment interrupted during such evaluation. If no explanation is found or if there is no improvement after dose reduction or treatment interruption, PAH should be considered. The diagnostic approach should follow standard clinical practices. If PAH is confirmed, dasatinib should be discontinued. Subsequent management should follow standard clinical practices. Improvement in hemodynamics and clinical parameters has been observed in patients with PAH after discontinuation of dasatinib.
QT interval prolongation.
In vitro studies confirm that dasatinib may prolong cardiac ventricular repolarization (QT interval). Among 258 patients treated with dasatinib and 258 patients treated with imatinib, with at least 60 months of follow-up in a phase III trial of newly diagnosed chronic-phase CML, 1 patient (<1%) in each group experienced QT prolongation as an adverse reaction. Median changes in QT interval corrected by Fridericia’s formula from baseline were 3.0 msec in patients treated with dasatinib compared to 8.2 msec in patients treated with imatinib. One patient (<1%) in each group had a QT interval corrected by Fridericia’s formula >500 msec. Among 865 patients with leukemia treated with dasatinib in phase II clinical trials, mean changes from baseline in QT interval corrected by Fridericia’s method (QTcF) were 4–6 msec; the upper 95% confidence limit of all mean changes from baseline was <7 msec (see section "Adverse reactions").
Among 2182 patients with resistance or intolerance to prior therapy, including imatinib, who received dasatinib in clinical trials, 15 (1%) experienced corrected QT interval prolongation as an adverse reaction. Twenty-one patients (1%) had QTcF >500 msec.
Dasatinib should be used with caution in patients who have or may develop corrected QT interval prolongation. These include patients with hypokalemia or hypomagnesemia, patients with congenital long QT syndrome, patients taking antiarrhythmic medicinal products or other medicinal products that prolong the QT interval, and those receiving cumulative high-dose anthracycline therapy. Hypokalemia or hypomagnesemia should be corrected before administering dasatinib.
Cardiac adverse reactions.
Dasatinib was evaluated in a randomized clinical trial of 519 patients with newly diagnosed chronic-phase CML, including patients with prior cardiac disease. Cardiac adverse reactions such as chronic heart failure/cardiac dysfunction, pericardial effusion, arrhythmia, palpitations, QT interval prolongation, and myocardial infarction (including fatal cases) were observed in patients receiving dasatinib. Cardiac adverse reactions occurred more frequently in patients with risk factors or a history of cardiac disease. Patients with risk factors (e.g., hypertension, hyperlipidemia, diabetes) or a history of cardiac disease (e.g., prior percutaneous coronary intervention, documented ischemic heart disease) should be closely monitored for clinical signs or symptoms indicating cardiac dysfunction, such as chest pain, dyspnea, and excessive sweating.
If these clinical signs or symptoms occur, physicians should interrupt dasatinib and consider alternative CML treatment. After resolution, a functional assessment should be performed before resuming dasatinib treatment. Dasatinib may be continued at the initial dose for mild to moderate adverse reactions (≤ grade 2) and at a reduced dose for severe adverse reactions (≥ grade 3) (see section "Posology and method of administration"). Patients continuing treatment should be monitored periodically. Patients with uncontrolled or serious cardiovascular disease were excluded from clinical trials.
Thrombotic microangiopathy (TMA).
BCR-ABL tyrosine kinase inhibitors have been associated with thrombotic microangiopathy (TMA) (see section "Adverse reactions"). If a patient receiving Dasatinib-Vista develops laboratory or clinical findings suggestive of TMA, the medicinal product should be discontinued, and a thorough evaluation for TMA should be performed, including ADAMTS13 activity and anti-ADAMTS13 antibody testing. If elevated anti-ADAMTS13 antibodies are found in combination with low ADAMTS13 activity, Dasatinib-Vista should not be resumed.
Hepatitis B reactivation.
Hepatitis B reactivation has occurred in patients who are chronic carriers of the virus after receiving BCR-ABL tyrosine kinase inhibitors. Some cases led to acute liver failure or fulminant hepatitis, resulting in liver transplantation or death.
Patients should be tested for HBV infection before starting dasatinib treatment. Patients with positive hepatitis B serology (including those with active disease) and patients who test positive for HBV infection during treatment should consult a specialist before starting treatment. Carriers of hepatitis B who require dasatinib treatment should be closely monitored for signs and symptoms of active HBV infection during treatment and for several months after its completion (see section "Adverse reactions").
Effects on growth and development in children.
During clinical trials in children with Ph+ CML in chronic phase resistant to or intolerant of prior therapy, including imatinib mesylate, and in children with Ph+ CML in chronic phase after at least 2 years of treatment, adverse reactions related to bone growth and development were reported in 6 (4.6%) patients, one of which was severe (grade 3 growth delay). These 6 cases included delayed epiphyseal fusion, osteopenia, growth delay, and gynecomastia. These effects are difficult to distinguish from chronic diseases such as CML and require long-term monitoring. During clinical trials of dasatinib in combination with chemotherapy in children with newly diagnosed Ph+ ALL after up to 2 years of treatment, adverse reactions related to bone growth and development were reported in 1 (0.6%) patient. This case was grade 1 osteopenia.
Growth delay was observed in children during clinical trials with dasatinib (see section "Adverse reactions"). After up to 2 years of treatment, a trend toward reduced expected height growth was observed, similar to that with chemotherapy alone, without impact on expected body weight or body mass index, and without association with hormonal abnormalities or other laboratory parameters. Monitoring of growth and bone development in children is recommended.
Important information on excipients.
Lactose.
This medicinal product contains lactose monohydrate. Patients with rare hereditary problems of galactose intolerance, total lactase deficiency, or glucose-galactose malabsorption should not take this medicinal product.
Use during pregnancy or breastfeeding.
Women of childbearing potential/contraception in women and men. Women and men of reproductive potential should use effective contraception during treatment.
Pregnancy. Animal studies have shown reproductive toxicity of dasatinib. Dasatinib has been shown to cause congenital malformations, including neural tube defects, and harmful pharmacological effects on the fetus when administered during pregnancy. Dasatinib-Vista should not be used during pregnancy. Dasatinib may be used during pregnancy only if the expected benefit to the mother outweighs the potential risk to the fetus. If dasatinib is used during pregnancy, the patient should be informed of the potential risk to the fetus.
Breastfeeding. Information on the passage of dasatinib into human or animal breast milk is insufficient. Available physicochemical and pharmacodynamic/toxicological data on dasatinib suggest passage into breast milk; therefore, risk to the infant cannot be excluded. Breastfeeding should be discontinued during dasatinib treatment.
Fertility. Studies in male and female rats showed that dasatinib does not affect fertility. Men are advised to consult a specialist about sperm cryopreservation before starting therapy due to the potential effect of dasatinib on fertility.
Ability to affect reaction speed when driving or operating machinery.
Dasatinib-Vista has minor influence on the ability to drive and use potentially dangerous machinery. Patients should be warned that they may experience adverse reactions such as dizziness or blurred vision during dasatinib treatment. Therefore, caution should be exercised when driving or operating potentially dangerous machinery.
Dosage and administration
Treatment should be administered by a physician experienced in the diagnosis and treatment of patients with leukemia.
Adult patients
The recommended starting dose for chronic phase chronic myeloid leukemia (CML) is 100 mg of dasatinib once daily.
The recommended starting dose for accelerated phase CML, or myeloid or lymphoid blast phase (progressive phase) Ph-positive acute lymphoblastic leukemia (Ph+ ALL) is 140 mg once daily (see section "Special precautions").
Children (Ph+ CML in chronic phase and Ph+ ALL)
Dosage of Dasatinib-Vista in children and adolescents should be based on body weight (see Table 1). Dasatinib-Vista should be administered orally once daily in the form of film-coated tablets. The dose should be recalculated every 3 months based on changes in body weight, or more frequently if necessary. The use of tablets is not recommended in children with body weight below 10 kg. Dose escalation or reduction should be based on individual patient response and tolerability. There is no experience with dasatinib treatment in children under 1 year of age.
Recommendations for dasatinib dosing in children are provided in Table 1.
Table 1
| Dosage of dasatinib in children with Ph+ CML in chronic phase or Ph+ ALL |
|
| Body weight (kg) a |
Daily dose (mg) |
| from 10 to 20 kg |
40 mg |
| from 20 to 30 kg |
60 mg |
| from 30 to 45 kg |
70 mg |
| from 45 kg |
100 mg |
a The medicinal product Dasatinib-Vista, film-coated tablets, is not recommended for use in patients with body weight less than 10 kg.
Duration of treatment.
In clinical studies, treatment with dasatinib in adults with Ph+ CML in chronic phase, accelerated phase, or blast phase (progressive phase) of CML, or Ph+ ALL, and in children with Ph+ CML in chronic phase, continued until disease progression or patient intolerance. The effect of discontinuing long-term treatment after achieving cytogenetic or molecular response [including complete cytogenetic response (CCyR), major molecular response (MMR), and MR4.5 molecular response] has not been investigated. In clinical studies of children with Ph+ ALL, dasatinib was administered continuously for up to 2 years in combination with standard chemotherapy. For patients undergoing subsequent stem cell transplantation, dasatinib may be continued for an additional year after transplantation. The required dose should be achieved by combining film-coated tablets of 20 mg, 50 mg, 70 mg, and 140 mg. Dose escalation or reduction is recommended based on patient response and tolerability.
Dose escalation.
In clinical studies of adult patients with CML and Ph+ ALL, dose escalation to 140 mg once daily (in chronic phase CML) or 180 mg once daily (in progressive phase CML or Ph+ ALL) was permitted for patients who did not achieve hematologic or cytogenetic response at the recommended initial dose. Recommendations for dose escalation in children with Ph+ CML in chronic phase who did not achieve hematologic, cytogenetic, or molecular response at the recommended initial dose and who tolerate treatment well are provided in Table 2.
Table 2
| Dose escalation in pediatric patients with Ph+ CML in chronic phase |
|
| Dose (maximum daily dose) |
|
| Initial dose |
Escalated dose |
| 40 mg |
50 mg |
| 60 mg |
70 mg |
| 70 mg |
90 mg |
| 100 mg |
120 mg |
Dose escalation is not recommended in children with Ph+ ALL, as dasatinib is used in combination with chemotherapy in these patients.
Dose modification in the event of adverse reactions.
Myelosuppression.
During clinical trials, myelosuppression was managed by temporary interruption of treatment, dose reduction, or discontinuation of therapy. Platelet and red blood cell transfusions were used as needed. Hematopoietic growth factors were used in patients with persistent myelosuppression.
Dose modification recommendations for adults are presented in Table 3.
Table 3
Dosing based on the levels of neutropenia and thrombocytopenia in adults
| CML chronic phase, initial dose – 100 mg once daily |
ANC < 0.5 x 10⁹/L and/or platelets < 50 x 10⁹/L |
|
| CML in blast crisis, accelerated phase, and Ph+ ALL, initial dose – 140 mg once daily |
ANC < 0.5 x 10⁹/L and/or platelets < 50 x 10⁹/L |
|
ANC – absolute neutrophil count.
Dose modification recommendations for pediatric patients with Ph+ CML in chronic phase are presented in Table 4.
Table 4
Dosing based on the level of neutropenia and thrombocytopenia in pediatric patients with Ph+ CML in chronic phase
|
Dose (maximum daily dose) |
|||
| Initial dose |
Single-level dose reduction |
Two-level dose reduction |
||
| Tablets |
40 mg |
20 mg |
* |
|
| 60 mg |
40 mg |
20 mg |
||
| 70 mg |
60 mg |
50 mg |
||
| 100 mg |
80 mg |
70 mg |
||
ANC – absolute neutrophil count.
*The lower tablet dose is unavailable.
In the event of grade ≥ 3 neutropenia or thrombocytopenia occurring during treatment of children with Ph+ CML in chronic phase, which recurs during complete hematologic response, dasatinib should be discontinued and may subsequently be resumed at a reduced dose. Temporary dose reduction for intermediate grades of cytopenia should be performed as necessary.
Dose modification is not recommended in children with Ph+ ALL in cases of hematologic toxicity of grades 1 to 4. If neutropenia and/or thrombocytopenia lead to a delay of the next treatment cycle by more than 14 days, dasatinib should be interrupted and restarted at the same dose level once the next treatment cycle begins. If neutropenia and/or thrombocytopenia persist and the next treatment cycle is delayed for an additional 7 days, a bone marrow assessment should be performed to evaluate cellularity and percentage of blasts. If bone marrow cellularity is < 10%, dasatinib treatment should be discontinued until ANC > 500/µL (0.5 x 10⁹/L), after which treatment may be resumed at the full dose. If bone marrow cellularity is > 10%, resumption of dasatinib treatment may be considered. Non-hematologic adverse reactions.
In the event of a moderate non-hematologic adverse reaction (grade 2) during dasatinib treatment, therapy should be withheld until the adverse reaction resolves or returns to baseline. If the adverse reaction occurs for the first time, the dose should be resumed; however, if the adverse reaction recurs, the dose should be reduced. In the event of a severe non-hematologic adverse reaction (grade 3 or 4) during dasatinib treatment, therapy should be discontinued until the adverse reaction resolves. Treatment may then be resumed, with dose reduction as necessary depending on the initial severity of the adverse reaction. For patients with chronic phase CML receiving 100 mg once daily, dose reduction to 80 mg once daily is recommended, followed by further reduction from 80 mg to 50 mg once daily if necessary. For patients with advanced phase CML or Ph-positive ALL receiving 140 mg once daily, dose reduction to 100 mg once daily is recommended, followed by further reduction from 100 mg to 50 mg once daily if necessary. For children with chronic phase CML experiencing non-hematologic adverse reactions, dose reduction recommendations should follow those for hematologic adverse reactions described above. For children with Ph+ ALL experiencing non-hematologic adverse reactions, a single level dose reduction should be considered as necessary, according to the dose reduction recommendations for hematologic adverse reactions described above.
Pleural effusion.
Upon diagnosis of pleural effusion, dasatinib should be interrupted until the patient is evaluated, symptoms resolve, or baseline status returns. If symptoms do not resolve within approximately one week, consideration should be given to initiating a course of diuretics or corticosteroids, or both (see sections "Special instructions" and "Adverse reactions"). After resolution of the first episode, resumption of dasatinib at the same dose level should be considered. After resolution of a subsequent episode, resumption of dasatinib at a reduced dose level should be considered. After resolution of a severe episode (grade 3 or 4), treatment may be resumed if necessary, with dose reduction based on the initial severity of the adverse reaction.
Dose reduction for concomitant use of strong CYP3A4 inhibitors. Concomitant use of strong CYP3A4 inhibitors and grapefruit or grapefruit juice with the medicinal product Dasatinib-Vista should be avoided (see section "Interaction with other medicinal products and other types of interactions"). If possible, an alternative concomitant medication with no or minimal CYP3A4 enzyme inhibition potential should be selected. If Dasatinib-Vista must be administered with a strong CYP3A4 inhibitor, dose reduction should be considered to:
- 40 mg once daily for patients receiving a dasatinib dose of 140 mg daily;
- 20 mg once daily for patients receiving a dasatinib dose of 100 mg daily;
- 20 mg once daily for patients receiving a dasatinib dose of 70 mg daily.
For patients receiving Dasatinib-Vista at 60 mg or 40 mg daily, discontinuation of the medicinal product should be considered until completion of the CYP3A4 inhibitor treatment or until switching to a lower dose. Reinitiation of Dasatinib-Vista should occur one week after discontinuation of the CYP3A4 inhibitor.
These reduced dasatinib doses are intended to adjust the AUC to the range observed in the absence of CYP3A4 inhibitors; however, clinical data on these dose adjustments in patients receiving strong CYP3A4 inhibitors are not available. If dasatinib is poorly tolerated after dose reduction, either the strong CYP3A4 inhibitor should be discontinued or Dasatinib-Vista should be discontinued until completion of the inhibitor treatment. The Dasatinib-Vista dose should be increased one week after discontinuation of the CYP3A4 inhibitor.
Special patient groups.
Elderly patients.
No clinically significant pharmacokinetic differences related to age have been observed in these patients. No specific dosage recommendations are necessary for elderly patients.
Hepatic impairment.
Patients with mild, moderate, or severe hepatic impairment may receive the recommended initial dose. However, dasatinib should be used with caution in such patients (see sections "Pharmacological properties" and "Special instructions").
Renal function impairment.
Clinical studies on the use of dasatinib in patients with impaired renal function have not been conducted (studies in patients with newly diagnosed chronic phase CML excluded patients with serum creatinine concentrations more than 3 times the upper limit of normal range; studies in patients with chronic phase CML resistant to or intolerant of prior therapy, including imatinib, excluded patients with serum creatinine concentrations more than 1.5 times the upper limit of normal range). Since renal clearance of dasatinib and its metabolite is < 4%, a reduction in total clearance is not expected in patients with renal impairment.
Method of administration.
The medicinal product Dasatinib-Vista should be administered orally.
Film-coated tablets must not be crushed, split, or chewed to ensure dose consistency and minimize the risk of skin exposure; they should be swallowed whole. Dasatinib-Vista may be taken independently of food intake, but should be taken regularly either in the morning or in the evening.
Dasatinib-Vista should not be taken with grapefruit or grapefruit juice (see section "Interaction with other medicinal products and other types of interactions").
Children.
The use of tablets is not recommended in children with body weight less than 10 kg. There is no experience with dasatinib treatment in children under 1 year of age.
Overdose.
Clinical experience with dasatinib overdose is limited to isolated cases. The maximum overdose dose reported was 280 mg daily for one week, observed in two patients, both of whom developed significant thrombocytopenia. Since dasatinib is associated with grade 3 or 4 myelosuppression (see section "Special instructions"), patients receiving doses exceeding the recommended dose should be closely monitored for myelosuppression and provided with appropriate supportive therapy.
Adverse Reactions
Safety Study Results
The data below reflect the experience with dasatinib in over 2900 patients who participated in clinical trials, including 324 patients with newly diagnosed chronic phase chronic myeloid leukemia (CP-CML), 2388 patients with CML or Ph-positive acute lymphoblastic leukemia (ALL) in chronic or advanced phases who were resistant to or intolerant of imatinib, and 188 pediatric patients. The median duration of treatment with dasatinib in 2712 patients was 19.2 months (range: 0–93.2 months). In the Phase III trial of patients with newly diagnosed CP-CML with at least 5 years of follow-up, the median duration of treatment was approximately 60 months for dasatinib (range: 0.03–72.7 months) and for imatinib (range: 0.3–74.6 months). The median duration of treatment in 1618 patients with CP-CML was 29 months (range: 0–92.9 months). For 1094 patients with CML or Ph-positive ALL, the median duration of treatment was 6.2 months (range: 0–9.32 months). Among 188 pediatric patients, the mean duration of therapy was 26.3 months (range: 0 to 99.6 months). In the subgroup of 130 pediatric patients with CP-CML treated with dasatinib, the mean duration of therapy was 42.3 months (range: 0 to 99.6 months).
Of the 2712 patients treated, 18% were aged 65 years or older, and 5% were aged 75 years or older.
The majority of patients treated with dasatinib experienced adverse reactions at some point during therapy. Among the 2712 patients treated with dasatinib, 520 (19%) experienced adverse reactions that required treatment discontinuation. Most of these reactions were mild or moderate in severity.
In the Phase III trial of patients with newly diagnosed CP-CML, treatment was discontinued due to adverse reactions in 5% of patients treated with dasatinib and 4% of patients treated with imatinib, with at least 12 years of follow-up. Cumulative rates of treatment discontinuation due to adverse reactions were 14% and 7%, respectively, after at least 60 months. Among 1618 patients with CP-CML treated with dasatinib, adverse reactions leading to treatment discontinuation occurred in 329 (20.3%) patients. Among 1094 patients with advanced-phase disease treated with dasatinib, adverse reactions requiring discontinuation occurred in 191 (17.5%) patients.
Most patients with imatinib intolerance and CP-CML were able to tolerate dasatinib therapy. In clinical trials of CP-CML with 24 months of follow-up, 10 out of 215 patients with prior imatinib intolerance experienced the same grade 3 or 4 non-hematologic toxicity with dasatinib as they had with imatinib; 8 out of these 10 patients were able to continue dasatinib treatment after dose reduction.
Based on data with at least 12 months of follow-up, the most common adverse reactions in patients with newly diagnosed CP-CML were: fluid retention (including pleural effusion) (19%), diarrhea (17%), headache (12%), rash (11%), bone and muscle pain (11%), nausea (8%), fatigue (8%), myalgia (6%), vomiting (5%), and myositis (4%). After 60 months of follow-up, cumulative incidences increased by ≤3% for rash (14%), bone and muscle pain (14%), headache (13%), fatigue (11%), nausea (10%), myalgia (7%), vomiting (5%), and myositis or muscle spasms (5%). Cumulative incidences of fluid retention and diarrhea were 39% and 22%, respectively.
The most common adverse reactions in patients with resistance or intolerance to prior imatinib therapy treated with dasatinib were: fluid retention (including pleural effusion), diarrhea, headache, nausea, skin rash, dyspnea, bleeding, fatigue, bone and muscle pain, infections, vomiting, cough, abdominal pain, and fever. Febrile neutropenia associated with the use of the drug occurred in 5% of patients treated with dasatinib who had resistance or intolerance to prior imatinib therapy.
Based on clinical trials in patients with resistance or intolerance to prior imatinib therapy, it is recommended to discontinue imatinib at least 7 days before initiating dasatinib treatment.
The overall safety profile of dasatinib in pediatric patients with Ph+ CP-CML was similar to that in adults, except for the absence of reported cases of pericardial effusion, pleural effusion, pulmonary edema, or pulmonary hypertension in children. Among 130 pediatric patients with CP-CML treated with dasatinib, 2 (1.5%) experienced adverse reactions leading to treatment discontinuation.
During clinical trials and post-marketing surveillance, the following adverse reactions have been observed in patients receiving dasatinib as monotherapy, in addition to laboratory abnormalities (see Table 5). These reactions are presented by system organ class and frequency of occurrence. The frequency of adverse reactions is categorized as follows: very common (≥ 1/10), common (≥ 1/100 to < 1/10), uncommon (≥ 1/1000 to < 1/100), rare (≥ 1/10,000 to < 1/1000), very rare (< 1/10,000), and not known (cannot be estimated from available data). Within each frequency category, adverse reactions are listed in order of decreasing severity.
Table 5
| Infections and infestations |
|
| Very common |
infection (including bacterial, viral, fungal, unspecified) |
| Common |
pneumonia (including bacterial, viral and fungal), upper respiratory tract infection/inflammation, herpesvirus infection (including cytomegalovirus (CMV)), enterocolitis, sepsis (including atypical cases with fatal outcome) |
| Frequency unknown |
hepatitis B reactivation |
| Blood and lymphatic system disorders |
|
| Very common |
myelosuppression (including anemia, neutropenia, thrombocytopenia) |
| Common |
febrile neutropenia |
| Uncommon |
lymphadenopathy, lymphopenia |
| Rare |
true red cell aplasia |
| Immune system disorders |
|
| Uncommon |
hypersensitivity (including nodular erythema) |
| Rare |
anaphylactic shock |
| Endocrine disorders |
|
| Uncommon |
hypothyroidism |
| Rare |
hyperthyroidism, thyroiditis |
| Metabolism and nutrition disorders |
|
| Common |
appetite disturbance, hyperuricemia |
| Uncommon |
tumor lysis syndrome, dehydration, hypoalbuminemia, hypercholesterolemia |
| Rare |
diabetes mellitus |
| Psychiatric disorders |
|
| Common |
depression, insomnia |
| Rare |
anxiety, confusion, emotional lability, decreased libido |
| Nervous system disorders |
|
| Very common |
headache |
| Common |
neuropathy (including peripheral neuropathy), dizziness, dysgeusia, somnolence |
| Uncommon |
CNS hemorrhage*b, syncope, tremor, amnesia, balance disorder |
| Rare |
cerebrovascular accident, transient ischemic attack, seizures, optic neuritis, facial nerve paralysis, dementia, ataxia |
| Eye disorders |
|
| Common |
vision disorders (including visual disturbances, blurred vision and decreased visual acuity), dry eyes |
| Uncommon |
refractive disorders, conjunctivitis, photophobia, lacrimation |
| Ear and labyrinth disorders |
|
| Common |
tinnitus |
| Uncommon |
hearing loss, vertigo |
| Cardiac disorders |
|
| Common |
congestive heart failure/cardiac dysfunction*с, pericardial effusion*, arrhythmia (including tachycardia), palpitations |
| Uncommon |
myocardial infarction (including fatal)*, QT interval prolongation on electrocardiogram (ECG)*, pericarditis, ventricular arrhythmia (including ventricular tachycardia), angina pectoris, cardiomegaly, ECG T-wave abnormality, troponin elevation |
| Rare |
pulmonary heart disease, myocarditis, acute coronary syndrome, cardiac arrest, PR prolongation on ECG, ischemic heart disease, pleuropericarditis |
| Frequency unknown |
atrial fibrillation/atrial flutter |
| Vascular disorders |
|
| Very common |
bleeding* d |
| Common |
arterial hypertension, flushing |
| Uncommon |
arterial hypotension, thrombophlebitis, thrombosis |
| Rare |
deep vein thrombosis, embolism, livedo reticularis |
| Frequency unknown |
thrombotic microangiopathy |
| Respiratory, thoracic and mediastinal disorders |
|
| Very common |
pleural effusion*, dyspnea |
| Common |
pulmonary edema*, pulmonary hypertension*, pulmonary infiltration, pneumonitis, cough |
| Uncommon |
pulmonary arterial hypertension, bronchospasm, asthma, chylothorax* |
| Rare |
pulmonary embolism, acute respiratory distress syndrome |
| Frequency unknown |
interstitial lung disease |
| Gastrointestinal disorders |
|
| Very common |
nausea, diarrhea, vomiting, dyspepsia, abdominal pain |
| Common |
gastrointestinal hemorrhage*, colitis (including neutropenic colitis), gastritis, mucosal inflammation (including mucositis/stomatitis), dyspepsia, bloating, constipation, oral ulceration |
| Uncommon |
pancreatitis (including acute pancreatitis), upper gastrointestinal ulcer, esophagitis, ascites*, anal fissure, dysphagia, gastroesophageal reflux disease |
| Rare |
protein-losing gastroenteropathy, intestinal obstruction, anal fistula |
| Frequency unknown |
fatal gastrointestinal hemorrhage* |
| Hepatobiliary disorders |
|
| Uncommon |
hepatitis, cholecystitis, cholestasis |
| Skin and subcutaneous tissue disorders |
|
| Very common |
skin rashе |
| Common |
alopecia, dermatitis (including eczema), pruritus, acne, dry skin, urticaria, hyperhidrosis |
| Uncommon |
neutrophilic dermatosis, photosensitivity, pigmentary disorder, panniculitis, skin ulcer, bullous eruptions, brittle nails, palmar-plantar erythrodysesthesia syndrome, hair quality deterioration |
| Rare |
leukocytoclastic vasculitis, skin fibrosis |
| Frequency unknown |
Stevens-Johnson syndromef |
| Musculoskeletal and connective tissue disorders |
|
| Very common |
musculoskeletal paing |
| Common |
arthralgia, myalgia, muscle weakness, musculoskeletal rigidity, muscle spasm |
| Uncommon |
rhabdomyolysis, osteonecrosis, myositis, tendinitis, arthritis |
| Rare |
epiphyseal fusion delayh, growth retardationh |
| Renal and urinary disorders |
|
| Uncommon |
renal function impairment (including renal failure), increased frequency of urination, proteinuria |
| Frequency unknown |
nephrotic syndrome |
| Pregnancy, puerperium and perinatal conditions |
|
| Rare |
abortion |
| Reproductive system and breast disorders |
|
| Uncommon |
gynecomastia, menstrual cycle disorder |
| General disorders and administration site conditions |
|
| Very common |
peripheral edemai, fatigue, pyrexia, facial edemaj |
| Common |
asthenia, pain, chest pain, generalized edema*k, chills |
| Uncommon |
malaise, other superficial edemal |
| Rare |
gait disturbance |
| Investigations |
|
| Common |
decreased body weight, increased body weight |
| Uncommon |
increased blood creatine phosphokinase, increased gamma-glutamyltransferase |
| Injury, poisoning and procedural complications |
|
| Common |
contusion |
a Includes decreased appetite, feeling of early satiety, increased appetite.
b Includes CNS hemorrhage, intracranial hematoma, intracerebral hemorrhage, epidural hematoma, intracranial hemorrhage, hemorrhagic stroke, subarachnoid hemorrhage, subdural hematoma, and subdural hemorrhage.
c Includes increased brain natriuretic peptide, ventricular dysfunction, left ventricular dysfunction, right ventricular dysfunction, heart failure, acute heart failure, chronic heart failure, congestive heart failure, cardiomyopathy, congestive cardiomyopathy, diastolic dysfunction, reduced ejection fraction, ventricular failure, left ventricular failure, right ventricular failure, and ventricular hypokinesis.
d Excludes gastrointestinal bleeding and CNS bleeding; these adverse reactions belong to the gastrointestinal system-organ class and CNS system-organ class disorders, respectively.
e Includes drug-induced dermatitis, skin erythema, polymorphous erythema, erythroderma, exfoliative rash, generalized erythema, genital rash, erythematous acne, white acne, miliaria, pustular psoriasis, rash, erythematous rash, vesicular rash, generalized rash, macular rash, maculopapular rash, papular rash, pruritic rash, pustular rash, vesicular rash, skin desquamation, pruritus, toxicoderma, vesiculobullous rash, and vasculitic rash.
f Isolated cases of Stevens-Johnson syndrome were reported in studies. A direct causal relationship between these adverse reactions and dasatinib or concomitantly administered drugs cannot be established.
g Musculoskeletal pain observed during or after discontinuation of treatment.
h Frequency reported as common in pediatric studies.
i Gravitational edema, localized edema, peripheral edema.
j Conjunctival edema, eye edema, eye swelling, eyelid edema, facial edema, lip edema, macular edema, mouth cavity edema, orbital edema, periorbital edema, facial swelling.
k Hypervolemia, fluid retention, gastrointestinal edema, generalized edema, edema, cardiac disease-related edema, perinephric effusion, post-procedural edema, visceral edema.
k Genital edema, incision site edema, genital swelling, penile edema, scrotal edema, skin swelling, testicular edema, vulvovaginal edema.
* For additional information, see section "Description of selected adverse reactions."
Description of selected adverse reactions.
Myelosuppression.
Treatment with dasatinib may cause anemia, neutropenia, and thrombocytopenia. These reactions occur earlier and more frequently in patients with CML or Ph+ ALL in advanced phases compared to patients with CML in chronic phase (see section "Special instructions").
Bleeding.
Adverse reactions in the form of bleeding, ranging from petechial hemorrhage and epistaxis to gastrointestinal bleeding and CNS bleeding of grade 3 or 4, have been observed in patients receiving dasatinib (see section "Special instructions").
Fluid retention.
Various adverse reactions such as pleural effusion, ascites, pulmonary edema, and pericardial effusion, with or without superficial edema, may collectively be described as "fluid retention." In a study of newly diagnosed CML in chronic phase with at least 60 months of follow-up, dasatinib-related fluid retention adverse reactions included pleural effusion (28%), superficial edema (14%), pulmonary hypertension (5%), generalized edema (4%), and pericardial effusion (4%). Congestive heart failure/cardiac dysfunction and pulmonary edema were observed in <2% of patients. The cumulative incidence rate of pleural effusion (all grades) associated with dasatinib over time was 10% at 12 months, 14% at 24 months, 19% at 36 months, 24% at 48 months, and 28% at 60 months. Among patients treated with dasatinib, 46 experienced recurrent pleural effusion: 17 had two separate adverse events, 6 had three adverse events, 18 had 4 to 8 adverse events, and 5 had >8 episodes of pleural effusion. The median time to first pleural effusion of grade 1 or 2 associated with dasatinib was 114 weeks (range: 4–299 weeks). Less than 10% of patients with pleural effusion experienced severe (grade 3 or 4) pleural effusion related to dasatinib. The median time to first occurrence of dasatinib-related pleural effusion ≥ grade 3 was 175 weeks (range: 114–274 weeks). The median duration of dasatinib-related pleural effusion (all grades) was 283 days (~40 weeks). Pleural effusion was usually reversible and resolved with treatment interruption and use of diuretics and other appropriate supportive measures (see sections "Dosage and administration" and "Special instructions"). Among patients treated with dasatinib who developed pleural effusion (n = 73), 45 (62%) had dose interruption and 30 (41%) had dose reduction. Additionally, 34 (47%) received diuretics, 23 (32%) received corticosteroids, and 20 (27%) received both corticosteroids and diuretics. Nine (12%) patients underwent therapeutic thoracentesis. Six percent of patients treated with dasatinib discontinued treatment due to drug-related pleural effusion. Pleural effusion did not affect patients' ability to achieve response. Among patients treated with dasatinib who developed pleural effusion, 96% achieved confirmed complete cytogenetic response, 82% achieved major molecular response, and 50% achieved MR4.5 molecular response, despite dose interruption or adjustment. See section "Special instructions" for additional information in patients with CML in chronic phase and CML or Ph+ ALL in advanced phases. Cases of chylothorax have been reported in patients with pleural effusion. Some cases of chylothorax resolved after discontinuation, interruption, or dose reduction of dasatinib, but most required additional treatment.
Pulmonary arterial hypertension (PAH).
PAH (precapillary pulmonary arterial hypertension, confirmed by right heart catheterization) may occur during dasatinib treatment. In these cases, PAH developed after initiation of dasatinib therapy, including after more than one year of treatment. Patients who developed PAH during dasatinib treatment often received concomitant medications or had comorbidities in addition to the primary malignancy. Improvement in hemodynamics and clinical status was observed in patients with PAH after discontinuation of dasatinib.
QT interval prolongation.
In the phase III study of patients with newly diagnosed CML in chronic phase, one patient (<1%) among the total number of patients treated with dasatinib had a QT interval corrected by Fridericia's formula (QTcF) >500 msec with at least 12 months of follow-up (see section "Special instructions"). No additional patients with QTcF >500 msec were observed with at least 60 months of follow-up. In five phase II clinical trials in patients resistant to or intolerant of prior therapy including imatinib, serial baseline and on-treatment ECGs were obtained at predefined time points and centrally read for 865 patients receiving dasatinib 70 mg twice daily. The QT interval was heart rate-corrected using Fridericia's method. At all post-dose time points on day 8, mean changes from baseline in QTcF were 4–6 msec; the upper bound of the 95% confidence interval was <7 msec. Among 2182 patients resistant to or intolerant of prior therapy including imatinib who received dasatinib in clinical trials, 15 (1%) experienced QT prolongation as an adverse reaction. Twenty-one patients (1%) had QTcF >500 msec (see section "Special instructions").
Cardiac adverse reactions.
Patients with risk factors or history of cardiac disease should be closely monitored for clinical signs or symptoms indicating cardiac dysfunction. They should be evaluated and treated appropriately (see section "Special instructions").
Hepatitis B reactivation.
Hepatitis B reactivation has been associated with BCR-ABL tyrosine kinase inhibitors. Some cases led to acute liver failure or fulminant hepatitis, resulting in liver transplantation or fatal outcome (see section "Special instructions").
In the phase III dose optimization study in patients with CML in chronic phase resistant to or intolerant of prior therapy including imatinib (median treatment duration 30 months), the incidence of pleural effusion and congestive heart failure/cardiac dysfunction was lower in patients receiving dasatinib 100 mg once daily compared to those receiving dasatinib 70 mg twice daily. Myelosuppression also occurred less frequently in the group receiving 100 mg once daily (see "Laboratory abnormalities" below). The median treatment duration in the group receiving 100 mg once daily was 37 months (range: 1–91 months). Cumulative incidence rates of selected adverse reactions after administration of 100 mg once daily as the recommended initial dose are presented in Table 6a.
Table 6a
| Selected adverse reactions observed in the phase 3 dose optimization study (imatinib intolerance or resistant chronic phase CML)a |
||||||
| Minimum 2 years of follow-up |
Minimum 5 years of follow-up |
Minimum 7 years of follow-up |
||||
| All cases |
Grade 3–4 |
All cases |
Grade 3–4 |
All cases |
Grade 3–4 |
|
| Preferred term |
Percentage (%) of patients |
|||||
| Diarrhea |
27 |
2 |
28 |
2 |
28 |
2 |
| Fluid retention |
34 |
4 |
42 |
6 |
48 |
7 |
| Superficial edema |
18 |
0 |
21 |
0 |
22 |
0 |
| Pleural effusion |
18 |
2 |
24 |
4 |
28 |
5 |
| Generalized edema |
3 |
0 |
4 |
0 |
4 |
0 |
| Pericardial effusion |
2 |
1 |
2 |
1 |
3 |
1 |
| Pulmonary hypertension |
0 |
0 |
0 |
0 |
2 |
1 |
| Bleeding |
11 |
1 |
11 |
1 |
12 |
1 |
| Gastrointestinal hemorrhage |
2 |
1 |
2 |
1 |
2 |
1 |
a- Phase 3 dose optimization studies presented in the recommended initial dose of 100 mg once daily (n = 165) population.
In the third stage of the dose optimization study in patients with CML and Ph-positive ALL in the progressive phase, the median duration of treatment was 14 months for accelerated phase CML, 3 months for myeloid blast CML, 4 months for lymphoid blast CML, and 3 months for Ph-positive ALL. Selected adverse reactions that occurred during treatment with the recommended initial dose of 140 mg once daily are presented in Table 6b. A treatment regimen with 70 mg of the drug twice daily was also investigated. The treatment regimen with 140 mg of the drug once daily showed a comparable efficacy profile compared to 70 mg of the drug twice daily, as well as more favorable safety outcomes.
Table 6b
| Selected adverse reactions observed in the phase 3 dose optimization study: accelerated phase CML and Ph+ ALL a |
||
| 140 mg once daily n = 304 |
||
| All cases |
Grade |
|
| Preferred term |
Percentage (%) of patients |
|
| Diarrhea |
28 |
3 |
| Fluid retention |
33 |
7 |
| Superficial edema |
15 |
< 1 |
| Pleural effusion |
20 |
6 |
| Generalized edema |
2 |
0 |
| Heart failure/cardiac dysfunction b |
1 |
0 |
| Pericardial effusion |
2 |
1 |
| Pulmonary edema |
1 |
1 |
| Hemorrhage |
23 |
8 |
| Gastrointestinal hemorrhage |
8 |
6 |
a Results from the 3rd phase dose optimization study conducted with the recommended initial dose of 140 mg once daily in (n = 304) patients during a two-year longitudinal study.
b Includes ventricular dysfunction, heart failure, congestive heart failure, cardiomyopathy, congestive cardiomyopathy, diastolic dysfunction, reduced ejection fraction, and ventricular failure.
Additionally, two pediatric studies were conducted involving a total of 161 patients with Ph+ ALL, in whom dasatinib was administered in combination with chemotherapy. In the main study, 106 children received dasatinib in combination with chemotherapy using a continuous dosing schedule. In the supportive study of 55 children, 35 received dasatinib in combination with chemotherapy using an interrupted dosing schedule (2 weeks on treatment, followed by 1 to 2 weeks off), and 20 received dasatinib in combination with chemotherapy on a continuous dosing schedule. Among the 126 children who received dasatinib under a continuous dosing regimen, the median duration of therapy was 23.6 months (range: 1.4 to 33 months).
Of the 126 children who received dasatinib under a continuous dosing regimen, 2 (1.6%) experienced adverse reactions leading to treatment discontinuation. Adverse reactions reported in these two pediatric studies with an incidence ≥ 10% in patients receiving the continuous dosing regimen are listed in Table 7. Pleural effusion was observed in 7 (5.6%) patients in this group and therefore was not included in Table 7. Adverse reactions observed in ≥ 10% of pediatric patients with Ph+ ALL who received dasatinib on a continuous dosing schedule in combination with chemotherapy (n = 126).
Table 7
| Percentage (%) of patients |
||
| Adverse reaction |
All cases |
Grade 3-4 |
| Febrile neutropenia |
27.0 |
26.2 |
| Nausea |
20.6 |
5.6 |
| Vomiting |
20.6 |
4.8 |
| Abdominal pain |
14.3 |
3.2 |
| Diarrhea |
12.7 |
4.8 |
| Pyrexia |
12.7 |
5.6 |
| Headache |
11.1 |
4.8 |
| Decreased appetite |
10.3 |
4.8 |
| Fatigue |
10.3 |
0 |
Laboratory Test Abnormalities
Hematology.
During the Phase 3 trial in newly diagnosed chronic phase chronic myeloid leukemia (CML), the following Grade 3 or 4 laboratory abnormalities were observed in patients treated with dasatinib, with a minimum of 12 months of follow-up: neutropenia (21%), thrombocytopenia (19%), and anemia (10%). With a minimum of 60 months of follow-up, the cumulative incidences of neutropenia, thrombocytopenia, and anemia were 29%, 22%, and 13%, respectively.
Among patients treated with dasatinib for newly diagnosed chronic phase CML who experienced Grade 3 or 4 myelosuppression, recovery generally occurred following interruption of treatment and/or dose reduction. Treatment discontinuation due to myelosuppression occurred in 1.6% of patients with a minimum of 12 months of follow-up. With a minimum of 60 months of follow-up, the cumulative rate of treatment discontinuation due to Grade 3 or 4 myelosuppression was 2.3%.
In patients with CML resistant to or intolerant of prior therapy, including imatinib, the most commonly observed adverse events were cytopenias (thrombocytopenia, neutropenia, and anemia). However, the occurrence of cytopenias also depended on the disease phase. The frequencies of Grade 3 and 4 hematologic abnormalities are presented in Table 8.
Table 8
| Incidence of hematologic abnormalities grade 3 and 4 in clinical studies in patients with resistance or intolerance to prior imatinib therapya |
||||
| Chronic phase (n = 165)b |
Accelerated phase (n = 157)c |
Myeloid blast phase (n = 74)c |
Lymphoid blast phase Ph+ ALL (n = 168)c |
|
| Percentage (%) of patients |
||||
| Hematologic parameters |
||||
| Neutropenia |
36 |
58 |
77 |
76 |
| Thrombocytopenia |
23 |
63 |
78 |
74 |
| Anemia |
13 |
47 |
74 |
44 |
a- Phase 3 dose optimization study presented with a two-year follow-up.
b- Results of study CA180-034 at the recommended starting dose of 100 mg once daily.
c- Results of study CA180-035 at the recommended starting dose of 140 mg once daily.
Hematologic abnormalities: neutropenia (Grade 3 ≥ 0.5– < 1.0 × 10⁹/L, Grade 4 < 0.5 × 10⁹/L); thrombocytopenia (Grade 3 ≥ 25– < 50 × 10⁹/L, Grade 4 < 25 × 10⁹/L); anemia (hemoglobin level Grade 3 ≥ 65– < 80 g/L, Grade 4 < 65 g/L). The cumulative incidence of Grade 3 or 4 cytopenia among patients treated with the drug at a dose of 100 mg once daily was similar during the 2- and 5-year periods, including neutropenia (35% vs 36%), thrombocytopenia (23% vs 24%), and anemia (13% vs 13%). Among patients who experienced Grade 3 or 4 myelosuppression, recovery generally occurred after interruption of treatment and/or dose reduction, and treatment was discontinued in 5% of patients. Most patients continued treatment without further episodes of myelosuppression.
Chemistry.
During the study in newly diagnosed chronic phase CML, Grade 3 or 4 hypophosphatemia occurred in 4% of patients treated with dasatinib, while Grade 3 or 4 elevations in transaminases, creatinine, and bilirubin occurred in ≤1% of patients, with at least 12 months of follow-up. With at least 60 months of follow-up, the cumulative incidence of Grade 3 or 4 hypophosphatemia was 7%, Grade 3 or 4 elevations in creatinine and bilirubin were 1%, and the incidence of Grade 3 or 4 transaminase elevations remained at 1%. Treatment with dasatinib was not discontinued due to these biochemical laboratory abnormalities.
Two-year follow-up.
Grade 3 or 4 elevations in transaminases or bilirubin occurred in 1% of patients with chronic phase CML (resistant or intolerant to imatinib), but were observed in 1–7% of patients with CML or Ph-positive ALL in advanced phases. These abnormalities were generally managed by dose reduction or treatment interruption. In the Phase 3 dose optimization study in chronic phase CML, Grade 3 or 4 elevations in transaminases or bilirubin occurred in ≤1% of patients across the four treatment groups. In the Phase 3 dose optimization study in advanced phase CML or Ph-positive ALL, Grade 3 or 4 elevations in transaminases or bilirubin occurred in 1–5% of patients across treatment groups. Approximately 5% of patients treated with dasatinib who initially had normal levels experienced transient Grade 3 or 4 hypocalcemia at some point during the study. Overall, no correlation was observed between decreased calcium levels and clinical symptoms. Patients with Grade 3 or 4 hypocalcemia often recovered with oral calcium supplementation. Grade 3 or 4 hypocalcemia, hypokalemia, and hypophosphatemia were observed in patients with CML in all phases, but most frequently in patients with myeloid or lymphoid blast phase CML and Ph-positive ALL. Grade 3 or 4 creatinine elevations occurred in <1% of patients with chronic phase CML and more frequently in 1–4% of patients with advanced phase CML.
Pediatric population.
The safety profile of dasatinib as monotherapy in children with Ph+ chronic phase CML was comparable to that in adults. The safety profile of dasatinib in combination with chemotherapy in children with Ph+ ALL was consistent with the known safety profile of dasatinib in adults and the expected effects of chemotherapy, except for a lower incidence of pleural effusion in children compared to adults. In pediatric CML studies, laboratory abnormalities were similar to the known laboratory profile in adults.
In pediatric ALL studies, laboratory abnormalities were consistent with the known laboratory profile in adults in the context of patients with acute leukemia receiving chemotherapy.
Special populations.
Although the safety results of dasatinib in elderly patients are similar to those in younger age groups, there is a higher likelihood of adverse reactions in patients aged 65 years and older, typically including fatigue, pleural effusion, dyspnea, cough, gastrointestinal hemorrhage, and decreased appetite, as well as a higher likelihood of less common adverse reactions such as abdominal distension, dizziness, pericardial effusion, congestive heart failure, and weight loss. Therefore, elderly patients should be closely monitored (see section "Dosage and Administration").
Reporting of suspected adverse reactions.
Reporting of adverse reactions after drug registration is of great importance. It allows continuous monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals and pharmacists, as well as patients or their legal representatives, should report all suspected adverse reactions and lack of efficacy through the Automated Information System for Pharmacovigilance at the following link: https://aisf.dec.gov.ua.
Shelf life. 3 years.
Storage conditions.
No special storage conditions required. Keep out of reach of children.
Packaging.
60 tablets in a high-density polyethylene bottle with a polypropylene child-resistant closure, 1 bottle in a cardboard box (for 20 mg, 50 mg, 70 mg strengths).
30 tablets in a high-density polyethylene bottle with a polypropylene child-resistant closure, 1 bottle in a cardboard box (for 140 mg strength).
Prescription status.
Prescription only.
Manufacturer.
Sandoz Spain, S.L.
Manufacturer's address and location of operations.
Calle C/ Castello, no 1, Sant Boi de Llobregat, Barcelona, 08830, Spain.