Dasatinib-teva
UkraineTable of Contents
INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT DASATINIB-TEVA (DASATINIB-TEVA)
Composition:
Active substance: dasatinib (as dasatinib monohydrate);
One film-coated tablet contains dasatinib (as dasatinib monohydrate) 50 mg or 70 mg;
Excipients: core: lactose monohydrate, microcrystalline cellulose (type 101), hydroxypropylcellulose (type E), sodium croscarmellose (type A), microcrystalline cellulose (type 102), magnesium stearate (E 572); film coating: hypromellose 2910 (E 464), titanium dioxide (E 171), triacetin.
Pharmaceutical form. Film-coated tablets.
Main physicochemical properties:
50 mg tablets: oval film-coated tablets, white to almost white in color, with beveled edges, and engraved "50" on one side of the tablet;
70 mg tablets: round film-coated tablets, white to almost white in color, with beveled edges, and engraved "70" on one side of the tablet.
Pharmacotherapeutic group. Antineoplastic agents. Protein kinase inhibitors. Dasatinib.
ATC code L01EA02.
Pharmacological properties.
Pharmacodynamics
Dasatinib inhibits the activity of BCR-ABL kinase and the SRC kinase family, as well as several other individual oncogenic kinases, including c-KIT, ephrin receptor (EPH) kinases, and PDGFβ receptor. Dasatinib is a potent subnanomolar inhibitor of BCR-ABL kinase, with activity already evident at concentrations of 0.6–0.8 nM. Dasatinib binds to both the active and inactive forms of the BCR-ABL enzyme.
Mechanism of action
In vitro, dasatinib acts on leukemia cell lines representing both imatinib-sensitive and imatinib-resistant disease variants. These preclinical studies demonstrate that dasatinib can overcome imatinib resistance associated with 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. In addition, dasatinib inhibits the SRC kinase family at subnanomolar concentrations.
In vivo, in individual experiments using mouse models of chronic myeloid leukemia (CML), dasatinib halted the progression of chronic-phase CML to blast crisis and prolonged survival in mice engrafted with patient-derived CML cell lines grown in various organs, including the central nervous system (CNS).
Pharmacokinetics
The pharmacokinetics of dasatinib were studied in 229 healthy adult volunteers and 84 patients.
Absorption
Dasatinib is rapidly absorbed after oral administration, with peak concentrations reached within 0.5–3 hours. Following oral administration, the increase in mean exposure (AUCτ) is approximately dose-proportional over the dose range of 25 mg to 120 mg twice daily. The overall mean terminal half-life of dasatinib in patients is approximately 5–6 hours.
In healthy volunteers who received a single 100 mg dose of dasatinib 30 minutes after a high-fat meal, a 14% increase in mean AUC of dasatinib was observed. Administration with a low-fat meal taken 30 minutes prior to dasatinib resulted in a 21% increase in mean AUC. The observed food effect did not lead to clinically significant changes in exposure. Variability in dasatinib exposure was greater when administered under fasting conditions (47% CV [coefficient of variation]) compared to administration with a low-fat meal (39% CV) or a high-fat meal (32% CV).
Population pharmacokinetic analysis in patients indicated that variability in dasatinib exposure is primarily driven by intrasubject variability in bioavailability (44% CV), with lesser contributions from intersubject variability in bioavailability and intersubject variability in clearance (30% and 32% CV, respectively). This inherent intrasubject variability in exposure is not expected to impact cumulative exposure or the efficacy and safety of the drug at any given time point.
Distribution
Dasatinib has a large apparent volume of distribution in patients (2505 L) and a coefficient of variation (93%), indicating extensive distribution of the drug into the extravascular space. In vitro studies show that binding of dasatinib to plasma proteins at clinically relevant concentrations is approximately 96%.
Biotransformation
Dasatinib is extensively metabolized in humans, with multiple enzymes involved in the formation of its metabolites. In healthy volunteers who received a 100 mg dose of carbon-14 labeled dasatinib, unchanged dasatinib accounted for 29% of circulating radioactivity in plasma. Plasma concentrations and activity measured in vitro suggest that dasatinib metabolites likely play no major role in the observed pharmacological activity of the drug. The CYP3A4 isoenzyme is the primary enzyme responsible for dasatinib metabolism.
Elimination
The mean terminal half-life of dasatinib ranges from 3 to 5 hours. The mean apparent clearance after oral administration is 363.8 L/h (CV 81.3%).
Hepatic and renal impairment
The effect of hepatic impairment on the pharmacokinetics of a single dose of dasatinib was studied in 8 patients with moderate hepatic impairment receiving 50 mg dasatinib and in 5 patients with severe hepatic impairment receiving 20 mg dasatinib, compared to healthy volunteers receiving 70 mg. Mean Cmax and AUC values of dasatinib, adjusted to a 70 mg dose, were reduced by 47% in patients with moderate hepatic impairment, compared to an 8% reduction in volunteers with normal hepatic function. In patients with severe hepatic impairment, mean Cmax and AUC values, adjusted to a 70 mg dose, were reduced by 43% and 28%, respectively, compared to volunteers with normal hepatic function (see sections "Administration and dosage" and "Special precautions"). Renal excretion of dasatinib and its metabolites is minimal.
Paediatric population
The pharmacokinetics of dasatinib were evaluated in 104 paediatric patients with leukemia or solid tumors (72 patients received the drug in tablet form and 32 in powder for oral suspension form).
In a pharmacokinetic study involving paediatric patients, dasatinib exposure (Cavg, Cmin, and Cmax), normalized by dose, was found to be similar in 21 patients with chronic-phase CML and 16 patients with Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL).
The pharmacokinetics of dasatinib in tablet form were evaluated in 72 paediatric patients with relapsed or refractory leukemia or solid tumors, receiving oral doses ranging from 60 to 120 mg/m² once daily and 50 to 110 mg/m² twice daily. Combined data from two studies showed that dasatinib is rapidly absorbed. Mean Tmax occurred between 0.5 and 6 hours post-dose, and the mean half-life ranged from 2 to 5 hours across all doses and age groups. Dasatinib pharmacokinetics showed dose proportionality, with dose-dependent increases in exposure observed in children. No significant differences in dasatinib pharmacokinetics were observed between children and adolescents. Dose-normalized geometric mean Cmax, AUC (0–t), and AUC (inf) values of dasatinib were similar in children and adolescents across different doses. Based on population pharmacokinetic modeling, the recommended body-weight-based dosing of tablets (see section "Administration and dosage") is expected to result in exposure comparable to that achieved with 60 mg/m² tablets. These data should be considered when switching patients between tablets and powder for oral suspension, or vice versa.
Clinical characteristics.
Indications.
The medicinal product Dasatinib-Teva is indicated for the treatment of adult patients with:
- newly diagnosed Philadelphia chromosome-positive (Ph+) chronic myeloid leukemia (CML) in the chronic phase;
- CML in chronic phase, accelerated phase, or blast phase with resistance or intolerance to prior therapy, including imatinib;
- Ph+ acute lymphoblastic leukemia (ALL) and lymphoid blast CML with resistance or intolerance to prior therapy.
The medicinal product Dasatinib-Teva is indicated for the treatment of children with:
- newly diagnosed Ph+ CML in chronic phase or Ph+ CML in chronic phase with resistance or intolerance to prior therapy, including imatinib;
- newly diagnosed Ph+ ALL in combination with chemotherapy.
Contraindications.
Hypersensitivity to the active substance or to any of the excipients of the medicinal product.
Safety precautions.
The tablets consist of a core and a film coating, which prevents exposure of healthcare personnel to the active substance. When handling accidentally crushed or broken tablets, latex or nitrile gloves are recommended to minimize the risk of drug exposure through the skin. Unused medicinal product or waste material must be disposed of in accordance with local regulations.
Interaction with other medicinal products and other forms of interaction.
Substances that may increase dasatinib plasma concentrations
In vitro studies have shown that dasatinib is a substrate of the CYP3A4 enzyme. Concomitant administration of dasatinib with medicinal products or substances that are potent inhibitors of CYP3A4 (e.g., ketoconazole, itraconazole, erythromycin, clarithromycin, ritonavir, telithromycin, grapefruit juice) may increase dasatinib plasma concentrations. Therefore, patients taking dasatinib should not systematically take medicinal products that are potent CYP3A4 inhibitors (see section "Dosage and administration").
In vitro studies have shown that the plasma protein binding of dasatinib at clinically relevant concentrations is approximately 96%. Interactions between dasatinib and other medicinal products that bind to plasma proteins have not been studied. The potential of dasatinib to displace other drugs from protein binding (and vice versa), and its clinical significance, are unknown.
Substances that may reduce dasatinib plasma concentrations
When dasatinib was administered after 8 days of daily treatment with 600 mg rifampicin, a potent CYP3A4 inducer, the AUC of dasatinib decreased by 82%. Other medicinal products that are CYP3A4 inducers (e.g., dexamethasone, phenytoin, carbamazepine, phenobarbital, or herbal preparations containing St. John's wort [Hypericum perforatum]) may also enhance the metabolism and reduce dasatinib plasma concentrations. Therefore, concomitant use of potent CYP3A4 inducers with dasatinib is not recommended.
For patients requiring rifampicin or other CYP3A4 inducers, alternative medicinal products with lower induction potential should be used. Concomitant use with dexamethasone, a weak CYP3A4 inducer, is acceptable. 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 exposure. In healthy volunteers, administration of famotidine 10 hours before a single dose of dasatinib reduced dasatinib exposure by 61%. In a study involving 14 healthy volunteers, a single 100 mg dose of dasatinib administered 22 hours after four days of omeprazole 40 mg at steady state reduced dasatinib AUC by 43% and Cmax by 42%. The use of antacids instead of H2-receptor antagonists or proton pump inhibitors should be considered for patients taking dasatinib (see section "Special precautions for use").
Antacids
Preclinical data indicate that dasatinib solubility is pH-dependent. In healthy volunteers, concomitant administration of antacids containing magnesium hydroxide and aluminum hydroxide with dasatinib reduced the AUC of a single dose of dasatinib by 55% and Cmax by 58%. However, when antacids were administered 2 hours before a single dose of dasatinib, no clinically significant changes in dasatinib concentration or exposure were observed. Therefore, antacids may be taken 2 hours before or after dasatinib administration (see section "Special precautions for use").
Substances whose plasma concentrations may be altered by dasatinib
Concomitant administration of dasatinib and a CYP3A4 substrate may increase exposure to the CYP3A4 substrate. In studies involving healthy volunteers, a single 100 mg dose of dasatinib increased 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 taking dasatinib. In vitro data suggest a potential risk of interaction with CYP2C8 substrates such as glitazones.
Children
Drug interaction studies have been conducted only in adults.
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 modulate the activity of CYP3A4 (see section "Interaction with other medicinal products and other forms of interaction").
Concomitant administration of dasatinib with medicinal products or substances that are strong inhibitors of CYP3A4 (e.g., ketoconazole, itraconazole, erythromycin, clarithromycin, ritonavir, telithromycin, grapefruit juice) may increase dasatinib exposure. Therefore, concomitant use of a strong CYP3A4 inhibitor 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 are inducers of CYP3A4 (e.g., dexamethasone, phenytoin, carbamazepine, rifampicin, phenobarbital, or herbal preparations containing St. John's wort [Hypericum perforatum]) may significantly reduce dasatinib exposure, potentially increasing the risk of treatment failure. Therefore, alternative medicinal products with a lower potential for CYP3A4 induction should be considered for patients receiving dasatinib (see section "Interaction with other medicinal products and other forms of interaction").
Concomitant administration of dasatinib and a CYP3A4 substrate may increase the effect of the CYP3A4 substrate. Therefore, caution is required when administering dasatinib concomitantly with CYP3A4 substrates with 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 antagonists (e.g., famotidine), proton pump inhibitors (e.g., omeprazole), or magnesium hydroxide/aluminium hydroxide-containing preparations may reduce dasatinib exposure. Therefore, H2-receptor antagonists and proton pump inhibitors are not recommended for concomitant use, and magnesium hydroxide/aluminium hydroxide-containing preparations should be administered at least 2 hours before or after dasatinib administration (see section "Interaction with other medicinal products and other forms of interaction").
Special patient groups
Based on the results of a single-dose pharmacokinetic study, patients with mild, moderate, or severe hepatic impairment may receive the recommended initial dose (see section "Pharmacological properties"). However, considering the limitations of this clinical study, dasatinib should be used with caution in patients with hepatic impairment.
Important adverse reactions
Myelosuppression. Treatment with dasatinib has been associated with anaemia, neutropenia, and thrombocytopenia. These reactions occur earlier and more frequently in patients with advanced-phase CML or Ph+ ALL than in patients with chronic-phase CML. Complete blood counts should be performed weekly for the first 2 months and then monthly or as clinically indicated in adult patients with advanced-phase CML or Ph+ ALL receiving dasatinib monotherapy. Complete blood counts should be performed every 2 weeks for the first 12 weeks and then every 3 months or as clinically indicated in adult and paediatric patients with chronic-phase CML. For paediatric patients with Ph+ ALL receiving dasatinib in combination with chemotherapy, complete blood counts should be 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 "Method of administration and dosage" and "Adverse reactions"). In general, myelosuppression is reversible and usually managed by temporary interruption of dasatinib or dose reduction.
Bleeding. Grade 3 or 4 bleeding occurred in 5 patients (1%) receiving dasatinib among patients with chronic-phase CML (n = 548). In clinical studies of patients with advanced-phase CML receiving the recommended dose of dasatinib (n = 304), severe CNS haemorrhage occurred in 1% of patients. One case, associated with grade 4 thrombocytopenia according to Common Toxicity Criteria (CTC), was fatal.
Grade 3 or 4 gastrointestinal bleeding occurred in 6% of patients with advanced-phase CML, generally requiring treatment interruption and blood transfusion. Other grade 3 or 4 bleeding 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"). Additional in vitro and in vivo studies suggest that dasatinib treatment has a reversible effect on platelet activation. Caution is required if patients are to receive medicinal products that impair platelet function or anticoagulants.
Fluid retention. Dasatinib is associated with fluid retention. In a phase III clinical trial involving 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 after 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 was reported in 32 patients (6%) receiving dasatinib at the recommended dose (n = 548). In clinical trials of patients with advanced-phase CML or Ph+ ALL receiving dasatinib at the recommended dose (n = 304), fluid retention of grade 3 or 4 was observed in 8% of patients, including pleural effusion of grade 3 or 4 in 7% and pericardial effusion of grade 3 or 4 in 1%. Among these patients, pulmonary oedema of grade 3 or 4 and pulmonary hypertension were each reported in 1%.
Patients who develop symptoms suggestive of pleural effusion, such as dyspnoea 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 supportive measures, including diuretics and a short course of corticosteroids (see sections "Method of administration and dosage" and "Adverse reactions"). Patients over 65 years of age have a higher incidence of pleural effusion, dyspnoea, cough, pericardial effusion, and congestive heart failure than younger patients; therefore, elderly patients require special monitoring. Cases of chylothorax have also been reported in patients with pleural effusion (see section "Adverse reactions").
Pulmonary arterial hypertension (PAH). Cases of PAH (precapillary pulmonary arterial hypertension confirmed by right heart catheterization) associated with dasatinib treatment have been reported (see section "Adverse reactions"). In these cases, PAH occurred after initiation of dasatinib treatment, particularly after more than 1 year of treatment.
Patients should be evaluated for signs and symptoms of underlying cardiopulmonary disease before starting dasatinib treatment. Echocardiography should be performed at the start of treatment in patients with cardiac symptoms and considered in patients with risk factors for cardiopulmonary disease. Patients who develop dyspnoea and fatigue after starting treatment should be evaluated for common causes of such symptoms, including pleural effusion, pulmonary oedema, anaemia, or lung infiltration. According to recommendations for managing non-haematological adverse reactions (see section "Method of administration and dosage"), the dose of dasatinib should be reduced or treatment interrupted during evaluation. If no explanation is found or if there is no improvement after dose reduction or treatment interruption, PAH should be considered. Diagnostic evaluation should follow standard clinical guidelines. If PAH is confirmed, dasatinib treatment must be permanently discontinued. Patients should be monitored according to standard recommendations. Improvement in haemodynamics and clinical status has been observed in patients with PAH after discontinuation of dasatinib.
QT interval prolongation. In vitro studies indicate that dasatinib may prolong ventricular repolarization (QT interval). Among 258 patients receiving dasatinib and 258 patients receiving imatinib after 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 prolonged QTc, reported as an adverse reaction. The median change in QTcF (Fridericia-corrected) from baseline was 3.0 ms in patients receiving dasatinib compared with 8.2 ms in patients receiving imatinib. One patient (< 1%) in each group had a QTcF > 500 ms. Among 865 patients with leukaemia who received dasatinib in phase II clinical trials, mean changes in QTcF from baseline were 4–6 ms; the upper limit of the 95% confidence interval for all mean changes from baseline was < 7 ms (see section "Adverse reactions").
Among 2182 patients with resistance or intolerance to prior imatinib treatment who received dasatinib in clinical trials, 15 (1%) experienced QTc prolongation as an adverse reaction, and 21 patients (1%) had QTcF > 500 ms.
Dasatinib should be used with caution in patients who have or may develop QTc prolongation. These include patients with hypokalaemia or hypomagnesaemia, patients with congenital long QT syndrome, patients taking antiarrhythmic drugs or other drugs that prolong the QT interval, and patients receiving high cumulative doses of anthracyclines. Hypokalaemia or hypomagnesaemia should be corrected before initiating dasatinib.
Cardiac adverse reactions. Dasatinib was evaluated in a randomized clinical trial of 519 patients with newly diagnosed chronic-phase CML, including patients with pre-existing cardiac conditions. Adverse cardiac reactions, including congestive heart failure/cardiac dysfunction, pericardial effusion, arrhythmia, palpitations, QT prolongation, and myocardial infarction (including fatal cases), have been reported in patients receiving dasatinib. Cardiac adverse reactions occurred most frequently in patients with risk factors or a history of cardiac disease. Patients with risk factors (e.g., hypertension, hyperlipidaemia, diabetes) or a history of cardiac disease (e.g., prior percutaneous coronary intervention, established ischaemic heart disease) should be closely monitored for clinical signs or symptoms suggestive of cardiac dysfunction, such as chest pain, dyspnoea, and excessive sweating.
If such clinical signs or symptoms develop, physicians should temporarily interrupt dasatinib and consider alternative treatment specific to patients with CML. Functional assessment should be performed before resuming dasatinib treatment after resolution. Dasatinib may be continued at the previous dose if adverse reactions were mild to moderate (≤ grade 2) or at a reduced dose if adverse reactions were severe (≥ grade 3) (see section "Method of administration and dosage"). Patients continuing treatment should be monitored periodically. Patients with uncontrolled or significant cardiovascular disease were excluded from clinical trials.
Thrombotic microangiopathy (TMA). The use of BCR-ABL tyrosine kinase inhibitors has been associated with TMA, including isolated reports with dasatinib (see section "Adverse reactions"). If a patient receiving dasatinib develops laboratory or clinical signs suggestive of TMA, dasatinib treatment should be discontinued and a thorough evaluation performed, including ADAMTS13 activity and anti-ADAMTS13 antibody testing. Dasatinib treatment should not be resumed if anti-ADAMTS13 antibodies are elevated in combination with low ADAMTS13 activity.
Hepatitis B reactivation. Hepatitis B reactivation has occurred in patients who are chronic carriers of the virus following treatment with BCR-ABL tyrosine kinase inhibitors. In some cases, acute liver failure or fulminant hepatitis occurred, requiring liver transplantation or resulting in death. Patients should be tested for hepatitis B virus (HBV) infection before starting dasatinib treatment. Patients with positive serological tests for hepatitis B (including those with active disease) and patients who test positive for HBV infection during treatment should be referred to specialists for evaluation and management of liver failure and hepatitis B.
Chronic carriers of hepatitis B virus requiring dasatinib treatment should be closely monitored for signs and symptoms of active HBV infection during treatment and for several months after treatment completion (see section "Adverse reactions").
Effects on growth and development in children. In studies of dasatinib in paediatric patients with Ph+ CML-CP (chronic phase) who were resistant/intolerant to imatinib, and in paediatric patients with Ph+ CML-CP who had not received prior treatment, drug-related adverse effects affecting bone growth and development were reported in 6 (4.6%) patients after at least 2 years of treatment, including one case of severe (grade 3 growth delay). These 6 cases included epiphyseal fusion delay, osteopenia, growth delay, and gynaecomastia (see section "Pharmacological properties"). These findings are difficult to interpret in the context of chronic diseases such as CML and require long-term follow-up.
In studies of dasatinib in combination with chemotherapy in paediatric patients with newly diagnosed Ph+ ALL, drug-related adverse effects affecting bone growth and development were reported in 1 (0.6%) patient after up to 2 years of treatment. This was grade 1 osteopenia.
During clinical trials in children receiving dasatinib, growth delay was observed (see section "Adverse reactions"). After up to 2 years of treatment, a trend toward reduced expected height was observed to a similar extent as with chemotherapy alone, without impact on expected body weight or body mass index (BMI), and without association with hormonal factors or other laboratory abnormalities. Monitoring of growth and bone development is recommended in children.
Lactose. This medicinal product contains 131.3 mg of lactose monohydrate in the 100 mg daily dose and 183.8 mg of lactose monohydrate in the 140 mg daily dose (two 70 mg tablets). Patients with rare hereditary problems of galactose intolerance, total lactase deficiency, or glucose-galactose malabsorption should not take this medicinal product.
Sodium. This medicinal product contains less than 1 mmol (23 mg) of sodium per tablet, i.e., essentially "sodium-free".
Use during pregnancy or breastfeeding.
Women of childbearing potential / contraception in women and men
Men and women of reproductive potential who are sexually active should use effective contraception during treatment.
Pregnancy
Clinical experience suggests that dasatinib may cause congenital malformations, including neural tube defects, and harmful pharmacological effects on the foetus when administered during pregnancy.
Animal studies have shown reproductive toxicity.
Dasatinib-Teva should not be used during pregnancy except when the woman's clinical condition requires treatment with dasatinib. If Dasatinib-Teva is used during pregnancy, the patient should be informed of the potential risk to the foetus.
Breastfeeding
Information on the passage of dasatinib into human or animal breast milk is insufficient/limited. Physicochemical and available pharmacodynamic/toxicological data indicate that dasatinib passes into breast milk; therefore, the risk to the infant cannot be excluded.
Breastfeeding should be discontinued during treatment with Dasatinib-Teva.
Fertility
Animal studies (male and female rats) showed that dasatinib does not affect fertility. Physicians and other healthcare professionals should counsel men of reproductive age regarding the potential effects of dasatinib on fertility. Such counselling may include consideration of sperm cryopreservation.
Ability to affect reaction speed when driving or operating machinery.
Dasatinib has a minor influence on the ability to drive and use machines. Patients should be advised that adverse reactions such as dizziness or blurred vision may occur during treatment with dasatinib. Therefore, caution should be exercised when driving or operating machinery.
Dosage and Administration
Treatment should be initiated by a physician experienced in the diagnosis and treatment of patients with leukemia.
Dosage
Adults
The recommended starting dose of dasatinib for chronic phase chronic myeloid leukemia (CML) is 100 mg dasatinib once daily.
The recommended starting dose of dasatinib for accelerated phase, myeloid or lymphoid blast phase (progressive phase) CML, or Ph+ ALL is 140 mg once daily (see section "Special Instructions for Use").
Children (Ph+ CML in chronic phase and Ph+ ALL)
The dose for pediatric and adolescent patients is determined based on body weight (see Table 1). Dasatinib is administered orally once daily in the form of film-coated tablets or oral suspension powder. 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 for children with body weight below 10 kg (for this patient group, oral suspension powder is recommended). Dose adjustments (increases or reductions) should be based on individual patient response and tolerability. There is no experience with dasatinib treatment in children under 1 year of age.
Dasatinib-Teva film-coated tablets and dasatinib powder for oral suspension are not bioequivalent. Patients who are able to swallow tablets and wish to switch from dasatinib powder for oral suspension to Dasatinib-Teva tablets, or patients who cannot swallow tablets and wish to switch from tablets to oral suspension, may do so only under strict adherence to the appropriate dosing recommendations for the chosen pharmaceutical form.
The recommended initial daily dose of dasatinib tablets for pediatric patients is shown in Table 1.
Table 1
Dosage of dasatinib tablets for children with Ph+ CML in chronic phase or Ph+ ALL
Note: The table content will follow in the next section.
| Body weight (kg)a |
Daily dose (mg) |
| From 10 to less than 20 kg |
40 mg |
| From 20 to less than 30 kg |
60 mg |
| From 30 to less than 45 kg |
70 mg |
| 45 kg and above |
100 mg |
a Tablets are not recommended for use in patients with body weight less than 10 kg. For this patient category, the powder for oral suspension is recommended.
Duration of treatment
In clinical studies, treatment with dasatinib in adults with Ph+ CML-CP, accelerated phase, myeloid or lymphoid blast phase (progressive phase), Ph+ ALL, and in children with Ph+ CML-CP was continued until disease progression or until intolerance was observed in the patient. The impact of treatment discontinuation on long-term outcomes after achieving cytogenetic or molecular response [specifically complete cytogenetic response (CCyR), major molecular response (MMR), and MR4.5 molecular response] has not been studied.
In clinical studies, treatment with dasatinib in pediatric patients with Ph+ ALL was administered continuously in addition to sequential blocks of backbone chemotherapy for up to 2 years. For patients undergoing subsequent stem cell transplantation, dasatinib may be continued for an additional year following transplantation.
To achieve the recommended dose, dasatinib is available in film-coated tablets of 20 mg, 50 mg, 70 mg, 80 mg, 100 mg, and 140 mg, as well as in the form of powder for oral suspension. Dose escalation or de-escalation is recommended based on patient response or drug tolerability.
Dose escalation
In clinical studies in 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-CP who do not achieve hematologic, cytogenetic, and molecular response within the time specified according to current treatment guidelines and who tolerate therapy well are presented in Table 2.
Table 2
Dose escalation for children with Ph+ CML in chronic phase
| Dose (maximum daily dose) |
||
| Initial dose |
Dose increase |
|
| Tablets |
40 mg |
50 mg |
| 60 mg |
70 mg |
|
| 70 mg |
90 mg |
|
| 100 mg |
120 mg |
|
Gradual dose escalation is not recommended in pediatric patients with Ph+ ALL, as dasatinib is used in combination with chemotherapy in these patients.
Dose modifications in the event of adverse reactions
Myelosuppression
In clinical studies, myelosuppression was managed by withholding doses, dose reduction, or discontinuation of the investigational drug. When necessary, platelet and red blood cell transfusions were used. Hematopoietic growth factors were administered to patients with persistent myelosuppression. Dose modification recommendations for adults are presented in Table 3. Dose modification recommendations for pediatric patients with Ph+ ALL-CP are presented in Table 4.
Dose modification recommendations for pediatric patients with Ph+ ALL receiving dasatinib in combination with chemotherapy are provided in a separate paragraph below the tables.
Table 3
Dose modifications for neutropenia and thrombocytopenia in adults
| Adults with CML in chronic phase (initial dose of 100 mg once daily) |
ANC < 0.5×10⁹/L and/or platelets < 50×10⁹/L |
|
| Adults in accelerated phase, blast phase CML, and Ph+ ALL (initial dose of 140 mg once daily) |
ANC < 0.5×10⁹/L and/or platelets < 10×10⁹/L |
|
ANC — absolute neutrophil count
Table 4
Dose adjustment for neutropenia and thrombocytopenia in pediatric patients with Ph+ CML in chronic phase
|
Dose (maximum daily dose) |
|||
| Initial starting 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 tablet with a lower dose is not available.
If grade ≥ 3 neutropenia or thrombocytopenia recurs during complete hematologic response in pediatric patients with Ph+ CML-CP treated with Dasatinib-Teva, administration of Dasatinib-Teva should be temporarily interrupted and may subsequently be resumed at a reduced dose. Temporary dose reduction for intermediate grades of cytopenia should be considered as necessary.
Dose modification is not recommended in children with Ph+ ALL for hematologic toxicity of grades 1 to 4. If neutropenia and/or thrombocytopenia delay the next treatment cycle by more than 14 days, Dasatinib-Teva should be interrupted and restarted at the same dose 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 examination should be performed to assess cellularity and percentage of blasts. If bone marrow cellularity is < 10%, dasatinib treatment should be temporarily discontinued until ANC > 500/µL (0.5×10⁹/L) is achieved, after which treatment may be resumed at the full dose.
If bone marrow cellularity is > 10%, resumption of treatment with Dasatinib-Teva may be considered.
Non-hematologic adverse reactions
In case of a moderate non-hematologic adverse reaction (grade 2) during dasatinib treatment, therapy should be withheld until resolution of the adverse reaction or return to baseline. If the adverse reaction occurs for the first time, treatment should be continued at the same dose; however, if the adverse reaction recurs, the dose should be reduced. In case 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 at a reduced dose, depending on the initial severity of the adverse reaction. For patients with chronic phase CML who were 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 needed. For patients with advanced phase CML or Ph+ 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 CML in chronic phase experiencing non-hematologic adverse reactions, dose reduction recommendations should follow those for hematologic adverse reactions outlined above. For children with Ph+ ALL experiencing non-hematologic adverse reactions, dose should be reduced by one level as needed, according to the dose reduction recommendations for hematologic adverse reactions described above.
Pleural effusion
If pleural effusion is diagnosed, dasatinib administration should be withheld until patient evaluation, symptom resolution, or return to baseline. If the episode does not resolve within approximately one week, consideration should be given to initiating diuretic or corticosteroid therapy, or both (see sections "Special warnings and precautions for use" and "Adverse reactions"). After resolution of the first episode, resumption of dasatinib at the same dose should be considered. After resolution of a subsequent episode, resumption of dasatinib at a reduced dose (one level lower) should be considered. After resolution of a severe episode (grade 3 or 4), treatment may be resumed with a dose reduction, as needed, depending 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 juice with Dasatinib-Teva should be avoided (see section "Interaction with other medicinal products and other forms of interaction"). If possible, an alternative concomitant medication with no or minimal CYP3A4 enzyme inhibition should be selected. If dasatinib must be used with a strong CYP3A4 inhibitor, consideration should be given to reducing the dose to:
- 40 mg once daily for patients taking 140 mg daily;
- 20 mg once daily for patients taking 100 mg daily;
- 20 mg once daily for patients taking 70 mg daily.
For patients taking 60 mg or 40 mg daily, temporary discontinuation of dasatinib until completion of the CYP3A4 inhibitor therapy or switching to a lower dose using oral suspension powder should be considered. Reinitiation of dasatinib should occur one week (elimination half-life period) after discontinuation of the CYP3A4 inhibitor.
These reduced doses are intended to adjust the area under the curve (AUC) to the range observed in the absence of CYP3A4 inhibitors; however, clinical data supporting these dose adjustments in patients receiving strong CYP3A4 inhibitors are lacking. If Dasatinib-Teva is poorly tolerated after dose reduction, either the strong CYP3A4 inhibitor should be discontinued or dasatinib therapy should be stopped until completion of the inhibitor treatment. The dasatinib dose should be increased one week (elimination half-life period) after discontinuation of the CYP3A4 inhibitor.
Special patient groups
Elderly patients
No clinically significant pharmacokinetic differences related to age have been observed. There is no need for specific dosing recommendations for elderly patients.
Patients with hepatic impairment
Patients with mild, moderate, or severe hepatic impairment may receive the recommended initial dose. However, dasatinib should be used with caution in these patients (see section "Pharmacological properties").
Patients with renal impairment
Clinical studies of dasatinib in patients with impaired renal function have not been conducted (patients with serum creatinine concentrations more than 3 times the upper limit of normal (ULN) were excluded from the study in patients with newly diagnosed chronic phase CML, and patients with serum creatinine > 1.5×ULN were excluded from the study in imatinib-resistant or -intolerant chronic phase CML). Since renal clearance of dasatinib and its metabolites is < 4%, a reduction in total clearance is not expected in patients with renal impairment.
Method of administration
Dasatinib-Teva is administered orally. Film-coated tablets must not be crushed, split, or chewed—they should be swallowed whole to ensure consistent dosing and minimize the risk of skin contact. Film-coated tablets must not be dissolved, as the drug exposure in patients taking dissolved tablets is lower than in those swallowing whole tablets.
Dasatinib-Teva can be taken with or without food, but should always be taken consistently in the morning or evening (see section "Pharmacological properties"). For patients unable to swallow tablets, an oral suspension powder is available. Dasatinib-Teva should not be taken with grapefruit or grapefruit juice (see section "Interaction with other medicinal products and other forms of interaction").
Children
Tablet administration is not recommended for children with body weight less than 10 kg (oral suspension powder is recommended for this patient group). 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 of 280 mg daily for one week was reported in two patients, both of whom subsequently developed significant thrombocytopenia. Since dasatinib is associated with grade 3 or 4 myelosuppression (see section "Special warnings and precautions for use"), patients receiving doses higher than recommended should be closely monitored for possible myelosuppression and provided with appropriate supportive therapy.
Adverse Reactions
Summary of safety profile
The data presented below reflect the effects of dasatinib monotherapy at all doses tested in clinical trials (N = 2900), including 324 adult patients with newly diagnosed chronic phase chronic myeloid leukemia (CML), 2388 adult patients with Ph+ ALL or CML in chronic or advanced phase who were resistant to or intolerant of imatinib, and 188 pediatric patients.
In 2712 adult patients with chronic phase CML, advanced phase CML, or Ph+ ALL, the median duration of treatment was 19.2 months (range 0–93.2 months). In a randomized clinical trial conducted in adult patients with newly diagnosed chronic phase CML, the median duration of treatment was approximately 60 months. The median duration of treatment in 1618 adult patients with chronic phase CML was 29 months (range 0–92.9 months). The median duration of treatment in 1094 adult patients with advanced phase CML or Ph+ ALL was 6.2 months (range 0.1–99.6 months).
The median duration of treatment among 188 patients in pediatric clinical trials was 26.3 months (range 0–99.6 months). In the subgroup of 130 pediatric patients with chronic phase CML treated with dasatinib, the median duration of treatment was 42.3 months (range 0.1–99.6 months).
Most patients receiving dasatinib experienced adverse reactions at some point during treatment. Among the overall population of 2712 adult patients receiving dasatinib, 520 (19%) experienced adverse reactions leading to treatment discontinuation.
The overall safety profile of dasatinib in pediatric patients with Ph+ chronic phase CML was similar to that in adults, regardless of dosage form, except that there were no cases of pericardial effusion, pleural effusion, pulmonary edema, or pulmonary hypertension reported in pediatric patients. Among the 130 pediatric patients with chronic phase CML treated with dasatinib, 2 (1.5%) experienced adverse reactions leading to treatment discontinuation.
List of adverse reactions
In patients receiving dasatinib as monotherapy in dasatinib clinical trials and during the post-marketing period, the following adverse reactions have been reported, excluding laboratory test abnormalities. Adverse reactions are categorized by system organ class and frequency. Frequency is defined as follows: very common (≥ 1/10); common (≥ 1/100 and < 1/10); uncommon (≥ 1/1,000 and < 1/100); rare (≥ 1/10,000 and < 1/1,000); frequency not known (cannot be estimated from available data).
Within each frequency category, adverse reactions are listed in decreasing order of severity.
Table 5
| Infections and infestations |
|
| Very common |
infections (including bacterial, viral, fungal, unspecified) |
| Common |
pneumonia (including bacterial, viral and fungal), upper respiratory tract infection/inflammation, herpesvirus infection (including cytomegalovirus infection), infectious enterocolitis, sepsis (including rare cases with fatal outcomes) |
| Frequency unknown |
hepatitis B reactivation |
| Blood and lymphatic system disorders |
|
| Very common |
myelosuppression (including anaemia, neutropenia, thrombocytopenia) |
| Common |
febrile neutropenia |
| Uncommon |
lymphadenopathy, lymphopenia |
| Rare |
pure 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, hyperuricaemia |
| Uncommon |
tumour lysis syndrome, dehydration, hypoalbuminaemia, hypercholesterolaemia |
| Rare |
diabetes mellitus |
| Psychiatric disorders |
|
| Common |
depression, insomnia |
| Uncommon |
anxiety, confusion, emotional instability, decreased libido |
| Nervous system disorders |
|
| Very common |
headache |
| Common |
neuropathy (including peripheral neuropathy), dizziness, dysgeusia, somnolence |
| Uncommon |
CNS haemorrhage*b, syncope, tremor, amnesia, balance disorder |
| Rare |
stroke, transient ischaemic attack, seizures, optic neuritis, facial nerve (VII cranial nerve) paralysis, dementia, ataxia |
| Eye disorders |
|
| Common |
vision disorders (including blurred vision, blurred vision and decreased visual acuity), dry eyes |
| Uncommon |
visual disturbance, conjunctivitis, photophobia, increased 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 cases)*, QT interval prolongation on ECG*, pericarditis, ventricular arrhythmia (including ventricular tachycardia), angina pectoris, cardiomegaly, ECG T wave abnormality, increased troponin level |
| Rare |
pulmonary heart disease, myocarditis, acute coronary syndrome, cardiac arrest, PR interval prolongation on ECG, ischaemic heart disease, pleuropericarditis |
| Frequency unknown |
atrial fibrillation/atrial flutter |
| Vascular disorders |
|
| Very common |
haemorrhage*d |
| Common |
hypertension, hot flushes |
| Uncommon |
hypotension, thrombophlebitis, thrombosis |
| Rare |
deep vein thrombosis, embolism, livedo reticularis |
| Frequency unknown |
thrombotic microangiopathy (TMA) |
| Respiratory, thoracic and mediastinal disorders |
|
| Very common |
pleural effusion*, dyspnoea |
| Common |
pulmonary oedema*, 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 |
diarrhoea, vomiting, nausea, abdominal pain |
| Common |
gastrointestinal haemorrhage*, colitis (including neutropenic colitis), gastritis, mucosal inflammation (including mucositis/stomatitis), dyspepsia, abdominal distension, constipation, soft tissue lesions of the oral cavity |
| Uncommon |
pancreatitis (including acute pancreatitis), upper gastrointestinal ulcer, oesophagitis, ascites*, anal fissure, dysphagia, gastroesophageal reflux disease |
| Rare |
protein-losing gastroenteropathy, intestinal obstruction, anal fistula |
| Frequency unknown |
fatal gastrointestinal haemorrhage* |
| Hepatobiliary disorders |
|
| Uncommon |
hepatitis, cholecystitis, cholestasis |
| Skin and subcutaneous tissue disorders |
|
| Very common |
skin rashese |
| Common |
alopecia, dermatitis (including eczema), pruritus, acne, dry skin, urticaria, hyperhidrosis |
| Uncommon |
neutrophilic dermatosis, photosensitivity, pigmentation disorders, panniculitis, skin ulcers, bullous epidermolysis, nail damage, palmar-plantar erythrodysesthesia, hair damage |
| 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 stiffness, 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 urinary frequency, proteinuria |
| Frequency unknown |
nephrotic syndrome |
| Pregnancy, puerperium and perinatal conditions |
|
| Rare |
abortion |
| Reproductive system and breast disorders |
|
| Uncommon |
gynaecomastia, menstrual cycle disturbance |
| General disorders and administration site conditions |
|
| Very common |
peripheral oedemai, fatigue, increased temperature, facial oedemaj |
| Common |
asthenia, pain, chest pain, generalized oedema*k, chills |
| Uncommon |
malaise, other superficial oedemal |
| Rare |
gait abnormality |
| Investigations |
|
| Common |
decreased body weight, increased body weight |
| Uncommon |
elevated creatine phosphokinase levels, elevated gamma-glutamyl transferase levels |
| Injury, poisoning and procedural complications |
|
| Common |
contusions |
a Includes decreased appetite, rapid satiety, increased appetite.
b Includes CNS hemorrhage, cerebral hematoma, cerebral hemorrhage, epidural hematoma, intracranial hemorrhage, hemorrhagic stroke, subarachnoid hemorrhage, subdural hematoma, and subdural hemorrhage.
c Includes elevated levels of 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 hemorrhage and CNS hemorrhage; these adverse reactions belong to the systemic-organ classes of gastrointestinal disorders and CNS disorders, respectively.
e Includes drug-related rashes, erythema, erythematous rash, exfoliative rash, generalized erythema, genital rash, miliaria, milia, miliaria rubra, pustular psoriasis, rash, erythematous rash, follicular rash, generalized rash, macular rash, maculopapular rash, papular rash, pruritus, pustular rash, vesicular rash, skin desquamation, skin irritation, toxicoderma, vesicular urticaria, and vasculitic rash.
f During the post-marketing period, isolated cases of Stevens-Johnson syndrome have been reported. It is not possible to determine whether this cutaneous-mucosal adverse reaction involving the skin and mucous membranes was directly related to dasatinib use or to concomitant medications.
g Musculoskeletal pain, reported during or after discontinuation of treatment.
h Frequency recorded 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 Fluid overload, fluid retention, gastrointestinal edema, generalized edema, peripheral edema, edema, edema due to cardiac disorders, perinephric effusion, post-procedural edema, visceral edema.
l Genital edema, incision site edema, genital swelling, penile edema, penile swelling, scrotal edema, skin induration, testicular edema, vulvovaginal swelling.
* See section "Description of selected adverse reactions" for details.
Description of selected adverse reactions
Myelosuppression. Treatment with dasatinib is associated with anemia, neutropenia, and thrombocytopenia. These reactions occur earlier and more frequently in patients with chronic-phase CML, accelerated-phase CML, and Ph+ ALL than in patients with chronic-phase CML (see section "Special warnings and precautions").
Hemorrhage. Adverse reactions related to bleeding, ranging from petechiae and epistaxis to gastrointestinal hemorrhage and CNS hemorrhage of grade 3 or 4, have been reported in patients receiving dasatinib (see section "Special warnings and precautions").
Fluid retention. Various adverse reactions such as pleural effusion, ascites, pulmonary edema, and pericardial effusion, with or without superficial edema, may be collectively described as "fluid retention." After at least 60 months of follow-up in a study involving patients with newly diagnosed chronic-phase CML, fluid retention adverse reactions associated with dasatinib use included: pleural effusion (28%), superficial edema (14%), pulmonary hypertension (5%), generalized edema (4%), and pericardial effusion (4%). Congestive heart failure/heart dysfunction and pulmonary edema were observed in <2% of patients. The cumulative incidence of dasatinib-induced pleural effusion (all grades) over time was: 10% at 12 months, 14% at 24 months, 19% at 36 months, 24% at 48 months, and 28% at 60 months. Overall, 46 patients receiving dasatinib experienced recurrent pleural effusion.
In 17 patients, 2 separate adverse events were recorded; in 6 patients, 3 adverse events; in 18 patients, 4–8 adverse events; and in 5 patients, more than 8 episodes of pleural effusion were observed.
The median time to first grade 1 or 2 pleural effusion induced by dasatinib was 114 weeks (range: 4–299 weeks). Less than 10% of patients with pleural effusion experienced severe (grade 3 or 4) dasatinib-induced cases.
The median time to first occurrence of pleural effusion ≥ grade 3 induced by dasatinib was 175 weeks (range: 114–274 weeks). The median duration of dasatinib-induced pleural effusion (all grades) was 283 days (~40 weeks).
Pleural effusion was usually reversible and resolved after temporary interruption of dasatinib and use of diuretics or other appropriate supportive measures (see sections "Dosage and administration" and "Special warnings and precautions"). Among patients receiving dasatinib who developed dasatinib-induced pleural effusion (n = 73), treatment was temporarily discontinued in 45 patients (62%), while dose reduction occurred in 30 patients (41%). Additionally, 34 (47%) patients received diuretics, 23 (32%) received corticosteroids, and 20 (27%) received both corticosteroids and diuretics. Therapeutic thoracentesis was performed in 9 patients (12%).
Six percent of patients treated with dasatinib discontinued treatment due to dasatinib-induced pleural effusion. Pleural effusion did not affect patients' ability to achieve response. Among patients with pleural effusion receiving dasatinib, 96% achieved confirmed complete cytogenetic response, 82% achieved major molecular response (MMR), and 50% achieved MR4.5 molecular response, despite temporary treatment interruption or dose adjustment.
For additional information on patients with chronic-phase CML, advanced-phase CML, or Ph+ ALL, see section "Special warnings and precautions".
Cases of chylothorax have been reported in patients with pleural effusion. Some cases of chylothorax resolved after permanent discontinuation, temporary interruption, or dose reduction of dasatinib, but additional treatment was required in most cases.
Pulmonary arterial hypertension (PAH). Cases of PAH associated with dasatinib use have been reported. In these cases, PAH was observed after initiation of dasatinib therapy and even after more than one year of treatment. Patients who developed PAH during dasatinib treatment often received other concomitant medications or had comorbidities in addition to the underlying malignancy. In patients with PAH, improvement in hemodynamic and clinical parameters was observed after discontinuation of dasatinib.
QT interval prolongation. In a phase III study in patients with newly diagnosed chronic-phase CML, after at least 12 months of follow-up (see section "Special warnings and precautions"), one patient (<1%) in the dasatinib group had QTcF > 500 ms. After at least 60 months of follow-up, no further patients with QTcF > 500 ms were identified.
In 5 phase II clinical trials involving patients with resistance or intolerance to prior imatinib therapy, ECGs were performed before and during treatment at predefined time points, with centralized reading of results in all 865 patients receiving dasatinib 70 mg twice daily. The QT interval was corrected for heart rate using Fridericia's method. At all post-dose time points on day 8, mean changes in QTcF from baseline were 4–6 ms, with the upper limit of the 95% confidence interval <7 ms. Among 2182 patients with resistance or intolerance to prior imatinib therapy who received dasatinib in clinical trials, prolonged QTc interval was reported as an adverse reaction in 15 patients (1%). Twenty-one (1%) patients had QTcF > 500 ms (see section "Special warnings and precautions").
Cardiac adverse reactions. Patients with risk factors or history of cardiac disease should be closely monitored for signs and symptoms of cardiac dysfunction and should be appropriately diagnosed and treated (see section "Special warnings and precautions").
Hepatitis B reactivation. Hepatitis B reactivation has been reported with BCR-ABL tyrosine kinase inhibitors. In some cases, acute liver failure or fulminant hepatitis occurred, requiring liver transplantation or resulting in fatal outcomes (see section "Special warnings and precautions").
In a phase III dose optimization study in patients with chronic-phase CML resistant or intolerant to prior imatinib therapy (median treatment duration 30 months), the incidence of pleural effusion and congestive heart failure/cardiac dysfunction was lower in the group receiving dasatinib 100 mg once daily compared to the group receiving dasatinib 70 mg twice daily. A lower incidence of myelosuppression was also observed in the 100 mg once-daily group (see below "Laboratory test abnormalities"). Median treatment duration in the 100 mg once-daily group was 37 months (range: 1–91 months). Cumulative incidence rates of selected adverse reactions observed in the group receiving the recommended starting dose of 100 mg once daily are presented in Table 6a.
Table 6a
Selected adverse reactions observed in the phase 3 dose optimization study (patients with chronic-phase CML resistant or intolerant to imatinib)ᵃ
| Minimum 2 years observation |
Minimum 5 years observation |
Minimum 7 years observation |
||||
| 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 |
2 |
1 |
2 |
1 |
2 |
1 |
| a Results from the Phase III dose optimization study are presented in the population treated with the recommended starting dose of 100 mg once daily (n = 165). |
||||||
In a Phase III dose-optimization study in patients with advanced-phase CML and Ph+ ALL, median duration of treatment was 14 months for accelerated-phase CML, 3 months for CML myeloid blast crisis, 4 months for CML lymphoid blast crisis, and 3 months for Ph+ ALL. Selected adverse reactions observed with the recommended starting dose of 140 mg once daily are listed in Table 6b. A schedule of 70 mg twice daily was also investigated. The 140 mg once-daily regimen demonstrated an efficacy profile similar to that of the 70 mg twice-daily regimen, but had a more favorable safety profile.
Table 6b
Selected adverse reactions observed in the Phase III dose-optimization study: advanced-phase CML and Ph+ ALLa
| 140 mg once daily, n = 304 |
||
| All cases |
Grade 3–4 |
|
| Preferred term |
Percentage (%) of patients |
|
| Diarrhea |
28 |
3 |
| Fluid retention |
33 |
7 |
| Peripheral edema |
15 |
< 1 |
| Pleural effusion |
20 |
6 |
| Generalized edema |
2 |
0 |
| Heart failure / cardiac dysfunctionb |
1 |
0 |
| Pericardial effusion |
2 |
1 |
| Pulmonary edema |
1 |
1 |
| Bleeding |
23 |
8 |
| Gastrointestinal hemorrhage |
8 |
6 |
a Results from the 3-phase dose optimization study in the population using the recommended starting dose of 140 mg once daily (n = 304), recorded after two years of follow-up within the study.
b Includes ventricular dysfunction, heart failure, congestive heart failure, cardiomyopathy, congestive cardiomyopathy, diastolic dysfunction, reduced ejection fraction, and ventricular failure.
Additionally, two studies were conducted in 161 pediatric patients with Ph+ ALL who received dasatinib in combination with chemotherapy. The main study included 106 pediatric patients who received dasatinib in combination with chemotherapy on a continuous schedule. In the supportive study involving 55 children, 35 received dasatinib in combination with chemotherapy on an intermittent schedule (two weeks of treatment followed by one to two weeks off treatment), and 20 patients received dasatinib in combination with chemotherapy on a continuous schedule. The median duration of treatment for 126 children with Ph+ ALL who received dasatinib on a continuous schedule was 23.6 months (range: 1.4–33 months).
Among the 126 pediatric patients with Ph+ ALL who received treatment on a continuous schedule, 2 patients (1.6%) experienced adverse reactions leading to treatment discontinuation. Adverse reactions observed in these two pediatric studies with an incidence ≥ 10% in patients receiving the drug on a continuous schedule are listed in Table 7. It should be noted that pleural effusion was observed in 7 (5.6%) patients in this group and therefore was not included in the table.
Table 7
Adverse reactions observed in ≥ 10% of pediatric patients with Ph+ ALL who received dasatinib on a continuous schedule in combination with chemotherapy (N = 126)a
| 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 (fever) |
12.7 |
5.6 |
| Headache |
11.1 |
4.8 |
| Decreased appetite |
10.3 |
4.8 |
| Fatigue |
10.3 |
0 |
Of the total of 106 patients in the main study, 24 patients received the oral suspension powder at least once, while 8 of them received only the oral suspension powder.
Laboratory test abnormalities
Hematology. In the Phase III study of newly diagnosed chronic phase CML, after at least 12 months of follow-up, grade 3 and 4 laboratory abnormalities observed in patients receiving dasatinib included neutropenia (21%), thrombocytopenia (19%), and anemia (10%). After a minimum of 60 months of follow-up, cumulative incidence rates of neutropenia were 29%, thrombocytopenia 22%, and anemia 13%.
Among patients with newly diagnosed chronic phase CML treated with dasatinib, those who developed grade 3 or 4 myelosuppression generally recovered following a brief treatment interruption and/or dose reduction, while permanent discontinuation of treatment occurred in 1.6% of patients. After a minimum of 60 months of follow-up, the cumulative rate of permanent discontinuation due to grade 3 or 4 myelosuppression was 2.3%.
Cytopenias (thrombocytopenia, neutropenia, and anemia) were consistently observed in patients with CML who were resistant to or intolerant of prior imatinib therapy. However, the occurrence of cytopenia also clearly depended on the disease stage. The frequency of hematologic abnormalities of grade 3 or 4 is presented in Table 8.
Table 8
Hematologic laboratory abnormalities of grade 3 and 4 CTC in clinical studies in patients resistant to or intolerant of 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 Results from a phase 3 dose optimization study, recorded after 2 years of follow-up within the study.
b Results from study CA180-034 with the recommended starting dose of 100 mg once daily.
c Results from study CA180-035 with the recommended starting dose of 140 mg once daily.
CTC grades: 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).
Cumulative incidence of grade 3 or 4 cytopenia among patients receiving 100 mg once daily was similar at 2 and 5 years, including: neutropenia (35% vs. 36%), thrombocytopenia (23% vs. 24%), and anemia (13% vs. 13%).
In patients who developed grade 3 or 4 myelosuppression, recovery usually occurred after short-term treatment interruptions and/or dose reductions, while in 5% of patients treatment was permanently discontinued. Most patients continued treatment without further signs of myelosuppression.
Biochemical investigations. In the study of newly diagnosed chronic phase CML, after at least 12 months of follow-up, grade 3 or 4 hypophosphatemia was observed in 4% of patients receiving dasatinib, and grade 3 or 4 elevations in transaminases, creatinine, and bilirubin were observed in ≤ 1% of patients. After a minimum of 60 months of follow-up, cumulative incidence of grade 3 or 4 hypophosphatemia was 7%, grade 3 or 4 creatinine elevation was 1%, and grade 3 or 4 transaminase elevation remained at 1%. Treatment with dasatinib was not discontinued due to these biochemical laboratory abnormalities.
2 years follow-up. Grade 3 or 4 elevations in transaminases or bilirubin were observed in 1% of patients with chronic phase CML (resistant or intolerant to prior imatinib therapy), and the frequency increased from 1% to 7% in patients with advanced phase CML and Ph+ ALL. Values usually returned to normal after dose reduction or temporary treatment interruption. In the phase 3 dose optimization study, grade 3 or 4 elevations in transaminases or bilirubin were observed in ≤ 1% of patients with chronic phase CML, with similarly low frequencies across all four treatment groups.
In the phase 3 dose optimization study in advanced phase CML and Ph+ ALL, grade 3 or 4 elevations in transaminases or bilirubin were observed in 1–5% of patients across all treatment groups.
Approximately 5% of patients receiving dasatinib who had normal baseline calcium levels experienced transient grade 3 or 4 hypocalcemia at some point during the study. Overall, decreased calcium levels were not associated with clinical symptoms. Patients who developed grade 3 or 4 hypocalcemia often recovered with oral calcium supplementation. Grade 3 or 4 hypocalcemia, hypokalemia, and hypophosphatemia were observed in patients at all phases of CML, but more frequently in patients with myeloid or lymphoid blast crisis CML and Ph+ ALL.
Grade 3 or 4 creatinine elevation was reported in < 1% of patients with chronic phase CML, with frequency increasing from 1% to 4% in patients with advanced phase CML.
Children
The safety profile of dasatinib as monotherapy in pediatric patients with Ph+ chronic phase CML was comparable to the safety profile in adults. The safety profile of dasatinib in combination with chemotherapy in pediatric patients 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 pediatric patients compared to adults.
In studies of CML treatment in pediatric patients, laboratory abnormality rates corresponded to the known laboratory profile in adults.
In studies of ALL treatment in pediatric patients, laboratory abnormality rates corresponded to the known laboratory profile in adults, including patients with acute leukemia receiving intensive chemotherapy.
Special populations
Although the safety profile of dasatinib in elderly patients was similar to that in younger populations, patients aged 65 years and older had a higher likelihood of experiencing commonly reported adverse reactions (such as fatigue, pleural effusion, dyspnea, cough, lower gastrointestinal bleeding, and appetite disturbances) and a higher likelihood of less frequently observed adverse reactions (such as abdominal distension, dizziness, pericardial effusion, congestive heart failure, and weight loss). Therefore, elderly patients should be closely monitored (see section "Special instructions").
Reporting suspected adverse reactions
All suspected adverse reactions and lack of drug efficacy should be reported via the following link: https://aisf.dec.gov.ua/
Shelf life. 3 years.
Storage conditions. The medicinal product does not require special storage temperature conditions. Store in the original packaging to protect from moisture. Keep out of reach of children.
Packaging. 10 tablets in a blister; 6 blisters in a cardboard box.
Prescription status. Prescription only.
Manufacturer. PLIVA Hrvatska d.o.o.
Manufacturer's address and location of its business operations.
Prilaz baruna Filipovića 25, 10000 Zagreb, Croatia.