ELPIDA is indicated for the treatment of adult patients with:

•  newly diagnosed Philadelphia chromosome positive (Ph+) chronic myelogenous leukaemia (CML) in the chronic phase.
•  chronic, accelerated or blast phase CML with resistance or intolerance to prior therapy including imatinib mesilate.
•  Ph+ acute lymphoblastic leukaemia (ALL) and lymphoid blast CML with resistance or intolerance to prior therapy.

ELPIDA is indicated for the treatment of paediatric patients with:

•  newly diagnosed Ph+ CML in chronic phase (Ph+ CML‐CP) or Ph+ CML‐CP resistant or intolerant to prior therapy including imatinib.

Therapy should be initiated by a physician experienced in the diagnosis and treatment of patients with leukaemia.

Posology

Adult patients

The recommended starting dose for chronic phase CML is 100 mg dasatinib once daily.

The recommended starting dose for accelerated, myeloid or lymphoid blast phase (advanced phase) CML or Ph+ ALL is 140 mg once daily (see section 4.4).

Paediatric population (Ph+ CML‐CP)

Dosing for children and adolescents is on the basis of body weight (see Table 1). Dasatinib is administered orally once daily in the form of either ELPIDA film‐coated tablets or ELPIDA powder for oral suspension (see Summary of Product Characteristics for ELPIDA powder for oral suspension). The dose should be recalculated every 3 months based on changes in body weight, or more often if necessary. The tablet is not recommended for patients weighing less than 10 kg; the powder for oral suspension should be used for these patients. Dose increase or reduction is recommended based on individual patient response and tolerability. There is no experience with ELPIDA treatment in children under 1 year of age.

ELPIDA film‐coated tablets and ELPIDA powder for oral suspension are not bioequivalent. Patients who are able to swallow tablets and who desire to switch from ELPIDA powder for oral suspension to ELPIDA tablets or patients who are not able to swallow tablets and who desire to switch from tablets to oral suspension, may do so, provided that the correct dosing recommendations for the dosage form are followed.

The recommended starting daily dosage of ELPIDA tablets in paediatric patients is shown in Table 1.

a The tablet is not recommended for patients weighing less than 10 kg; the powder for oral suspension should be used for these patients.

Treatment duration

In clinical studies, treatment with ELPIDA in adults and paediatric patients was continued until disease progression or until no longer tolerated by the patient. The effect of stopping treatment on long‐term disease outcome after the achievement of a cytogenetic or

molecular response [including complete cytogenetic response (CCyR), major molecular response (MMR) and MR4.5] has not been investigated.

To achieve the recommended dose, ELPIDA is available as 20 mg, 50 mg, 70 mg, 80 mg, 100 mg and 140 mg film‐coated tablets and powder for oral suspension (10 mg/mL suspension upon constitution). Dose increase or reduction is recommended based on patient response and tolerability.

Dose escalation

In clinical studies in adult CML and Ph+ ALL patients, dose escalation to 140 mg once daily (chronic phase CML) or 180 mg once daily (advanced phase CML or Ph+ ALL) was allowed in patients who did not achieve a haematologic or cytogenetic response at the recommended starting dose.

The following dose escalations shown in Table 2 are recommended in paediatric patients who do not achieve a haematologic, cytogenetic and molecular response at the recommended time points, per current treatment guidelines.

Dose adjustment for adverse reactions

Myelosuppression

In clinical studies, myelosuppression was managed by dose interruption, dose reduction, or discontinuation of study therapy. Platelet transfusion and red cell transfusion were used as appropriate. Haematopoietic growth factor has been used in patients with resistant myelosuppression.

Guidelines for dose modifications are summarised in Tables 3 and 4.

ANC: absolute neutrophil count

ANC: absolute neutrophil count

*lower tablet dose not available

For paediatric patients with Ph+ CML‐CP, if Grade ≥3 neutropaenia or thrombocytopaenia recurs during complete hematologic response (CHR), ELPIDA should be interrupted, and may be subsequently resumed at a reduced dose. Temporary dose reductions for intermediate degrees of cytopaenia and disease response should be implemented as needed.

Non‐haematologic adverse reactions

If a moderate, grade 2, non‐haematologic adverse reaction develops with dasatinib, treatment should be interrupted until the adverse reaction has resolved or returned to baseline. The same dose should be resumed if this is the first occurrence and the dose should be reduced if this is a recurrent adverse reaction. If a severe grade 3 or 4, nonhaematologic adverse reaction develops with dasatinib, treatment must be withheld until the adverse reaction has resolved. Thereafter, treatment can be resumed as appropriate at a reduced dose depending on the initial severity of the adverse reaction. For patients with chronic phase CML who received 100 mg once daily, dose reduction to 80 mg once daily with further reduction from 80 mg once daily to 50 mg once daily, if needed, is

recommended. For patients with advanced phase CML or Ph+ ALL who received 140 mg once daily, dose reduction to 100 mg once daily with further reduction from 100 mg once daily to 50 mg once daily, if needed, is recommended. In CML‐CP paediatric patients with non‐haematologic adverse reactions; the dose reduction recommendations for haematologic adverse reactions that are described above should be followed.

Pleural effusion

If a pleural effusion is diagnosed, dasatinib should be interrupted until patient is examined, asymptomatic or has returned to baseline. If the episode does not improve within approximately one week, a course of diuretics or corticosteroids or both concurrently should be considered

(see sections 4.4 and 4.8). Following resolution of the first episode, reintroduction of dasatinib at the same dose level should be considered.

Following resolution of a subsequent episode, dasatinib at one dose level reduction should be reintroduced. Following resolution of a severe

(grade 3 or 4) episode, treatment can be resumed as appropriate at a reduced dose depending on the initial severity of the adverse reaction.

Special populations

Paediatric population

The safety and efficacy of ELPIDA in children and adolescents below 18 years of age with Ph+ ALL have not yet been established. No data are available (see section 5.1).

Elderly

No clinically relevant age‐related pharmacokinetic differences have been observed in these patients. No specific dose recommendation is necessary in elderly.

Hepatic impairment

Patients with mild, moderate or severe hepatic impairment may receive the recommended starting dose. However, ELPIDA should be used with caution in patients with hepatic impairment (see section 5.2).

Renal impairment

No clinical studies were conducted with ELPIDA in patients with decreased renal function (the study in patients with newly diagnosed chronic phase CML excluded patients with serum creatinine concentration > 3 times the upper limit of the normal range, and studies in

patients with chronic phase CML with resistance or intolerance to prior imatinib therapy excluded patients with serum creatinine concentration > 1.5 times the upper limit of the normal range). Since the renal clearance of dasatinib and its metabolites is < 4%, a decrease

in total body clearance is not expected in patients with renal insufficiency.

Method of administration

ELPIDA must be administered orally.

The film‐coated tablets must not be crushed, cut or chewed in order to maintain dosing consistency and minimise the risk of dermal exposure; they must be swallowed whole. Filmcoated tablets should not be dispersed as the exposure in patients receiving a dispersed

tablet is lower than in those swallowing a whole tablet. ELPIDA powder for oral suspension is also available for patients who cannot swallow tablets.

ELPIDA can be taken with or without a meal and should be taken consistently either in the morning or in the evening. ELPIDA should not be taken with grapefruit or grapefruit juice (see section 4.5).

Clinically relevant interactions

Dasatinib is a substrate and an inhibitor of cytochrome P450 (CYP) 3A4. Therefore, there is a potential for interaction with other concomitantly administered medicinal products that are metabolised primarily by or modulate the activity of CYP3A4 (see section 4.5).

Concomitant use of dasatinib and medicinal products or substances that potently inhibit CYP3A4 (e.g. ketoconazole, itraconazole, erythromycin, clarithromycin, ritonavir, telithromycin, grapefruit juice) may increase exposure to dasatinib. Therefore, in patients receiving dasatinib, coadministration of a potent CYP3A4 inhibitor is not recommended (see section 4.5). Concomitant use of dasatinib and medicinal products that induce CYP3A4 (e.g. dexamethasone, phenytoin, carbamazepine, rifampicin, phenobarbital or herbal preparations

containing Hypericum perforatum, also known as St. John's Wort) may substantially reduce exposure to dasatinib, potentially increasing the risk of therapeutic failure. Therefore, in patients receiving dasatinib, coadministration of alternative medicinal products with less

potential for CYP3A4 induction should be selected (see section 4.5). Concomitant use of dasatinib and a CYP3A4 substrate may increase exposure to the CYP3A4 substrate. Therefore, caution is warranted when dasatinib is coadministered with CYP3A4 substrates of narrow therapeutic index, such as astemizole, terfenadine, cisapride, pimozide, quinidine, bepridil or ergot alkaloids (ergotamine, dihydroergotamine) (see section 4.5).

The concomitant use of dasatinib and a histamine‐2 (H2) antagonist (e.g. famotidine), proton pump inhibitor (e.g. omeprazole), or aluminium hydroxide/magnesium hydroxide may reduce the exposure to dasatinib. Thus, H2 antagonists and proton pump inhibitors are not recommended and aluminium hydroxide/magnesium hydroxide products should be administered up to 2 hours prior to, or 2 hours following the administration of dasatinib (see section 4.5).

Special populations

Based on the findings from a single‐dose pharmacokinetic study, patients with mild, moderate or severe hepatic impairment may receive the recommended starting dose (see section 5.2). Due to the limitations of this clinical study, caution is recommended when administering

dasatinib to patients with hepatic impairment.

Important adverse reactions

Myelosuppression

Treatment with dasatinib is associated with anaemia, neutropaenia and thrombocytopaenia. Their occurrence is earlier and more frequent in patients with advanced phase CML or Ph+ ALL than in chronic phase CML. In patients with advanced phase CML or Ph+ ALL, complete blood

counts should be performed weekly for the first 2 months, and then monthly thereafter, or as clinically indicated. In patients with chronic phase CML, complete blood counts should be performed every 2 weeks for 12 weeks, then every 3 months thereafter or as clinically indicated.

Myelosuppression is generally reversible and usually managed by withholding dasatinib temporarily or by dose reduction (see sections 4.2 and 4.8).

Bleeding

In patients with chronic phase CML (n=548), 5 patients (1%) receiving dasatinib had grade 3 or 4 haemorrhage. In clinical studies in patients with advanced phase CML receiving the recommended dose of ELPIDA (n=304), severe central nervous system (CNS) haemorrhage

occurred in 1% of patients. One case was fatal and was associated with Common Toxicity Criteria (CTC) grade 4 thrombocytopaenia. Grade 3 or 4 gastrointestinal haemorrhage occurred in 6% of patients with advanced phase CML and generally required treatment interruptions and

transfusions. Other grade 3 or 4 haemorrhage occurred in 2% of patients with advanced phase CML. Most bleeding related adverse reactions in these patients were typically associated with grade 3 or 4 thrombocytopaenia (see section 4.8). Additionally, in vitro and in vivo platelet

assays suggest that ELPIDA treatment reversibly affects platelet activation. Caution should be exercised if patients are required to take medicinal products that inhibit platelet function or anticoagulants.

Fluid retention

Dasatinib is associated with fluid retention. In the Phase III clinical study in patients with newly diagnosed chronic phase CML, grade 3 or 4 fluid retention was reported in 13 patients (5%) in the dasatinib‐treatment group and in 2 patients (1%) in the imatinib‐treatment group after a

minimum of 60 months follow‐up (see section 4.8). In all ELPIDA treated patients with chronic phase CML, severe fluid retention occurred in 32 patients (6%) receiving ELPIDA at the recommended dose (n=548). In clinical studies in patients with advanced phase CML receiving

ELPIDA at the recommended dose (n=304), grade 3 or 4 fluid retention was reported in 8% of patients, including grade 3 or 4 pleural and pericardial effusion reported in 7% and 1% of patients, respectively. In these patients grade 3 or 4 pulmonary oedema and pulmonary hypertension were each reported in 1% of patients.

Patients who develop symptoms suggestive of pleural effusion such as dyspnoea or dry cough should be evaluated by chest X‐ray. Grade 3 or 4 pleural effusion may require thoracocentesis and oxygen therapy. Fluid retention adverse reactions were typically managed by supportive care measures that include diuretics and short courses of steroids (see sections 4.2 and 4.8). Patients aged 65 years and older are more likely than younger patients to experience pleural effusion, dyspnoea, cough, pericardial effusion and congestive heart failure, and should be monitored closely.

Pulmonary arterial hypertension (PAH)

PAH (pre‐capillary pulmonary arterial hypertension confirmed by right heart catheterization) has been reported in association with dasatinib treatment (see section 4.8). In these cases, PAH was reported after initiation of dasatinib therapy, including after more than one year of treatment.

Patients should be evaluated for signs and symptoms of underlying cardiopulmonary disease prior to initiating dasatinib therapy. An echocardiography should be performed at treatment initiation in every patient presenting symptoms of cardiac disease and considered in patients

with risk factors for cardiac or pulmonary disease. Patients who develop dyspnoea and fatigue after initiation of therapy should be evaluated for common etiologies including pleural effusion, pulmonary oedema, anaemia, or lung infiltration. In accordance with recommendations for

management of non‐haematologic adverse reactions (see section 4.2) the dose of dasatinib should be reduced or therapy interrupted during this evaluation. If no explanation is found, or if there is no improvement with dose reduction or interruption, the diagnosis of PAH should be

considered. The diagnostic approach should follow standard practice guidelines. If PAH is confirmed, dasatinib should be permanently discontinued. Follow up should be performed according to standard practice guidelines. Improvements in haemodynamic and clinical parameters have been observed in dasatinib‐treated patients with PAH following cessation of dasatinib therapy.

QT Prolongation

In vitro data suggest that dasatinib has the potential to prolong cardiac ventricular repolarisation (QT Interval) (see section 5.3). In 258 dasatinib‐treated patients and 258 imatinibtreated patients with a minimum of 60 months follow‐up in the Phase III study in newly

diagnosed chronic phase CML, 1 patient (< 1%) in each group had QTc prolongation reported as an adverse reaction. The median changes in QTcF from baseline were 3.0 msec in dasatinibtreated patients compared to 8.2 msec in imatinib‐treated patients. One patient (< 1%) in each group experienced a QTcF > 500 msec. In 865 patients with leukaemia treated with dasatinib in Phase II clinical studies, the mean changes from baseline in QTc interval using Fridericia's method (QTcF) were 4 ‐ 6 msec; the upper 95% confidence intervals for all mean changes from baseline were < 7 msec (see section 4.8).

Of the 2,182 patients with resistance or intolerance to prior imatinib therapy who received dasatinib in clinical studies, 15 (1%) had QTc prolongation reported as an adverse reaction. Twenty‐one of these patients (1%) experienced a QTcF > 500 msec. Dasatinib should be administered with caution to patients who have or may develop prolongation of QTc. These include patients with hypokalaemia or hypomagnesaemia, patients with congenital long QT syndrome, patients taking anti‐arrhythmic medicinal products or other

medicinal products which lead to QT prolongation, and cumulative high dose anthracycline therapy. Hypokalaemia or hypomagnesaemia should be corrected prior to dasatinib administration.

Cardiac adverse reactions

Dasatinib was studied in a randomised clinical study of 519 patients with newly diagnosed CML in chronic phase which included patients with prior cardiac disease. The cardiac adverse reactions of congestive heart failure/cardiac dysfunction, pericardial effusion, arrhythmias,m palpitations, QT prolongation and myocardial infarction (including fatal) were reported in patients taking dasatinib. Cardiac adverse reactions were more frequent 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, documented coronary artery disease) should be monitored carefully for clinical signs or symptoms consistent with cardiac dysfunction such as chest pain, shortness of breath, and diaphoresis.

If these clinical signs or symptoms develop, physicians are advised to interrupt dasatinib administration and consider the need for alternative CML‐specific treatment. After resolution, a functional assessment should be performed prior to resuming treatment with dasatinib.

Dasatinib may be resumed at the original dose for mild/moderate adverse reactions (≤ grade 2) and resumed at a dose level reduction for severe adverse reactions (≥ grade 3) (see section 4.2). Patients continuing treatment should be monitored periodically. Patients with uncontrolled or significant cardiovascular disease were not included in the clinical studies.

Hepatitis B reactivation

Reactivation of hepatitis B in patients who are chronic carriers of this virus has occurred after these patients received BCR‐ABL tyrosine kinase inhibitors. Some cases resulted in acute hepatic failure or fulminant hepatitis leading to liver transplantation or a fatal outcome. Patients should be tested for HBV infection before initiating treatment with ELPIDA. Experts in liver disease and in the treatment of hepatitis B should be consulted before treatment is initiated in patients with positive hepatitis B serology (including those with active disease) and for patients who test positive for HBV infection during treatment. Carriers of HBV who require mtreatment with ELPIDA should be closely monitored for signs and symptoms of active HBV

infection throughout therapy and for several months following termination of therapy (see section 4.8).

Effects on growth and development in paediatric patients

In paediatric trials of ELPIDA in imatinib‐resistant/intolerant paediatric patients and treatmentnaive paediatric patients after at least 2 years of treatment, treatment‐related adverse events associated with bone growth and development were reported in 6 (4.6%) patients, one of which

was severe in intensity (Growth Retardation Grade 3). These 6 cases included cases of epiphyses delayed fusion, osteopaenia, growth retardation, and gynecomastia (see section 5.1). These results are difficult to interpret in the context of chronic diseases such as CML, and require longterm follow‐up.

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.

Active substances that may increase dasatinib plasma concentrations

In vitro studies indicate that dasatinib is a CYP3A4 substrate. Concomitant use of dasatinib and medicinal products or substances which potently inhibit CYP3A4 (e.g. ketoconazole, itraconazole, erythromycin, clarithromycin, ritonavir, telithromycin, grapefruit juice) may

increase exposure to dasatinib. Therefore, in patients receiving dasatinib, systemic administration of a potent CYP3A4 inhibitor is not recommended.

At clinically relevant concentrations, binding of dasatinib to plasma proteins is approximately 96% on the basis of in vitroexperiments. No studies have been performed to evaluate dasatinib interaction with other protein‐bound medicinal products. The potential for displacement and its clinical relevance are unknown.

Active substances that may decrease dasatinib plasma concentrations

When dasatinib was administered following 8 daily evening administrations of 600 mg rifampicin, a potent CYP3A4 inducer, the AUC of dasatinib was decreased by 82%. Other medicinal products that induce CYP3A4 activity (e.g. dexamethasone, phenytoin, carbamazepine, phenobarbital or herbal preparations containing Hypericum perforatum, also known as St. John s Wort) may also increase metabolism and decrease dasatinib plasma

concentrations. Therefore, concomitant use of potent CYP3A4 inducers with dasatinib is not recommended. In patients in whom rifampicin or other CYP3A4 inducers are indicated, alternative medicinal products with less enzyme induction potential should be used.

Histamine‐2 antagonists and proton pump inhibitors

Long‐term suppression of gastric acid secretion by H2 antagonists or proton pump inhibitors (e.g. famotidine and omeprazole) is likely to reduce dasatinib exposure. In a single‐dose study in healthy subjects, the administration of famotidine 10 hours prior to a single dose of ELPIDA

reduced dasatinib exposure by 61%. In a study of 14 healthy subjects, administration of a single 100‐mg dose of ELPIDA 22 hours following a 4‐day, 40‐mg omeprazole dose at steady state reduced the AUC of dasatinib by 43% and the Cmax of dasatinib by 42%. The use of antacids

should be considered in place of H2 antagonists or proton pump inhibitors in patients receiving ELPIDA therapy (see section 4.4).

Antacids

Non‐clinical data demonstrate that the solubility of dasatinib is pH‐dependent. In healthy subjects, the concomitant use of aluminium hydroxide/magnesium hydroxide antacids with ELPIDA reduced the AUC of a single dose of ELPIDA by 55% and the Cmax by 58%. However, when

antacids were administered 2 hours prior to a single dose of ELPIDA, no relevant changes in dasatinib concentration or exposure were observed. Thus, antacids may be administered up to 2 hours prior to or 2 hours following ELPIDA (see section 4.4).

Active substances that may have their plasma concentrations altered by dasatinib

Concomitant use of dasatinib and a CYP3A4 substrate may increase exposure to the CYP3A4 substrate. In a study in healthy subjects, a single 100 mg dose of dasatinib increased AUC and Cmax exposure to simvastatin, a known CYP3A4 substrate, by 20 and 37% respectively. It cannot

be excluded that the effect is larger after multiple doses of dasatinib. Therefore, CYP3A4 substrates known to have a narrow therapeutic index (e.g. astemizole, terfenadine, cisapride, pimozide, quinidine, bepridil or ergot alkaloids [ergotamine, dihydroergotamine]) should be

administered with caution in patients receiving dasatinib (see section 4.4). In vitro data indicate a potential risk for interaction with CYP2C8 substrates, such as glitazones.

Paediatric population

Interaction studies have only been performed in adults.

Women of childbearing potential/contraception in males and females

Both sexually active men and women of childbearing potential should use effective methods of contraception during treatment.

Pregnancy

Based on human experience, dasatinib is suspected to cause congenital malformations including neural tube defects, and harmful pharmacological effects on the foetus when administered during pregnancy. Studies in animals have shown reproductive toxicity (see section 5.3).

ELPIDA should not be used during pregnancy unless the clinical condition of the woman requires treatment with dasatinib. If ELPIDA is used during pregnancy, the patient must be informed of the potential risk to the foetus.

Breast‐feeding

There is insufficient/limited information on the excretion of dasatinib in human or animal breast milk. Physico‐chemical and available pharmacodynamic/toxicological data on dasatinib point to excretion in breast milk and a risk to the suckling child cannot be excluded.

Breast‐feeding should be stopped during treatment with ELPIDA.

Fertility

In animal studies, the fertility of male and female rats was not affected by treatment with dasatinib (see section 5.3). Physicians and other healthcare providers should counsel male patients of appropriate age about possible effects of ELPIDA on fertility, and this counseling may include consideration of semen deposition.

ELPIDA has minor influence on the ability to drive and use machines. Patients should be advised that they may experience adverse reactions such as dizziness or blurred vision during treatment with dasatinib. Therefore, caution should be recommended when driving a car or operating machines.

Summary of the safety profile

The data described below reflect the exposure to ELPIDA at all doses tested in clinical studies (N=2,900), including 324 adult patients with newly diagnosed chronic phase CML, 2,388 adult patients with imatinib‐resistant or ‐intolerant chronic or advanced phase CML or

Ph+ ALL, and 188 paediatric patients. In the 2,712 adult patients with either chronic phase CML, advanced phase CML or Ph+ ALL, the median duration of therapy was 19.2 months (range 0 to 93.2 months). In a randomized trial in patients with newly diagnosed chronic phase CML, the median duration of therapy was approximately 60 months. The median duration of therapy in 1,618 adult patients with chronic phase CML was 20 months (range 0 to 92.9 months). The median duration of therapy in 1,094 adult patients with advanced phase CML or Ph+ ALL was 6.2 months (range 0.1 to 99.6 months). Among 188 patients in paediatric studies, the median duration of therapy was 26.3 months (range 0 to 99.6 months). In the subset of 130 chronic phase CML ELPIDA‐treated paediatric patients, the median duration of therapy was 42.3 months (range 0.1 to 99.6 months).

The majority of ELPIDA‐treated patients experienced adverse reactions at some time. In the overall population of 2,712 ELPIDA‐treated adult subjects, 520 (19%) experienced adverse reactions leading to treatment discontinuation. The overall safety profile of ELPIDA in the paediatric population was similar to that of the adult population, regardless of formulation, with the exception of no reported pericardial effusion, pleural effusion, pulmonary oedema, or pulmonary hypertension in the paediatric population. Of the 130 ELPIDA‐treated paediatric subjects with CML‐CP, 2 (1.5%) experienced adverse reactions leading to treatment discontinuation.

Tabulated list of adverse reactions

The following adverse reactions, excluding laboratory abnormalities, were reported in patients in ELPIDA clinical studies and post‐marketing experience (Table 5). These reactions are presented by system organ class and by frequency. Frequencies are defined as: very common (≥ 1/10); common (≥ 1/100 to < 1/10); uncommon (≥ 1/1,000 to < 1/100); rare (≥ 1/10,000 to < 1/1,000); not known (cannot be estimated from available post‐marketing data).

Within each frequency grouping, adverse reactions are presented in order of decreasing seriousness.

a Includes decreased appetite, early satiety, increased appetite.

b Includes central nervous system haemorrhage, cerebral haematoma, cerebral haemorrhage, extradural haematoma, haemorrhage intracranial, haemorrhagic stroke, subarachnoid haemorrhage, subdural haematoma, and subdural haemorrhage.

c Includes brain natriuretic peptide increased, ventricular dysfunction, left ventricular dysfunction, right ventricular dysfunction, cardiac failure, cardiac failure acute, cardiac failure chronic, cardiac failure congestive, cardiomyopathy, congestive cardiomyopathy, diastolic dysfunction, ejection fraction decreased and ventricular failure, left ventricular failure, right ventricular failure, and ventricular hypokinesia.

d Excludes gastrointestinal bleeding and CNS bleeding; these adverse reactions are reported under the gastrointestinal disorders system organ class and the nervous system disorders system organ class, respectively.

e Includes drug eruption, erythema, erythema multiforme, erythrosis, exfoliative rash, generalised erythema, genital rash, heat rash, milia, miliaria, pustular psoriaisis, rash, rash erythematous, rash follicular, rash generalised, rash macular, rash maculo‐papular, rash

papular, rash pruritic, rash pustular, rash vesicular, skin exfoliation, skin irritation, toxic skin eruption, urticaria vesiculosa, and vasculitic rash.

f In the post‐marketing setting, individual cases of Stevens‐Johnson syndrome have been reported. It could not be determined whether these mucocutaneous adverse reactions were directly related to ELPIDA or to concomitant medicinal product.

g Frequency reported as common in paediatric studies.

h Gravitational oedema, localised oedema, oedema peripheral.

i Conjunctival oedema, eye oedema, eye swelling, eyelid oedema, face oedema, lip oedema, macular oedema, oedema mouth, orbital oedema, periorbital oedema, swelling face. Fluid overload, fluid retention, gastrointestinal oedema, generalised oedema, peripheral swelling, oedema, oedema due to cardiac disease, perinephric effusion, post procedural oedema, visceral oedema.

k Genital swelling, incision site oedema, oedema genital, penile oedema, penile swelling, scrotal oedema, skin swelling, testicular swelling, vulvovaginal swelling.

* For additional details, see section "Description of selected adverse reactions"

Description of selected adverse reactions

Myelosuppression

Treatment with ELPIDA is associated with anaemia, neutropaenia and thrombocytopaenia. Their occurrence is earlier and more frequent in patients with advanced phase CML or Ph+ ALL than in chronic phase CML (see section 4.4).

Bleeding

Bleeding drug‐related adverse reactions, ranging from petechiae and epistaxis to grade 3 or 4 gastrointestinal haemorrhage and CNS bleeding, were reported in patients taking ELPIDA (see section 4.4).

Fluid retention

Miscellaneous adverse reactions such as pleural effusion, ascites, pulmonary oedema and pericardial effusion with or without superficial oedema may be collectively described as “fluid retention”. In the newly diagnosed chronic phase CML study after a minimum of 60 months follow‐up, dasatinib‐related fluid retention adverse reactions included pleural effusion (28%), superficial oedema (14%), pulmonary hypertension (5%), generalised oedema (4%), and pericardial effusion (4%). Congestive heart failure/cardiac dysfunction and pulmonary oedema were reported in < 2% of patients. The cumulative rate of dasatinib‐related 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. A total of 46 dasatinib‐treated patients had recurrent pleural effusions. Seventeen patients had 2 separate adverse reactions, 6 had 3 adverse reactions, 18 had 4 to 8 adverse reactions and 5 had > 8 episodes of pleural effusions. The median time to first dasatinib‐related grade 1 or 2 pleural effusion was 114 weeks (range: 4 to 299 weeks). Less than 10% of patients with pleural effusion had severe (grade 3 or 4) dasatinib‐related pleural effusions. The median time to first occurrence of grade ≥ 3 dasatinibrelated pleural effusion was 175 weeks (range: 114 to 274 weeks). The median duration of dasatinib‐related pleural effusion (all grades) was 283 days (~40 weeks). Pleural effusion was usually reversible and managed by interrupting ELPIDA treatment and using diuretics or other appropriate supportive care measures (see sections 4.2 and 4.4). Among dasatinib‐treated patients with drug‐related pleural effusion (n=73), 45 (62%) had dose interruptions and 30 (41%) had dose reductions. 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 dasatinib‐treated patients discontinued treatment due to drug‐related pleural effusion. Pleural effusion did not impair the ability of patients to obtain a response. Among the dasatinibtreated patients with pleural effusion, 96% achieved a cCCyR, 82% achieved a MMR, and 50% achieved a MR4.5 despite dose interruptions or dose adjustment. See section 4.4 for further information on patients with chronic phase CML and advanced phase CML or Ph+ ALL.

Pulmonary arterial hypertension (PAH)

PAH (pre‐capillary pulmonary arterial hypertension confirmed by right heart catheterization) has been reported in association with dasatinib exposure. In these cases, PAH was reported after initiation of dasatinib therapy, including after more than one year of treatment. Patients with

PAH reported during dasatinib treatment were often taking concomitant medicinal products or had co‐morbidities in addition to the underlying malignancy. Improvements in haemodynamic and clinical parameters have been observed in patients with PAH following discontinuation of dasatinib.

QT Prolongation

In the Phase III study in patients with newly diagnosed chronic phase CML, one patient (< 1%) of the ELPIDA‐treated patients had a QTcF > 500 msec after a minimum of 12 months follow‐up (see section 4.4). No additional patients were reported to have QTcF > 500 msec after a minimum of 60 months follow‐up. In 5 Phase II clinical studies in patients with resistance or intolerance to prior imatinib therapy, repeated baseline and on‐treatment ECGs were obtained at pre‐specified time points and read centrally for 865 patients receiving ELPIDA 70 mg twice daily. QT interval was corrected for heart rate by Fridericia's method. At all post‐dose time points on day 8, the mean changes from baseline in QTcF interval were 4 ‐ 6 msec, with associated upper 95% confidence intervals < 7 msec. Of the 2,182 patients with resistance or intolerance to prior imatinib therapy who received ELPIDA in clinical studies, 15 (1%) had QTc prolongation reported as an adverse reaction. Twenty‐one patients (1%) experienced a QTcF > 500 msec (see section 4.4).

Cardiac adverse reactions

Patients with risk factors or a history of cardiac disease should be monitored carefully for signs or symptoms consistent with cardiac dysfunction and should be evaluated and treated appropriately (see section 4.4).

Hepatitis B reactivation

Hepatitis B reactivation has been reported in association with BCR‐ABL TKIs. Some cases resulted in acute hepatic failure or fulminant hepatitis leading to liver transplantation or a fatal outcome (see section 4.4). In the Phase III dose‐optimisation study in patients with chronic phase CML with resistance or intolerance to prior imatinib therapy (median duration of treatment of 30 months), the incidence of pleural effusion and congestive heart failure/cardiac dysfunction was lower in patients treated with ELPIDA 100 mg once daily than in those treated with ELPIDA 70 mg twice daily. Myelosuppression was also reported less frequently in the 100 mg once daily treatment group (see Laboratory test abnormalities below). The median duration of therapy in the 100 mg once daily group was 37 months (range 1‐91 months). Cumulative rates of selected adverse reactions that were reported in the 100 mg once daily recommended starting dose are shown in Table 6a.

a Phase 3 dose optimisation study results reported in recommended starting dose of 100 mg once daily (n=165) population

In the Phase III dose‐optimisation study in patients with advanced phase CML and Ph+ ALL, 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+ ALL. Selected adverse reactions that were reported in the recommended starting dose of 140 mg once daily are shown in Table 6b. A 70 mg twice daily regimen was also studied. The 140 mg once daily regimen showed a comparable efficacy profile to the 70 mg twice daily regimen but a more favourable safety profile.

a Phase 3 dose optimisation study results reported at the recommended starting dose of 140 mg once daily (n=304) population at 2 year final study follow up.

b Includes ventricular dysfunction, cardiac failure, cardiac failure congestive, cardiomyopathy, congestive cardiomyopathy, diastolic dysfunction, ejection fraction decreased, and ventricular failure.

Laboratory test abnormalities

Haematology

In the Phase III newly diagnosed chronic phase CML study, the following grade 3 or 4 laboratory abnormalities were reported after a minimum of 12 months follow‐up in patients taking ELPIDA: neutropaenia (21%), thrombocytopaenia (19%), and anaemia (10%). After a minimum of 60 months follow‐up, the cumulative rates of neutropaenia, thrombocytopaenia, and anaemia were 29%, 22% and 13%, respectively.

In ELPIDA‐treated patients with newly diagnosed chronic phase CML who experienced grade 3 or 4 myelosuppression, recovery generally occurred following brief dose interruptions and/or reductions and permanent discontinuation of treatment occurred in 1.6% of patients after a minimum of 12 months follow‐up. After a minimum of 60 months follow‐up the cumulative rate of permanent discontinuation due to grade 3 or 4 myelosuppression was 2.3%. In patients with CML with resistance or intolerance to prior imatinib therapy, cytopaenias (thrombocytopaenia, neutropaenia, and anaemia) were a consistent finding. However, the occurrence of cytopaenias was also clearly dependent on the stage of the disease. The frequency of grade 3 and 4 haematological abnormalities is presented in Table 7.

a Phase 3 dose optimisation study results reported at 2 year study follow up.

b CA180‐034 study results in recommended starting dose of 100 mg once daily.

c CA180‐035 study results in recommended starting dose of 140 mg once daily. CTC grades: neutropaenia (Grade 3 ≥ 0.5– < 1.0   109/l, Grade 4 < 0.5   109/l); thrombocytopaenia (Grade 3 ≥ 25 – < 50   109/l, Grade 4 < 25   109/l); anaemia (haemoglobin Grade 3 ≥ 65 – < 80 g/l, Grade 4 < 65 g/l).

Cumulative grade 3 or 4 cytopaenias among patients treated with 100 mg once daily were similar at 2 and 5 years including: neutropaenia (35% vs. 36%), thrombocytopaenia (23% vs. 24%) and anaemia (13% vs. 13%).

In patients who experienced grade 3 or 4 myelosuppression, recovery generally occurred following brief dose interruptions and/or reductions and permanent discontinuation of treatment occurred in 5% of patients. Most patients continued treatment without further evidence of myelosuppression.

Biochemistry

In the newly diagnosed chronic phase CML study, grade 3 or 4 hypophosphataemia was reported in 4% of ELPIDA‐treated patients, and grade 3 or 4 elevations of transaminases, creatinine, and bilirubin were reported in ≤ 1% of patients after a minimum of 12 months follow‐up. After a minimum of 60 months follow‐up the cumulative rate of grade 3 or 4 hypophosphataemia was 7%, grade 3 or 4 elevations of creatinine and bilirubin was 1% and grade 3 or 4 elevations of transaminases remained 1%. There were no discontinuations of ELPIDA therapy due to these biochemical laboratory parameters.

2 year follow‐up

Grade 3 or 4 elevations of transaminases or bilirubin were reported in 1% of patients with chronic phase CML (resistant or intolerant to imatinib), but elevations were reported with an increased frequency of 1 to 7% of patients with advanced phase CML and Ph+ ALL. It was usually managed with dose reduction or interruption. In the Phase III dose‐optimisation study in chronic phase CML, grade 3 or 4 elevations of transaminases or bilirubin were reported in ≤ 1% of patients with similar low incidence in the four treatment groups. In the Phase III doseoptimisation study in advanced phase CML and Ph+ALL, grade 3 or 4 elevations of transaminases or bilirubin were reported in 1% to 5% of patients across treatment groups.

Approximately 5% of the ELPIDA‐treated patients who had normal baseline levels experienced grade 3 or 4 transient hypocalcaemia at some time during the course of the study. In general, there was no association of decreased calcium with clinical symptoms. Patients developing grade 3 or 4 hypocalcaemia often had recovery with oral calcium supplementation. Grade 3 or 4 hypocalcaemia, hypokalaemia, and hypophosphataemia were reported in patients with all phases of CML but were reported with an increased frequency in patients with myeloid or lymphoid blast phase CML and Ph+ ALL. Grade 3 or 4 elevations in creatinine were reported in < 1% of patients with chronic phase CML and were reported with an increased frequency of 1 to 4% of patients with advanced phase CML.

Special population

While the safety profile of ELPIDA in elderly was similar to that in the younger population, patients aged 65 years and older are more likely to experience the commonly reported adverse reactions such as fatigue, pleural effusion, dyspnoea, cough, lower gastrointestinal haemorrhage, and appetite disturbance and more likely to experience less frequently reported adverse reactions such as abdominal distention, dizziness, pericardial effusion, congestive heart failure, and weight decrease and should be monitored closely (see section 4.4).

Paediatric population

The safety profile in paediatric patients was comparable to the safety profile in adults. Frequency, type and severity of adverse reactions in children are expected to be the same as in adults.

In the paediatric CML studies, the rate of laboratory anomalies was consistent with the known profile for laboratory parameters in adults.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important.

It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via:

• Saudi Arabia

The National Pharmacovigilance and Drug Safety Centrer (NPC)

Fax: + (966‐11) 2057662

Toll free: 800‐249‐0000

Phone No.: + (966‐11) 2038222, Exts: 2317‐2356‐2353‐2354‐2334‐2340.

e‐mail: npc.drug@sfda.gov.sa

Website: www.sfda.gov.sa/npc

•  Other GCC States

Please contact the relevant competent authority

Experience with overdose of ELPIDA in clinical studies is limited to isolated cases. The highest overdose of 280 mg per day for one week was reported in two patients and both developed a significant decrease in platelet counts. Since dasatinib is associated with grade 3 or 4 myelosuppression (see section 4.4), patients who ingest more than the recommended dose should be closely monitored for myelosuppression and given appropriate supportive treatment.

Pharmacotherapeutic group: antineoplastic agents, protein kinase inhibitors, ATC code: L01XE06

Pharmacodynamics

Dasatinib inhibits the activity of the BCR‐ABL kinase and SRC family kinases along with a number of other selected oncogenic kinases including c‐KIT, ephrin (EPH) receptor kinases, and PDGFβ receptor. Dasatinib is a potent, subnanomolar inhibitor of the BCR‐ABL kinase with potency at concentration of 0.6‐0.8 nM. It binds to both the inactive and active conformations of the BCRABL enzyme.

Mechanism of action

In vitro, dasatinib is active in leukaemic cell lines representing variants of imatinib‐sensitive and resistant disease. These non‐clinical studies show that dasatinib can overcome imatinib resistance resulting from BCR‐ABL overexpression, BCR‐ABL kinase domain mutations, activation of alternate signalling pathways involving the SRC family kinases (LYN, HCK), and multidrug resistance gene overexpression. Additionally, dasatinib inhibits SRC family kinases at

subnanomolar concentrations.

In vivo, in separate experiments using murine models of CML, dasatinib prevented the progression of chronic CML to blast phase and prolonged the survival of mice bearing patientderived CML cell lines grown at various sites, including the central nervous system.

Clinical efficacy and safety

In the Phase I study, haematologic and cytogenetic responses were observed in all phases of CML and in Ph+ ALL in the first 84 patients treated and followed for up to 27 months. Responses were durable across all phases of CML and Ph+ ALL.

Four single‐arm, uncontrolled, open‐label Phase II clinical studies were conducted to determine the safety and efficacy of dasatinib in patients with CML in chronic, accelerated, or myeloid blast phase, who were either resistant or intolerant to imatinib. One randomised non‐comparative study was conducted in chronic phase patients who failed initial treatment with 400 or 600 mg imatinib. The starting dose was 70 mg dasatinib twice daily. Dose modifications were allowed for improving activity or management of toxicity (see section 4.2). Two randomised, open‐label Phase III studies were conducted to evaluate the efficacy of dasatinib administered once daily compared with dasatinib administered twice daily. In addition, one open‐label, randomised, comparative Phase III study was conducted in adult patients with newly diagnosed chronic phase CML.

The efficacy of dasatinib is based on haematological and cytogenetic response rates. Durability of response and estimated survival rates provide additional evidence of dasatinib clinical benefit.

A total of 2,712 patients were evaluated in clinical studies; of these 23% were ≥ 65 years of age and 5% were ≥ 75 years of age. 

Chronic phase CML ‐ Newly diagnosed

An international open‐label, multicentre, randomised, comparative Phase III study was conducted in adult patients with newly diagnosed chronic phase CML. Patients were randomised to receive either ELPIDA 100 mg once daily or imatinib 400 mg once daily. The primary endpoint was the rate of confirmed complete cytogenetic response (cCCyR) within 12 months. Secondary endpoints included time in cCCyR (measure of durability of response), time to cCCyR, major molecular response (MMR) rate, time to MMR, progression free survival (PFS) and overall survival (OS). Other relevant efficacy results included CCyR and complete molecular response (CMR) rates. The study is ongoing.

A total of 519 patients were randomised to a treatment group: 259 to ELPIDA and 260 to imatinib. Baseline characteristics were well balanced between the two treatment groups with respect to age (median age was 46 years for the ELPIDA group and 49 years for the imatinib group with 10% and 11% of patients 65 years of age or older, respectively), gender (women 44% and 37%, respectively), and race (Caucasian 51% and 55%; Asian 42% and 37%, respectively). At baseline, the distribution of Hasford Scores was similar in the ELPIDA and imatinib treatment groups (low risk: 33% and 34%; intermediate risk 48% and 47%; high risk: 19% and 19%, respectively).

With a minimum of 12 months follow‐up, 85% of patients randomised to the ELPIDA group and 81% of patients randomised to the imatinib group were still receiving first‐line treatment. Discontinuation within 12 months due to disease progression occurred in 3% of ELPIDA‐treated patients and 5% of imatinib‐treated patients. With a minimum of 60 months follow‐up, 60% of patients randomised to the ELPIDA group and 63% of patients randomised to the imatinib group were still receiving first‐line treatment. Discontinuation within 60 months due to disease progression occurred in 11% of ELPIDA‐treated patients and 14% of imatinib‐treated patients.

Efficacy results are presented in Table 8. A statistically significantly greater proportion of patients in the ELPIDA group achieved a cCCyR compared with patients in the imatinib group within the first 12 months of treatment. Efficacy of ELPIDA was consistently demonstrated across different subgroups, including age, gender, and baseline Hasford score.

a Confirmed complete cytogenetic response (cCCyR) is defined as a response noted on two consecutive occasions (at least 28 days apart).

b Complete cytogenetic response (CCyR) is based on a single bone marrow cytogeneticevaluation.

c Major molecular response (at any time) was defined as BCR ABL ratios ≤ 0.1% by RQ PCR in peripheral blood samples standardised on the International scale. These are cumulative rates representing minimum follow up for the timeframe specified.

*Adjusted for Hasford Score and indicated statistical significance at a pre‐defined nominal level of significance.

CI = confidence interval After 60 months of follow‐up, median time to cCCyR was 3.1 months in the ELPIDA group and 5.8 months in the imatinib group in patients with a confirmed CCyR. Median time to MMR after 60 months of follow‐up was 9.3 months in the ELPIDA group and 15.0 months in the imatinib group in patients with a MMR. These results are consistent with those seen at 12, 24 and 36 months.

The time to MMR is displayed graphically in Figure 1. The time to MMR was consistently shorter in dasatinib‐treated patients compared with imatinib‐treated patients.

Figure 1: Kaplan‐Meier estimate of time to major molecular response (MMR)

The rates of cCCyR in the ELPIDA and imatinib treatment groups, respectively, within 3 months (54% and 30%), 6 months (70% and 56%), 9 months (75% and 63%), 24 months (80% and 74%), 36 months (83% and 77%), 48 months (83% and 79%) and 60 months (83% and 79%) were consistent with the primary endpoint. The rates of MMR in the ELPIDA and imatinib treatment groups, respectively, within 3 months (8% and 0.4%), 6 months (27% and 8%), 9 months (39% and 18%), 12 months (46% and 28%), 24 months (64% and 46%) , 36 months (67% and 55%), 48 months (73% and 60%) and 60 months (76% and 64%)were also consistent with the primary endpoint.

MMR rates by specific time point are displayed graphically in Figure 2. Rates of MMR were consistently higher in dasatinib‐treated patients compared with imatinib‐treated patients.

Figure 2: MMR rates over time ‐ all randomised patients in a phase 3 study of newlydiagnosed patients with chronic phase CML

The proportion of patients achieving BCR‐ABL ratio of ≤0.01% (4‐log reduction) at any time was higher in the ELPIDA group compared to the imatinib group (54.1% versus 45%). The proportion of patients achieving BCR‐ABL ratio of ≤0.0032% (4.5‐log reduction) at any time was higher in the ELPIDA group compared to the imatinib group (44% versus 34%). MR4.5 rates over time are displayed graphically in Figure 3. Rates of MR4.5 over time were consistently higher in dasatinib‐treated patients compared with imatinib‐treated patients.

Figure 3: MR4.5 rates over time ‐ all randomised patients in a phase 3 study of newly

diagnosed patients with chronic phase CML

The rate of MMR at any time in each risk group determined by Hasford score was higher in theELPIDA group compared with the imatinib group (low risk: 90% and 69%; intermediate risk: 71% and 65%; high risk: 67% and 54%, respectively). In an additional analysis, more dasatinib‐treated patients (84%) achieved early molecular response (defined as BCR‐ABL levels ≤ 10% at 3 months) compared with imatinib‐treated patients (64%). Patients achieving early molecular response had a lower risk of transformation, higher rate of progression‐free survival (PFS) and higher rate of overall survival (OS), as shown in Table 9.

The OS rate by specific time point is displayed graphically in Figure 4. Rate of OS was consistently higher in dasatinib treated patients who achieved BCR‐ABL level ≤ 10% at 3 months than those who did not.

Figure 4: Landmark plot for overall survival for dasatinib by BCR‐ABL level (≤ 10% or > 10%)

at 3 months in a phase 3 study of newly diagnosed patients with chronic phase CML

Disease progression was defined as increasing white blood cells despite appropriate therapeutic management, loss of CHR, partial CyR or CCyR, progression to accelerated phase or blast phase, or death. The estimated 60‐month PFS rate was 88.9% (CI: 84% ‐ 92.4%) for both the dasatinib and imatinib treatment groups. At 60 months, transformation to accelerated or blast phase occurred in fewer dasatinib‐treated patients (n=8; 3%) compared with imatinib‐treated patients (n=15; 5.8%). The estimated 60‐month survival rates for dasatinib and imatinib‐treated patients were 90.9% (CI: 86.6% ‐ 93.8%) and 89.6% (CI: 85.2% ‐ 92.8%), respectively. There was no difference in OS (HR 1.01, 95% CI: 0.58‐1.73, p= 0.9800) and PFS (HR 1.00, 95% CI: 0.58‐1.72, p = 0.9998) between dasatinib and imatinib. In patients who report disease progression or discontinue dasatinib or imatinib therapy, BCRABL sequencing was performed on blood samples from patients where these are available. Similar rates of mutation were observed in both the treatment arms. The mutations detected among the dasatinib‐treated patients were T315I, F317I/L and V299L. A different spectrum of mutation was detected in the imatinib treatment arm. Dasatinib does not appear to be active against the T315I mutation, based on in vitro data.

Chronic phase CML ‐ Resistance or intolerance to prior imatinib therapy

Two clinical studies were conducted in patients resistant or intolerant to imatinib; the primary efficacy endpoint in these studies was Major Cytogenetic Response (MCyR).

Study 1

An open‐label, randomised, non‐comparative multicentre study was conducted in patients who failed initial treatment with 400 or 600 mg imatinib. They were randomised (2:1) to either dasatinib (70 mg twice daily) or imatinib (400 mg twice daily). Crossover to the alternative treatment arm was allowed if patients showed evidence of disease progression or intolerance that could not be managed by dose modification. The primary endpoint was MCyR at 12 weeks.

Results are available for 150 patients: 101 were randomised to dasatinib and 49 to imatinib (all imatinib‐resistant). The median time from diagnosis to randomisation was 64 months in the dasatinib group and 52 months in the imatinib group. All patients were extensively pretreated.

Prior complete haematologic response (CHR) to imatinib was achieved in 93% of the overall patient population. A prior MCyR to imatinib was achieved in 28% and 29% of the patients in the dasatinib and imatinib arms, respectively. Median duration of treatment was 23 months for dasatinib (with 44% of patients treated for > 24 months to date) and 3 months for imatinib (with 10% of patients treated for > 24 months to date). Ninety‐three percent of patients in the dasatinib arm and 82% of patients in the imatinib arm achieved a CHR prior to crossover. At 3 months, a MCyR occurred more often in the dasatinib arm (36%) than in the imatinib arm (29%). Notably, 22% of patients reported a complete cytogenetic response (CCyR) in the dasatinib arm while only 8% achieved a CCyR in the imatinib arm. With longer treatment and follow‐up (median of 24 months), MCyR was achieved in 53% of the dasatinib‐treated patients (CCyR in 44%) and 33% of the imatinib‐treated patients (CCyR in 18%) prior tocrossover. Among patients who had received imatinib 400 mg prior to study entry, MCyR was achieved in 61% of patients in the dasatinib arm and 50% in the imatinib arm.

Based on the Kaplan‐Meier estimates, the proportion of patients who maintained MCyR for 1 year was 92% (95% CI: [85%‐100%]) for dasatinib (CCyR 97%, 95% CI: [92%‐100%]) and 74% (95% CI: [49%‐100%]) for imatinib (CCyR 100%). The proportion of patients who maintained MCyR for 18 months was 90% (95% CI: [82%‐98%]) for dasatinib (CCyR 94%, 95% CI: [87%‐100%]) and 74% (95% CI: [49%‐100%]) for imatinib (CCyR 100%).

Based on the Kaplan‐Meier estimates, the proportion of patients who had progression‐free survival (PFS) for 1 year was 91% (95% CI: [85%‐97%]) for dasatinib and 73% (95% CI: [54%‐91%]) for imatinib. The proportion of patients who had PFS at 2 years was 86% (95% CI: [78%‐93%]) for dasatinib and 65% (95% CI: [43%‐87%]) for imatinib. A total of 43% of the patients in the dasatinib arm, and 82% in the imatinib arm had treatment failure, defined as disease progression or cross‐over to the other treatment (lack of response, intolerance of study medicinal product, etc.).

The rate of major molecular response (defined as BCR‐ABL/control transcripts ≤ 0.1% by RQ‐PCR in peripheral blood samples) prior to crossover was 29% for dasatinib and 12% for imatinib.

Study 2

An open‐label, single‐arm, multicentre study was conducted in patients resistant or intolerant to imatinib (i.e. patients who experienced significant toxicity during treatment with imatinib that precluded further treatment). A total of 387 patients received dasatinib 70 mg twice daily (288 resistant and 99 intolerant).

The median time from diagnosis to start of treatment was 61 months. The majority of the patients (53%) had received prior imatinib treatment for more than 3 years. Most resistant patients (72%) had received > 600 mg imatinib. In addition to imatinib, 35% of patients had received prior cytotoxic chemotherapy, 65% had received prior interferon, and 10% had received a prior stem cell transplant. Thirty‐eight percent of patients had baseline mutations known to confer imatinib resistance. Median duration of treatment on dasatinib was 24 months with 51% of patients treated for > 24 months to date. Efficacy results are reported in Table 10. MCyR was achieved in 55% of imatinib‐resistant patients and 82% of imatinib‐intolerant patients. With a minimum of 24 months follow‐up, 21 of the 240 patients who had achieved a MCyR had progressed and the median duration of MCyR had not been reached.

Based on the Kaplan‐Meier estimates, 95% (95% CI: [92%‐98%]) of the patients maintained MCyR for 1 year and 88% (95% CI: [83%‐93%]) maintained MCyR for 2 years. The proportion of patients who maintained CCyR for 1 year was 97% (95% CI: [94%‐99%]) and for 2 years was 90% (95% CI: [86%‐95%]). Forty‐two percent of the imatinib‐resistant patients with no prior MCyR to imatinib (n= 188) achieved a MCyR with dasatinib.

There were 45 different BCR‐ABL mutations in 38% of patients enrolled in this study. Complete haematologic response or MCyR was achieved in patients harbouring a variety of BCR‐ABL mutations associated with imatinib resistance except T315I. The rates of MCyR at 2 years were similar whether patients had any baseline BCR‐ABL mutation, P‐loop mutation, or no mutation (63%, 61% and 62%, respectively). Among imatinib‐resistant patients, the estimated rate of PFS was 88% (95% CI: [84%‐92%]) at 1 year and 75% (95% CI: [69%‐81%]) at 2 years. Among imatinib‐intolerant patients, the estimated rate of PFS was 98% (95% CI: [95%‐100%]) at 1 year and 94% (95% CI: [88%‐99%]) at 2 years. The rate of major molecular response at 24 months was 45% (35% for imatinib‐resistant patients and 74% for imatinib‐intolerant patients).

Accelerated phase CML

An open‐label, single‐arm, multicentre study was conducted in patients intolerant or resistant to imatinib. A total of 174 patients received dasatinib 70 mg twice daily (161 resistant and 13 intolerant to imatinib). The median time from diagnosis to start of treatment was 82 months. Median duration of treatment on dasatinib was 14 months with 31% of patients treated for > 24 months to date. The rate of major molecular response (assessed in 41 patients with a CCyR) was 46% at 24 months. Further efficacy results are reported in Table 10.

Myeloid blast phase CML

An open‐label, single‐arm, multicentre study was conducted in patients intolerant or resistant to imatinib. A total of 109 patients received dasatinib 70 mg twice daily (99 resistant and 10 intolerant to imatinib). The median time from diagnosis to start of treatment was 48 months.

Median duration of treatment on dasatinib was 3.5 months with 12% of patients treated for > 24 months to date. The rate of major molecular response (assessed in 19 patients with a CCyR) was 68% at 24 months. Further efficacy results are reported in Table 10.

Lymphoid blast phase CML and Ph+ ALL

An open‐label, single‐arm, multicentre study was conducted in patients with lymphoid blast phase CML or Ph+ ALL who were resistant or intolerant to prior imatinib therapy. A total of 48 patients with lymphoid blast CML received dasatinib 70 mg twice daily (42 resistant and 6 intolerant to imatinib). The median time from diagnosis to start of treatment was 28 months. Median duration of treatment on dasatinib was 3 months with 2% treated for > 24 months to date. The rate of major molecular response (all 22 treated patients with a CCyR) was 50% at 24 months. In addition, 46 patients with Ph+ ALL received dasatinib 70 mg twice daily (44 resistant and 2 intolerant to imatinib). The median time from diagnosis to start of treatment was 18 months. Median duration of treatment on dasatinib was 3 months with 7% of patients treated for > 24 months to date. The rate of major molecular response (all 25 treated patients with a CCyR) was 52% at 24 months. Further efficacy results are reported in Table 10. Of note, major haematologic responses (MaHR) were achieved quickly (most within 35 days of first dasatinib administration for patients with lymphoid blast CML, and within 55 days for patients with Ph+ ALL).

Data described in this table are from studies using a starting dose of 70 mg twice daily. See section 4.2 for the recommended starting dose.

a Numbers in bold font are the results of primary endpoints.

b Haematologic response criteria (all responses confirmed after 4 weeks): Major haematologic response (MaHR) = complete haematologic response (CHR) + no evidence of leukaemia (NEL).

CHR (chronic CML): WBC ≤ institutional ULN, platelets < 450,000/mm3, no blasts or promyelocytes in peripheral blood, < 5% myelocytes plus metamyelocytes in peripheral blood, basophils in peripheral blood < 20%, and no extramedullary involvement.

CHR (advanced CML/Ph+ ALL): WBC ≤ institutional ULN, ANC ≥ 1,000/mm3, platelets ≥ 100,000/mm3, no blasts or promyelocytes in peripheral blood, bone marrow blasts ≤ 5%, < 5% myelocytes plus metamyelocytes in peripheral blood, basophils in peripheral blood < 20%, and no extramedullary involvement. NEL: same criteria as for CHR but ANC ≥ 500/mm3 and < 1,000/mm3, or platelets ≥ 20,000/mm3 and ≤ 100,000/mm3.

c Cytogenetic response criteria: complete (0% Ph+ metaphases) or partial (> 0%‐35%). MCyR (0%‐35%) combines both complete and partial responses.

n/a = not applicable; CI = confidence interval; ULN = upper limit of normal range. The outcome of patients with bone marrow transplantation after dasatinib treatment has not been fully evaluated.

Phase III clinical studies in patients with CML in chronic, accelerated, or myeloid blast phase, and Ph+ ALL who were resistant or intolerant to imatinib

Two randomised, open‐label studies were conducted to evaluate the efficacy of dasatinib administered once daily compared with dasatinib administered twice daily. Results described below are based on a minimum of 2 years and 7 years follow‐up after the start of dasatinib therapy.

Study 1

In the study in chronic phase CML, the primary endpoint was MCyR in imatinib‐resistant patients. The main secondary endpoint was MCyR by total daily dose level in the imatinibresistant patients. Other secondary endpoints included duration of MCyR, PFS, and overall survival. A total of 670 patients, of whom 497 were imatinib‐resistant, were randomised to the dasatinib 100 mg once daily, 140 mg once daily, 50 mg twice daily, or 70 mg twice daily group. The median duration of treatment for all patients still on therapy with a minimum of 5 years of follow‐up (n=205) was 59 months (range 28‐66 months). Median duration of treatment for all patients at 7 years of follow‐up was 29.8 months (range < 1‐92.9 months). Efficacy was achieved across all dasatinib treatment groups with the once daily schedule demonstrating comparable efficacy (non‐inferiority) to the twice daily schedule on the primary efficacy endpoint (difference in MCyR 1.9%; 95% confidence interval [‐6.8% ‐ 10.6%]); however, the 100 mg once daily regimen demonstrated improved safety and tolerability. Efficacy results are presented in Tables 11 and 12.

a Results reported in recommended starting dose of 100 mg once daily.

b Haematologic response criteria (all responses confirmed after 4 weeks): Complete haematologic response (CHR) (chronic CML): WBC ≤ institutional ULN, platelets <450,000/mm3, no blasts or promyelocytes in peripheral blood, <5% myelocytes plus metamyelocytes in peripheral blood, basophils in peripheral blood <20%, and no extramedullary involvement.

c Cytogenetic response criteria: complete (0% Ph+ metaphases) or partial (>0%–35%). MCyR (0%–35%) combines both complete and partial responses.

d Major molecular response criteria: Defined as BCR‐ABL/control transcripts ≤0.1% by RQPCR in peripheral blood samples

a Results reported in recommended starting dose of 100 mg once daily.

b Progression was defined as increasing WBC count, loss of CHR or MCyR, ≥30% increase in Ph+ metaphases, confirmed AP/BP disease or death. PFS was analysed on an intent‐to‐treat principle and patients were followed to events including subsequent therapy. Based on the Kaplan‐Meier estimates, the proportion of patients treated with dasatinib 100 mg once daily who maintained MCyR for 18 months was 93% (95% CI: [88%‐98%]). Efficacy was also assessed in patients who were intolerant to imatinib. In this population of patients who received 100 mg once daily, MCyR was achieved in 77% and CCyR in 67%.

Study 2

In the study in advanced phase CML and Ph+ ALL, the primary endpoint was MaHR. A total of 611 patients were randomised to either the dasatinib 140 mg once daily or 70 mg twice daily group. Median duration of treatment was approximately 6 months (range 0.03‐31 months).

The once daily schedule demonstrated comparable efficacy (non‐inferiority) to the twice daily schedule on the primary efficacy endpoint (difference in MaHR 0.8%; 95% confidence interval [‐ 7.1% ‐ 8.7%]); however, the 140 mg once daily regimen demonstrated improved safety and tolerability.

Response rates are presented in Table 13.

a Results reported in recommended starting dose of 140 mg once daily (see section 4.2).

b Haematologic response criteria (all responses confirmed after 4 weeks): Major haematologic response (MaHR) = complete haematologic response (CHR) + no evidence of leukaemia (NEL).

CHR: WBC ≤ institutional ULN, ANC ≥ 1,000/mm3, platelets ≥ 100,000/mm3, no blasts or promyelocytes in peripheral blood, bone marrow blasts ≤ 5%, < 5% myelocytes plus metamyelocytes in peripheral blood, basophils in peripheral blood < 20%, and no extramedullary involvement.

NEL: same criteria as for CHR but ANC ≥ 500/mm3 and < 1,000/mm3, or platelets ≥ 20,000/mm3 and ≤ 100,000/mm3.

c MCyR combines both complete (0% Ph+ metaphases) and partial (> 0%‐35%) responses. CI = confidence interval; ULN = upper limit of normal range. In patients with accelerated phase CML treated with the 140 mg once daily regimen, the median duration of MaHR and the median overall survival was not reached and the median PFS was 25 months.

In patients with myeloid blast phase CML treated with the 140 mg once daily regimen, the median duration of MaHR was 8 months, the median PFS was 4 months, and the median overall survival was 8 months. In patients with lymphoid blast phase CML treated with the 140 mg once daily regimen, the median duration of MaHR was 5 months, the median PFS was 5 months, and the median overall survival was 11 months.

In patients with Ph+ ALL treated with the 140 mg once daily regimen, the median duration of MaHR was 5 months the median PFS was 4 months, and the median overall survival was 7 months.

Paediatric population

The European Medicines Agency has deferred the obligation to submit the results of studies with ELPIDA in one or more subsets of the paediatric population in Philadelphia chromosome (BCR‐ABL translocation)‐positive acute lymphoblastic leukaemia (see section 4.2 for information on paediatric use).

Paediatric patients with CML

Among 130 patients with chronic phase CML (CML‐CP) treated in two paediatric studies, a Phase I, open‐label, nonrandomized dose‐ranging trial and a Phase II, open‐label, nonrandomized trial, 84 patients (exclusively from the Phase II trial) were newly diagnosed with CML‐CP and 46 patients (17 from the Phase I trial and 29 from the Phase II trial) were resistant or intolerant to previous treatment with imatinib. Ninety‐seven of the 130 paediatric patients with CML‐CP were treated with ELPIDA tablets 60 mg/m2 once daily (maximum dose of 100 mg once daily for patients with high BSA). Patients were treated until disease progression or unacceptable toxicity.

Key efficacy endpoints were: complete cytogenetic response (CCyR), major cytogenetic response (MCyR) and major molecular response (MMR). Results are shown in Table 14.

a Patients from Phase II paediatric study of newly diagnosed CML‐CP receiving oral tablet formulation

b Patients from Phase I and Phase II paediatric studies of imatinib‐resistant or intolerant CML‐CP receiving oral tablet formulation

In the Phase I paediatric study, after a minimum of 7 years of follow‐up among the 17 patients with imatinib‐resistant or intolerant CML‐CP, the median duration of PFS was 53.6 months and the rate of OS was 82.4%.

In the Phase II paediatric study, in patients receiving the tablet formulation, estimated 24‐month PFS rate among the 51 patients with newly diagnosed CML‐CP was 94.0% (82.6, 98.0), and 81.7% (61.4, 92.0) among the 29 patients with imatinib‐resistant/intolerant CML‐CP. After 24 months of follow‐up, OS in newly diagnosed patients was 100%, and 96.6% in imatinib‐resistant or intolerant patients. In the Phase II paediatric study, 1 newly diagnosed patient and 2 imatinib‐resistant or intolerant patients progressed to blast phase CML. There were 33 newly diagnosed paediatric patients with CML‐CP who received ELPIDA powder for oral suspension at a dose of 72 mg/m2. This dose represents 30% lower exposure compared to the recommended dose (see section 5.2. of Summary of Product Characteristics for ELPIDA powder for oral suspension). In these patients, CCyR and MMR were CCyR: 87.9% [95% CI: (71.8‐96.6)] and MMR: 45.5% [95% CI: (28.1‐63.6)] at 12 months.

Among dasatinib‐treated CML‐CP paediatric patients previously exposed to imatinib, the mutations detected at the end of treatment were: T315A, E255K and F317L. However, E255K and F317L were also detected prior to treatment. There were no mutations detected in newly diagnosed CML‐CP patients at the end of treatment.

The pharmacokinetics of dasatinib were evaluated in 229 adult healthy subjects and in 84 patients.

Absorption

Dasatinib is rapidly absorbed in patients following oral administration, with peak concentrations between 0.5‐3 hours. Following oral administration, the increase in the mean exposure (AUC ) is approximately proportional to the dose increment across doses ranging from 25 mg to 120 mg twice daily. The overall mean terminal half‐life of dasatinib is approximately 5‐6 hours in patients.

Data from healthy subjects administered a single 100 mg dose of dasatinib 30 minutes following a high‐fat meal indicated a 14% increase in the mean AUC of dasatinib. A low‐fat meal 30 minutes prior to dasatinib resulted in a 21% increase in the mean AUC of dasatinib. Then observed food effects do not represent clinically relevant changes in exposure.

Distribution

In patients, dasatinib has a large apparent volume of distribution (2,505 l) suggesting that the medicinal product is extensively distributed in the extravascular space. At clinically relevant concentrations of dasatinib, binding to plasma proteins was approximately 96% on the basis of in vitro experiments.

Biotransformation

Dasatinib is extensively metabolised in humans with multiple enzymes involved in the generation of the metabolites. In healthy subjects administered 100 mg of [14C]‐labelled dasatinib, unchanged dasatinib represented 29% of circulating radioactivity in plasma. Plasma concentration and measured in vitro activity indicate that metabolites of dasatinib are unlikely to play a major role in the observed pharmacology of the product. CYP3A4 is a major enzyme responsible for the metabolism of dasatinib.

Elimination

Elimination is predominantly in the faeces, mostly as metabolites. Following a single oral dose of [14C]‐labelled dasatinib, approximately 89% of the dose was eliminated within 10 days, with 4% and 85% of the radioactivity recovered in the urine and faeces, respectively. Unchanged dasatinib accounted for 0.1% and 19% of the dose in urine and faeces, respectively, with the remainder of the dose as metabolites.

Hepatic and renal impairment

The effect of hepatic impairment on the single‐dose pharmacokinetics of dasatinib was assessed in 8 moderately hepatic‐impaired subjects who received a 50 mg dose and 5 severely hepaticimpaired subjects who received a 20 mg dose compared to matched healthy subjects who received a 70 mg dose of dasatinib. The mean Cmax and AUC of dasatinib adjusted for the 70 mg dose were decreased by 47% and 8%, respectively, in subjects with moderate hepatic impairment compared to subjects with normal hepatic function. In severely hepatic‐impaired subjects, the mean Cmax and AUC adjusted for the 70 mg dose were decreased by 43% and 28%, respectively, compared to subjects with normal hepatic function (see sections 4.2 and 4.4). Dasatinib and its metabolites are minimally excreted via the kidney.

Paediatric population

The pharmacokinetics of dasatinib have been evaluated in 104 paediatric patients with leukaemia or solid tumours (72 who received the tablet formulation and 32 who received the powder for oral suspension). Pharmacokinetics of the tablet formulation of dasatinib were evaluated for 72 paediatric patients with relapsed or refractory leukaemia or solid tumours at oral doses ranging from 60 to 120 mg/m2 once daily and 50 to 110 mg/m2 twice daily. Data was pooled across two studies and showed that dasatinib was rapidly absorbed. Mean Tmax was observed between 0.5 and 6 hours and mean half‐life ranged from 2 to 5 hours across all dose levels and age groups. Dasatinib PK showed dose proportionality with a dose‐related increase in exposure observed in paediatric patients. There was no significant difference of dasatinib PK between children and adolescents.

The geometric means of dose‐normalized dasatinib Cmax, AUC (0‐T), and AUC (INF) appeared to be similar between children and adolescents at different dose levels. A PPK model‐based simulation predicted that the body weight tiered dosing recommendation described for the tablet, in section 4.2, is expected to provide similar exposure to a tablet dose of 60 mg/m2. These data should be considered if patients are to switch from tablets to powder for oral suspension or vice versa.

The non‐clinical safety profile of dasatinib was assessed in a battery of in vitro and in vivo studies in mice, rats, monkeys, and rabbits.

The primary toxicities occurred in the gastrointestinal, haematopoietic, and lymphoid systems. Gastrointestinal toxicity was dose‐limiting in rats and monkeys, as the intestine was a consistent target organ. In rats, minimal to mild decreases in erythrocyte parameters were accompanied by bone marrow changes; similar changes occurred in monkeys at a lower incidence. Lymphoid toxicity in rats consisted of lymphoid depletion of the lymph nodes, spleen, and thymus, and decreased lymphoid organ weights. Changes in the gastrointestinal, haematopoietic and lymphoid systems were reversible following cessation of treatment. Renal changes in monkeys treated for up to 9 months were limited to an increase in background kidney mineralisation. Cutaneous haemorrhage was observed in an acute, single‐dose oral study in monkeys but was not observed in repeat‐dose studies in either monkeys or rats. In rats, dasatinib inhibited platelet aggregation in vitro and prolonged cuticle bleeding time in vivo, but did not invoke spontaneous haemorrhage. Dasatinib activity in vitro in hERG and Purkinje fiber assays suggested a potential for prolongation of cardiac ventricular repolarisation (QT interval). However, in an in vivo singledose study in conscious telemetered monkeys, there were no changes in QT interval or ECG wave form. Dasatinib was not mutagenic in in vitro bacterial cell assays (Ames test) and was not genotoxic in an in vivo rat micronucleus study. Dasatinib was clastogenic in vitro to dividing Chinese Hamster Ovary (CHO) cells.

Dasatinib did not affect male or female fertility in a conventional rat fertility and early embryonic development study, but induced embryolethality at dose levels approximating human clinical exposures. In embryofoetal development studies, dasatinib likewise induced embryolethality with associated decreases in litter size in rats, as well as foetal skeletal alterations in both rats and rabbits. These effects occurred at doses that did not produce maternal toxicity, indicating that dasatinib is a selective reproductive toxicant from implantation through the completion of organogenesis.

In mice, dasatinib induced immunosuppression, which was dose‐related and effectively managed by dose reduction and/or changes in dosing schedule. Dasatinib had phototoxic potential in an in vitro neutral red uptake phototoxicity assay in mouse fibroblasts. Dasatinib was considered to be non‐phototoxic in vivo after a single oral administration to female hairless mice at exposures up to 3‐fold the human exposure following administration of the recommended therapeutic dose (based on AUC). In a two‐year carcinogenicity study, rats were administered oral doses of dasatinib at 0.3, 1, and 3 mg/kg/day. The highest dose resulted in a plasma exposure (AUC) level generally equivalent to the human exposure at the recommended range of starting doses from 100 mg to 140 mg daily. A statistically significant increase in the combined incidence of squamous cell carcinomas and papillomas in the uterus and cervix of high‐dose females and of prostate adenoma in low‐dose males was noted. The relevance of the findings from the rat carcinogenicity study for humans is not known.

Core excipients:

• Lactose monohydrate
• Microcrystalline cellulose 101
• Croscarmellose
• Hydroxypropyl cellulose
• Microcrystalline cellulose 102
• Magnesium stearate.   

Coating excipient:

• Opadry ll white 85F 18422

Not applicable.

Do not store above 30ᵒC.

Aluminum/aluminum blisters in carton boxes.

Pack size: 60 tablets.

Elpida is an antineoplastic product. Follow special handling and disposal procedures.

Elpida tablets consist of a core tablet (containing the active drug substance), surrounded by a film coating to prevent exposure of pharmacy and clinical personnel to the active drug substance. However, if tablets are inadvertently crushed or broken, pharmacy and clinical personnel should wear disposable chemotherapy gloves. Personnel who are pregnant should avoid exposure to crushed or broken tablets.