SPRYCEL Film-coated tablet Ref.[8962] Active ingredients: Dasatinib

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 adult patients with advanced phase CML or Ph+ ALL treated with dasatinib as monotherapy, complete blood counts (CBCs) should be performed weekly for the first 2 months, and then monthly thereafter, or as clinically indicated. In adult and paediatric 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. In paediatric patients with Ph+ ALL treated with dasatinib in combination with chemotherapy, CBCs should be performed prior to the start of each block of chemotherapy and as clinically indicated. During the consolidation blocks of chemotherapy, CBCs should be performed every 2 days until recovery (see sections 4.2 and 4.8). Myelosuppression is generally reversible and usually managed by withholding dasatinib temporarily or by dose reduction.

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 SPRYCEL (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 SPRYCEL 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 SPRYCEL treated patients with chronic phase CML, severe fluid retention occurred in 32 patients (6%) receiving SPRYCEL at the recommended dose (n=548). In clinical studies in patients with advanced phase CML or Ph+ ALL receiving SPRYCEL 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 imatinib-treated 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 dasatinib-treated 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, 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.

Thrombotic microangiopathy (TMA)

BCR-ABL tyrosine kinase inhibitors have been associated with thrombotic microangiopathy (TMA), including individual case reports for SPRYCEL (see section 4.8). If laboratory or clinical findings associated with TMA occur in a patient receiving SPRYCEL, treatment with SPRYCEL should be discontinued and thorough evaluation for TMA, including ADAMTS13 activity and anti- ADAMTS13-antibody determination, should be completed. If anti-ADAMTS13-antibody is elevated in conjunction with low ADAMTS13 activity, treatment with SPRYCEL should not be resumed.

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 SPRYCEL. 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 treatment with SPRYCEL 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 SPRYCEL in imatinib-resistant/intolerant Ph+ CML-CP paediatric patients and treatment-naive Ph+ CML-CP 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 long-term follow-up.

In paediatric trials of SPRYCEL in combination with chemotherapy in newly diagnosed Ph+ ALL paediatric patients after a maximum of 2 years of treatment, treatment-related adverse events associated with bone growth and development were reported in 1 (0.6%) patient. This case was a Grade 1 osteopenia.

Excipients

Lactose

This medicinal product contains lactose monohydrate. Patients with rare hereditary problems of galactose intolerance, total lactase deficiency or glucose-galactose malabsorption should not take this medicinal product.

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 (see section 4.2).

At clinically relevant concentrations, binding of dasatinib to plasma proteins is approximately 96% on the basis of in vitro experiments. 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. Concomitant use of dexamethasone, a weak CYP3A4 inducer, with dasatinib is allowed; dasatinib AUC is predicted to decrease approximately 25% with concomitant use of dexamethasone, which is not likely to be clinically meaningful.

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 SPRYCEL reduced dasatinib exposure by 61%. In a study of 14 healthy subjects, administration of a single 100-mg dose of SPRYCEL 22 hours following a 4-day, 40-mg omeprazole dose at steady state reduced the AUC of dasatinib by 43% and the C_max of dasatinib by 42%. The use of antacids should be considered in place of H₂ antagonists or proton pump inhibitors in patients receiving SPRYCEL 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 SPRYCEL reduced the AUC of a single dose of SPRYCEL by 55% and the C_max by 58%. However, when antacids were administered 2 hours prior to a single dose of SPRYCEL, 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 SPRYCEL (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 C_max 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). SPRYCEL should not be used during pregnancy unless the clinical condition of the woman requires treatment with dasatinib. If SPRYCEL 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 SPRYCEL.

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 SPRYCEL on fertility, and this counseling may include consideration of semen deposition.

SPRYCEL 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 SPRYCEL as single-agent therapy 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 29 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 to 93.2 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 SPRYCEL-treated paediatric patients, the median duration of therapy was 42.3 months (range 0.1 to 99.6 months).

The majority of SPRYCEL-treated patients experienced adverse reactions at some time. In the overall population of 2,712 SPRYCEL-treated adult subjects, 520 (19%) experienced adverse reactions leading to treatment discontinuation.

The overall safety profile of SPRYCEL in the paediatric Ph+ CML-CP 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 SPRYCEL-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 treated with SPRYCEL used as single-agent therapy in 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.

Table 5. Tabulated summary of adverse reactions:

^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 SPRYCEL or to concomitant medicinal product.
^g Musculoskeletal pain reported during or after discontinuing treatment.
^h Frequency reported as common in paediatric studies.
ⁱ Gravitational oedema, localised oedema, oedema peripheral.
^j Conjunctival oedema, eye oedema, eye swelling, eyelid oedema, face oedema, lip oedema, macular oedema, oedema mouth, orbital oedema, periorbital oedema, swelling face.
^k Fluid overload, fluid retention, gastrointestinal oedema, generalised oedema, peripheral swelling, oedema, oedema due to cardiac disease, perinephric effusion, post procedural oedema, visceral oedema.
^l 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 SPRYCEL 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 SPRYCEL (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 dasatinib-related 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 SPRYCEL 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 dasatinib-treated 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 SPRYCEL-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 SPRYCEL 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 SPRYCEL 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 SPRYCEL 100 mg once daily than in those treated with SPRYCEL 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.

Table 6a. Selected adverse reactions reported in a phase 3 dose optimisation study (imatinib intolerant or resistant chronic phase CML)^a:

^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.

Table 6b. Selected adverse reactions reported in phase III dose-optimisation study: Advanced phase CML and Ph+ ALL^a:

^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.

In addition, there were two studies in a total of 161 paediatric patients with Ph+ ALL in which SPRYCEL was administered in combination with chemotherapy. In the pivotal study, 106 paediatric patients received SPRYCEL in combination with chemotherapy on a continuous dosing regimen. In a supportive study, of 55 paediatric patients, 35 received SPRYCEL in combination with chemotherapy on a discontinuous dosing regimen (two weeks on treatment followed by one to two weeks off) and 20 received SPRYCEL in combination with chemotherapy on a continuous dosing regimen. Among the 126 Ph+ ALL paediatric patients treated with SPRYCEL on a continuous dosing regimen, the median duration of therapy was 23.6 months (range 1.4 to 33 months).

Of the 126 Ph+ ALL paediatric patients on a continuous dosing regimen, 2 (1.6%) experienced adverse reactions leading to treatment discontinuation. Adverse reactions reported in these two paediatric studies at a frequency of ≥10% in patients on a continuous dosing regimen are shown in Table 7. Of note, pleural effusion was reported in 7 (5.6%) patients in this group, and is therefore not included in the table.

Table 7. Adverse reactions reported in ≥10% of paediatric patients with Ph+ ALL treated with SPRYCEL on a continuous dosing regimen in combination with chemotherapy (N=126)^a:

^a In the pivotal study, among 106 total patients, 24 patients received the powder for oral suspension at least once, 8 of whom received the powder for oral suspension formulation exclusively

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 SPRYCEL: 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 SPRYCEL-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 8.

Table 8. CTC grades ¾ haematological laboratory abnormalities in clinical studies in patients with resistance or intolerance to prior imatinib therapy^a:

^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 SPRYCEL-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 SPRYCEL 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 dose-optimisation 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 SPRYCEL-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.

Paediatric population

The safety profile of SPRYCEL administered as single-agent therapy in paediatric patients with Ph+ CML-CP was comparable to the safety profile in adults. The safety profile of SPRYCEL administered in combination with chemotherapy in paediatric patients with Ph+ ALL was consistent with the known safety profile of SPRYCEL in adults and the expected effects of chemotherapy, with the exception of a lower pleural effusion rate in paediatric patients as compared to adults.

In the paediatric CML studies, the rates of laboratory abnormalities were consistent with the known profile for laboratory parameters in adults.

In the paediatric ALL studies, the rates of laboratory abnormalities were consistent with the known profile for laboratory parameters in adults, within the context of an acute leukaemia patient receiving a background chemotherapy regimen.

Special population

While the safety profile of SPRYCEL 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).

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 the national reporting system listed in Appendix V.

Not applicable.