Adverse reactions : תופעות לוואי

4.8   Undesirable effects

Summary of the safety profile
The data described below reflect the exposure to SPRYCEL at all doses tested in clinical studies (N=2,712) , including 324 patients with newly diagnosed chronic phase CML and 2,388 patients with imatinib resistant or intolerant chronic or advanced phase CML or Ph+ ALL. In the 2,712 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 patients with chronic phase CML was 29 months (range 0 to 92.9 months). The median duration of therapy in 1,094 patients with advanced phase CML or Ph+ ALL, was 6.2 months (range 0 to 93.2 months).

The majority of SPRYCEL-treated patients experienced adverse reactions at some time. In the overall population of 2,712 SPRYCEL treated subjects, 520 (19%) 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 2). 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 2:     Tabulated summary of adverse reactions
Infections and infestations
Very common        infection (including bacterial, viral, fungal, non-specified) Common             pneumonia (including bacterial, viral, and fungal), upper respiratory tract infection/inflammation, herpes virus infection, (including cytomegalovirus - CMV), enterocolitis infection, sepsis (including uncommon cases with fatal outcomes)
Not known          hepatitis B reactivation
Blood and lymphatic system disorders
Very Common        myelosuppression (including anaemia, neutropaenia, thrombocytopaenia) Common             febrile neutropaenia
Uncommon           lymphadenopathy, lymphopaenia
Rare               aplasia pure red cell
Immune system disorders
Uncommon           hypersensitivity (including erythema nodosum)
Rare               anaphylactic shock
Endocrine disorders
Uncommon           Hypothyroidism
Rare               hyperthyroidism, thyroiditis
Metabolism and nutrition disorders
Common             appetite disturbances a, hyperuricaemia
Uncommon           tumour lysis syndrome, dehydration, hypoalbuminemia, hypercholesterolemia Rare               diabetes mellitus
Psychiatric disorders
Common             depression, insomnia
Uncommon           anxiety, confusional state, affect lability, libido decreased Nervous system disorders
Very common        Headache
Common             neuropathy (including peripheral neuropathy), dizziness, dysgeusia, somnolence
Uncommon           CNS bleeding*b, syncope, tremor, amnesia, balance disorder Rare               cerebrovascular accident, transient ischaemic attack, convulsion, optic neuritis, VIIth nerve paralysis, dementia, ataxia
Eye disorders
Common             visual disorder (including visual disturbance, vision blurred, and visual acuity reduced), dry eye
Uncommon           visual impairment, conjunctivitis, photophobia, lacrimation increased Ear and labyrinth disorders
Common             Tinnitus
Uncommon           hearing loss, vertigo
Cardiac disorders
Common             congestive heart failure/cardiac dysfunction*c, pericardial effusion*, arrhythmia (including tachycardia), palpitations
Uncommon          myocardial infarction (including fatal outcome)*, electrocardiogram QT prolonged*, pericarditis, ventricular arrhythmia (including ventricular tachycardia), angina pectoris, cardiomegaly, electrocardiogram T wave abnormal, troponin increased
Rare              cor pulmonale, myocarditis, acute coronary syndrome, cardiac arrest, electrocardiogram PR prolongation, coronary artery disease, pleuropericarditis Not known         atrial fibrillation/atrial flutter
Vascular disorders
Very common       haemorrhage*d
Common            hypertension, flushing
Uncommon          hypotension, thrombophlebitis, thrombosis
Rare              deep vein thrombosis, embolism, livedo reticularis
Not Known         thrombotic microangiopathy
Respiratory, thoracic and mediastinal disorders
Very common       pleural effusion*, dyspnoea
Common            pulmonary oedema*, pulmonary hypertension*, lung infiltration, pneumonitis, cough
Uncommon          pulmonary arterial hypertension, bronchospasm, asthma, chylothorax* Rare              pulmonary embolism, acute respiratory distress syndrome Not known         interstitial lung disease
Gastrointestinal disorders
Very common       diarrhoea, vomiting, nausea, abdominal pain
Common            gastrointestinal bleeding*, colitis (including neutropaenic colitis), gastritis, mucosal inflammation (including mucositis/stomatitis), dyspepsia, abdominal distension, constipation, oral soft tissue disorder
Uncommon          pancreatitis (including acute pancreatitis), upper gastrointestinal ulcer, oesophagitis, ascites*, anal fissure, dysphagia, gastroesophageal reflux disease Rare              protein-losing gastroenteropathy, ileus, anal fistula Not known         fatal gastrointestinal haemorrhage*
Hepatobiliary disorders
Uncommon          hepatitis, cholecystitis, cholestasis
Skin and subcutaneous tissue disorders
Very common       skin rashe
Common            alopecia, dermatitis (including eczema), pruritus, acne, dry skin, urticaria, hyperhidrosis
Uncommon          neutrophilic dermatosis, photosensitivity, pigmentation disorder, panniculitis, skin ulcer, bullous conditions, nail disorder, palmar-plantar erythrodysesthesia syndrome, hair disorder
Rare              leukocytoclastic vasculitis, skin fibrosis
Not known         Stevens-Johnson syndromef
Musculoskeletal and connective tissue disorders
Very common       musculoskeletal paing
Common            arthralgia, myalgia, muscular weakness, musculoskeletal stiffness, muscle spasm
Uncommon          rhabdomyolysis, osteonecrosis, muscle inflammation, tendonitis, arthritis Renal and urinary disorders
Uncommon          renal impairment (including renal failure), urinary frequency, proteinuria Not known         nephrotic syndrome
Pregnancy, puerperium and perinatal conditions
Rare              Abortion
Reproductive system and breast disorders
Uncommon          gynecomastia, menstrual disorder
General disorders and administration site conditions
Very common       peripheral oedemah, fatigue, pyrexia, face oedemai
Common            asthenia, pain, chest pain, generalised oedema*j, chills Uncommon          malaise, other superficial oedemak
Rare              gait disturbance
Investigations
Common            weight decreased, weight increased
Uncommon          blood creatine phosphokinase increased, gamma-glutamyltransferase increased Injury, poisoning, and procedural complications
Common            Contusion 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
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.
j
Fluid overload, fluid retention, gastrointestinal oedema, generalised oedema, 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 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.
Cases of chylothorax have been reported in patients presenting with pleural effusion. Some cases of chylothorax resolved upon dasatinib discontinuation, interruption, or dose reduction, but most cases also required additional treatment.

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 3a.



Table 3a:     Selected adverse reactions reported in a phase 3 dose optimisation study (imatinib intolerant or resistant chronic phase CML)a
Minimum of 2 years        Minimum of 5 years         Minimum of 7 years follow up                follow up                  follow up
All                                                             Grade Grade 3/4 All grades      Grade 3/4 All grades grades                                                              3/4 Preferred term                                          Percent (%) of patients Diarrhoea                       27            2          28             2           28             2 Fluid retention                 34           4           42             6           48             7 Superficial oedema          18           0           21             0           22             0 Pleural effusion            18           2           24             4           28             5 Generalised oedema           3           0            4             0            4             0 Pericardial effusion         2           1            2             1            3             1 Pulmonary
0           0            0             0            2             1 hypertension
Haemorrhage                     11           1           11             1           12             1 Gastrointestinal
2           1            2             1            2             1 bleeding a
3TP
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 3b. 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 3b:         Selected adverse reactions reported in phase III dose-optimisation study: Advanced phase CML and Ph+ ALLa
140 mg once daily n = 304
All grades                       Grade 3/4
Percent (%) of patients
Preferred term
Diarrhoea                                                   28                                         3 Fluid retention                                             33                                         7 Superficial oedema                                        15                                        <1 Pleural effusion                                          20                                         6 Generalised oedema                                         2                                         0 Congestive heart failure/                                  1                                         0 cardiac dysfunctionb
Pericardial effusion                                       2                                         1 Pulmonary oedema                                           1                                         1 Haemorrhage                                                 23                                         8 Gastrointestinal bleeding                                  8                                         6 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 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 4.

Table 4:                     CTC grades 3/4 haematological laboratory abnormalities in clinical studies in patients with resistance or intolerance to prior imatinib therapya
Lymphoid blast phase
Myeloid blast                and
Chronic phase        Accelerated phase      phase                 Ph+ ALL (n= 165)b              (n= 157) c
(n= 74)c               (n= 168)c
Percent (%) of patients
Haematology parameters
Neutropaenia                              36                    58                      77                76 Thrombocytopaenia                         23                    63                      78                74 Anaemia                                   13                    47                      74                44 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.
Table 4:                     CTC grades 3/4 haematological laboratory abnormalities in clinical studies in patients with resistance or intolerance to prior imatinib therapya
Lymphoid blast phase
Myeloid blast        and
Chronic phase       Accelerated phase         phase          Ph+ ALL b                     c                   c                c
(n= 165)              (n= 157)             (n= 74)         (n= 168) 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.

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.
Any suspected adverse events should be reported to the Ministry of Health according to the National Regulation by using an online form https://sideeffects.health.gov.il/