Adverse reactions : תופעות לוואי

4.8     Undesirable effects

Summary of the safety profile
The adverse reactions described in this section were identified in a single-arm, open-label, international, multicenter trial in 449 CML and Ph+ ALL patients who were resistant or intolerant to prior TKI therapy including those with a BCR-ABL T315I mutation. All patients received 45 mg Iclusig once daily. Dose adjustments to 30 mg once daily or 15 mg once daily were allowed for the management of treatment toxicity. Additionally, after approximately 2 years of follow-up, all patients who were still taking a 45 mg daily dose were recommended to undergo a dose reduction, even in the absence of adverse events, in response to the continued occurrence of vascular occlusive events in the clinical trial. At the time of reporting, all ongoing patients had a minimum follow-up of 64 months.
The median duration of treatment with Iclusig was 32.2 months in CP-CML patients, 19.4 months in AP-CML patients, and 2.9 months in BP-CML/Ph+ ALL patients. The median dose intensity was 28 mg/day in CP-CML patients or, 63% of the expected 45 mg dose; median dose intensity was greater in advanced disease states (32 mg/day in the AP-CML patients and 44 mg/day in the BP CML/Ph+ ALL patients).

The most common serious adverse reactions > 2% (treatment-emergent frequencies) were pneumonia (7.3%), pancreatitis (5.8%), abdominal pain (4.7 atrial fibrillation (4.5%), pyrexia (4.5%), myocardial infarction (4.0%), peripheral arterial occlusive disease (3.8%), anaemia (3.8%), angina pectoris (3.3%), platelet count decreased (3.1%), febrile neutropenia (2.9%), hypertension (2.9%), coronary artery disease (2.7%), cardiac failure congestive (2.4%), cerebrovascular accident (2.4%), sepsis (2.4%), cellulitis (2.2%), acute kidney injury (2.0%), urinary tract infection (2.0%) and lipase increased (2.0%).

Serious arterial cardiovascular, cerebrovascular, and peripheral vascular occlusive adverse reactions (treatment-emergent frequencies) occurred in 10%, 7%, and 9% of Iclusig treated patients, respectively. Serious venous occlusive reactions (treatment-emergent frequencies) occurred in 5% of patients.


Arterial cardiovascular, cerebrovascular, and peripheral vascular occlusive adverse reactions (treatment-emergent frequencies) occurred in 13%, 9%, and 11% of Iclusig-treated patients, respectivelyOverall arterial occlusive adverse reactions have occurred in 25% of Iclusig-treated patients from the phase 2 trial, with serious adverse reactions occurring in 20% of patients. Some patients experienced more than one type of event.

Venous thromboembolic reactions (treatment-emergent frequencies) occurred in 6% of patients. The incidence of thromboembolic events is higher in patients with Ph+ ALL or BP-CML than those with AP-CML or CP-CML. No venous occlusive events were fatal.

After a minimum follow-up of 64 months, the rates of adverse reactions resulting in discontinuation were 20% in CP-CML, 11% in AP-CML, 15% in BP-CML and 9% in Ph+ ALL.

Tabulated list of adverse reactions
Adverse reactions reported in all CML and Ph+ ALL patients are presented in Table 4. Frequency categories are very common (≥ 1/10), common (≥ 1/100 to < 1/10) and uncommon (≥ 1/1000 to < 1/100), rare (≥ 1/10,000 to < 1/1,000), very rare (< 1/10,000), and not known (cannot be estimated from the available data). Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness.


Table 4      Adverse reactions observed in CML and Ph+ ALL patients – frequency reported by incidence of treatment emergent events
System organ class              Frequency                   Adverse reactions Very common         upper respiratory tract infection
Infections and infestations
Common              pneumonia, sepsis, folliculitis, cellulitis anaemia, platelet count decreased, neutrophil
Very common count decreased
Blood and lymphatic system pancytopenia, febrile neutropenia, white disorders
Common              blood cell count decreased, lymphocyte count decreased

Endocrine disorders              Common                   hypothyroidism Very common              decreased appetite dehydration, fluid retention, hypocalcaemia,
hyperglycaemia, hyperuricaemia,
Metabolism and nutrition
Common                   hypophosphataemia, hypertriglyceridaemia,
disorders hypokalaemia, weight decreased,
hyponatraemia
Uncommon                 tumour lysis syndrome
Psychiatric disorders            Very common              insomnia
Very common              headache, dizziness cerebrovascular accident, cerebral infarction,
neuropathy peripheral, lethargy, migraine,
Common hyperaesthesia, hypoaesthesia, paraesthesia,
Nervous system disorders                                  transient ischaemic attack cerebral artery stenosis, cerebral haemorrhage, haemorrhage intracranial,
Uncommon posterior reversible encephalopathy syndrome * vision blurred, dry eye, periorbital oedema,
Common                   eyelid oedema, conjunctivitis, visual
Eye disorders                                             impairment retinal vein thrombosis, retinal vein
Uncommon occlusion, retinal artery occlusion cardiac failure, myocardial infarction,
cardiac failure congestive, coronary artery
Common                   disease, angina pectoris, pericardial effusion, atrial fibrillation, ejection fraction decreased,
Cardiac disorders acute coronary syndrome, atrial flutter myocardial ischemia, cardiac discomfort,
Uncommon                 ischemic cardiomyopathy, arteriospasm coronary, left ventricular dysfunction,
Vascular disorders               Very common              hypertension 
System organ class                 Frequency                      Adverse reactions peripheral arterial occlusive disease,
peripheral ischaemia, peripheral artery
Common stenosis, intermittent claudication, deep vein thrombosis, hot flush, flushing poor peripheral circulation, splenic infarction, embolism venous, venous
Uncommon thrombosis, hypertensive crisis, renal artery stenosis
Not Known               Aneurysms and artery dissections
Very common             dyspnoea, cough
Respiratory, thoracic and                                pulmonary embolism, pleural effusion, mediastinal disorders            Common                  epistaxis, dysphonia, pulmonary hypertension abdominal pain, diarrhoea, vomiting,
Very common constipation, nausea, lipase increased pancreatitis, blood amylase increased,
Gastrointestinal disorders gastrooesophageal reflux disease, stomatitis,
Common dyspepsia, abdominal distension, abdominal discomfort, dry mouth, gastric haemorrhage alanine aminotransferase increased, aspartate
Very common aminotransferase increased blood bilirubin increased, blood alkaline
Hepatobiliary disorders
Common                  phosphatase increased, gamma- glutamyltransferase increased
Uncommon                hepatotoxicity, hepatic failure, jaundice
Very common             rash, dry skin, pruritus rash pruritic, exfoliative rash, erythema,
alopecia, skin exfoliation, night sweats,
Common                  hyperhidrosis, petechia, ecchymosis, pain of
Skin and subcutaneous tissue                             skin, dermatitis exfoliative, hyperkeratosis, disorders                                                skin hyperpigmentation 

Rare                    panniculitis(including erythema nodosum)
 bone pain, arthralgia, myalgia, pain in
Very common
Musculoskeletal and                                      extremity, back pain, muscle spasms connective tissue disorders                              musculoskeletal pain, neck pain, Common musculoskeletal chest pain
Reproductive system and
Common                  erectile dysfunction breast disorders fatigue, asthenia, oedema peripheral,
Very common
General disorders and                                    pyrexia, pain administrative site conditions                           chills, influenza like illness, non-cardiac Common chest pain, mass, face oedema
* Spontaneous reports from post-marketing experience

Description of selected adverse reactions

Vascular occlusion (see section 4.2 and 4.4).
Serious vascular occlusion has occurred in patients treated with Iclusig, including cardiovascular, cerebrovascular and peripheral vascular events, and venous thrombotic events. Patients with and without cardiovascular risk factors, including patients age 50 years or younger, experienced these events. Arterial occlusive adverse events were more frequent with increasing age and in patients with history of ischaemia, hypertension, diabetes, or hyperlipidaemia.
Myelosuppression
Myelosuppression was commonly reported in all patient populations. The frequency of Grade 3 or 4 thrombocytopenia, neutropenia, and anaemia was higher in patients with AP-CML and BP-CML/Ph+ ALL than in patients with CP-CML (see Table 5). Myelosuppression was reported in patients with normal baseline laboratory values as well as in patients with pre-existing laboratory abnormalities.

Discontinuation due to myelosuppression was infrequent (thrombocytopenia 4%, neutropenia and anaemia < 1% each).

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).

Severe Cutaneous Adverse Reactions (SCARs)
Severe skin reactions (such as Stevens-Johnson Syndrome) have been reported with some BCR-ABL Tyrosine Kinase Inhibitors. Patients should be warned to immediately report suspected skin reactions, especially if associated with blistering, peeling, mucosal involvement or systemic symptoms.

Table 5      Incidence of clinically relevant grade 3/4* laboratory abnormalities in ≥ 2% of patients in any disease group from the Phase 2 Trial (N=449): minimum follow-up of 64 month for all ongoing patients
Laboratory test               All patients CP-CML         AP-CML        BP-CML/Ph+ (N=449)        (N=270)      (N=85)        ALL (N=94)
(%)           (%)         (%)              (%)
Haematology
Thrombocytopenia (platelet count             40            35          49               46 decreased)
Neutropenia (ANC decreased)                  34            23          52               52 Leukopenia (WBC decreased)                   25            12          37               53 Anaemia (Hgb decreased)                      20             8          31               46 Lymphopenia                                  17            10          25               28 Biochemistry
Lipase increased                             14            14          13               14 Phosphorus decreased                         10            10          13                9 Glucose increased                             7             8          13                1 ALT increased                                 6             4           8                7 Sodium decreased                              5             6           6                2 AST increased                                 4             3           5                3 Amylase increased                             4             4           4                3 Potassium decreased                           2            <1           6                2 Potassium increased                           2             2           1                3 Alkaline phosphatase increased                2             2           4                2 Bilirubin                                     1            <1           2                1 Calcium decreased                             1            <1           2                1 ALT=alanine aminotransferase, ANC=absolute neutrophil count, AST=aspartate aminotransferase, Hgb=haemoglobin, WBC=white blood cell count.
*Reported using National Cancer Institute Common Terminology Criteria for Adverse Events version 4.0.



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/