Adverse reactions : תופעות לוואי

4.8    Undesirable effects

Summary of the safety profile

The safety profile is based on pooled data from 3,422 patients treated with Tasigna in 13 clinical studies in the approved indications: adults patients with newly diagnosed Philadelphia chromosome positive chronic myelogenous leukaemia (CML) in the chronic phase (5 clinical studies with 2,414 patients), adult patients with chronic phase and accelerated phase Philadelphia chromosome positive CML with resistance or intolerance to prior therapy including imatinib (6 clinical studies with 939 patients). These pooled data represents 9,039.34 patient-years of exposure.

The safety profile of nilotinib is consistent across indications.

TAS API SEP22 V14                                                                       EU SmPC 15JUN22 The most common adverse reactions (incidence ≥15%) from the pooled safety data were: rash (26.4%), upper respiratory tract infection (including pharyngitis, nasopharyngitis, rhinitis) (24.8%) headache (21.9%), hyperbilirubinaemia (including blood bilirubin increased) (18.6%), arthralgia (15.8%), fatigue (15.4%), nausea (16.8%), pruritus (16.7%) and thrombocytopenia (16.4%).

Tabulated list of adverse reactions

Adverse reactions from clinical studies and post-marketing reports (Table 2) are listed by MedDRA system organ class and frequency category. Frequency categories are defined using the following convention: 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); very rare (<1/10,000); not known (cannot be estimated from the available data).


Table 2      Adverse drug reactions
Infections and infestations
Very common             upper respiratory tract infection (including pharyngitis, nasopharyngitis, rhinitis)
Common:                 Folliculitis, bronchitis, candidiasis (including oral candidiasis) pneumonia, gastroenteritis , Urinary tract infection,
Uncommon:               , Herpes virus infection, candidiasis (candida infection) anal abscess, furuncle, sepsis, subcutaneous abscess, tinea pedis
Rare                    hepatitis B reactivation
Neoplasms benign, malignant and unspecified (including cysts and polyps) Uncommon:               Skin papilloma
Rare:                   Oral papilloma, paraproteinaemia
Blood and lymphatic system disorders
Very common:            Anaemia, thrombocytopenia,
Common:                 Leukopenia, leukocytosis, neutropenia, thrombocythaemia Uncommon:               Eosinophilia, febrile neutropenia, lymphopenia, pancytopenia, Immune system disorders
Uncommon:               Hypersensitivity
Endocrine disorders
Common:                 Hypothyroidism
Uncommon:               Hyperthyroidism,
Rare:                   Hyperparathyroidism secondary, thyroiditis
Metabolism and nutrition disorders
Common:                 Electrolyte imbalance (including hypomagnesaemia, hyperkalaemia, hypokalaemia, hyponatraemia, hypocalcaemia, hypercalcaemia,
hyperphosphataemia), diabetes mellitus, hyperglycaemia,
hypercholesterolaemia, hyperlipidaemia, hypertriglyceridaemia decreased appetite, hypophosphataemia (including blood phosphorus decreased), gout, Hyperuricaemia,
Uncommon:               Dehydration, increased appetite, dyslipidaemia, hypoglycaemia Rare:                   appetite disorder, tumour lysis syndrome
Psychiatric disorders
Common:                 Depression, insomnia, anxiety
Uncommon                Amnesia, confusional state, disorientation
Rare:                   dysphoria



TAS API SEP22 V14                                                                       EU SmPC 15JUN22 Nervous system disorders
Very common:           Headache
Common:                Dizziness, hypoaesthesia, paraesthesia, migraine Uncommon:              Cerebrovascular accident , intracranial/cerebral haemorrhage, ischaemic stroke, transient ischaemic attack, cerebral infarction, , loss of consciousness (including syncope), tremor, disturbance in attention, hyperaesthesia, dysaesthesia, lethargy, peripheral neuropathy, restless legs syndrome, facial paralysis
Rare:                  , Brain oedema, optic neuritis, basilar artery stenosis Eye disorders
Common:                Conjunctivitis, dry eye (including xerophthalmia), eye irritation, hyperaemia (scleral, conjunctival, ocular), vision blurred
Uncommon:              Visual impairment, conjunctival haemorrhage, visual acuity reduced, eyelid oedema, blepharitis, photopsia, conjunctivitis allergic, diplopia, eye haemorrhage, eye pain, eye pruritus, eye swelling, ocular surface disease, periorbital oedema, photophobia
Rare:                  Papilloedema, chorioretinopathy,
Ear and labyrinth disorders
Common:                Vertigo, ear pain, tinnitus
Uncommon:              Hearing impaired (hypoacusis)
Cardiac disorders
Common:                Angina pectoris, arrhythmia (including atroventricular block, cardiac flutter, extrasystoles, tachycardia, atrial fibrillation, ventricular extrasystoles, bradycardia), palpitations, electrocardiogram QT prolonged, coronary artery disease
Uncommon:              Myocardial infarction, cardiac failure, cardiac murmur, pericardial effusion, diastolic dysfunction, left bundle branch block, pericarditis,
Rare:                  Cyanosis, ejection fraction decreased
Not known:             Ventricular dysfunction,
Vascular disorders
Common:                Hypertension, flushing, peripheral arterial occlusive disease Uncommon:              Hypertensive crisis, intermittent claudication, peripheral artery stenosis, haematoma, arteriosclerosis, hypotension, thrombosis
Rare:                  Shock haemorrhagic, arterial stenosis limb
Respiratory, thoracic and mediastinal disorders
Very common:           Cough
Common:                Dyspnoea, dyspnoea exertional, epistaxis, oropharyngeal pain Uncommon:              Pulmonary oedema, pleural effusion, interstitial lung disease, pleuritic pain, pleurisy, throat irritation, dysphonia, Pulmonary hypertension, wheezing Rare:                  Pharyngolaryngeal pain
Gastrointestinal disorders
Very common            Nausea, upper abdominal pain, constipation, diarrhoea, vomiting Common:                Pancreatitis, abdominal discomfort, abdominal distension, flatulence, abdominal pain, dyspepsia, gastritis, gastroesophageal reflux, haemorrhoids, stomatitis
Uncommon:              Gastrointestinal haemorrhage, melaena, mouth ulceration, oesophageal pain, dry mouth, sensitivity of teeth (hyperaesthesia teeth), dysgeusia, enterocolitis, gastric ulcer, gingivitis, hiatus hernia, rectal haemorrhage
Rare:                  Gastrointestinal ulcer perforation, retroperitoneal haemorrhage, haematemesis, oesophagitis ulcerative, subileus.



TAS API SEP22 V14                                                                      EU SmPC 15JUN22 Hepatobiliary disorders
Very common:          Hyperbilirubinaemia (including blood bilirubin increased) Common:               Hepatic function abnormal
Uncommon:             Hepatotoxicity, toxic hepatitis, jaundice, cholestasis, hepatomegaly Skin and subcutaneous tissue disorders
Very common:          Rash, pruritus, alopecia
Common:               Night sweats, eczema, urticaria, erythema, hyperhidrosis, contusion, acne, dermatitis (including allergic, exfoliative and acneiform), dry skin
Uncommon:             Exfoliative rash, drug eruption, skin pain, ecchymosis, swelling face, blister, dermal cysts, erythema nodosum, hyperkeratosis, petechiae, photosensitivity, psoriasis, skin discolouration, skin exfoliation, skin hyperpigmentation, skin hypertrophy, skin ulcer,
Rare:                 Erythema multiforme, palmar-plantar erythrodysaesthesia syndrome, sebaceous hyperplasia, skin atrophy,
Musculoskeletal and connective tissue disorders
Very common:          Myalgia, arthralgia, back pain, pain in extremity Common:               Musculoskeletal chest pain, musculoskeletal pain, neck pain, muscular weakness, muscle spasms, bone pain
Uncommon:             Musculoskeletal stiffness, joint swelling, arthritis, flank pain, Renal and urinary disorders
Common:               Pollakiuria, dysuria
Uncommon:             Micturition urgency, nocturia, chromaturia, haematuria, renal failure, urinary incontinence
Reproductive system and breast disorders
Common                Erectile dysfunction, menorrhagia
Uncommon:             Breast pain, gynaecomastia, nipple swelling
Rare:                 Breast induration,
General disorders and administration site conditions
Very common           Fatigue, pyrexia
Common:               Chest pain (including non-cardiac chest pain), pain, , chest discomfort, malaise, asthenia and oedema peripheral, chills, influenza-like illness Uncommon:             Face oedema, gravitational oedema, feeling body temperature change (including feeling hot, feeling cold), localised oedema
Rare:                 Sudden death
Investigations
Very common:          Alanine aminotransferase increased, lipase increased, Common:               Haemoglobin decreased, blood amylase increased, aspartate aminotransferase increased, blood alkaline phosphatase increased, gamma-glutamyltransferase increased, blood creatinine phosphokinase increased, weight decreased, weight increased, elevated creatinine, total cholesterol increased
Uncommon:             Blood lactate dehydrogenase increased, blood urea increased, blood bilirubin unconjugated increased, blood parathyroid hormone increased, blood triglycerides increased, globulins decreased, lipoprotein cholesterol (including low density and high density) increased, troponin increased
Rare                   Blood glucose decreased, blood insulin decreased, blood insulin increased, insulin C-peptide decreased


Description of selected adverse reactions

Sudden death
Uncommon cases (0.1 to 1%) of sudden deaths have been reported in Tasigna clinical studies and/or compassionate use programs in patients with imatinib-resistant or intolerant CML in chronic phase or TAS API SEP22 V14                                                                     EU SmPC 15JUN22 accelerated phase with a past medical history of cardiac disease or significant cardiac risk factors (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).


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