Tasigna Adverse Reactions

Description of selected adverse reactions: 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 Precautions).
Paediatric population: The safety of nilotinib in paediatric patients (from 2 to <18 years of age) with Philadelphia chromosome positive CML in chronic phase (n=58) has been investigated in one main study over a period of 60 months (see Pharmacology: Pharmacodynamics under Actions). In paediatric patients, the frequency, type and severity of adverse reactions observed have been generally consistent with those observed in adults, with the exception of hyperbilirubinaemia/blood bilirubin increase (Grade 3/4: 10.3%) and transaminase elevation (AST Grade 3/4: 1.7%, ALT Grade 3/4: 12.1%) which were reported at a higher frequency than in adult patients. Bilirubin and hepatic transaminase levels should be monitored during treatment (see Dosage & Administration and Precautions).
Growth retardation in paediatric population: In a study conducted in the CML paediatric population, with a median exposure of 51.9 months in newly diagnosed patients and 59.9 months in imatinib/dasatinib-resistant or imatinib-intolerant Ph+ CML-CP patients, growth deceleration (crossing at least two main percentile lines from baseline) was observed in eight patients: five (8.6%) crossed two main percentile lines from baseline and three (5.2%) crossed three main percentile lines from baseline. Growth retardation related events were reported in 3 patients (5.2%). Close monitoring of growth in paediatric patients under nilotinib treatment is recommended (see Precautions).
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.
150 mg: Summary of the safety profile: The data described as follows reflect exposure to nilotinib in 279 adult patients from a randomised Phase III study in patients with newly diagnosed Ph+ CML in chronic phase treated with 300 mg of nilotinib twice daily. Safety information from a Tasigna treatment discontinuation study in CML patients who have been treated with nilotinib as first-line therapy is also provided.
The median duration of exposure was 60.5 months (range 0.1-70.8 months).
The most frequent (≥10%) non-haematological adverse reactions were rash, pruritus, headache, nausea, fatigue, alopecia, myalgia and upper abdominal pain. Most of these adverse reactions were mild to moderate in severity. Constipation, dry skin, asthenia, muscle spasms, diarrhoea, arthralgia, abdominal pain, vomiting and peripheral oedema were observed less commonly (<10% and ≥5%), were of mild to moderate severity, manageable and generally did not require dose reduction.
Treatment-emergent haematological toxicities include myelosuppression: thrombocytopenia (18%), neutropenia (15%) and anaemia (8%). Biochemical adverse drug reactions include alanine aminotransferase increased (24%), hyperbilirubinaemia (16%), aspartate aminotransferase increased (12%), lipase increased (11%), blood bilirubin increased (10%), hyperglycaemia (4%), hypercholesterolaemia (3%) and hypertriglyceridaemia (<1%). Pleural and pericardial effusions, regardless of causality, occurred in 2% and <1% of patients, respectively, receiving nilotinib 300 mg twice daily. Gastrointestinal haemorrhage, regardless of causality, was reported in 3% of these patients.
The change from baseline in mean time-averaged QTcF interval at steady state was 6 msec. No patient had an absolute QTcF >500 msec while on the study medicinal product. QTcF increase from baseline exceeding 60 msec was observed in <1% of patients while on the study medicinal product. No sudden deaths or episodes of torsade de pointes (transient or sustained) were observed. No decrease from baseline in mean left ventricular ejection fraction (LVEF) was observed at any time during treatment. No patient had a LVEF of <45% during treatment nor an absolute reduction in LVEF of more than 15%.
Discontinuation due to adverse drug reactions was observed in 10% of patients.
Tabulated list of adverse reactions: The adverse reactions are ranked under heading of frequency 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) and not known (cannot be estimated from the available data). Within each frequency grouping, adverse reactions are presented in order of decreasing seriousness.
Most frequently reported adverse reactions in Tasigna clinical studies: Non-haematological adverse reactions (excluding laboratory abnormalities) that are reported in at least 5% of the adult patients treated with 300 mg of nilotinib twice daily in the randomised Phase III study are shown in Table 13. (See Table 13.)

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Adverse reactions that were reported in adult patients in the Tasigna Phase III study at a frequency of less than 5% are shown in Table 14. For laboratory abnormalities, very common events (≥1/10) not included in Table 13 are also reported. These adverse reactions are included based on clinical relevance and ranked in order of decreasing seriousness within each category using the following convention: very common (≥1/10), common (≥1/100 to <1/10), uncommon (≥1/1,000 to <1/100), not known (cannot be estimated from the available data). (See Table 14.)

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Clinically relevant or severe abnormalities of routine haematological or biochemistry laboratory values in adult patients are presented in Table 15. (See Table 15.)

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Treatment discontinuation in adult Ph+ CML patients in chronic phase who have achieved a sustained deep molecular response: After discontinuation of nilotinib therapy within the framework of attempting TFR, patients may experience musculoskeletal symptoms more frequently than before treatment discontinuation, e.g., myalgia, pain in extremity, arthralgia, bone pain, spinal pain or musculoskeletal pain.
In a Phase II clinical study with newly diagnosed adult patients with Ph+ CML in chronic phase (N=190), musculoskeletal symptoms were reported within a year of Tasigna discontinuation in 24.7% versus 16.3% within the previous year on nilotinib treatment.
Post-marketing experience: The following adverse reactions have been derived from post-marketing experience with Tasigna via spontaneous case reports, literature cases, expanded access programmes, and clinical studies other than the global registration trials. Since these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to nilotinib exposure.
Frequency very common: Growth retardation has been documented in paediatric patients treated with nilotinib.
Frequency rare: Cases of tumour lysis syndrome have been reported in patients treated with nilotinib.
Frequency unknown: Cases of facial paralysis have been reported in patients treated with nilotinib.
200 mg: 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 and paediatric 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) and paediatric patients with chronic phase Philadelphia chromosome positive CML with resistance or intolerance to prior therapy including imatinib (2 clinical studies with 69 patients). These pooled data represents 9,039.34 patient-years of exposure.
The safety profile of nilotinib is consistent across indications.
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 16) 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). (See Table 16.)

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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 accelerated phase with a past medical history of cardiac disease or significant cardiac risk factors (see Precautions).