The most common serious adverse reactions (≥ 2%) reported in patients treated with Alunbrig at the recommended dosing regimen other than events related to neoplasm progression were pneumonia, pneumonitis, dyspnoea and pyrexia.
Tabulated list of adverse reactions: The data described as follows reflect exposure to Alunbrig at the recommended dosing regimen in three clinical trials: a Phase 3 trial (ALTA 1L) in patients with advanced ALK-positive NSCLC previously not treated with an ALK-inhibitor (N = 136), a Phase 2 trial (ALTA) in patients treated with Alunbrig with ALK-positive NSCLC who previously progressed on crizotinib (N = 110), and a phase 1/2 dose escalation/expansion trial in patients with advanced malignancies (N = 28). Across these studies, the median duration of exposure in patients receiving Alunbrig at the recommended dosing regimen was 21.8 months.
Adverse reactions reported are presented in Table 7 and are listed by system organ class, preferred term and frequency. Frequency categories are very common (≥ 1/10), common (≥ 1/100 to < 1/10) and uncommon (≥ 1/1,000 to < 1/100). Within each frequency grouping, undesirable effects are presented in order of frequency. (See Table 7.)
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Description of selected adverse reactions: Pulmonary Adverse Reactions: In ALTA 1L, 2.9% of patients experienced any Grade ILD/pneumonitis early in treatment (within 8 days), with Grade 3-4 ILD/pneumonitis in 2.2% of patients. There were no fatal ILD/pneumonitis. Additionally, 3.7% of patients experienced pneumonitis later in treatment.
In ALTA, 6.4% of patients experienced pulmonary adverse reactions of any grade, including ILD/pneumonitis, pneumonia and dyspnoea, early in treatment (within 9 days, median onset: 2 days); 2.7% of patients had Grade 3-4 pulmonary adverse reactions and 1 patient (0.5%) had fatal pneumonia. Following Grade 1-2 pulmonary adverse reactions, treatment with Alunbrig was either interrupted and then restarted or the dose was reduced. Early pulmonary adverse reactions also occurred in a dose escalation study in patients (N = 137) (Study 101) including three fatal cases (hypoxia, acute respiratory distress syndrome and pneumonia). Additionally, 2.3% of patients in ALTA experienced pneumonitis later in treatment, with 2 patients having Grade 3 pneumonitis (see Dosage & Administration and Precautions).
Elderly: Early pulmonary adverse reaction was reported in 10.1% of patients ≥ 65 years of age compared with 3.1% of patients < 65 years of age.
Hypertension: Hypertension was reported in 30% of patients treated with Alunbrig at the 180 mg regimen with 11% having Grade 3 hypertension. Dose reduction for hypertension occurred in 1.5% at the 180 mg regimen. Mean systolic and diastolic blood pressure, in all patients, increased over time (see Dosage & Administration and Precautions).
Bradycardia: Bradycardia was reported in 8.4% of patients treated with Alunbrig at the 180 mg regimen.
Heart rates of less than 50 beats per minute (bpm) were reported in 8.4% of patients at the 180 mg regimen (see Dosage & Administration and Precautions).
Visual disturbance: Visual disturbance adverse reactions were reported in 14% of patients treated with Alunbrig at the 180 mg regimen. Of these, three Grade 3 adverse reactions (1.1%) including macular oedema and cataract were reported.
Dose reduction for visual disturbance occurred in two patients (0.7%) at the 180 mg regimen (see Dosage & Administration and Precautions).
Peripheral neuropathy: Peripheral neuropathy adverse reactions were reported in 20% of patients treated at the 180 mg regimen. Thirty-three percent of patients had resolution of all peripheral neuropathy adverse reactions. The median duration of peripheral neuropathy adverse reactions was 6.6 months, with a maximum duration of 28.9 months.
Creatine phosphokinase (CPK) elevation: In ALTA 1L and ALTA, elevations of CPK were reported in 64% of patients treated with Alunbrig at the 180 mg regimen. The incidence of Grade 3-4 elevations of CPK was 18%. The median time to onset for CPK elevations was 28 days.
Dose reduction for CPK elevation occurred in 10% of patients at the 180 mg regimen (see Dosage & Administration and Precautions).
Elevations of pancreatic enzymes: Elevations of amylase and lipase were reported in 47% and 54% of patients treated with Alunbrig, respectively at the 180 mg regimen. For elevations to Grade 3 and 4, the incidences for amylase and lipase were 7.7% and 15%, respectively. The median time to onset for amylase elevations and lipase elevations was 17 days and 29 days, respectively.
Dose reduction for elevation of lipase and amylase occurred in 4.7% and 2.9% of patients, respectively at the 180 mg regimen (see Dosage & Administration and Precautions).
Elevation of hepatic enzymes: Elevations of ALT and AST were reported in 49% and 68% of patients treated with Alunbrig, respectively at the 180 mg regimen. For elevations to Grade 3 and 4, the incidences for ALT and AST were 4.7% and 3.6%, respectively.
Dose reduction for elevation of ALT and AST occurred in 0.7% and 1.1% of patients, respectively at the 180 mg regimen (see Dosage & Administration and Precautions).
Hyperglycaemia: Sixty one percent of patients experienced hyperglycaemia. Grade 3 hyperglycemia occurred in 6.6% of patients.
No patients had dose reductions due to hyperglycaemia.
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.
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