Nubeqa Adverse Reactions

Summary of the safety profile: The most frequently observed adverse reactions in patients with: nmCRPC receiving darolutamide are fatigue/asthenic conditions (15.8%); mHSPC receiving darolutamide in combination with docetaxel are rash (16.6%) and hypertension (13.8%).
For additional safety information when darolutamide is administered in combination, refer to the product information of the individual medicinal products.
Tabulated list of adverse reactions: The adverse reactions observed in patients with nmCRPC treated with darolutamide are listed in Table 3. The adverse reactions observed in patients with mHSPC treated with darolutamide in combination with docetaxel are listed in Table 4. (See Tables 3 and 4.)
Adverse reactions are classified according to System Organ Class. They are grouped according to their frequencies. Frequency groups are defined by 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).
Within each frequency group, adverse reactions are presented in order of decreasing seriousness.

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Description of selected adverse reactions: Hepatic transaminase elevations: Cases of idiosyncratic drug-induced liver injury with grade 3 and 4 increases in alanine aminotransferase (ALT) and aspartate aminotransferase (AST) to ≥ 5 and ≥ 20 x upper limit of normal (ULN) have been reported in darolutamide clinical studies including 1 case of increased transaminases along with a simultaneous increase in total bilirubin to 3 x ULN. Time to onset ranged from 1 month to 10.5 months after initiation of darolutamide. The ALT and AST elevations were reversible upon darolutamide discontinuation. For specific recommendations, see Precautions.
non-metastatic castration resistant prostate cancer (nmCRPC): Fatigue: Fatigue/asthenic conditions were reported in 15.8% of patients treated with darolutamide and in 11.4% of patients treated with placebo. Events with worst grade of 3 were reported in 0.6% of patients treated with darolutamide and in 1.1% of patients treated with placebo. Fatigue (not including asthenia, lethargy or malaise) occurred in the majority of patients (12.1% of patients treated with darolutamide and 8.7% of patients treated with placebo).
Fractures: Fractures occurred in 4.2% of patients treated with darolutamide and in 3.6% of patients treated with placebo.
Ischaemic heart disease and heart failure: Ischaemic heart disease occurred in 3.2% of patients treated with darolutamide and in 2.5% of patients treated with placebo. Grade 5 events occurred in 0.3% of patients treated with darolutamide and 0.2% of patients treated with placebo. Heart failure occurred in 1.9% of patients treated with darolutamide and in 0.9% of patients treated with placebo.
Neutrophil count decreased: Neutrophil count decreased was reported as a laboratory abnormality in 19.6% of patients treated with darolutamide and in 9.4% of patients treated with placebo. The median time to nadir was 256 days.
The laboratory tests abnormalities manifested predominantly as grade 1 or 2 intensity. Neutrophil count decreased of grade 3 and 4 was reported in 3.5% and 0.5% of patients, respectively. Only one patient permanently discontinued darolutamide due to neutropenia. Neutropenia was either transient or reversible (88% of patients) and were not associated with any clinically relevant signs or symptoms.
Blood bilirubin increased: Bilirubin increased was reported as a laboratory abnormality in 16.4% of patients treated with darolutamide and in 6.9% of patients treated with placebo. The episodes were predominantly of grade 1 or 2 intensity, not associated with any clinically relevant signs or symptoms, and reversible after darolutamide was discontinued. Bilirubin increased of grade 3 was reported in 0.1% of patients treated with darolutamide and in 0% of patients treated with placebo. In the darolutamide arm, the mean time to first onset of increased bilirubin was 153 days, and the mean duration of the first episode was 182 days. No patients were discontinued from treatment due to increase in bilirubin.
AST increased: AST increased was reported as a laboratory abnormality in 22.5% of patients treated with darolutamide and in 13.6% of patients treated with placebo. The episodes were predominantly of grade 1 or 2 intensity, not associated with any clinically relevant signs or symptoms, and reversible after darolutamide was discontinued. AST increased of grade 3 was reported in 0.5% of patients treated with darolutamide and in 0.2% of patients treated with placebo. In the darolutamide arm, the mean time to first onset of increased AST was 258 days, and the mean duration of the first episode was 118 days. No patients were discontinued from treatment due to increase in AST.
metastatic hormone-sensitive prostate cancer (mHSPC): Hypertension: In the ARASENS study hypertension was reported in 13.8% of patients treated with darolutamide+docetaxel and 9.4% of patients treated with placebo+docetaxel.
Grade 3 hypertension was reported in 6.4% of patients treated with darolutamide+docetaxel compared to 3.5% of patients treated with placebo+docetaxel. One patient had grade 4 hypertension in each treatment arm.
One case was reported as grade 5 hypertension with grade 5 arteriosclerosis in the darolutamide+docetaxel arm. This patient had a long-standing history of hypertension and smoking and the case occurred more than 3 years after starting darolutamide treatment. Events of hypertension were reported more commonly in patients with no medical history of hypertension in both treatment arms.
Fractures: Fractures occurred in 7.5% of patients treated with darolutamide+docetaxel and in 5.1% of patients treated with placebo+docetaxel.
Neutrophil count decreased: Neutrophil count decreased was reported as a laboratory abnormality in 50.6% of patients treated with darolutamide+docetaxel and in 45.5% of patients treated with placebo+docetaxel. Grade 3 and 4 neutrophil count decreased was reported in 34.4% of patients treated with darolutamide+docetaxel and in 31.4% of patients treated with placebo+docetaxel. In both treatment arms, the incidences of neutrophil count decreased and neutropenia were highest during the first months of treatment, after which the incidence and severity of the events decreased.
Blood bilirubin increased: Bilirubin increased was reported as a laboratory abnormality in 19.6% of patients treated with darolutamide+docetaxel and in 10.0% of patients treated with placebo+docetaxel. The events were predominantly of grade 1 or 2 intensity. Grade 3 and 4 bilirubin increased was reported in 0.5% of patients treated with darolutamide+docetaxel and in 0.3% of patients treated with placebo+docetaxel.
ALT and AST increased: Alanine aminotransferase (ALT) increased was reported as a laboratory abnormality in 42.3% of patients treated with darolutamide+docetaxel and in 38.0% of patients treated with placebo+docetaxel. Aspartate aminotransferase (AST) increased was reported as a laboratory abnormality in 43.9% of patients treated with darolutamide+docetaxel and in 39.3% of patients treated with placebo+docetaxel. ALT and AST elevations were predominantly of grade 1 intensity. Grade 3 and 4 ALT increased was reported in 3.7% of patients treated with darolutamide+docetaxel and in 3.0% of patients treated with placebo+docetaxel. Grade 3 and 4 AST increased was reported in 3.6% of patients treated with darolutamide+docetaxel and in 2.3% of patients treated with placebo+docetaxel.
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 local reporting system.