Adverse reactions : תופעות לוואי

4.8         Undesirable effects

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 1. The adverse reactions observed in patients with mHSPC treated with darolutamide in combination with docetaxel are listed in Table 2.
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.

Table 1: Adverse reactions reported in the ARAMIS studya
System organ class                   Very common                                Common (MedDRA)
Cardiac disorders                                                               Ischaemic heart diseaseb Heart failurec
Skin and subcutaneous tissue                                                 Rashd disorders
Musculoskeletal and connective                                               Pain in extremity tissue disorders                                                             Musculoskeletal pain Fractures
General disorders and administration Fatigue/asthenic conditionse site conditions
Investigationsf                      Neutrophil count decreased
Blood bilirubin increased
AST increased a
The median duration of exposure was 14.8 months (range: 0.0 to 44.3 months) in patients treated with darolutamide and 11.0 months (range: 0.1 to 40.5 months) in patients treated with placebo.
b
Includes arteriosclerosis coronary artery, coronary artery disease, coronary artery occlusion, coronary artery stenosis, acute coronary syndrome, acute myocardial infarction, angina pectoris, angina unstable, myocardial infarction, myocardial ischaemia.
c
Includes cardiac failure, cardiac failure acute, cardiac failure chronic, cardiac failure congestive, cardiogenic shock.
d
Includes rash, rash macular, rash maculo-papular, rash papular, rash pustular, erythema, dermatitis.
e
Includes fatigue and asthenia, lethargy and malaise.

f
Common Terminology Criteria for Adverse Events (CTCAE) version 4.03. The incidence is based on values reported as laboratory abnormalities.

Table 2: Adverse reactions reported in mHSPC patients treated with darolutamide in combination with docetaxel in the ARASENS studya, b
System organ class                     Very common                Common (MedDRA)
Vascular disorders                     Hypertensionc
Skin and subcutaneous tissue disorders Rashd, e
Musculoskeletal and connective tissue                             Fractures disorders
Reproductive system and breast                                    Gynaecomastia disorders
Investigationsf                        Neutrophil count decreased
Blood bilirubin increased
ALT increased
AST increased a
The median duration of exposure was 41.0 months (range: 0.1 to 56.5 months) in patients treated with darolutamide+docetaxel and 16.7 months (range: 0.3 to 55.8 months) in patients treated with placebo+docetaxel.
b
Adverse reactions incidences may not be attributable to darolutamide alone but may contain contributions from other medicinal products used in combination.
c
Includes hypertension, blood pressure increased, hypertensive emergency.
d
Includes rash, drug eruption, rash erythematous, rash follicular, rash macular, rash maculo-papular, rash papular, rash pruritic, rash pustular, rash vesicular, erythema, dermatitis.
e
The incidence was highest during the first 6 months of treatment.
f
Common Terminology Criteria for Adverse Events (CTCAE) version 4.03. The incidence is based on values reported as laboratory abnormalities.

Description of selected adverse reactions

Liver function tests
Cases of idiosyncratic drug-induced liver injury with grade 3 and 4 increases in alanine aminotransferase (ALT) and/or aspartate aminotransferase (AST) to ≥ 5 and ≥ 20 x upper limit of normal (ULN) have been reported with darolutamide treatment including increased transaminases along with a simultaneous increase in total bilirubin to ≥ 2 x ULN. Time to onset ranged from 1 month to 12 months after initiation of darolutamide. In many cases the ALT and AST elevations were reversible upon darolutamide discontinuation. For specific recommendations, see section 4.4.
 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.
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