Adverse reactions : תופעות לוואי

8 ADVERSE REACTIONS
The following are discussed in more detail in other sections of the labeling: 
•    Cerebrovascular and Ischemic Cardiovascular Events [see Warnings and Precautions (5.1)].

•    Fractures [see Warnings and Precautions (7.2)].
•    Falls [see Warnings and Precautions (7.3)].

•    Seizure [see Warnings and Precautions (7.4)].

•    Severe Cutaneous Adverse Reactions (SCARs) [see Warnings and Precautions (7.5)].

8.1 Clinical Trial Experience
Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.


The most common adverse reactions (≥ 10%) that occurred more frequently in the ERLEADA-treated patients (≥ 2% over placebo) from the randomized placebo-controlled clinical trials (TITAN and SPARTAN) were fatigue,
arthralgia, rash, decreased appetite, fall, weight decreased, hypertension, hot flush, diarrhea, and fracture.
Metastatic Castration-sensitive Prostate Cancer (mCSPC)
TITAN, a randomized (1:1), double-blind, placebo-controlled, multi-center clinical study, enrolled patients who had mCSPC. In this study, patients received either ERLEADA at a dose of 240 mg daily or placebo. All patients in the TITAN study received a concomitant gonadotropin-releasing hormone (GnRH) analog or had prior bilateral orchiectomy. The median duration of exposure was 20 months (range: 0 to 34 months) in patients who received ERLEADA and 18 months (range: 0.1 to 34 months) in patients who received placebo.
Ten patients (1.9%) who were treated with ERLEADA died from adverse reactions. The reasons for death were ischemic cardiovascular events (n=3), acute kidney injury (n=2), cardio-respiratory arrest (n=1), sudden cardiac death (n=1), respiratory failure (n=1), cerebrovascular accident (n=1), and large intestinal ulcer perforation (n=1).
ERLEADA was discontinued due to adverse reactions in 8% of patients, most commonly from rash (2.3%). Adverse reactions leading to dose interruption or reduction of ERLEADA occurred in 23% of patients; the most frequent (>1%) were rash, fatigue, and hypertension. Serious adverse reactions occurred in 20% of ERLEADA-treated patients and 20% in patients receiving placebo.
Table 1 shows adverse reactions occurring in ≥10% on the ERLEADA arm in TITAN that occurred with a ≥2% absolute increase in frequency compared to placebo. Table 2 shows laboratory abnormalities that occurred in ≥15% of patients, and more frequently (>5%) in the ERLEADA arm compared to placebo.

Table 1:              Adverse Reactions in TITAN (mCSPC)
ERLEADA                                        Placebo
N=524                                        N=527
System/Organ Class                                                                       All Grades    Grade 3-4                      All Grades     Grade 3-4 Adverse reaction                                                                             %            %                               %             % Musculoskeletal and connective tissue disorders
Arthralgiaa                                                                                  17                    0.4                    15                    0.9 Skin and subcutaneous tissue disorders
Rashb                                                                                        28                     6                     9                     0.6 Pruritus                                                                                     11                    0.2                   4.6                    0.2 Vascular disorders
Hot flush                                                                                    23                     0                     16                     0 Hypertension                                                                                 18                     8                     16                     9 a
Per the Common Terminology Criteria for Adverse Reactions (CTCAE), the highest severity for these events is Grade 3 b
Includes rash, rash maculo-papular, rash generalized, urticaria, rash pruritic, rash macular, conjunctivitis, erythema multiforme, rash papular, skin exfoliation, genital rash, rash erythematous, stomatitis, drug eruption, mouth ulceration, rash pustular, blister, papule, pemphigoid, skin erosion, dermatitis, and rash vesicular 

Additional adverse reactions of interest occurring in 2%, but less than 10% of patients treated with ERLEADA included diarrhea (9% versus 6% on placebo), muscle spasm (3.1% versus 1.9% on placebo), dysgeusia (3.2% versus 0.6% on placebo), and hypothyroidism (3.6% versus 0.6% on placebo).



Table 2:    Laboratory Abnormalities Occurring in ≥ 15% of ERLEADA-Treated Patients and at a Higher Incidence than Placebo (Between Arm Difference > 5% All Grades) in TITAN (mCSPC)
ERLEADA                                    Placebo
N=524                                    N=527
All Grades          Grade 3-4         All Grades            Grade 3-4 Laboratory Abnormality
%                   %                 %                     %
Hematology
White blood cell decreased                   27                   0.4              19                    0.6 Chemistry
Hypertriglyceridemiaa                        17                   2.5              12                    2.3 a
Does not reflect fasting values


Non-metastatic Castration-resistant Prostate Cancer (nmCRPC)
SPARTAN, a randomized (2:1), double-blind, placebo-controlled, multi-center clinical study, enrolled patients who had nmCRPC. In this study, patients received either ERLEADA at a dose of 240 mg daily or a placebo. All patients in the SPARTAN study received a concomitant gonadotropin-releasing hormone (GnRH) analog or had a bilateral orchiectomy. The median duration of exposure was 33 months (range: 0.1 to 75 months) in patients who received ERLEADA and 11 months (range: 0.1 to 37 months) in patients who received placebo.
Twenty-four patients (3%) who were treated with ERLEADA died from adverse reactions. The reasons for death with ≥ 2 patients included infection (n=7), myocardial infarction (n=3), cerebrovascular event (n=2), and unknown reason (n=3). ERLEADA was discontinued due to adverse reactions in 11% of patients, most commonly from rash (3.2%). Adverse reactions leading to dose interruption or reduction of ERLEADA occurred in 33% of patients; the most common (>1%) were rash, diarrhea, fatigue, nausea, vomiting, hypertension, and hematuria. Serious adverse reactions occurred in 25% of ERLEADA-treated patients and 23% in patients receiving placebo. The most frequent serious adverse reactions (>2%) were fracture (3.4%) in the ERLEADA arm and urinary retention (3.8%) in the placebo arm.
Table 3 shows adverse reactions occurring in ≥10% on the ERLEADA arm in SPARTAN that occurred with a ≥2% absolute increase in frequency compared to placebo. Table 4 shows laboratory abnormalities that occurred in ≥15% of patients, and more frequently (>5%) in the ERLEADA arm compared to placebo.

Table 3:              Adverse Reactions in SPARTAN (nmCRPC)
ERLEADA                        Placebo
N=803                        N=398
System/Organ Class                                                  All Grades    Grade 3-4      All Grades     Grade 3-4 Adverse reaction                                                        %            %               %             % General disorders and administration site conditions
Fatiguea,b                                                              39           1.4          28             0.3 Musculoskeletal and connective tissue disorders
Arthralgiab                                                             16           0             8             0 Skin and subcutaneous tissue disorders
Rashc                                                                   25           5.2           6             0.3 Metabolism and nutrition disorders
Decreased appetited                                                     12           0.1           9             0 Peripheral edemae                                                       11            0            9             0 Injury, poisoning and procedural complications
Fallb                                                                   16           1.7           9             0.8 Fracturef                                                               12           2.7           7             0.8 Investigations
Weight decreasedb                                                       16           1.1           6             0.3 Vascular disorders
Hypertension                                                                                   25                     14                    20                     12 Hot flush                                                                                      14                      0                    9                       0 Gastrointestinal disorders
Diarrhea                                                                                       20                    1.1                    15                    0.5 Nausea                                                                                         18                     0                     16                     0 a
Includes fatigue and asthenia b
Per the Common Terminology Criteria for Adverse Reactions (CTCAE), the highest severity for these events is Grade 3 c
Includes rash, rash maculo-papular, rash generalized, urticaria, rash pruritic, rash macular, conjunctivitis, erythema multiforme, rash papular, skin exfoliation, genital rash, rash erythematous, stomatitis, drug eruption, mouth ulceration, rash pustular, blister, papule, pemphigoid, skin erosion, dermatitis, and rash vesicular d
Includes appetite disorder, decreased appetite, early satiety, and hypophagia e
Includes peripheral edema, generalized edema, edema, edema genital, penile edema, peripheral swelling, scrotal edema, lymphedema, swelling, and localized edema f
Includes rib fracture, lumbar vertebral fracture, spinal compression fracture, spinal fracture, foot fracture, hip fracture, humerus fracture, thoracic vertebral fracture, upper limb fracture, fractured sacrum, hand fracture, pubis fracture, acetabulum fracture, ankle fracture, compression fracture, costal cartilage fracture, facial bones fracture, lower limb fracture, osteoporotic fracture, wrist fracture, avulsion fracture, fibula fracture, fractured coccyx, pelvic fracture, radius fracture, sternal fracture, stress fracture, traumatic fracture, cervical vertebral fracture, femoral neck fracture, and tibia fracture 

Additional clinically significant adverse reactions occurring in 2% or more of patients treated with ERLEADA included hypothyroidism (8% versus 2% on placebo), pruritus (6% versus 1.5% on placebo), and heart failure (2.2% versus 1% on placebo).


Table 4:    Laboratory Abnormalities Occurring in ≥ 15% of ERLEADA-Treated Patients and at a Higher Incidence than Placebo (Between Arm Difference > 5% All Grades) in SPARTAN (nmCRPC)
ERLEADA                                    Placebo
N=803                                    N=398
All Grades          Grade 3-4         All Grades            Grade 3-4 Laboratory Abnormality
%                   %                 %                     %
Hematology
Anemia                                       70                   0.4              64                    0.5 Leukopenia                                   47                   0.3              29                     0 Lymphopenia                                  41                   1.8              21                    1.6 Chemistry
Hypercholesterolemiaa                        76                   0.1              46                     0 Hyperglycemiaa                               70                    2               59                    1.0 Hypertriglyceridemiaa                        67                   1.6              49                    0.8 Hyperkalemia                                 32                   1.9              22                    0.5 a
Does not reflect fasting values


Rash
In the combined data of two randomized, placebo-controlled clinical studies, SPARTAN and TITAN, rash associated with ERLEADA was most commonly described as macular or maculo-papular. Adverse reactions of rash were reported for 26% of patients treated with ERLEADA versus 8% of patients treated with placebo. Grade 3 rashes (defined as covering > 30% body surface area [BSA]) were reported with ERLEADA treatment (6%) versus placebo (0.5%).
The onset of rash occurred at a median of 83 days of ERLEADA treatment. Rash resolved in 78% of patients within a median of 78 days from onset of rash. Rash was commonly managed with oral antihistamines, topical corticosteroids, and 19% of patients received systemic corticosteroids. Dose reduction or dose interruption occurred 
in 14% and 28% of patients, respectively. Of the patients who had dose interruption, 59% experienced recurrence of rash upon reintroduction of ERLEADA.
Hypothyroidism
In the combined data of two randomized, placebo-controlled clinical studies, SPARTAN and TITAN, hypothyroidism was reported for 8% of patients treated with ERLEADA and 1.5% of patients treated with placebo based on assessments of thyroid-stimulating hormone (TSH) every 4 months. Elevated TSH occurred in 25% of patients treated with ERLEADA and 7% of patients treated with placebo. The median onset was at the first scheduled assessment. There were no Grade 3 or 4 adverse reactions. Thyroid replacement therapy was initiated in 4.9% of patients treated with ERLEADA. Thyroid replacement therapy, when clinically indicated, should be initiated or dose-adjusted [see Drug Interactions (7.2)].
8.2 Post-Marketing Experience
The following additional adverse reactions have been identified during post-approval use of ERLEADA. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate the frequency or establish a causal relationship to drug exposure.
Respiratory, Thoracic and Mediastinal Disorders: interstitial lung disease Skin and Subcutaneous Tissue Disorders: Stevens-Johnson syndrome/toxic epidermal necrolysis (SJS/TEN) and drug reaction with eosinophilia and systemic symptoms (DRESS).


Reporting of suspected adverse reactions
Reporting suspected adverse reactions after authorization 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 http://sideeffects.health.gov.il