Adverse reactions : תופעות לוואי

4.8 Undesirable effects
Summary of the safety profile
The most commonly observed adverse reactions during degarelix therapy in the confirmatory phase III study (N=409) were due to the expected physiological effects of testosterone suppression, including hot flushes and weight increase (reported in 25% and 7%, respectively, of patients receiving treatment 

for one year), or injection site adverse events. Transient chills, fever or influenza like illness were reported to occur hours after dosing (in 3%, 2% and 1% of patients, respectively).

The injection site adverse events reported were mainly pain and erythema, reported in 28% and 17% of patients, respectively, less frequently reported were swelling (6%), induration (4%) and nodule (3%). These events occurred primarily with the starting dose whereas during maintenance therapy with the 80 mg dose, the incidence of these events pr 100 injections was: 3 for pain and <1 for erythema, swelling, nodule and induration. The reported events were mostly transient, of mild to moderate intensity and led to very few discontinuations (<1%). Serious injection site reactions were very rarely reported such as injection site infection, injection site abscess or injection site necrosis that could require surgical treatment/drainage.

Tabulated list of adverse reactions
The frequency of undesirable effects listed below is 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) and very rare (<1/10,000). Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness.

Table 1: Frequency of adverse drug reactions reported in 1,259 patients treated for a total of 1781 patient years (phase II and III studies) and from post-marketing reports 

MedDRA System            Very            Common                   Uncommon                   Rare Organ Class         common
(SOC)
Blood and                                                                               Neutropenic lymphatic system                     Anaemia*                                           fever disorders
Immune system                                             Hypersensitivity              Anaphylactic disorders                                                                               reactions Metabolism and                       Weight increase*     Hyperglycemia/Diabetes nutrition                                                 mellitus, cholesterol disorders                                                 increased, weight decreased, appetite decreased, changes in blood calcium

Psychiatric                          Insomnia             Depression, libido disorders                                                 decreased*
Nervous system                       Dizziness,           Mental impairment, disorders                            headache             hypoaesthesia Eye disorders                                             Vision blurred Cardiac disorders                                         Cardiac arrhythmia (incl.     Myocardial atrial fibrillation),         infarction,
palpitations,                 cardiac
QT prolongation*(see          failure sections 4.4 and 4.5)
Vascular              Hot flush*                          Hypertension, vasovagal disorders                                                 reaction (incl.
hypotension)
Respiratory,                                              Dyspnoea thoracic and mediastinal disorders


Gastrointestinal                      Diarrhoea,           Constipation, vomiting, disorders                             Nausea               abdominal pain, abdominal discomfort,
dry mouth
Hepatobiliary                         Liver                Bilirubin increased, disorders                             transaminases        alkoline phosphatase increased            increased
Skin and                              Hyperhidrosis        Urticaria, skin nodule, subcutaneous                          (incl. night         alopecia, pruritus, tissue disorders                      sweats)*, rash       erythema
Musculoskeletal,                      Musculoskeletal      Osteoporosis/osteopenia,     Rhabdomyo- connective tissue                     pain and             arthralgia, musclar          lysis and bone                              discomfort           weakness, muscle disorders                                                  spasms, jount swelling/stiffness
Renal and urinary                                          Pollakiuria, micturition disorders                                                  urgency, dysuria, nocturia, renal impairment, incontinence
Reproductive                          Gynaecomastia*,      Testicular pain, breast system and breast                     testicular           pain, pelvic pain, genital disorders                             atrophy*, erectile   irritation, ejaculation dysfunction*         failure
General disorders    Injection        Chills, pyrexia,     Malaise, peripheral and                  site             asthenia,            oedema administration       adverse          fatigue*,
site conditions      events           Influenza-like illness
*Known physiological consequence of testosterone suppression



Description of selected adverse reactions

Changes in laboratory parameters
Changes in laboratory values seen during one year of treatment in the confirmatory phase III study (N=409) were in the same range for degarelix and a GnRH-agonist (leuprorelin) used as comparator.
Markedly abnormal (>3*ULN) liver transaminase values (ALT, AST and GGT) were seen in 2-6% of patients with normal values prior to treatment, following treatment with both medicinal products.
Marked decrease in haematological values, hematocrit (≤0.37) and hemoglobin (≤115 g/l) were seen in 40% and 13-15%, respectively, of patients with normal values prior to treatment, following treatment with both medicinal products. It is unknown to what extent this decrease in haematological values was caused by the underlying prostate cancer and to what extent it was a consequence of androgen deprivation therapy. Markedly abnormal values of potassium (≥5.8 mmol/l), creatinine (≥177 μmol/l) and BUN (≥10.7 mmol/l) in patients with normal values prior to treatment, were seen in 6%, 2% and 15% of degarelix treated patients and 3%, 2% and 14% of leuprorelin treated patients, respectively.

Changes in ECG measurements
Changes in ECG measurements seen during one year of treatment in the confirmatory phase III study (N=409) were in the same range for degarelix and a GnRH-agonist (leuprorelin) used as comparator.
Three (<1%) out of 409 patients in the degarelix group and four (2%) out of 201 patients in the leuprorelin 7.5 mg group, had a QTcF ≥ 500 msec. From baseline to end of study the median change in QTcF for degarelix was 12.0 msec and for leuprorelin was 16.7 msec.
The lack of intrinsic effect of degarelix on cardiac repolarisation (QTcF), heart rate, AV conduction, cardiac depolarisation, or T or U wave morphology was confirmed in a thorough QT study in healthy subjects (N=80) receiving an i.v. infusion of degarelix over 60 min, reaching a mean Cmax of 222 ng/mL, approx. 3-4-fold the Cmax obtained during prostate cancer treatment.
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/