Adverse reactions : תופעות לוואי

4.8   Undesirable effects
General tolerance in men
Since patients suffering from locally advanced or metastatic, hormone-dependent prostate cancerare generally old and have other diseases frequently encountered in this aged population, more than 90 % of the patients included in clinical trials reported adverse events, and often the causalityis difficult to assess. As seen with other GnRH agonist therapies or after surgical castration, the most commonly observed adverse events related to triptorelin treatment were due to its expectedpharmacological effects. These effects included hot flushes and decreased libido.
With the exception of immuno-allergic (rare) and injection site (< 5%) reactions, all adverse events are known to be related to testosterone changes.
The following adverse reactions considered as at least possibly related to triptorelin treatmentwere reported. Most of these events are known to be related to biochemical or surgical castration.
The frequency of these side effects is classified as follows: very common (≥1/10); common (≥1/100, <1/10); uncommon (≥1/1000, <1/100); rare (≥1/10000, <1/1000); very rare (,1/10,000), uncommon (≥1/1000, <1/100); rare (≥1/10000, <1/1000); not known (cannot be estimated from the available data).


System           Very       Common            Uncommon                Rare              Additional Organ Class      Common                                                                 post- marketing
Frequency not known
Infections and                                                        Nasopharyngitis infestations
Neoplasms                   Temporary tumour flare
Blood and lymphatic                                     Thrombocytosis system disorders
Cardiac                                       Palpitations                              QT prolongation* disorders
(see sections
4.4 and 4.5)
Investigations              Weight increase   Alanine                 Blood alkaline aminotransferase phosphatase increased, Aspartate aminotransferase        increased increased, Blood creatinine increased,
Blood pressure increased, Blood urea increased
Gamma-glutamyl transferase increased
Weight decreased


System           Very             Common             Uncommon              Rare                 Additional Organ Class      Common                                                                         post- marketing
Frequency not known
Immune                            Hypersensitivity                         Anaphylactic         Anaphylactic system                                                                     reaction             shock disorders
Endocrine                                                                                       Pituitary disorders                                                                                       apoplexy** Metabolism                                            Anorexia
Diabetes mellitus and nutrition
Gout disorders                                             Hyperlipidaemia Increased appetite
Psychiatric      Libido           Loss of libido     Insomnia,             Confusional state, Anxiety Decreased activity,
disorders        decreased        Depression*        Irritability
Euphoric mood
Mood changes*
Nervous          Paraesthesia     Dizziness          Paraesthesia          Memory system           in lower limbs   ,Headache                                impairment disorders
Eye disorders                                        Visual impairment     Abnormal sensation in eye,
visual disturbance
Ear and                                              Tinnitus,
labyrinth                                            Vertigo disorders vascular         Hot flash        Hypertension                             Hypotension disorders
Respiratory                                          Dyspnoea, Epistaxis   Orthopnoea tract

Gastrointestin                    Dry mouth,         Abdominal pain        Abdominal al disorders                      Nausea             ,Constipation,        distension, Diarrhoea,            Dysgeusia,
Vomiting              Flatulence



Skin and         Hyperhidrosis                       Acne,                 Blister, Purpura     Angioneurotic Alopecia,
subcutaneous                                                                                    oedema Erythema, Pruritus tissue
Rash, Urticaria disorders
Musculo-         Back pain        Musculoskeletal    Arthralgia, Bone      Joint stiffness, pain,              pain, Muscle skeletal and                                                               Joint swelling, Pain in            cramp, Muscular connective                                           weakness, Myalgia     Musculoskeletal extremity
Tissue                                                                     stiffness, disorders                                                                  Osteoarthritis Renal and                                            Nocturia,                                  Urinary urinary                                              Urinary retention                          incontinence disorders


System             Very          Common              Uncommon              Rare                 Additional Organ Class        Common                                                                       post- marketing
Frequency not known
Reproductive       Erectile      Pelvic plain        Gynaecomastia,
dysfunction system and                                           Breast pain,
(including breasts            ejaculation                       Testicular atrophy, failure,                          Testicular pain ejaculation disorder)
General            Asthenia      Injection site      Lethargy,             Chest pain,          Malaise reaction            Oedema disorders and                                                              Dysstasia, (including          peripheral,
administration                   erythema            Pain, Rigors,         Influenza like site conditions                  inflammation        Somnolence            illness, and pain)                                 Pyrexia
Oedema
*This frequency is based on class-effect frequencies common for all GnRH agonists **Reported following initial administration in patients with pituitary adenoma 

Triptorelin causes a transient increase in circulating testosterone levels within the first week after the initial injection of the sustained release formulation. With this initial increase in circulating testosterone levels, a small percentage of patients ( ≤5 %) may experience a temporary worsening of signs and symptoms of their prostate cancer (tumour flare), usually manifested by an increase in urinary symptoms (< 2%) and metastatic pain (5%) , which can be managed symptomatically.These symptoms are transient and usually disappear in one to two weeks.
Isolated cases of exacerbation of disease symptoms, either urethral obstruction or spinal cord compression by metastasis have occurred. Therefore, patients with metastatic vertebral lesions and/or with upper or lower urinary tract obstruction should be closely observed during the first few weeks of therapy (see section 4.4 Special warnings and precautions for use).
The use of GnRH agonists to treat prostate cancer may be associated with increased bone loss and may lead to osteoporosis and increases the risk of bone fracture. This may also lead to an incorrect diagnosis of bone metastases.

Patients receiving long-term treatment with GnRH analogue in combination with radiation therapy may have more side effects, mostly gastrointestinal and related to radiotherapy.
General tolerance in children (see section 4.4)
The frequency of the adverse reactions is classified as follows: very common (≥1/10); common (≥1/100 to <1/10); uncommon (≥1/1000, < 1/100).
System Organ          Very Common      Common                    Uncommon             Additional Post- Class                 Treatment        Treatment related         Treatment            marketing related AEs      AEs                       related AEs          Frequency unknown
Eye disorders                                                    Visual impairment    Visual disturbance Gastrointestinal                       Abdominal pain            Vomiting, disorders                                                        Constipation, Nausea
General disorders                      Injection site reaction   Malaise and                                    (including injection administration                         site pain, injection site conditions                        site erythema and injection site inflammation)


System Organ        Very Common        Common              Uncommon       Additional Post- Class               Treatment          Treatment related   Treatment      marketing related AEs        AEs                 related AEs    Frequency unknown
Immune system                          Hypersensitivity                   Anaphylactic shock disorders
Investigations                         Weight increased                   Blood pressure increased, Blood prolactin increased
Metabolism and                                             Obesity nutrition disorders
Musculoskeletal                                            Neck pain      Myalgia and connective tissue disorders
Nervous system                         Headache                           Idiopathic intracranial disorders                                                                 hypertension (pseudotumor cerebri)
(see section 4.4)
Psychiatric                                                Mood altered   Affect lability, disorders                                                                 Depression, Nervousness
Reproductive        Vaginal bleeding                       Breast pain system and breast   (including disorders           vaginal haemorrhage,
withdrawal bleed, uterine haemorrhage,
vaginal discharge,
vaginal bleeding including spotting)
Respiratory,                                               Epistaxis thoracic and mediastinal disorders
Skin and                               Acne                Pruritus ,     Angioneurotic oedema subcutaneous                                               Rash,
tissue disorders                                           Urticaria
Vascular                               Hot flush                          Hypertension disorders


General
Increased lymphocytes count has been reported with patients undergoing GnRH analogue treatment. This secondary lymphocytosis is apparently related to GnRH induced castration and seems to indicate that gonadal hormones are involved in thymic involution.
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 https://sideeffects.health.gov.il/