Adverse reactions : תופעות לוואי

4.8   Undesirable effects
Clinical trials experience
Experience from clinical trials

General tolerance in men
Since patients with locally advanced or metastatic, hormone-dependent prostate cancer are usually older and have other, for this age group, frequently occurring diseases more than 90 % of the patients included in clinical trials have reported adverse reactions, It is often difficult to determine whether there is a causal link. The most commonly reported adverse reactions related to triptorelin treatment, just as for other GnRH agonists or in cases of surgical castration, were caused by expected pharmacological effects. These effects included hot flushes and reduced libido.
With the exception of allergic reactions (rare) and injection site reactions (< 5 %), all adverse events are expected in conjunction with changes in the level of testosterone.

The following adverse reactions that have been reported are considered as at least possibly related to triptorelin treatment. Most are known to occur in conjunction with biochemical or surgical castration.

The frequency of the adverse reactions is classified as follows: 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); not known (cannot be estimated from the available data).

Additional post-
System
Very           Common         Uncommon                             marketing AE Organ Class                                                         Rare Common                                                             Frequency not known
Infections and                                                      nasopharyng infestations                                                        itis 
Blood and lymphatic                                      thrombocytosis system disorders

Immune system                   hyper-                              anaphylaxis     anaphylactic shock disorders                       sensitivity
Endocrine                                                                           pituitary disorders                                                                           apoplexy** Metabolism and                                 anorexia, diabetes nutrition                                      mellitus,
disorders                                      gout,
hyperlipidaemia,
increased appetite

Psychiatric      reduced        mood                                confusion, disorders        libido         swings*,       insomnia,            reduced         anxiety loss of        irritability         activity,
libido,                             euphoria depression*


Nervous system   paraesthesia   headache,      praesthesia          impaired disorders        of the legs    dizziness,                          memory 

Eye disorders                                  visual impairment    visual disturbances,
abnormal sensation in eye


Ear and                                        tinnitus, vertigo labyrinth disorders
Cardiac                                        palpitations                         QT prolongation* disorders                                                                           (see sections 4.4 and 4.5)
Vascular         hot flushes    hypertension                        hypotension disorders
Respiratory thoracic and                                   dyspnoea,            orthopnoea mediastinal                                    epistaxis disorders

Additional post-
System
Very            Common           Uncommon                                marketing AE Organ Class                                                               Rare Common                                                                   Frequency not known
Gastrointestinal                   nausea,          stomach pain,         distended disorders                          dry mouth,       constipation,         abdomen, diarrhoea,            taste sense vomiting              altered,
flatulence


Skin and           hyperhidrosis                    acne,
subcutaneous                                        alopecia,             blisters, tissue disorders                                    erythema,             purpura           angioneurotic pruritus,                               oedema itching, skin rash,
urticaria

Musculoskeletal                    musculoskel      muscle weakness and connective     back pain       etal pain,       arthralgia,           joint tissue disorders                   pain in arms     skeletal pain,        stiffness, and legs         muscle cramp,         joint myalgia               swelling,
musculoskel etal stiffness,
osteoarthritis

Renal and                                           nocturia,
urinary                                             urinary retention                       urinary disorders                                                                                   incontinence Reproductive       erectile        pelvic plain     gynaecomastia,
system and         dysfunction                      breast pain,
breast disorders   (including                       testicular atrophy, testicular pain failure to ejaculate,
ejaculation disorder)
General            asthenia        injection site   lethargy, oedema      chest pain, disorders and                      reaction         peripheral, pain,     difficulty        malaise administration                     (including       rigors, drowsiness    standing, site conditions                    erythema                               influenza inflammatio                            like illness,
n and pain),                           fever oedema
Investigations                     weight           alanine               blood increase         aminotransferase      alkaline increased,            phosphatase aspartate             increased aminotransferase increased,
blood creatinine increased, blood pressure increased,
blood urea increased,
gamma-glutamyl
Additional post-
System
Very           Common          Uncommon                               marketing AE Organ Class                                                           Rare Common                                                                Frequency not known transferase increased,
weight decreased

* This frequency is based on class-effect frequencies common for all GnRH agonists ** Reported after initial administration in patients with a pituitary adenoma.

Triptorelin causes a transient increase in circulating testosterone levels within the first week after the initial injection of the prolonged-release formulation. As a result of the initial increase in circulating testosterone levels, a small number of patients (≤ 5 %) may experience a temporary worsened prostate cancer symptom (tumour flare), usually in the form of an increase in urinary tract symptoms (< 2%) and metastasis pain (5%), which can be treated symptomatically. These symptoms are transient and usually disappear in one to two weeks.

Isolated cases of worsened disease symptoms, either urinary tract obstruction or medullary compression caused by metastases, have been observed. For that reason, patients with vertebral metastasis and/or upper or lower urinary tract obstruction should be monitored closely the first few weeks of treatment (see section 4.4).

Use of GnRH agonists, to treat prostate cancer may be associated with increased loss of bone mass and may lead to osteoporosis and increase the risk of bone fracture.

Patients receiving long-term treatment with GnRH analogues in combination with radiotherapy may get more adverse reactions, primarily gastrointestinal reactions that may stem from the radiotherapy.


General tolerance in women (see section 4.4)
As a result of reduced oestrogen levels, the most commonly reported adverse reactions (expected in 10% of women or more) were headache, libido decreased, sleep disorders, mood swings, pain on intercourse, dysmenorrhoea, genital bleeding, ovarian hyperstimulation syndrome, ovarian hypertrophy, pelvic pain, stomach pain, vaginal dryness, hyperhidrosis, hot flushes and asthenia.

The following adverse reactions, considered as at least possibly related to triptorelin treatment, were reported. Most of these are known to be related to biochemical or surgical castration.


The frequency of the adverse reactions is classified as follows: 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); not known (cannot be estimated from the available data).

System Organ          Very Common           Common                  Uncommon                Additional post- Class                 AEs                   AEs                     AEs                     marketing AEs Frequency not known
Immune system                               hypersensitivity                                anaphylactic shock disorders
Endocrine disorders                                                                         pituitary apoplexy***
Metabolism and                                                      reduced appetite, System Organ          Very Common            Common                Uncommon               Additional post- Class                 AEs                    AEs                   AEs                    marketing AEs Frequency not known nutrition disorders                                                fluid retention Psychiatric           libido decreased,      depression*,          affect lability,       confusion disorders             mood swings, sleep     nervousness           anxiety, disturbances                                 depression**,
(including                                   disorientation insomnia),
Nervous system        headache               dizziness             taste sense altered, disorders                                                          hypoesthesia, syncope, impaired memory, attention deficit disorder,
paraesthesia, tremor

Eye disorders                                                      dry eye,               visual disturbance visual impairment
Ear and labyrinth                                                  vertigo disorders
Cardiac disorders                                                  palpitations Vascular disorders    hot flushes                                                         hypertension Respiratory,                                                       dyspnoea, epistaxis thoracic and mediastinal disorders
Gastrointestinal                             nausea, stomach       distended abdomen,     diarrhoea disorders                                    pain, upset stomach   dry mouth, flatulence, mouth ulceration, vomiting
Skin and              acne, hyperhidrosis,                         alopecia, dry skin,    angioneurotic subcutaneous tissue   seborrhoea                                   hirsutism, cracked     oedema, urticaria disorders                                                          nails itching, skin rash
Musculoskeletal                              arthralgia, muscle    back pain, myalgia     muscle weakness and connective                               spasms, pain in tissue disorders                             arms and legs
Reproductive          changes in breast,     pain in breasts       coital bleeding,       amenorrhoea system and breast     pain on intercourse,                         cystocele, disorders             genital bleeding                             menstruation (including vaginal                           disturbances bleeding,                                    (including withdrawal                                   dysmenorrhoea,
bleeding), ovarian                           breakthrough hyperstimulation                             bleeding and heavy syndrome, ovarian                            menstrual hypertrophy, pelvic                          bleeding), ovarian pain, vaginal                                cyst, vaginal dryness                                      discharge
General disorders                            injection site                               pyrexia, malaise and administration    asthenia               reaction (including site conditions                              pain, swelling,
erythema and inflammation),
oedema peripheral,
fatigue
Investigations                               weight increase       weight loss            blood alkaline phosphatase increased, blood pressure increased
*Long term use. This frequency is based on class-effect frequencies common for all GnRH agonists ** Short term use. This frequency is based on class-effect frequencies common for all GnRH agonists *** Reported after initial administration in patients with a pituitary adenoma.

At the start of treatment, during the initial increase in oestradiol levels in plasma, it is very common ((≥ 10%) for the symptoms of endometriosis including pelvic pain, dysmenorrhea, to worsen. These symptoms are transient and usually disappear within one or two weeks. Genital bleeding including heavy menstrual bleeding and breakthrough bleeding may occur in the month following the first injection.

Long-term use of GnRH analogues may lead to loss of bone mass which is a risk factor of osteoporosis.

Breast Cancer
During the 5 years during which the TEXT and SOFT studies were conducted, the most commonly observed adverse reactions for triptorelin treatment in combination with tamoxifen or an aromatase inhibitor were hot flashes, musculoskeletal symptoms, fatigue, insomnia, hyperhidrosis, vaginal dryness and depression.

The frequencies of the adverse reactions reported with triptorelin in combination with tamoxifen (N = 2325) or exemestane (N = 2318) are shown in the following table. The classifications are as follows: very common (≥1/10); common (≥1/100 to <1/10); uncommon (≥1/1,000 to <1/100), rare (≥1/10,000 to <1/1000).

System Organ Classes      Very Common          Common                  Uncommon              Rare 
Cardiac disorders                                                      myocardial            QT prolongation ischaemia
Endocrine disorders                            diabetes mellitus
(glucose intolerance) hyperglycaemia
Gastrointestinal          nausea disorders
General disorders and     fatigue              injection site administration site                            reaction conditions

Immune system                                  hypersensitivity disorders
Musculoskeletal and       musculoskeletal      fracture connective tissue         disorder,
disorders                 osteoporosis
Nervous system                                                         cerebral ischaemia, disorders                                                              central nervous system bleeding
Psychiatric disorders     insomnia, reduced libido,
depression
Renal and urinary         urinary disorders                 incontinence
Reproductive system       pain on and breast disorders      intercourse,
vaginal dryness
Skin and subcutaneous     hyperhidrosis tissue disorders


System Organ Classes    Very Common         Common               Uncommon           Rare 
Vascular disorders      hot flush,          embolism hypertension


The adverse reactions listed above must only be considered supplemental to those adverse reactions already identified in men and women in the tables above; these describe the adverse reaction profile for use of ovarian function suppression (OFS) in combination with either exemestane or tamoxifen.

A higher frequency of osteoporosis has been reported when triptorelin has been used in combination with exemestane than in combination with tamoxifen (39% versus 25%) (see section 4.4).

Musculoskeletal symptoms and fractures have also been reported more often in combination with exemestane than in combination with tamoxifen (89% versus 76% and 6.8% versus 5.2% respectively).

Hypertension, which has been studied closely, has been reported to be a “very common” adverse reaction both when triptorelin has been combined with exemestane and when it has been combined with tamoxifen (23% and 22% respectively).

Hyperglycaemia and diabetes, which have also been studied closely, have been reported with the same frequency both when triptorelin has been combined with exemestane and when it has been combined with tamoxifen (hyperglycaemia: 2.6% and 3.4%; diabetes: 2.3% and 2.3%).


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 (≥1/1,000 to <1/100); rare (≥1/10,000 to <1/1,000); not known (cannot be estimated from the available data).
System Organ          Very Common AEs       Common              Uncommon             Additional post- Class                                       AEs                                      marketing AEs Frequency not known
Immune system                               hypersensitivity                         anaphylactic shock disorders
Metabolism and                                                  obesity nutrition disorders
Psychiatric                                                     mood swings          affect lability, disorders                                                                            depression, nervousness
Nervous system                              headache                                 Idiopathic disorders                                                                            intracranial hypertension
(pseudotumor cerebri) (see section 4.4)
Eye disorders                                                   Visual impairment    visual disturbance Vascular disorders                          hot flushes                              hypertension Respiratory,                                                    epistaxis thoracic and mediastinal disorders
Gastrointestinal                            stomach pain        vomiting, disorders                                                       constipation, nausea
Skin and                                    acne                itching, skin        angioneurotic System Organ           Very Common AEs        Common                Uncommon         Additional post- Class                                         AEs                                    marketing AEs Frequency not known subcutaneous tissue                                                 rash,            oedema disorders                                                           urticaria Musculoskeletal and                                                 neck pain        myalgia connective tissue disorders
Reproductive system    vaginal bleeding                             breast pain and breast disorders   (including bleeding,
withdrawal bleeding,
uterine bleeding,
vaginal discharge,
vaginal bleeding including spotting)
General disorders                             injection site        malaise and administration                            reaction (including site conditions                               pain, erythema and inflammation)
Investigations                                weight increased                       blood prolactin increased,
blood pressure increased
Vaginal bleeding may occur in the month after the first injection.

Pressure sensitive infiltrations at the injection site have been reported as an uncommon adverse reaction for other triptorelin products after subcutaneous injection.

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/