Adverse reactions : תופעות לוואי

4.8     Undesirable effects

Presentation of undesireable effects is based on MedDRA.
The most appropriate MedDRA term is used to describe a certain reaction and its synonyms and related conditions.
Undesirable effects are more common during the first months after the start of treatment with Visabelle, and subside with continued treatment. There may be changes in bleeding pattern, such as spotting, irregular bleeding or amenorrhea.The following undesirable effects have been reported in users of Visabelle.

The most frequently reported undesirable effects under treatment with Visabelle are headache (9.0 %), breast discomfort (5.4 %), depressed mood (5.1 %) and acne (5.1 %).

In addition, the majority of patients treated with Visabelle experience changes in their menstrual bleeding pattern. Menstrual bleeding patterns were assessed systematically using patient diaries and were analyzed using the WHO 90 days reference period method. During the first 90 days of treatment with Visabelle the following bleeding patterns were observed (n=290; 100%): Amenorrhea (1.7%), infrequent bleeding (27.2%), frequent bleeding (13.4%), irregular bleeding (35.2%), prolonged bleeding (38.3%), normal bleeding, i.e. none of the previous categories (19.7%). During the fourth reference period the following bleeding patterns were observed (n=149; 100%): Amenorrhea (28.2%), infrequent bleeding (24.2%), frequent bleeding (2.7%), irregular bleeding (21.5%), prolonged bleeding (4.0%), normal bleeding, i.e. none of the previous categories (22.8%). Changes in menstrual bleeding patterns were only occasionly reported as adverse event by the patients (See adverse event table).

The frequencies of adverse drug reactions (ADRs) by MedDRA system organ classes (MedDRA SOCs) reported with Visabelle are summarized in the table below. Within each frequency grouping, undesirable effects are presented in order of decreasing frequency. Frequencies are defined as common (≥1/100 to <1/10) and uncommon (≥1/1,000 to <1/100). The frequencies are based on pooled data of four clinical trials, including 332 patients (100%).


Table 1, Adverse reactions table, phase III clinical trials, N= 332

System Organ Class       Common                              Uncommon 
Blood and lymphatic                                          Anemia system disorders
Metabolism and           Weight increase                     Weight decrease nutrition disorders                                          Increased appetite System Organ Class      Common                       Uncommon

Psychiatric disorders   Depressed mood               Anxiety
Sleep disorder               Depression
Nervousness                  Mood swings
Loss of libido altered mood
Nervous system          Headache                     Autonomic nervous system imbalance disorders
Migraine
Disturbance in attention
Eye disorders                                        Dry eye
Ear and labyrinth                                    Tinnitus disorders
Cardiac disorders                                    Unspecified circulatory system disorder 
Palpitations
Vascular disorders                                   Hypotension
Respiratory, thoracic                                Dyspnoea and mediastinal disorders

Gastrointestinal        Nausea                       Diarrhoea disorders               Abdominal pain               Constipation
Flatulence                   Abdominal discomfort
Abdominal distension         Gastrointestinal inflammation
Vomiting                     Gingivitis
Skin and subcutaneous   Acne                         Dry skin tissue disorders        Alopecia                     Hyperhidrosis
Pruritus
Hirsutism
Onychoclasis
Dandruff
Dermatitis
Abnormal hair growth
Photosensitivity reaction pigmentation disorder
Musculoskeletal and     Back pain                    Bone pain connective tissue                                    Muscle spasms disorders                                            Pain in extremity Heaviness in extremities
Renal and urinary                                    Urinary tract infection disorders
Reproductive system     Breast discomfort            Vaginal candidiasis and breast disorders    Ovarian cyst                 Vulvovaginal dryness Hot flushes                  Genital discharge
Uterine / Vaginal bleeding   Pelvic pain including spotting           Atrophic vulvovaginitis
System Organ Class        Common                               Uncommon 
Breast mass
Fibrocystic breast disease
Breast induration
General disorders and     Asthenic conditions                  Oedema administration site       Irritability conditions


Decrease of bone mineral density
In an uncontrolled clinical trial with 111 adolescent women (12 to <18 years) who were treated with Visabelle, 103 had BMD measurements. Approximately 72% of these study participants experienced a decrease in BMD of the lumbar spine (L2-L4) after 12 months of use (see section 4.4).

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/