Adverse reactions : תופעות לוואי

4.8   Undesirable effects
The table below reports adverse reactions by MedDRA system organ classes (MedDRA SOCs). The f requencies are based on clinical trial data. The adverse reactions were recorded in 7 Phase III clinical studies (n=2424 women) and considered as at least possibly causally related to Angeliq (E2 1 mg / DRSP doses 0.5, 1, 2, or 3 mg).

The most commonly reported adverse reactions were breast pain (> 10%) and during the f irst f ew months of treatment, bleeding and spotting (> 10%). Bleeding irregularities usually subside during continued treatment (see section 5.1). The f requency of bleeding decreases with the duration of treatment.

System Organ Class Common                           Uncommon                   Rare (≥ 1/100 to < 1/10)             (≥ 1/1000 to < 1/100)      (< 1/1000) Blood and lymphatic                                                            Anemia system disorders
Metabolism and                              Weight increase or nutrition disorders                         weight decrease,
anorexia, increased appetite, hyperlipemia
Psychiatric disorders Depression, emotional Sleep disorder, anxiety,
lability, nervousness libido decreased
Nervous system        Headache              Paresthesia,             Vertigo disorders                                   concentration ability impaired, dizziness
Eye disorders                               Eye disorder, visual disturbance
System Organ Class Common                                                   Uncommon                              Rare (≥ 1/100 to < 1/10)                                      (≥ 1/1000 to < 1/100)                 (< 1/1000) Ear and labyrinth                                                                                                 Tinnitus disorders
Cardiac disorders                                                           Palpitation Vascular disorders                                                          Embolism, venous thrombosis,
hypertension, migraine,
thrombophlebitis,
varicose veins
Respiratory, thoracic                                                       Dyspnoea and mediastinal disorders
Gastrointestinal      Abdominal pain,                          Gastrointestinal disorders             nausea, abdomen                          disorder, diarrhea, enlarged                                 constipation, vomiting,
dry mouth, f latulence,
taste disturbance
Hepatobiliary                                                  Liver f unction test                               Cholelithiasis disorders                                                      abnormal Skin and                                                       Skin disorder, acne, subcutaneous tissue                                            alopecia, pruritus, rash, disorders                                                      hirsutism, hair disorder Musculoskeletal and                                            Pain in extremity, back                            Myalgia connective tissue                                              pain, arthralgia, muscle disorders                                                      cramps Renal and urinary                                              Urinary tract disorder, disorders                                                      urinary tract inf ection Reproductive system                 Benign breast              Breast carcinoma,                                  Salpingitis, and breast disorders                neoplasm, breast           endometrial hyperplasia,                           galactorrhoea enlargement, uterine       benign uterine f ibroids enlarged, benign neoplasm, f ibrocystic neoplasm of cervix uteri, breast, uterine disorder,
menstrual disorder,        ovarian disorder, cervix vaginal discharge          disorder, pelvic pain,
vulvovaginal disorder,
vaginal candidiasis,
vaginitis, vaginal dryness
General disorders and               Asthenia, localized        Generalized oedema,                                Chills administration site                 oedema                     chest pain, malaise, conditions                                                     sweating increased The most appropriate MedDRA term is used to describe a certain reaction and its synonyms and related conditions.


Additional inf ormation on special populations
The f ollowing, undesirable effects classified as at least possibly related to Angeliq treatment by the investigator, were recorded in 2 clinical studies in hypertensive women.

Metabolism and nutrition disorders
Hyperkalemia.

Cardiac disorders
Cardiac f ailure, atrial f lutter, QT interval prolonged, cardiomegaly.
Investigations
Blood aldosterone increased.

The f ollowing undesirable ef f ects have been reported in association with HRT products: Erythema nodosum, erythema multif orme, chloasma and hemorrhagic dermatitis.
Breast cancer risk

•   An up to 2-f old increased risk of having breast cancer diagnosed is reported in women taking combined oestrogen-progestagen therapy f or more than 5 years.
•   The increased risk in users of oestrogen-only therapy is lower than that seen in users of oestrogen-progestagen combinations.
•   The level of risk is dependent on the duration of use (see section 4.4).
•   Absolute risk estimations based on results of the largest randomised placebo- controlled trial (WHI study) and the largest meta-analysis of prospective epidemiological studies are presented.

Largest meta-analysis of prospective epidemiological studies –

Estimated additional risk of breast cancer after 5 years' use in women with BMI 27 (kg/m2) Age at         Incidence per 1000 never-                Risk ratio         Additional cases per 1000 start HRT       users of HRT over a 5-year                                   HRT users after 5 years (years)           period (50-54 years)a
Oestrogen-only HRT
50            13.3                              1.2                         2.7 Combined oestrogen-progestagen
50            13.3                                 1.6                      8.0 a Taken f rom baseline incidence rates in England in 2015 in women with BMI 27 (kg/m2).
Note: Since the background incidence of breast cancer dif f ers by EU country, the number of additional cases of breast cancer will also change proportionately.

Estimated additional risk of breast cancer af ter 10 years’ use in women with BMI 27 (kg/m2) 

Age at start     Incidence per 1000
HRT              never-users of HRT over Risk ratio                  Additional cases per 1000 HRT a 10 year period (50-59                             users af ter 10 years (years)          years) *
Estrogen only HRT
50               26.6                       1.3                      7.1 Combined estrogen-progestogen
50               26.6                       1.8                      20.8 *Taken f rom baseline incidence rates in England in 2015 in women with BMI 27 (kg/m2) Note: Since the background incidence of breast cancer dif f ers by EU country, the number of additional cases of breast cancer will also change proportionately.


US WHI studies - additional risk of breast cancer after 5 years of use Age range       Incidence per 1000 women        Risk ratio & 95% CI         Additional cases per 1000 (years)        in placebo arm over 5 years                                 HRT users over 5 years (95% CI)
CEE oestrogen-only
50 - 79         21                              0.8 (0.7 - 1.0)              -4 (-6 - 0) a b
CEE + MPA oestrogen & progestagen
50 - 79         17                              1.2 (1.0 - 1.5)              +4 (0 - 9) a WHI study in women with no uterus, which did not show an increased in risk of breast cancer.
b When the analysis was restricted to women who had not used HRT prior to the study there was no increased risk apparent during the first 5 years of treatment: after 5 years the risk was higher than in non-users.

Endometrial cancer risk

Postmenopausal women with a uterus
The endometrial cancer risk is about 5 in every 1000 women with an uterus not using HRT. In women with a uterus, use of oestrogen-only HRT is not recommended because it increases the risk of endometrial cancer (see section 4.4). Depending on the duration of oestrogen-only use and oestrogen dose, the increase in risk of endometrial cancer in epidemiology studies varied f rom between 5 and 55 extra cases diagnosed in every 1000 women between the ages of 50 and 65.

Adding a progestagen to oestrogen-only therapy for at least 12 days per cycle can prevent this increased risk. In the Million Women Study the use of f ive years of combined (sequential or continuous) HRT did not increase risk of endometrial cancer (RR of 1.0 (0.8-1.2)).

Ovarian cancer

Use of oestrogen-only or combined oestrogen-progestagen HRT has been associated with a slightly increased risk of having ovarian cancer diagnosed (see Section 4.4).

A meta-analysis from 52 epidemiological studies reported an increased risk of ovarian cancer in women currently using HRT compared to women who have never used HRT (RR 1.43, 95% CI 1.31-1.56). For women aged 50 to 54 years taking 5 years of HRT, this results in about 1 extra case per 2000 users. In women aged 50 to 54 who are not taking HRT, about 2 women in 2000 will be diagnosed with ovarian cancer over a 5-year period.

Risk of venous thromboembolism

HRT is associated with a 1.3 - 3-f old increased relative risk of developing venous thromboembolism (VTE), i.e. deep vein thrombosis or pulmonary embolism. The occurrence of such an event is more likely in the first year of using HRT (see section 4.4). Results of the WHI studies are presented:

WHI Studies - additional risk of VTE over 5 years of use
Age range     Incidence per 1000           Risk ratio & 95% CI        Additional cases per 1000 (years)     women in placebo arm                                            HRT users over 5 years
Oral oestrogen-only a
50 - 59                 7                     1.2 (0.6 - 2.4)                  1 (-3 - 10) Oral combined oestrogen-progestagen
50 - 59                 4                     2.3 (1.2 - 4.3)                  5 (1 - 13) a
Study in women with no uterus.

Risk of coronary artery disease

The risk of coronary artery disease is slightly increased in users of combined oestrogen- progestagen HRT over the age of 60 (see section 4.4).

Risk of ischaemic stroke
The use of oestrogen-only and oestrogen-progestagen therapy is associated with an up to 1.5- f old increased relative risk of ischaemic stroke. The risk of haemorrhagic stroke is not increased during use of HRT.

This relative risk is not dependent on age or on duration of use, but as the baseline risk is strongly age-dependent, the overall risk of stroke in women who use HRT will increase with age, see section 4.4.

WHI studies combined - additional risk of ischaemic stroke a over 5 years of use Age range       Incidence per 1000 women        Risk ratio & 95%      Additional cases per 1000 HRT (years)       in placebo arm over 5 years             CI                   users over 5 year 50 - 59                  8                    1.3 (1.1 – 1.6)                  3 (1 – 5) a
No dif f erentiation was made between ischaemic and haemorrhagic stroke.

Other adverse reactions have been reported in association with estrogen/progestogen treatment
- Gall bladder disease.
- Skin and subcutaneous disorders: chloasma, erythema multiforme, erythema nodosum, vascular purpura.
- Probable dementia over the age of 65 (see section 4.4).

Reporting of suspected adverse reactions
Reporting suspected adverse reactions af ter 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 f orm https://sideeffects.health.gov.il