Estrofem Adverse Reactions

Clinical experience: In clinical trials less than 10% of the patients experienced adverse drug reactions. The most frequently reported adverse reactions are breast tenderness/breast pain, abdominal pain, oedema, and headache. The adverse reactions listed as follows occurred in the clinical trials during Estrofem treatment.
Common: ≥ 1/100 and < 1/10: Psychiatric disorders: Depression.
Nervous system disorders: Headache.
Gastrointestinal disorders: Abdominal pain or nausea.
Musculoskeletal and connective tissue disorders: Leg cramps.
Reproductive system and breast disorders: Breast tenderness, breast enlargement or breast pain.
General disorders and administration site conditions: Oedema.
Investigations: Weight increased.
Uncommon: ≥ 1/1,000 and < 1/100: Eye disorders: Vision abnormal.
Vascular disorders: Venous embolism.
Gastrointestinal disorders: Dyspepsia; Vomiting; Flatulence or bloating.
Hepatobiliary disorders: Cholelithiasis.
Skin and subcutaneous tissue disorders: Rash or urticaria.
Post-marketing experience: In addition to the previously mentioned adverse drug reactions, those presented as follows have been spontaneously reported, and are by an overall judgment considered possibly related to Estrofem treatment. The reporting rate of these spontaneous adverse drug reactions is very rare (< 1/10,000, not known (cannot be estimated from the available data)). Post-marketing experience is subject to underreporting especially with regard to trivial and well-known adverse drug reactions. The presented frequencies should be interpreted in that light: Immune system disorder: Generalised hypersensitivity reactions (e.g. anaphylactic reaction/shock).
Nervous system disorder: Deterioration of migraine, stroke, dizziness, depression.
Gastrointestinal disorder: Diarrhoea.
Skin and subcutaneous tissue disorders: Alopecia.
Reproductive system and breast disorders: Irregular vaginal bleeding*.
Investigations: Increased blood pressure.
The following adverse reactions have been reported in association with other oestrogen treatment: Myocardial infarction, congestive heart disease; Venous thromboembolism, i.e. deep leg or pelvic venous thrombosis and pulmonary embolism; Gall bladder disease; Skin and subcutaneous disorders: chloasma, erythema multiforme, erythema nodosum, vascular purpura, pruritus; Vaginal candidiasis; Oestrogen-dependent neoplasms benign and malignant e.g. endometrial cancer (see Precautions), endometrial hyperplasia or increase in size of uterine fibroids*; Insomnia; Epilepsy; Libido disorder NOS (not otherwise specified); Deterioration of asthma; Probable dementia (see Precautions).
*In non-hysterectomised women.
Breast cancer risk: 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 Precautions).
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 as follows.
Largest meta-analysis of prospective epidemiological studies: Estimated additional risk of breast cancer after 5 years' use in women with BMI 27 (kg/m²): Oestrogen-only HRT: Age at start HRT (years): 50.
Incidence per 1,000 never-users of HRT over a 5-year period (50-54 years)*: 13.3.
Risk ratio: 1.2.
Additional cases per 1,000 HRT users after 5 years: 2.7.
Combined oestrogen-progestagen: Age at start HRT (years): 50.
Incidence per 1,000 never-users of HRT over a 5-year period (50-54 years)*: 13.3.
Risk ratio: 1.6.
Additional cases per 1,000 HRT users after 5 years: 8.0.
*Taken from baseline incidence rates in England in 2015 in women with BMI 27 (kg/m²).
Note: Since the background incidence of breast cancer differs by EU country, the number of additional cases of breast cancer will also change proportionally.
Estimated additional risk of breast cancer after 10 years' use in women with BMI 27 (kg/m²): Oestrogen-only HRT: Age at start HRT (years): 50.
Incidence per 1,000 never-users of HRT over a 10-year period (50-59 years)*: 26.6.
Risk ratio: 1.3.
Additional cases per 1,000 HRT users after 10 years: 7.1.
Combined oestrogen-progestagen: Age at start HRT (years): 50.
Incidence per 1,000 never-users of HRT over a 10-year period (50-59 years)*: 26.6.
Risk ratio: 1.8.
Additional cases per 1,000 HRT users after 10 years: 20.8.
*Taken from baseline incidence rates in England in 2015 in women with BMI 27 (kg/m²).
Note: Since the background incidence of breast cancer differs 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' use: CEE oestrogen-only: Age range (years): 50-79.
Incidence per 1,000 women in placebo arm over 5 years: 21.
Risk ratio and 95% CI: 0.8 (0.7-1.0).
Additional cases per 1,000 HRT users over 5 years (95% CI): -4 (-6-0)*.
CEE+MPA oestrogen-progestagen**: Age range (years): 50-79.
Incidence per 1,000 women in placebo arm over 5 years: 17.
Risk ratio and 95% CI: 1.2 (1.0-1.5).
Additional cases per 1,000 HRT users over 5 years (95% CI): 4 (0-9).
*WHI study in women with no uterus which did not show an increase in risk of breast cancer.
**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 1,000 women with a 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 Precautions) .
Depending on the duration of oestrogen-only use and oestrogen dose, the increase in risk of endometrial cancer in epidemiological studies varied from between 5 and 55 extra cases diagnosed in every 1,000 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 5 years of combined (sequential or continuous) HRT did not increase the risk of endometrial cancer (RR of 1.0 (0.8-1.2)).
Ovarian cancer risk: Use of oestrogen-only or combined oestrogen-progestagen HRT has been associated with a slightly increased risk of having ovarian cancer diagnosed (see Precautions).
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 2,000 users. In women aged 50 to 54 who are not taking HRT, about 2 women in 2,000 will be diagnosed with ovarian cancer over a 5-year period.
Risk of venous thromboembolism: HRT is associated with a 1.3- to 3-fold 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 Precautions). Results of the WHI studies are presented as follows.
WHI Studies - Additional risk of VTE over 5 years' use: Oral oestrogen-only*: Age range (years): 50-59.
Incidence per 1,000 women in placebo arm over 5 years: 7.
Risk ratio and 95% CI: 1.2 (0.6-2.4).
Additional cases per 1,000 HRT users over 5 years (95% CI): 1 (-3-10).
Oral combined oestrogen-progestagen: Age range (years): 50-59.
Incidence per 1,000 women in placebo arm over 5 years: 4.
Risk ratio and 95% CI: 2.3 (1.2-4.3).
Additional cases per 1,000 HRT users over 5 years (95% CI): 5 (1-13).
*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 Precautions).
Risk of ischaemic stroke: The use of oestrogen-only and oestrogen-progestagen therapy is associated with an up to 1.5-fold 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 the baseline risk is strongly age-dependent. The overall risk of stroke in women who use HRT will increase with age (see Precautions).
WHI Studies Combined - Additional risk of ischaemic stroke* over 5 years' use: Age range (years): 50-59.
Incidence per 1,000 women in placebo arm over 5 years: 8.
Risk ratio and 95% CI: 1.3 (1.1-1.6).
Additional cases per 1,000 HRT users over 5 years (95% CI): 3 (1-5).
*No differentiation was made between ischaemic and haemorrhagic stroke.