Adverse reactions : תופעות לוואי

4.8   Undesirable effects

The following adverse reactions, associated with estrogen treatment may occur during estriol therapy or overdose: Nausea and vomiting, breast tenderness or pain in the breasts, vaginal bleeding or spotting during or on withdrawal of therapy, excessive production of cervical mucus, headache.

From Literature and safety surveillance monitoring, the following adverse reactions have been reported:

System organ class                        Adverse reactions*
General disorders and                   Application site irritation and administration site conditions          pruritus
Influenza-like illness
Reproductive system and breast          Breast discomfort and pain disorders
*MedDRA version 9.1
These adverse reactions are usually transient, but may also be indicative of too high a dosage.

Class effects associated with systemic HRT
The following risks have been associated with systemic HRT and apply to a lesser extent for Ovestin vaginal cream of which the systemic exposure to estriol remains closely to the normal postmenopausal range when used in a twice weekly administration.

Ovarian cancer
Use of systemic 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 systemic 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

Systemic HRT is associated with a 1.3-3-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 HT (see section 4.4). Results of the WHI studies are presented:
WHI Studies - Additional risk of VTE over 5 years’ use
Age        Incidence per 1000      Risk ratio &         Additional cases range     women in placebo arm         95%CI              per 1000 HRT (yrs)          over 5 years                                    users
Oral estrogen-only
50-59               7              1.2 (0.6 – 2.4)          1 (-3 – 10) * Study in women with no uterus

Risk of ischaemic stroke

•   The use of systemic HRT 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 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* over 5 years’ use
Age           Incidence per 1000          Risk ratio        Additional cases range           women in placebo          and 95%CI           per 1000 HRT (years)          arm over 5 years                            users over 5 years 50-59                  8                 1.3 (1.1– 1.6)           3 (1-5) *no differentiation was made between ischaemic and haemorrhagic stroke.

Other adverse reactions have been reported in association with estrogen-only and estrogen/progestagen combined treatment:
• Estrogen-dependent neoplasms benign and malignant, e.g. endometrial cancer. For further information see sections 4.3 and 4.4
•    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 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: http://sideeffects.health.gov.il
Additionally, you can also report to Padagis via the following address: Padagis.co.il