Adverse reactions : תופעות לוואי

4.8   Undesirable effects

Adverse events from clinical trials:

More than 673 patients have been treated with Vagifem 10 micrograms in clinical trials, including over 497 patients treated up to 52 weeks.

Oestrogen-related adverse events such as breast pain, peripheral oedema and postmenopausal bleedings have been reported with Vagifem 10 micrograms at very low rates, similar to placebo, but if they occur, they are most likely present only at the beginning of the treatment. The adverse events observed with a higher frequency in patients treated with Vagifem 10 micrograms as compared to placebo and which are possibly related to treatment are presented below.

System organ class            Common                 Uncommon                  Rare 1/100 to <1/10        1/1,000 to <1/100        1/10,000 to
<1/1,000
Infections and                                       Vulvovaginal mycotic infestations                                         infection

Nervous system disorders      Headache

Gastrointestinal              Abdominal pain         Nausea disorders
Reproductive system and       Vaginal breast disorders              haemorrhage, vaginal discharge or vaginal discomfort
Skin and subcutaneous                                Rash tissue disorders

Investigations                                       Weight increased Vascular disorders                                   Hot flush
Hypertension

Post-marketing experience:

In addition to the above mentioned adverse drug reactions, those presented below have been spontaneously reported for patients being treated with Vagifem 10 micrograms and are considered possibly related to treatment. The frequencies for the below mentioned adverse drug reactions cannot be interpreted because these reactions are reported voluntarily from a population of uncertain size: 
•     Neoplasms benign and malignant (including cysts and polyps): breast cancer, endometrial cancer
•     Immune system disorders: generalised hypersensitivity reactions (e.g. anaphylactic reaction/shock)
•     Metabolism and nutrition disorders: fluid retention
•     Psychiatric disorders: insomnia
•     Nervous system disorders: migraine aggravated
•     Vascular disorders: deep vein thrombosis
•     Gastrointestinal disorders: diarrhoea
•     Skin and subcutaneous tissue disorders: pruritus, rash, urticaria
•     Reproductive system and breast disorders: endometrial hyperplasia, vulvovaginal pain 1, pruritus genital• General disorders and administration site conditions: application site reaction2, drug ineffective, injury associated with device3
1
Including Vulvovaginal burning sensation
2
Local allergic reactions including Vulvovaginal erythema, Genital erythema, Vulvovaginal rash, Genital rash
3
Minor local trauma caused by intravaginal applicator

Other adverse reactions have been reported in association with systemic oestrogen/progestagen treatment. As risk estimates have been drawn from systemic exposure it is not known how these apply to local treatments:

•     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).

Class effects associated with systemic HRT

The following risks have been associated with systemic HRT and apply to a lesser extent for oestrogen products for vaginal application of which the systemic exposure to oestrogen remains within the normal postmenopausal range.

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 who have been taking HRT for 5 years, this results in about 1 extra case per 2,000 users. In women aged 50 to 54 who do not take 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- 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 section 4.4). Results of the WHI studies are presented below:

WHI Studies – Additional risk of VTE over 5 years’ use
Age range (years)      Incidence per          Risk ratio and               Additional cases per 1,000 women in         95% CI                       1,000 HRT users placebo arm over
5 years
Oral oestrogen-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 the 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 range (years)        Incidence per           Risk ratio and 95% Additional cases 1,000 women in          CI                   per 1,000 HRT placebo arm over                             users over 5 years
5 years
50 – 59                  8                       1.3 (1.1 – 1.6)      3 (1 – 5) * No differentiation was made between ischaemic and haemorrhagic stroke.

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