Vagifem Adverse Reactions

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 as follows.
Common (≥1/100; <1/10): Nervous system disorders: headache.
Gastrointestinal disorders: abdominal pain.
Reproductive system and breast disorders: vaginal haemorrhage, vaginal discharge or vaginal discomfort.
Uncommon (≥1/1,000; <1/100): Infections and infestations: vulvovaginal mycotic infection.
Gastrointestinal disorders: nausea.
Skin and subcutaneous tissue disorders: rash.
Investigations: weight increased.
Vascular disorders: hot flush, hypertension.
Post-marketing experience: In addition to the previously mentioned adverse drug reactions, those presented as follows have been spontaneously reported for patients being treated with Vagifem 25 micrograms and are considered possibly related to treatment. The reporting rate of these spontaneous adverse reactions is very rare (<1/10,000 patient years).
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 venous thrombosis.
Gastrointestinal disorders: diarrhoea.
Skin and subcutaneous tissue disorders: urticaria, rash erythematous, rash pruritic, genital pruritus.
Reproductive system and breast disorders: endometrial hyperplasia, vaginal irritation, vaginal pain, vaginismus, vaginal ulceration.
General disorders and administration site conditions: drug ineffective.
Investigations: weight increased, blood oestrogen increased.
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 Precautions).
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 Precautions).
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 2,000 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 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: 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 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: 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.