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 at very low rates, similar to placebo, with Vagifem 10 micrograms, 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 to <1/10): Nervous system disorders: headache.
Gastrointestinal disorders: abdominal pain.
Reproductive system and breast disorders: vaginal haemorrhage, vaginal discharge or vaginal discomfort.
Uncommon (≥1/1000 to <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 below 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, depression.
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 oestrogen treatment.
Risk estimates have been drawn from systemic exposure and it is not known how these apply to local treatments: Myocardial infarction; congestive heart disease; stroke; gallbladder disease; skin and subcutaneous disorders (chloasma, erythema multiforme, erythema nodosum, vascular purpura); increase in size of fibroids; epilepsy; libido disorder; deterioration of asthma; probable dementia over the age of 65 (see Precautions).
Breast cancer risk: Risk estimates have been drawn from systemic exposure and it is not known how these apply to local treatments.
An up to 2-fold increased risk of having breast cancer diagnosed is reported in women taking combined oestrogen-progestagen therapy for more than 5 years.
Any increased risk in users of oestrogen-only therapy is substantially lower than that seen in users of oestrogen-progestagen combinations.
The level of risk is dependent on the duration of use (see Precautions).
Results of the largest randomised placebo-controlled trial (WHI study) and largest epidemiological study (MWS) are presented.
Million Women Study - Estimated additional risk of breast cancer after 5-years' use: Oestrogen-only HRT: Age range (years): 50-65.
Incidence per 1,000 never-users of HRT over a 5-year period*: 9-12.
Risk ratio and 95% CI**: 1.2.
Additional cases per 1,000 HRT users over 5 years (95% CI): 1-2 (0-3).
Combined oestrogen-progestagen: Age range (years): 50-65.
Incidence per 1,000 never-users of HRT over a 5-year period*: 9-12.
Risk ratio and 95% CI**: 1.7.
Additional cases per 1,000 HRT users over 5 years (95% CI): 6 (5-7).
*Taken from baseline incidence rates in developed countries.
**Overall risk ratio. The risk ratio is not constant but will increase with increasing duration on use.
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 systemic oestrogen-only HRT is not recommended because it increases the risk of endometrial cancer (see Precautions).
Depending on the duration of systemic oestrogen-only use and oestrogen dose, the increase in risk of endometrial cancer in epidemiology 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 systemic oestrogen-only therapy for at least 12 days per cycle can prevent this increased risk. In the Million Women Study the use of five years of combined (sequential or continuous) HRT did not increase risk of endometrial cancer (RR of 1.0 (0.8-1.2)). (See Precautions.)
Ovarian cancer: Risk estimates have been drawn from systemic exposure and it is not known how these apply to local treatments.
Long-term use of oestrogen-only and combined oestrogen-progestagen HRT has been associated with a slightly increased risk of ovarian cancer. In the Million Women Study, 5 years of HRT resulted in 1 extra case per 2,500 users.
Risk of venous thromboembolism: Risk estimates have been drawn from systemic exposure and it is not known how these apply to local treatments.
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.
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).
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: 5 (1-13).
*Study in women with no uterus.
Risk of coronary artery disease: Risk estimates have been drawn from systemic exposure and it is not known how these apply to local treatments.
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: Risk estimates have been drawn from systemic exposure and it is not known how these apply to local treatments.
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 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.