Activelle Adverse Reactions

Clinical experience: The most frequently reported adverse events in the clinical trials with Activelle were vaginal bleeding and breast pain/tenderness, reported in approximately 10% to 20% of patients. Vaginal bleeding usually occurred in the first months of treatment. Breast pain usually disappeared after a few months of therapy. All adverse events observed in the randomised clinical trials with a higher frequency in patients treated with Activelle as compared to placebo, and which on an overall judgement are possibly related to treatment, are presented as follows.
Very common (≥1/10): Reproductive system and breast disorders: Breast pain or breast tenderness; Vaginal haemorrhage.
Common (≥1/100; <1/10): Infections and infestations: Genital candidiasis or vaginitis (see also Reproductive system and breast disorders as follows).
Metabolism and nutrition disorders: Fluid retention (see also General disorders and administration site conditions as follows).
Psychiatric disorders: Depression or depression aggravated.
Nervous system disorders: Headache; Migraine or migraine aggravated.
Gastrointestinal disorders: Nausea.
Musculoskeletal and connective tissue disorders: Back pain.
Reproductive system and breast disorders: Breast oedema or breast enlargement; Uterine fibroids aggravated or uterine fibroids recurrence or uterine fibroids.
General disorders and administration site conditions: Oedema peripheral.
Investigations: Weight increased.
Uncommon (≥1/1,000; <1/100): Immune system disorders: Hypersensitivity (see also Skin and subcutaneous tissue disorders as follows).
Psychiatric disorders: Nervousness.
Vascular disorders: Thrombophlebitis superficial.
Gastrointestinal disorders: Abdominal pain; Abdominal distension; Abdominal discomfort; Flatulence or bloating.
Skin and subcutaneous tissue disorders: Alopecia; Hirsutism or acne; Pruritus or urticaria.
Musculoskeletal, connective tissue and bone disorders: Leg cramps.
General disorders and administration site conditions: Drug ineffective.
Rare (≥1/10,000; <1/1,000): Vascular disorders: Pulmonary embolism; Thrombophlebitis deep.
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 judgement considered possibly related to Activelle 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: Neoplasms benign and malignant (including cysts and polyps): Endometrial cancer.
Immune system disorders: Generalised hypersensitivity reactions (e.g. anaphylactic reaction/shock).
Psychiatric disorders: Insomnia, anxiety, libido decreased, libido increased.
Nervous system disorders: Dizziness, stroke.
Eye disorders: Visual disturbances.
Cardiac disorders: Myocardial infarction.
Vascular disorders: Hypertension aggravated.
Gastrointestinal disorders: Dyspepsia, vomiting.
Hepatobiliary disorders: Gallbladder disease, cholelithiasis, cholelithiasis aggravated, cholelithiasis recurrence.
Skin and subcutaneous tissue disorders: Seborrhoea, rash, angioneurotic oedema.
Reproductive system and breast disorders: Endometrial hyperplasia, vulvovaginal pruritus.
Investigations: Weight decreased, blood pressure increased.
Other adverse reactions have been reported in association with oestrogen/progestagen treatment: Skin and subcutaneous disorders (alopecia, chloasma, erythema multiforme, erythema nodosum, vascular purpura); Probable dementia over the age of 65 (see Precautions).
Breast cancer risk: 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 as follows: 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 5 years*: 9-12.
Risk ratio**: 1.2.
Additional cases per 1,000 HRT users over 5 years' use (95% CI): 1-2 (0-3).
Combined oestrogen-progestagen: Age range (years): 50-65.
Incidence per 1,000 never-users of HRT over 5 years*: 9-12.
Risk ratio**: 1.7.
Additional cases per 1,000 HRT users over 5 years' use (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' use (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' use (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: 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' use (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' use (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' use (95% CI): 3 (1-5).
* No differentiation was made between ischaemic and haemorrhagic stroke.