Novofem Adverse Reactions

Clinical experience: The most frequently reported adverse events during treatment in clinical trials conducted with an HRT product similar to Novofem were breast tenderness and headache (reported in ≥10% of patients).
The adverse events listed below may occur during oestrogen-progestagen treatment.
The frequencies are derived from clinical trials conducted with an HRT product similar to Novofem and from a Post-marketing Surveillance study on Novofem.
Very common: ≥1/10: Nervous system disorders: Headache.
Reproductive system and breast disorders: Breast tenderness.
Common: ≥1/100; <1/10: Infections and infestations: Vaginal candidiasis.
Nervous system disorders: Dizziness, insomnia, depression.
Vascular disorders: Increased blood pressure, aggravated hypertension.
Gastrointestinal disorders: Dyspepsia, abdominal pain, flatulence, nausea.
Skin and subcutaneous tissue disorders: Rash, pruritus.
Reproductive system and breast disorders: Vaginal haemorrhage, uterine fibroids aggravated.
General disorders and administration site conditions: Oedema.
Investigations: Weight increased.
Uncommon: ≥1/1,000; <1/100: Nervous system disorders: Migraine, libido disorder NOS (not otherwise specified).
Vascular disorders: Peripheral embolism and thrombosis.
Gastrointestinal disorders: Vomiting.
Hepatobiliary disorders: Gall bladder disease, gallstones.
Skin and subcutaneous tissue disorders: Alopecia.
Musculoskeletal and connective tissue disorders: Muscle cramps.
Rare: ≥1/10,000; <1/1,000: Immune system disorders: Allergic reaction.
Psychiatric disorders: Nervousness.
Nervous system disorders: Vertigo.
Gastrointestinal disorders: Diarrhoea, bloating.
Skin and subcutaneous tissue disorders: Acne.
Reproductive system and breast disorders: Uterine fibroid.
Post-marketing experience: In addition to the above mentioned adverse drug reactions, those presented below have been spontaneously reported, and are by an overall judgement considered possibly related to Novofem treatment. Frequencies of these adverse events cannot be estimated from the available data.
Neoplasms benign and malignant (including cysts and polyps): Endometrial cancer.
Immune system disorders: Generalised hypersensitivity reactions (e.g. anaphylactic reaction/shock).
Psychiatric disorders: Anxiety.
Nervous system disorders: Stroke.
Eye disorders: Visual disturbances.
Cardiac disorders: Myocardial infarction.
Vascular disorders: Hypertension aggravated.
Hepatobiliary disorders: Cholelithiasis aggravated, cholelithiasis recurrence.
Skin and subcutaneous tissue disorders: Seborrhoea, angioneurotic oedema, hirsutism.
Reproductive system and breast disorders: Endometrial hyperplasia, vulvovaginal pruritus.
Investigations: Weight decreased.
Other adverse reactions have been reported in association with oestrogen/progestagen treatment: Skin and subcutaneous disorders: Chloasma, erythema multiforme, erythema nodosum, haemorrhagic eruption, vascular purpura.
Probable dementia over the age of 65 (see Precautions); dry eyes; tear film composition changes.
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: 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: 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 for use).
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.