Source: Medicines & Healthcare Products Regulatory Agency (GB) Revision Year: 2016 Publisher: Pfizer Limited, Ramsgate Road, Sandwich, Kent, CT13 9NJ, United Kingdom
For the treatment of postmenopausal symptoms, HRT should only be initiated for symptoms that adversely affect quality of life. In all cases, a careful appraisal of the risks and benefits should be undertaken at least annually and HRT should only be continued as long as the benefit outweighs the risk.
Evidence regarding the risks associated with HRT in the treatment of premature menopause is limited. Due to the low level of absolute risk in younger women, however, the balance of benefits and risks for these women may be more favourable than in older women.
Before initiating or reinstituting HRT, a complete personal and family medical history should be taken. Physical (including pelvic and breast) examination should be guided by this and by the contraindications and warnings for use. During treatment, periodic check-ups are recommended of a frequency and nature adapted to the individual women. Women should be advised what changes in their breasts should be reported to their doctor or nurse (see ‘Breast Cancer’ below). Investigations, including appropriate imaging tools, e.g. mammography, should be carried out in accordance with currently accepted screening practices, modified to the clinical needs of the individual.
If any of the following conditions are present, have occurred previously, and/or have been aggravated during pregnancy or previous hormone treatment, the patient should be closely supervised. It should be taken into account that these conditions may recur or be aggravated during treatment with Premarin, in particular:
Therapy should be discontinued if a contra-indication is discovered and in the following situations:
In women with an intact uterus the risk of endometrial hyperplasia and carcinoma is increased when estrogens are administered alone for prolonged periods. The reported increase in endometrial cancer risk among estrogen-only users varies from 2-to 12-fold greater compared with non-users, depending on the duration of treatment and estrogen dose (see section 4.8). After stopping treatment risk may remain elevated for at least 10 years.
The addition of a progestogen for at least 12 days per month/28 day cycle or continuous combined estrogen-progestogen therapy in non-hysterectomised women prevents the excess risk associated with estrogen-only HRT.
For oral doses of conjugated equine estrogens >0.625 mg the endometrial safety of added progestogens has not been demonstrated. The reduction in risk to the endometrium should be weighed against the increase in the risk of breast cancer of added progestogen (see ‘Breast Cancer’ below and section 4.8).
Breakthrough bleeding and spotting may occur during the first months of treatment. If break-through bleeding or spotting appears after some time on therapy, or continues after treatment has been discontinued, the reason should be investigated, which may include endometrial biopsy to exclude endometrial malignancy.
Unopposed estrogen stimulation may lead to pre-malignant or malignant transformation in the residual foci of endometriosis. Therefore, the addition of progestogens to estrogen replacement therapy should be considered in women who have undergone hysterectomy because of endometriosis, if they are known to have residual endometriosis (but see above).
The overall evidence suggests an increased risk of breast cancer in women taking combined estrogen-progestogen and possibly also estrogen-only HRT, that is dependent on the duration of taking HRT.
The Women’s Health Initiative trial (WHI) found no increase in the risk of breast cancer in hysterectomised women using estrogen-only HRT. Observational studies have mostly reported a small increase in risk of having breast cancer diagnosed that is substantially lower than that found in users of estrogen-progestogen combinations (see section 4.8).
For all HRT, an excess risk becomes apparent within a few years of use and increases with the duration of intake but returns to baseline within a few (at most five) years after stopping treatment.
HRT, especially estrogen-progestogen combined treatment, increases the density of mammographic images which may adversely affect the radiological detection of breast cancer.
Ovarian cancer is much rarer than breast cancer.
Epidemiological evidence from a large meta-analysis suggests a slightly increased risk in women taking estrogen-only or combined estrogen-progestogen HRT, which becomes apparent within 5 years of use and diminishes over time after stopping.
Some other studies, including the WHI trial, suggest that the use of combined HRTs may be associated with a similar or slightly smaller risk (see section 4.8).
Hormone replacement therapy (HRT) is associated with a 1.3-3 fold 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 HRT than later (see section 4.8).
Patients with a history of VTE or known thrombophilic states have an increased risk of VTE. HRT may add to this risk. HRT is therefore contraindicated in these patients (see section 4.3). Personal or strong family history of thromboembolism or recurrent spontaneous abortion should be investigated in order to exclude a thrombophilic predisposition.
Generally recognised risk factors for VTE include, use of estrogens, older age, major surgery, prolonged immobilisation, obesity (Body Mass Index >30kg/m2), pregnancy/postpartum period, systemic lupus erythematosus (SLE) and cancer. There is no consensus about the possible role of varicose veins in VTE.
As in all postoperative patients scrupulous attention should be given to prophylactic measures to prevent VTE following surgery. If prolonged immobilisation is liable to follow elective surgery, particularly abdominal or orthopaedic surgery to the lower limbs temporarily stopping HRT 4 to 6 weeks earlier is recommended. Treatment should not be restarted until the woman is completely mobilised.
In women with no personal history of VTE but with a first degree relative with a history of thrombosis at young age, screening may be offered after careful counselling regarding its limitations (only a proportion of thrombophilic defects are identified by screening). If a thrombophilic defect is identified which segregates with thrombosis in family members or if the defect is ‘severe’ (e.g., antithrombin, protein S, or protein C deficiencies or a combination of defects) HRT is contraindicated.
Women already on chronic anticoagulant treatment require careful consideration of the benefit-risk of use of HRT.
If VTE develops after initiating therapy, the drug should be discontinued. Patients should be told to contact their doctors immediately when they are aware of potential thromboembolic symptoms (e.g. painful swelling of a leg, sudden pain in the chest, dyspnoea).
There is no evidence from randomised controlled trials of protection against myocardial infarction in women with or without existing CAD who received combined estrogen-progestogen or estrogen-only HRT. Randomised controlled data found no increased risk of CAD in hysterectomised women using estrogen-only therapy.
Combined estrogen-progestogen and estrogen-only therapy are associated with an up to 1.5-fold increase in risk of ischaemic stroke. The relative risk does not change with age or time since menopause. However, as the baseline risk of stroke is strongly age-dependent, the overall risk of stroke in women who use HRT will increase with age (see section 4.8).
In the WHI estrogen-alone substudy, a statistically significant increased risk of stroke was reported in women 50 to 79 years of age receiving daily CE (0.625 mg) compared to women receiving placebo (45 versus 33 per 10,000 women-years). The increase in risk was demonstrated in year one and persisted. Subgroup analyses of women 50 to 59 years of age suggest no increased risk of stroke for those women receiving CE (0.625 mg) versus those receiving placebo (18 versus 21 per 10,000 women-years).
Estrogens increase thyroid binding globulin (TBG), leading to increased circulating total thyroid hormone, as measured by protein-bound iodine (PBI), T4 levels (by column or by radio-immunoassay) or T3 levels (by radio-immunoassay). T3 resin uptake is decreased, reflecting the elevated TBG. Free T4 and free T3 concentrations are unaltered.
Other binding proteins may be elevated in serum, i.e. corticoid binding globulin (CBG), sex-hormone-binding globulin (SHBG) leading to increased circulating corticosteroids and sex steroids, respectively. Free or biologically active hormone concentrations are unchanged. Other plasma proteins may be increased (angiotensinogen/renin substrate, alpha-I-antitrypsin, ceruloplasmin).
Some patients dependent on thyroid hormone replacement therapy may require increased doses in order to maintain their free thyroid hormone levels in an acceptable range. Therefore, patients should have their thyroid function monitored more frequently when commencing concurrent treatment in order to maintain their free thyroid hormone levels in an acceptable range.
Estrogen administration should be guided by clinical response rather than by hormone levels (e.g. estradiol, FSH).
The metabolism of estrogens may be increased by concomitant use of substances known to induce drug-metabolising enzymes, specifically cytochrome P450 3A4 (CYP3A4) enzymes. Therefore, inducers or inhibitors of CYP3A4 may affect estrogen drug metabolism. Inducers of CYP3A4, such as St. John’s wort (Hypericum perforatum) preparations, phenobarbital, phenytoin, carbamazepine, rifampicin, rifabutin, nevirapine, efavirenz and dexamethasone, may reduce plasma concentrations of estrogens, possibly resulting in a decrease in therapeutic effects and/or changes in the uterine bleeding profile. Inhibitors of CYP3A4, such as cimetidine, erythromycin, clarithromycin, ketoconazole, itraconazole, ritonavir, nelfinavir and grapefruit juice, may increase plasma concentrations of estrogens and may result in side effects.
Increased platelet count decreased levels of antithrombin III, and increased plasminogen antigen and activity.
Estrogens increase thyroid-binding globulin (TBG) leading to increased circulating total thyroid hormone, as measured by protein-bound iodine (PBI), T4 levels by column or by radioimmunoassay or T3 levels by radioimmunoassay. T3 resin uptake is decreased, reflecting the elevated TBG. Free T4 and free T3 concentrations are unaltered.
Other binding proteins may be elevated in serum, i.e., corticosteroid binding globulin (CBG), sex hormone-binding globulin (SHBG) leading to increased circulating corticosteroid and sex steroids, respectively. Free or biologically active hormone concentrations may be decreased.
Increased plasma HDL and HDL2 cholesterol subfraction concentrations, reduced LDL cholesterol concentrations, increased triglyceride levels.
Impaired glucose tolerance.
The response to metyrapone may be reduced.
Premarin is not indicated during pregnancy.
If pregnancy occurs during medication with Premarin treatment should be withdrawn immediately. The results of most epidemiological studies to date relevant to inadvertent foetal exposure to estrogens indicate no teratogenic or foetotoxic effects.
Premarin is not indicated during lactation.
No studies on the effect of ability to drive or use machines have been performed.
See also section 4.4.
The adverse reactions listed in the table are based on post-marketing spontaneous (reporting rate), clinical trials and class-effects.
Common ADRs (>1/100, < 1/10)
Uncommon ADRs (>1/1000, <1/100)
Rare ADRs (>1/10000, <1/1000)
Very Rare ADRs (<1/10000), isolated reports
Uncommon: Vaginitis, including vaginal candidiasis
Rare: Fibrocystic breast changes; Ovarian cancer; Growth potentiation of benign meningioma
Very rare: Enlargement of hepatic haemangiomas
Uncommon: Hypersensitivity
Rare: Anaphylactic/anaphylactoid reactions, including urticaria and angioedema
Rare: Glucose intolerance
Very rare: Exacerbation of porphyria; Hypocalcaemia
Common: Depression
Uncommon: Changes in libido; Mood disturbances;
Rare: Irritability
Uncommon: Dizziness; Headache; Migraine; Anxiety
Rare: Stroke; Exacerbation of epilepsy
Very rare: Exacerbation of chorea
Uncommon: Intolerance to contact lenses
Very rare: Retinal vascular thrombosis
Rare: Myocardial infarction
Uncommon: Venous thrombosis; Pulmonary embolism
Rare: Superficial thrombophlebitis
Rare: Exacerbation of asthma
Uncommon: Nausea; Bloating; Abdominal pain
Rare: Vomiting; Pancreatitis; Ischaemic colitis
Uncommon: Gallbladder disease
Very rare: Cholestatic jaundice
Common: Alopecia
Uncommon: Chloasma/melasma; Hirsutism; Pruritus; Rash
Common: Arthralgias; Leg cramps
Common: Abnormal uterine bleeding (Breakthrough bleeding/spotting); Breast pain, tenderness, enlargement, discharge; Leucorrhoea
Uncommon: Change in menstrual flow; Change in cervical ectropion and secretion
Rare: Dysmenorrhoea/pelvic pain; Galactorrhoea; Increased size of uterine leiomyomata
Uncommon: Oedema
Common: Changes in weight (increase or decrease); Increased triglycerides
Very rare: Increases in blood pressure
Million Women study– Estimated additional risk of breast cancer after 5 years' use
US WHI studies – additional risk of breast cancer after 5 years' use
The endometrial cancer risk is about 5 in every 1000 women with a uterus not using HRT.
In women with a uterus, use of estrogen-only HRT is not recommended because it increases the risk of endometrial cancer (see section 4.4).
Depending on the duration of estrogen-only use and estrogen dose, the increase in risk of endometrial cancer in epidemiology studies varied from between 5 and 55 extra cases diagnosed in every 1000 women between the ages of 50 and 65.
Adding a progestogen to estrogen-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)).
Use of estrogen-only and combined estrogen-progestogen 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 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 2000 users. In women aged 50 to 54 who are not taking HRT, about 2 women in 2000 will be diagnosed with ovarian cancer over a 5-year period.
HRT is associated with a 1.3-3-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 HT (see section 4.4). Results of the WHI studies are presented:
WHI studies – Additional risk of VTE over 5 years' use
| Age range (years) | Incidence per 1000 women in placebo arm over 5 years | Risk ratio and 95%CI | Additional cases per 1000 HRT users |
|---|---|---|---|
| Oral estrogen-only* | |||
| 50-59 | 7 | 1.2 (0.6-2.4) | 1 (-3 – 10) |
| Oral combined estrogen-progestogen | |||
| 50-59 | 4 | 2.3 (1.2 – 4.3) | 5 (1 – 13) |
* Study in women with no uterus
WHI studies combined – Additional risk of ischaemic stroke* over 5 years' use
| Age range (years) | Incidence per 1000 women in placebo arm over 5 years | Risk ratio and 95%CI | Additional cases per 1000 HRT users over 5 years |
|---|---|---|---|
| 50-59 | 8 | 1.3 (1.1 1.6) | 3 (1-5) |
* no differentiation was made between ischaemic and haemorrhagic stroke.
Other adverse reactions reported in association with estrogen/progestogen treatment including Premarin:
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. Healthcare professionals are asked to report any suspected adverse reactions via the Yellow Card Scheme at www.mhra.gov.uk/yellowcard.
Not applicable.
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