Chemical formula: C₁₈H₂₄O₂ Molecular mass: 272.382 g/mol PubChem compound: 5757
Estradiol interacts in the following cases:
Herbal preparations containing St. John’s wort (Hypericum Perforatum) may induce the metabolism of oestrogens.
Oestrogens 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 biological active hormone concentrations are unchanged. Other plasma proteins may be increased (angiotensinogen/renin substrate, alpha-1-antitrypsin, ceruloplasmin).
The metabolism of oestrogens may be increased by concomitant use of substances known to induce drug-metabolising enzymes, specifically cytochrome P450 enzymes, such as anticonvulsants (e.g. phenobarbital, phenytoin, carbamazepine) and anti-infectives (e.g. rifampicin, rifabutin, nevirapine, efavirenz).
Oestrogens per se may inhibit CYP450 drug-metabolising enzymes via competitive inhibition. This is in particular to be considered for substrates with a narrow therapeutic index, such as
Clinically this may lead to a plasma increase of the affected substances up to toxic levels. Thus, careful drug monitoring for an extended period of time might be indicated and a dosage decrease of tacrolimus, fentanyl, cyclosporin A, and theophylline may be necessary.
Women with pre-existing hypertriglyceridemia should be followed closely during oestrogen replacement or hormone replacement therapy, since rare cases of large increases of plasma triglycerides leading to pancreatitis have been reported with oestrogen therapy in this condition.
Combined oestrogen-progestogen and oestrogen-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.
Oestrogens may cause fluid retention, and therefore patients with cardiac or renal dysfunction should be carefully observed.
Estradiol is not indicated during pregnancy. If pregnancy occurs during medication with estradiol, treatment should be withdrawn immediately.
The results of most epidemiological studies to date relevant to inadvertant foetal exposure to oestrogens indicate no teratogenic or foetotoxic effects.
Estradiol is not indicated during lactation.
Estradiol has no or negligible influence on the ability to drive and use machines.
More than 1100 patients have been treated with estradiol 10 micrograms vaginal tablets 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 estradiol 10 micrograms vaginal tablets 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 estradiol 10 micrograms vaginal tablets as compared to placebo and which are possibly related to treatment are presented below.
| System organ class | Common ≥1/100 to <1/10 | Uncommon ≥1/1,000 to <1/100 |
|---|---|---|
| Infections and infestations | Vulvovaginal mycotic infection | |
| Nervous system disorders | Headache | |
| Vascular disorders | Hot flush, Hypertension | |
| Gastrointestinal disorders | Abdominal pain | Nausea |
| Skin and subcutaneous tissue disorders | Rash | |
| Reproductive system and breast disorders | Vaginal haemorrhage, vaginal discharge or vaginal discomfort | |
| Investigations | Weight increased |
In addition to the above mentioned adverse drug reactions, those presented below have been spontaneously reported for patients being treated with estradiol 25 micrograms vaginal tablets and are considered possibly related to treatment. The reporting rate of these spontaneous adverse reactions is very rare (<1/10,000 patient years).
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:
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.
Use of systemic HRT has been associated with a slightly increased risk of having ovarian cancer diagnosed.
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 2000 will be diagnosed with ovarian cancer over a 5-year period.
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. Results of the WHI studies are presented below:
WHI Studies – Additional risk of VTE over 5 years' use:
| Age range (years) | Incidence per 1,000 women in placebo arm over 5 years | Risk ratio and 95% CI | Additional cases per 1,000 HRT users |
|---|---|---|---|
| Oral oestrogen-only* | |||
| 50 – 59 | 7 | 1.2 (0.6 – 2.4) | 1 (-3 – 10) |
* Study in women with no uterus.
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.
WHI studies combined – Additional risk of ischaemic stroke* over 5 years' use:
| Age range (years) | Incidence per 1,000 women in placebo arm over 5 years | Risk ratio and 95% CI | Additional cases per 1,000 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.
The list below reports undesirable effects, that have been reported in users of hormone replacement therapy (HRT) by MedDRA system organ classes (MedDRA SOCs).
Uncommon: Vaginal candidiasis
Uncommon: Hypersensitivity
Common: Weight increased, Weight decreased
Very rare: Haemolytic anaemia
Uncommon: Nervousness, Depressed mood
Rare: Anxiety, libido decreased, libido increased
Common: Headache
Uncommon: Dizziness
Rare: Migraine
Uncommon: Visual disturbances
Rare: Intolerance to contact lenses
Uncommon: Palpitations
Uncommon: Hypertension, Peripheral vascular disease, Varicose vein, Venous thromboembolism
Common: Nausea, Abdominal pain
Uncommon: Dyspepsia
Rare: Bloating, Vomiting
Uncommon: Gall bladder disorder
Common: Rash, Pruritus
Uncommon: Urticaria Erythema nodosum,
Rare: Hirsutism, Acne
Common: Leg cramps
Uncommon: Back pain
Rare: Muscle cramps
Common: Metrorrhagia, Uterine/vaginal bleeding including spotting, Pelvic pain
Uncommon: Change in cervical secretion, Menorrhagia, Breast pain/tenderness,
Rare: Breast enlargement, Premenstrual-like symptoms, Vaginal discharge, Dysmenorrhoea,
Common: Asthenia
Uncommon: Peripheral oedema, Oedema
Rare: Fatigue
Other adverse reactions have been reported in association with estradiol treatment (frequency unknown):
Neoplasms benign, malignant and unspecified (incl. cysts and polyps): Breast cancera, Oestrogen dependent neoplasms benign and malignant, e.g. endometrial cancerb, ovarian cancerc, Increase in size of leiomyoma
Nervous system disorders: Probable dementia over the age of 65, Chorea, Exacerbation of epilepsy
Vascular disorders: Strokef, Arterial thromboembolism, i.e. anginae and myocardial infarctione, Venous thromboembolismd, i.e. deep leg or pelvic venous thrombosis and pulmonary embolism.
Gastrointestinal disorders: Pancreatitis (in women with pre-existing hypertriglyceridaemia), Gastroesophageal reflux disease
Hepatobiliary disorders: Hepatic function abnormal, sometimes with jaundice
Skin and subcutaneous tissue disorders: Angioedema, chloasma, erythema multiforme, vascular purpura.
Renal and urinary disorders: Urinary incontinence
Reproductive system and breast disorders: Fibrocystic breast disease
Largest meta-analysis of prospective epidemiological studies – Estimated additional risk of breast cancer after 5 years' use in women with BMI 27 (kg/m²):
| Age at start HRT (years) | Incidence per 1000 never-users of HRT over a 5 year period (50-54 years)*1 | Risk ratio | Additional cases per 1000 HRT users after 5 years |
|---|---|---|---|
| Oestrogen only HRT | |||
| 50 | 13.3 | 1.2 | 2.7 |
| Combined oestrogen-progestogen | |||
| 50 | 13.3 | 1.6 | 8.0 |
*1 Taken from baseline incidence rates in England in 2015 in women with BMI 27 (kg/m²)
Note: Since the background incidence of breast cancer differs by EU country, the number of additional cases of breast cancer will also change proportionately.
Estimated additional risk of breast cancer after 10 years' use in women with BMI 27 (kg/m²):
| Age at start HRT (years) | Incidence per 1000 never-users of HRT over a 10 year period (50-59 years)* | Risk ratio | Additional cases per 1000 HRT users after 10 years |
|---|---|---|---|
| Oestrogen only HRT | |||
| 50 | 26.6 | 1.3 | 7.1 |
| Combined oestrogen-progestagen | |||
| 50 | 26.6 | 1.8 | 20.8 |
* Taken from baseline incidence rates in England in 2015 in women with BMI 27 (kg/m²)
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:
| Age range (years) | Incidence per 1000 women in placebo arm over 5 years | Risk ratio & 95%CI# | Additional cases per 1000 HRT users over 5 years (95%CI) |
|---|---|---|---|
| CEE oestrogen-only | |||
| 50-79 | 21 | 0.8 (0.7–1.0) | -4 (-6 – 0)*2 |
| CEE+MPA oestrogen & progestogen‡ | |||
| 50-79 | 17 | 1.2 (1.0–1.5) | +4 (0–9) |
*2 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.
The endometrial cancer risk is about 5 in every 1000 women with an 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.
Depending on the duration of 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 1000 women between the ages of 50 and 65.
Adding a progestogen to 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)).
Use of oestrogen-only or combined oestrogen-progestogen HRT has been associated with a slightly increased risk of having ovarian cancer diagnosed. 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. 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 oestrogen-only*3 | |||
| 50-59 | 7 | 1.2 (0.6-2.4) | 1 (-3 – 10) |
| Oral combined oestrogen-progestogen | |||
| 50-59 | 4 | 2.3 (1.2–4.3) | 5 (1-13) |
*3 Study in women with no uterus
The risk of coronary artery disease is slightly increased in users of combined oestrogen-progestogen HRT over the age of 60.
WHI studies combined – Additional risk of ischaemic stroke*4 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 |
|---|---|---|---|
| 50-59 | 8 | 1.3 (1.1-1.6) | 3 (1–5) |
*4 no differentiation was made between ischaemic and haemorrhagic stroke.
The following serious adverse reactions are discussed elsewhere in the labeling:
Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.
The data described below reflect pooled data from 5 clinical trials of Climara. A total of 614 women were exposed to Climara for 3 months (193 women at 0.025 mg per day, 201 women at 0.05 mg per day, 194 women at 0.1 mg per day) in randomized, double-blind trials of clinical efficacy versus placebo and versus active comparator. All women were postmenopausal, had a serum estradiol level of less than 20 pg/mL, and a minimum of five moderate to severe hot flushes per week or a minimum of 15 hot flushes per week of any severity at baseline. Included in this table are an additional 25 postmenopausal hysterectomized women exposed to Climara 0.025 mg per day for 6 to 24 months (N=16 at 24 months) in a randomized, double-blind, placebo-controlled study of Climara for the prevention of osteoporosis.
Treatment-Emergent Adverse Reactions Reported at a Frequency of ≥5 Percent and More Frequent in Women Receiving Climara:
| Climara | ||||
|---|---|---|---|---|
| Body System Adverse Reactions | 0.025 mg/day* (N=219) | 0.05 mg/day† (N=201) | 0.1 mg/day† (N=194) | Placebo‡ (N=72) |
| Body as a Whole | ||||
| Headache Pain Back Pain Edema | 21% 5% 1% 4% 0.5% | 39% 18% 8% 8% 13% | 37% 13% 11% 9% 10% | 29% 10% 7% 6% 6% |
| Digestive System | ||||
| Abdominal Pain Nausea Flatulence | 9% 0% 1% 1% | 21% 11% 5% 3% | 29% 16% 6% 7% | 18% 8% 3% 1% |
| Musculoskeletal System | ||||
| Arthralgia | 7% 1% | 9% 5% | 11% 5% | 4% 3% |
| Nervous System | ||||
| Depression | 13% 1% | 10% 5% | 11% 8% | 1% 0% |
| Urogenital System | ||||
| Breast Pain Leukorrhea | 12% 5% 1% | 18% 8% 6% | 41% 29% 7% | 11% 4% 1% |
| Respiratory System | ||||
| URTI Pharyngitis Sinusitis Rhinitis | 15% 6% 0.5% 4% 2% | 26% 17% 3% 4% 4% | 29% 17% 7% 5% 6% | 14% 8% 3% 3% 1% |
| Skin and Appendages | ||||
| Pruritus | 19% 0.5% | 12% 6% | 12% 3% | 15% 6% |
* Adverse reactions occurring at rate of ≥5 percent in Climara trials of clinical efficacy versus placebo and versus active comparator; and trial of Climara versus placebo for the prevention of osteoporosis.
† Adverse reactions occurring at rate of ≥5 percent in Climara trials of clinical efficacy versus placebo and versus active comparator.
‡ Adverse reactions occurring in placebo group in Climara trial of clinical efficacy versus placebo.
The following adverse reactions have been identified during post-approval use of the Climara transdermal system. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.
Genitourinary System: Changes in bleeding pattern, pelvic pain
Breast: Breast cancer, breast pain, breast tenderness
Cardiovascular: Changes in blood pressure, palpitations, hot flashes
Gastrointestinal: Vomiting, abdominal pain, abdominal distension, nausea
Skin: Alopecia, hyperhidrosis, night sweats, urticaria, rash
Eyes: Visual disturbances, contact lens intolerance,
Central Nervous System: Depression, migraine, paresthesia, dizziness, anxiety, irritability, mood swings, nervousness, insomnia, headache
Miscellaneous: Fatigue, menopausal symptoms, weight increase, application site reaction, anaphylactic reactions
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