Vagifem is intended for intravaginal use and the dose of estradiol is very low. Overdose is therefore unlikely, but if it occurs, treatment is symptomatic.
Overdosage of estrogen may cause nausea, vomiting, breast tenderness, abdominal pain, drowsiness and fatigue, and withdrawal bleeding may occur in women. Treatment of overdose consists of discontinuation of Duavive (Estrogens conjugated) therapy with institution of appropriate symptomatic care.
Not applicable.
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 below.
| System organ class | Common > 1/100 to <1/10 | Uncommon > 1/1,000 to <1/100 | Rare > 1/10,000 to <1/1,000 |
| Infections and infestations | Vulvovaginal mycotic infection | ||
| Nervous system disorders | Headache | ||
| Gastrointestinal disorders | Abdominal pain | Nausea | |
| Reproductive system and breast disorders | Vaginal haemorrhage, vaginal discharge or vaginal discomfort | ||
| Skin and subcutaneous tissue disorders | Rash | ||
| Investigations | Weight increased | ||
| Vascular disorders | Hot flush Hypertension |
Post-marketing experience:
In addition to the above 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
- 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
- Gall bladder 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.
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.
- 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
| Age range (years) | Incidence per 1,000 never-users of HRT over a 5 year period* | Risk ratio and 95% CI # | Additional cases per 1,000 HRT users over 5 years (95% CI) |
| Oestrogen only HRT | |||
| 50 - 65 | 9 - 12 | 1.2 | 1 - 2 (0 - 3) |
| Combined oestrogen-progestagen | |||
| 50 - 65 | 9 - 12 | 1.7 | 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
| 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 (95% CI) |
| CEE oestrogen-only | |||
| 50 - 79 | 21 | 0.8 (0.7 - 1.0) | -4 (-6 - 0)* |
| CEE+MPA oestrogen & progestagen‡ | |||
| 50 - 79 | 17 | 1.2 (1.0 - 1.5) | +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 1000 women with an 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.
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 1000 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.
Ovarian cancer
Risk estimates have been drawn from systemic exposure and it is not known how these apply to local treatments.
Use of oestrogen-only or combined oestrogen-progestagen 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 2,000 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.
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. Results of the WHI studies are presented:
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) |
| Oral combined oestrogen-progestagen | |||
| 50 - 59 | 4 | 2.3 (1.2 - 4.3) | 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.
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.
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.
Reporting of suspected adverse reactions
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 Website: www.mhra.gov.uk/yellowcard
The following serious adverse reactions are discussed elsewhere in 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 clinical practice.
During the first year of a 2-year clinical trial with 2,333 postmenopausal women with a uterus between 40 and 65 years of age (88 percent Caucasian), 1,012 women were treated with conjugated estrogens, and 332 were treated with placebo.
Table 1 summarizes treatment-related adverse reactions that occurred at a rate of ≥ 1 percent in any treatment group.
Table 1: TREATMENT RELATED ADVERSE REACTIONS AT A FREQUENCY ≥ 1 PERCENT
| Duavive (Estrogens conjugated)0.625 mg (n=348) | Duavive (Estrogens conjugated)0.45 mg (n=338) | Duavive (Estrogens conjugated)0.3 mg (n=326) | Placebo (n=332) | |
| Body as a whole | ||||
| Abdominal pain | 38 (11) | 28 (8) | 30 (9) | 21 (6) |
| Asthenia | 16 (5) | 8 (2) | 14 (4) | 3 (1) |
| Back pain | 18 (5) | 11 (3) | 13 (4) | 4 (1) |
| Chest pain | 2 (1) | 3 (1) | 4 (1) | 2 (1) |
| Generalized edema | 7 (2) | 6 (2) | 4 (1) | 8 (2) |
| Headache | 45 (13) | 47 (14) | 44 (13) | 46 (14) |
| Moniliasis | 5 (1) | 4 (1) | 4 (1) | 1 (0) |
| Pain | 17 (5) | 10 (3) | 12 (4) | 14 (4) |
| Pelvic pain | 10 (3) | 9 (3) | 8 (2) | 4 (1) |
| Cardiovascular system | ||||
| Hypertension | 4 (1) | 4 (1) | 7 (2) | 5 (2) |
| Migraine | 7 (2) | 1 (0) | 0 | 3 (1) |
| Palpitation | 3 (1) | 3 (1) | 3 (1) | 4 (1) |
| Vasodilatation | 2 (1) | 2 (1) | 3 (1) | 5 (2) |
| Digestive system | ||||
| Constipation | 7 (2) | 6 (2) | 4 (1) | 3 (1) |
| Diarrhea | 4 (1) | 5 (1) | 5 (2) | 8 (2) |
| Dyspepsia | 7 (2) | 5 (1) | 6 (2) | 14 (4) |
| Eructation | 1 (0) | 1 (0) | 4 (1) | 1 (0) |
| Flatulence | 22 (6) | 18 (5) | 13 (4) | 8 (2) |
| Increased appetite | 4 (1) | 1 (0) | 1 (0) | 2 (1) |
| Nausea | 16 (5) | 10 (3) | 15 (5) | 16 (5) |
| Metabolic and nutritional | ||||
| Hyperlipidemia | 2 (1) | 4 (1) | 3 (1) | 2 (1) |
| Peripheral edema | 5 (1) | 2 (1) | 4 (1) | 3 (1) |
| Weight gain | 11 (3) | 10 (3) | 8 (2) | 14 (4) |
| Musculoskeletal system | ||||
| Arthralgia | 6 (2) | 3 (1) | 2 (1) | 5 (2) |
| Leg cramps | 10 (3) | 5 (1) | 9 (3) | 4 (1) |
| Myalgia | 2 (1) | 1 (0) | 4 (1) | 1 (0) |
| Nervous system | ||||
| Anxiety | 6 (2) | 4 (1) | 2 (1) | 4 (1) |
| Depression | 17 (5) | 15 (4) | 10 (3) | 17 (5) |
| Dizziness | 9 (3) | 7 (2) | 4 (1) | 5 (2) |
| Emotional lability | 3 (1) | 4 (1) | 5 (2) | 8 (2) |
| Hypertonia | 1 (0) | 1 (0) | 5 (2) | 3 (1) |
| Insomnia | 16 (5) | 10 (3) | 13 (4) | 14 (4) |
| Nervousness | 9 (3) | 12 (4) | 2 (1) | 6 (2) |
| Skin and appendages | ||||
| Acne | 3 (1) | 1 (0) | 8 (2) | 3 (1) |
| Alopecia | 6 (2) | 6 (2) | 5 (2) | 2 (1) |
| Hirsutism | 4 (1) | 2 (1) | 1 (0) | 0 |
| Pruritus | 11 (3) | 11 (3) | 10 (3) | 3 (1) |
| Rash | 6 (2) | 3 (1) | 1 (0) | 2 (1) |
| Skin discoloration | 4 (1) | 2 (1) | 0 | 1 (0) |
| Sweating | 4 (1) | 1 (0) | 3 (1) | 4 (1) |
| Urogenital system | ||||
| Breast disorder | 6 (2) | 3 (1) | 3 (1) | 6 (2) |
| Breast enlargement | 3 (1) | 4 (1) | 7 (2) | 3 (1) |
| Breast neoplasm | 4 (1) | 4 (1) | 7 (2) | 7 (2) |
| Breast pain | 37 (11) | 39 (12) | 24 (7) | 26 (8) |
| Cervix disorder | 8 (2) | 4 (1) | 5 (2) | 0 |
| Dysmenorrhea | 12 (3) | 10 (3) | 4 (1) | 2 (1) |
| Endometrial disorder | 4 (1) | 2 (1) | 2 (1) | 0 |
| Endometrial hyperplasia | 16 (5) | 8 (2) | 1 (0) | 0 |
| Leukorrhea | 17 (5) | 17 (5) | 12 (4) | 6 (2) |
| Metrorrhagia | 11 (3) | 4 (1) | 3 (1) | 1 (0) |
| Urinary tract infection | 1 (0) | 2 (1) | 1 (0) | 4 (1) |
| Uterine fibroids enlarged | 6 (2) | 1 (0) | 2 (1) | 2 (1) |
| Uterine spasm | 11 (3) | 5 (1) | 3 (1) | 2 (1) |
| Vaginal dryness | 1 (0) | 2 (1) | 1 (0) | 6 (2) |
| Vaginal hemorrhage | 46 (13) | 13 (4) | 6 (2) | 0 |
| Vaginal moniliasis | 14 (4) | 10 (3) | 12 (4) | 5 (2) |
| Vaginitis | 18 (5) | 7 (2) | 9 (3) | 1 (0) |
The following additional adverse reactions have been identified during post-approval use of Duavive (Estrogens conjugated). Because these reactions are reported voluntarily from a population of uncertain size, it is not possible always to reliably estimate their frequency or establish a causal relationship to drug exposure.
Genitourinary systemAbnormal uterine bleeding; dysmenorrheal or pelvic pain, increase in size of uterine leiomyomata, vaginitis, including vaginal candidiasis, change in cervical secretion, ovarian cancer, endometrial hyperplasia, endometrial cancer, leukorrhea.
BreastsTenderness, enlargement, pain, discharge, galactorrhea, fibrocystic breast changes, breast cancer, gynecomastia in males.
CardiovascularDeep and superficial venous thrombosis, pulmonary embolism, thrombophlebitis, myocardial infarction, stroke, increase in blood pressure.
GastrointestinalNausea, vomiting, abdominal pain, bloating, cholestatic jaundice, increased incidence of gallbladder disease, pancreatitis, enlargement of hepatic hemangiomas, ischemic colitis.
SkinChloasma or melasma that may persist when drug is discontinued, erythema multiforme, erythema nodosum, loss of scalp hair, hirsutism, pruritus, rash.
EyesRetinal vascular thrombosis, intolerance to contact lenses.
Central nervous systemHeadache, migraine, dizziness , mental depression, nervousness, mood disturbances, irritability, exacerbation of epilepsy, dementia, possible growth potentiation of benign meningioma.
MiscellaneousIncrease or decrease in weight, glucose intolerance, aggravation of porphyria, edema, arthralgias, leg cramps, changes in libido, urticaria, exacerbation of asthma, increased triglycerides, hypersensitivity.
17β-Estradiol is a well-known substance. Non-clinical studies provided no additional data of relevance to clinical safety beyond those already included in other sections of the SPC.
Pharmacotherapeutic group: Natural and semisynthetic oestrogens, plain.
ATC code: G03CA03
The active ingredient, synthetic 17β-estradiol, is chemically and biologically identical to endogenous human estradiol.
Endogenous 17β-estradiol induces and maintains the primary and secondary female sexual characteristics. The biological effect of 17β-estradiol is carried out through a number of specific oestrogen receptors. The steroid receptor complex is bound to the cells DNA and induces synthesis of specific proteins.
Maturation of the vaginal epithelium is dependent upon oestrogens. Oestrogens increase the number of superficial and intermediate cells and decrease the number of basal cells in vaginal smear.
Oestrogens maintain vaginal pH around normal range (4.5) which enhances normal bacterial flora.
A 12-months, double-blind, randomised, parallel group, placebo-controlled, multicentre study was conducted to evaluate the efficacy and safety of Vagifem 10 micrograms in the treatment of postmenopausal vaginal atrophy symptoms.
After 12 weeks of treatment with Vagifem 10 micrograms the change from baseline, in comparison with placebo treatment, demonstrated significant improvements in the three primary endpoints: Vaginal Maturation Index and Value, normalisation of vaginal pH and relief of the moderate/severe urogenital symptoms considered most bothersome by the subjects.
Endometrial safety of Vagifem 10 micrograms was evaluated in the above mentioned trial and a second, open-label, multicentre trial. In total, 386 women underwent endometrial biopsy at the beginning and at the end of 52 weeks treatment. Incidence rate of hyperplasia and/or carcinoma was 0.52% (95% CI 0.06%, 1.86%), indicating no increased risk.
There are no pharmacodynamic data for Duavive (Estrogens conjugated).
Absorption
Oestrogens are well absorbed through the skin, mucous membranes and the gastrointestinal tract. After vaginal administration, estradiol is absorbed circumventing first-pass metabolism.
A 12-weeks, single-centre, randomised, open label, multiple dose, parallel-group trial was conducted to evaluate the extent of systemic absorption of estradiol from the Vagifem 10 micrograms tablet. Subjects were randomised 1:1 to receive either 10 micrograms or 25 micrograms Vagifem. Plasma levels of estradiol (E2), oestrone (E1) and oestrone sulfate (E1S) were determined. The AUC(0-24) for plasma E2 levels increased almost proportionally after the administration of 10 micrograms and 25 micrograms Vagifem. The AUC(0-24) indicated higher systemic estradiol levels for the 10 micrograms E2 tablet as compared to baseline on treatment days 1, 14 and 83, being statistically significant at days 1 and 14 (Table 1). However, average plasma E2 concentrations (Cave (0-24)) at all evaluated days remained within the normal postmenopausal range in all subjects. The data from days 82 and 83 as compared to baseline indicate that there is no cumulative effect during twice weekly maintenance therapy.
Table 1 Values of PK parameters from plasma Estradiol (E2) concentrations:
| Vagifem 10 micrograms | ||
| AUC(0-24) pg.h/ml (geom. mean) | Cave (0-24) pg/ml (geom. mean) | |
| Day -1 | 75.65 | 3.15 |
| Day 1 | 225.35 | 9.39 |
| Day 14 | 157.47 | 6.56 |
| Day 82 | 44.95 | 1.87 |
| Day 83 | 111.41 | 4.64 |
The levels of oestrone and oestrone sulfate seen after 12 weeks of Vagifem 10 micrograms administration did not exceed baseline levels, i.e. no accumulation of oestrone or oestrone sulfate was observed.
Distribution
The distribution of exogenous oestrogens is similar to that of endogenous oestrogens. Oestrogens are widely distributed in the body and are generally found in higher concentrations in the sex hormone target organs. Oestrogens circulate in the blood largely bound to sex hormone binding globulin (SHBG) and albumin.
Biotransformation
Exogenous oestrogens are metabolized in the same manner as endogenous oestrogens. The metabolic transformations take place mainly in the liver. Estradiol is converted reversibly to oestrone, and both can be converted to estriol, which is the major urinary metabolite. In postmenopausal women, a significant portion of the circulating oestrogens exist as sulfate conjugates, especially oestrone sulfate, which serves as a circulating reservoir for the formation of more active oestrogens.
Elimination
Estradiol, oestrone and estriol are excreted in the urine along with glucuronide and sulfate conjugates.
Special patient groups
The extent of systemic absorption of estradiol during treatment with Vagifem 10 micrograms has been evaluated in postmenopausal women aged 60-70 (mean age 65.4) only.
AbsorptionConjugated estrogens are water-soluble and are absorbed from the gastrointestinal tract after release from the drug formulation. The Duavive (Estrogens conjugated) tablet releases conjugated estrogens slowly over several hours. Table 2 summarizes the mean pharmacokinetic parameters for unconjugated and conjugated estrogens following administration of 1 x 0.625 mg and 1 x 1.25 mg tablets to healthy postmenopausal women.
Food effect: The pharmacokinetics of Duavive (Estrogens conjugated) 0.45 mg and 1.25 mg tablets were assessed following a single dose with a high-fat breakfast and with fasting administration. The Cmax and AUC of estrogens were altered approximately 3-13%. The changes to Cmax and AUC are not considered clinically meaningful, therefore Duavive (Estrogens conjugated) may be taken without regard to meals.
TABLE 2: PHARMACOKINETIC PARAMETERS FOR Duavive (Estrogens conjugated)
| Pharmacokinetic Profile of Unconjugated Estrogens Following a Dose of 1 x 0.625 mg | ||||
| PK Parameter | ||||
| Arithmetic Mean (%CV) | Cmax (pg/mL) | tmax (h) | t½ (h) | AUC (pg•h/mL) |
| Estrone | 87 (33) | 9.6 (33) | 50.7 (35) | 5557 (59) |
| Baseline- adjusted estrone | 64 (42) | 9.6 (33) | 20.2 (40) | 1723 (52) |
| Equilin | 31 (38) | 7.9 (32) | 12.9 (112) | 602 (54) |
| Pharmacokinetic Profile of Conjugated Estrogens Following a Dose of 1 x 0.625 mg | ||||
| PK Parameter | ||||
| Arithmetic Mean (%CV) | Cmax (ng/mL) | tmax (h) | t½ (h) | AUC (ng•h/mL) |
| Total Estrone | 2.7 (43) | 6.9 (25) | 26.7 (33) | 75(52) |
| Baseline-adjusted total estrone | 2.5 (45) | 6.9 (25) | 14.8 (35) | 46 (48) |
| Total Equilin | 1.8 (56) | 5.6 (45) | 11.4 (31) | 27 (56) |
| Pharmacokinetic Profile of Unconjugated Estrogens Following a Dose of 1 x 1.25 mg | ||||
| PK Parameter | ||||
| Arithmetic Mean (%CV) | Cmax (pg/mL) | tmax (h) | t½ (h) | AUC (pg•h/mL) |
| Estrone | 124 (30) | 10.0 (32) | 38.1 (37) | 6332 (44) |
| Baseline- adjusted estrone | 102 (35) | 10.0 (32) | 19.7 (48) | 3159 (53) |
| Equilin | 59 (43) | 8.8 (36) | 10.9 (47) | 1182 (42) |
| Pharmacokinetic Profile of Conjugated Estrogens Following a Dose of 1 x 1.25 mg | ||||
| PK Parameter | ||||
| Arithmetic Mean (%CV) | Cmax (ng/mL) | tmax (h) | t½ (h) | AUC (ng•h/mL) |
| Total Estrone | 4.5 (39) | 8.2 (58) | 26.5 (40) | 109 (46) |
| Baseline-adjusted total estrone | 4.3 (41) | 8.2 (58) | 17.5 (41) | 87 (44) |
| Total equilin | 2.9 (42) | 6.8 (49) | 12.5 (34) | 48 (51) |
The distribution of exogenous estrogens is similar to that of endogenous estrogens. Estrogens are widely distributed in the body and are generally found in higher concentration in the sex hormone target organs. Estrogens circulate in the blood largely bound to sex hormone-binding globulin (SHBG) and albumin.
MetabolismExogenous estrogens are metabolized in the same manner as endogenous estrogens. Circulating estrogens exist in a dynamic equilibrium of metabolic interconversions. These transformations take place mainly in the liver. Estradiol is converted reversibly to estrone, and both can be converted to estriol, which is a major urinary metabolite. Estrogens also undergo enterohepatic recirculation via sulfate and glucuronide conjugation in the liver, biliary secretion of conjugates into the intestine, and hydrolysis in the intestine followed by reabsorption. In postmenopausal women, a significant portion of the circulating estrogens exists as sulfate conjugates, especially estrone sulfate, which serves as a circulating reservoir for the formation of more active estrogens.
ExcretionEstradiol, estrone, and estriol are excreted in the urine, along with glucuronide and sulfate conjugates.
Vagifem may be used in women with or without an intact uterus.
Vaginal infections should be treated before start of the Vagifem therapy.
Administration:
1. Open the blister pack at the plunger end.
2. Insert the applicator in the vagina until resistance is met (8-10 cm).
3. Release the tablet by pressing the plunger.
4. Withdraw the applicator and discard.
4.3 Contraindications- Known, past or suspected breast cancer
- Known, past or suspected oestrogen-dependent malignant tumours (e.g. endometrial cancer)
- Undiagnosed genital bleeding
- Untreated endometrial hyperplasia
- Previous or current venous thromboembolism (deep venous thrombosis, pulmonary embolism)
- Known thrombophilic disorders
- Active or recent arterial thromboembolic disease (e.g. angina, myocardial infarction)
- Acute liver disease, or a history of liver disease as long as liver function tests have failed to return to normal
- Known hypersensitivity to the active substances or to any of the excipients
- Porphyria.
4.4 Special warnings and precautions for useFor 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.
Medical examination/follow-up
Before initiating or reinstituting hormone therapy, a complete personal and family medical history should be obtained. 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 woman. Women should be advised what changes in their breasts should be reported to their doctor or nurse. 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.
The pharmacokinetic profile of Vagifem shows that there is very low systemic absorption of estradiol during treatment , however, being a HRT product the following need to be considered, especially for long term or repeated use of this product.
Conditions which need supervision
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 oestrogen treatment, in particular:
- Leiomyoma (uterine fibroids) or endometriosis
- Risk factors for thromboembolic disorders (see below)
- Risk factors for oestrogen-dependent tumours, e.g. 1st degree heredity for breast cancer
- Hypertension
- Liver disorders (e.g. liver adenoma)
- Diabetes mellitus with or without vascular involvement
- Cholelithiasis
- Migraine or (severe) headache
- Systemic lupus erythematosus
- A history of endometrial hyperplasia (see below)
- Epilepsy
- Asthma
- Otosclerosis.
The pharmacokinetic profile of Vagifem shows that there is very low absorption of estradiol during treatment. Due to this, the recurrence or aggravation of the above mentioned conditions is less likely than with systemic oestrogen treatment.
Reasons for immediate withdrawal of therapy
Therapy should be discontinued in case a contraindication is discovered and in the following situations:
- Jaundice or deterioration in liver function
- Significant increase in blood pressure
- New onset of migraine-type headache
- Pregnancy
Vagifem is a locally acting low dose estradiol preparation and therefore the occurrence of the below mentioned conditions is less likely than with systemic oestrogen treatment.
Endometrial hyperplasia and carcinoma
Women with an intact uterus with abnormal bleeding of unknown aetiology or women with an intact uterus who have previously been treated with unopposed oestrogens should be examined with special care in order to exclude hyperstimulation/malignancy of the endometrium before initiation of treatment with Vagifem.
In women with an intact uterus the risk of endometrial hyperplasia and carcinoma is increased when oestrogens are administered alone for prolonged periods. The reported increase in endometrial cancer risk among systemic oestrogen-only users varies from 2- to 12-fold compared with non-users, depending on both duration of treatment and on oestrogen dose. After stopping treatment, risk may remain elevated for at least 10 years.
During Vagifem treatment, a minor degree of systemic absorption may occur in some patients, especially during the first two weeks of once daily administration. However, average plasma E2 concentrations (Cave (0-24)) at all evaluated days remained within the normal postmenopausal range in all subjects.
Endometrial safety of long-term (more than one year) or repeated use of local vaginally administered oestrogen is uncertain. Therefore, if repeated, treatment should be reviewed at least annually, with special consideration given to any symptoms of endometrial hyperplasia or carcinoma.
As a general rule, oestrogen replacement therapy should not be prescribed for longer than one year without another physical, including gynaecological, examination being performed. If bleeding or spotting appears at any time during therapy, the reason should be investigated, which may include endometrial biopsy to exclude endometrial malignancy.
The woman should be advised to contact her doctor in case bleeding or spotting occurs during treatment with Vagifem.
Unopposed oestrogen stimulation may lead to premalignant or malignant transformation in the residual foci of endometriosis. Therefore caution is advised when using this product in women who have undergone hysterectomy because of endometriosis, especially if they are known to have residual endometriosis.
Breast cancer
The overall evidence suggests an increased risk of breast cancer in women taking combined oestrogen-progestagen and possibly also oestrogen-only HRT, that is dependent on the duration of taking HRT.
The WHI trial found no increase in risk of breast cancer in hysterectomised women using oestrogen-only HRT. Observational studies have mostly reported a small increase in risk of having breast cancer diagnosed that is substantially lower than found in users of oestrogen-progestagen combinations.
The excess risk becomes apparent within a few years of use but returns to baseline within a few (at most five) years after stopping treatment.
A relationship between breast cancer risk and low dose local vaginal oestrogen therapy is uncertain.
HRT, especially oestrogen-progestagen combined treatment, increases the density of mammographic images which may adversely affect the radiological detection of breast cancer.
Ovarian cancer
Ovarian cancer is much rarer than breast cancer.
Epidemiological evidence from a large meta-analysis suggests a slightly increased risk in women taking oestrogen-only or combined oestrogen-progestagen HRT, which becomes apparent within 5 years of use and diminishes over time after stopping.
Some other studies, including the WHI trial, suggest that use of combined HRTs may be associated with a similar or slightly smaller risk.
A relationship between ovarian cancer risk and low dose local vaginal oestrogen therapy is uncertain.
Venous thromboembolism
HRT is associated with a 1.3- to 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.
Patients with known thrombophilic states have an increased risk of VTE and HRT may add to this risk. HRT is therefore contraindicated in these patients.
Generally recognised risk factors for VTE include use of oestrogens, older age, major surgery, prolonged immobilisation, obesity (BMI >30 kg/m²), pregnancy/postpartum period, systemic lupus erythematosus (SLE) and cancer. There is no consensus about the possible role of varicose veins in VTE.
A relationship between venous thromboembolism and low dose local vaginal oestrogen therapy is uncertain.
As in all postoperative patients, prophylactic measures need to be considered to prevent VTE following surgery. If prolonged immobilisation is to follow elective surgery, 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 a 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 a potential thromboembolic symptom (e.g. painful swelling of a leg, sudden pain in the chest, dyspnoea).
Coronary artery disease (CAD)
There is no evidence from randomised controlled trials of protection against myocardial infarction in women with or without existing CAD who received combined oestrogen-progestagen or oestrogen-only therapy.
Randomised controlled data found no increased risk of CAD in hysterectomised women using oestrogen-only therapy.
Ischaemic stroke
Combined oestrogen-progestagen 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 increase with age.
A relationship between ischaemic stroke and low dose local vaginal oestrogen therapy is uncertain.
Other conditions
Oestrogens may cause fluid retention, and therefore patients with cardiac or renal dysfunction should be carefully observed.
Women with pre-existing hypertriglyceridaemia 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.
The relationship between pre-existing hypertriglyceridaemia and low dose local vaginal oestrogen therapy is unknown.
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 radioimmunoassay) or T3 levels (by radioimmunoassay).'Pharmacokinetic Properties') is likely to result in less pronounced effects on plasma binding proteins than with systemic hormones.
HRT does not improve cognitive function. There is some evidence from the WHI trial of increased risk of probable dementia in women who start using continuous combined or oestrogen-only HRT after the age of 65.
Intravaginal applicator may cause minor local trauma, especially in women with serious vaginal atrophy.
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.
WARNINGSIncluded as part of the PRECAUTIONS section.
PRECAUTIONS Cardiovascular DisordersAn increased risk of stroke and DVT has been reported with estrogen-alone therapy. An increased risk of PE, DVT, stroke and MI has been reported with estrogen plus progestin therapy. Should any of these events occur or be suspected, estrogen with or without progestin therapy should be discontinued immediately.
Risk factors for arterial vascular disease (for example, hypertension, diabetes mellitus, tobacco use, hypercholesterolemia, and obesity) and/or venous thromboembolism (VTE) (for example, personal or family history of VTE, obesity, and systemic lupus erythematosus) should be managed appropriately.
StrokeIn 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)-alone compared to women in the same age group receiving placebo (45 versus 33 per 10,000 women-years). The increase in risk was demonstrated in year 1 and persisted. Should a stroke occur or be suspected, estrogen-alone therapy should be discontinued immediately.
Subgroup analyses of women 50 to 59 years of age suggest no increased risk of stroke for those women receiving CE (0.625 mg)-alone versus those receiving placebo (18 versus 21 per 10,000 women-years).1
In the WHI estrogen plus progestin substudy, a statistically significant increased risk of stroke was reported in women 50 to 79 years of age receiving daily CE (0.625 mg) plus MPA (2.5 mg) compared to women in the same age group receiving placebo (33 versus 25 per 10,000 women-years). The increase in risk was demonstrated after the first year and persisted.1 Should a stroke occur or be suspected, estrogen plus progestin therapy should be discontinued immediately.
Coronary Heart DiseaseIn the WHI estrogen-alone substudy, no overall effect on coronary heart disease (CHD) events (defined as nonfatal MI, silent MI, or CHD death) was reported in women receiving estrogen-alone compared to placebo2.
Subgroup analyses of women 50 to 59 years of age suggest a statistically non-significant reduction in CHD events (CE [0.625 mg]-alone compared to placebo) in women with less than 10 years since menopause (8 versus 16 per 10,000 women-years).1
In the WHI estrogen plus progestin substudy, there was a statistically non-significant increased risk of CHD events reported in women receiving daily CE (0.625 mg) plus MPA (2.5 mg) compared to women receiving placebo (41 versus 34 per 10,000 women-years).1 An increase in relative risk was demonstrated in year 1, and a trend toward decreasing relative risk was reported in years 2 through 5.
In postmenopausal women with documented heart disease (n = 2,763, average 66.7 years of age), in a controlled clinical trial of secondary prevention of cardiovascular disease (Heart and Estrogen/Progestin Replacement Study; HERS), treatment with daily CE (0.625 mg) plus MPA (2.5 mg) demonstrated no cardiovascular benefit. During an average follow-up of 4.1 years, treatment with CE plus MPA did not reduce the overall rate of CHD events in postmenopausal women with established CHD. There were more CHD events in the CE plus MPA-treated group than in the placebo group in year 1, but not during the subsequent years. Two thousand, three hundred and twenty-one (2,321) women from the original HERS trial agreed to participate in an open label extension of HERS, HERS II. Average follow-up in HERS II was an additional 2.7 years, for a total of 6.8 years overall. Rates of CHD events were comparable among women in the CE (0.625 mg) plus MPA (2.5 mg) group and the placebo group in HERS, HERS II, and overall.
Venous Thromboembolism (VTE)In the WHI estrogen-alone substudy, the risk of VTE (DVT and PE), was increased for women receiving daily CE (0.625 mg)-alone compared to placebo (30 versus 22 per 10,000 women-years), although only the increased risk of DVT reached statistical significance (23 versus 15 per 10,000 women-years). The increase in VTE risk was demonstrated during the first 2 years3. Should a VTE occur or be suspected, estrogen-alone therapy should be discontinued immediately.
In the WHI estrogen plus progestin substudy, a statistically significant 2-fold greater rate of VTE was reported in women receiving daily CE (0.625 mg) plus MPA (2.5 mg) compared to women receiving placebo (35 versus 17 per 10,000 women-years). Statistically significant increases in risk for both DVT (26 versus 13 per 10,000 women-years) and PE (18 versus 8 per 10,000 women-years) were also demonstrated. The increase in VTE risk was demonstrated during the first year and persisted4. Should a VTE occur or be suspected, estrogen plus progestin therapy should be discontinued immediately.
If feasible, estrogens should be discontinued at least 4 to 6 weeks before surgery of the type associated with an increased risk of thromboembolism, or during periods of prolonged immobilization.
Malignant Neoplasms Endometrial CancerAn increased risk of endometrial cancer has been reported with the use of unopposed estrogen therapy in a woman with a uterus. The reported endometrial cancer risk among unopposed estrogen users is about 2 to 12 times greater than in non-users, and appears dependent on duration of treatment and on estrogen dose. Most studies show no significant increased risk associated with use of estrogens for less than 1 year. The greatest risk appears associated with prolonged use, with increased risks of 15-to 24-fold for 5 to 10 years or more, and this risk has been shown to persist for at least 8 to 15 years after estrogen therapy is discontinued.
Clinical surveillance of all women using estrogen-alone or estrogen plus progestin therapy is important. Adequate diagnostic measures, including directed or random endometrial sampling when indicated, should be undertaken to rule out malignancy in postmenopausal women with undiagnosed persistent or recurring abnormal genital bleeding. There is no evidence that the use of natural estrogens results in a different endometrial risk profile than synthetic estrogens of equivalent estrogen dose. Adding a progestin to postmenopausal estrogen therapy has been shown to reduce the risk of endometrial hyperplasia, which may be a precursor to endometrial cancer.
Breast CancerThe most important randomized clinical trial providing information about breast cancer in estrogen-alone users is the WHI substudy of daily CE (0.625 mg)-alone. In the WHI estrogen-alone substudy, after an average follow-up of 7.1 years, daily CE (0.625 mg)-alone was not associated with an increased risk of invasive breast cancer [relative risk (RR) 0.80]5.
The most important randomized clinical trial providing information about breast cancer in estrogen plus progestin users is the WHI substudy of daily CE (0.625 mg) plus MPA (2.5 mg). After a mean follow-up of 5.6 years, the estrogen plus progestin substudy reported an increased risk of invasive breast cancer in women who took daily CE plus MPA. In this substudy, prior use of estrogen-alone or estrogen plus progestin therapy was reported by 26 percent of the women. The relative risk of invasive breast cancer was 1.24, and the absolute risk was 41 versus 33 cases per 10,000 women-years, for CE plus MPA compared with placebo.6 Among women who reported prior use of hormone therapy, the relative risk of invasive breast cancer was 1.86, and the absolute risk was 46 versus 25 cases per 10,000 women-years for CE plus MPA compared with placebo. Among women who reported no prior use of hormone therapy, the relative risk of invasive breast cancer was 1.09, and the absolute risk was 40 versus 36 cases per 10,000 women-years for CE plus MPA compared with placebo. In the same substudy, invasive breast cancers were larger, were more likely to be node positive, and were diagnosed at a more advanced stage in the CE (0.625 mg) plus MPA (2.5 mg) group compared with the placebo group. Metastatic disease was rare, with no apparent difference between the two groups. Other prognostic factors, such as histologic subtype, grade and hormone receptor status did not differ between the groups.
Consistent with the WHI clinical trial, observational studies have also reported an increased risk of breast cancer for estrogen plus progestin therapy, and a smaller increased risk for estrogen-alone therapy, after several years of use. The risk increased with duration of use, and appeared to return to baseline over about 5 years after stopping treatment (only the observational studies have substantial data on risk after stopping). Observational studies also suggest that the risk of breast cancer was greater, and became apparent earlier, with estrogen plus progestin therapy as compared to estrogen-alone therapy. However, these studies have not found significant variation in the risk of breast cancer among different estrogen plus progestin combinations, doses, or routes of administration.
The use of estrogen-alone and estrogen plus progestin has been reported to result in an increase in abnormal mammograms, requiring further evaluation.
All women should receive yearly breast examinations by a healthcare provider and perform monthly breast self-examinations. In addition, mammography examinations should be scheduled based on patient age, risk factors, and prior mammogram results.
Ovarian CancerThe WHI estrogen plus progestin substudy reported a statistically non-significant increased risk of ovarian cancer. After an average follow-up of 5.6 years, the relative risk for ovarian cancer for CE plus MPA versus placebo was 1.58 (95 percent CI 0.77-3.24). The absolute risk for CE plus MPA versus placebo was 4 versus 3 cases per 10,000 women-years.7 In some epidemiologic studies, the use of estrogen plus progestin and estrogen-only products, in particular for 5 or more years, has been associated with an increased risk of ovarian cancer. However, the duration of exposure associated with increased risk is not consistent across all epidemiologic studies, and some report no association.
Probable DementiaIn the WHIMS estrogen-alone ancillary study of WHI, a population of 2,947 hysterectomized women 65 to 79 years of age was randomized to daily CE (0.625 mg)-alone or placebo.
After an average follow-up of 5.2 years, 28 women in the estrogen-alone group and 19 women in the placebo group were diagnosed with probable dementia. The relative risk of probable dementia for CE-alone versus placebo was 1.49 (95 percent CI 0.83-2.66). The absolute risk of probable dementia for CE-alone versus placebo was 37 versus 25 cases per 10,000 women-years8 .
In the WHIMS estrogen plus progestin ancillary study of WHI, a population of 4,532 postmenopausal women 65 to 79 years of age was randomized to daily CE (0.625 mg) plus MPA (2.5 mg) or placebo. After an average follow-up of 4 years, 40 women in the CE plus MPA group and 21 women in the placebo group were diagnosed with probable dementia. The relative risk of probable dementia for CE plus MPA versus placebo was 2.05 (95 percent CI 1.21-3.48). The absolute risk of probable dementia for CE plus MPA versus placebo was 45 versus 22 cases per 10,000 women-years8.
When data from the two populations in the WHIMS estrogen-alone and estrogen plus progestin ancillary studies were pooled as planned in the WHIMS protocol, the reported overall relative risk for probable dementia was 1.76 (95 percent CI 1.19-2.60). Since both ancillary studies were conducted in women 65 to 79 years of age, it is unknown whether these findings apply to younger postmenopausal women8.
Gallbladder DiseaseA 2-to 4-fold increase in the risk of gallbladder disease requiring surgery in postmenopausal women receiving estrogens has been reported.
HypercalcemiaEstrogen administration may lead to severe hypercalcemia in patients with breast cancer and bone metastases. If hypercalcemia occurs, use of the drug should be stopped and appropriate measures taken to reduce the serum calcium level.
Visual AbnormalitiesRetinal vascular thrombosis has been reported in patients receiving estrogens. Discontinue medication pending examination if there is sudden partial or complete loss of vision, or a sudden onset of proptosis, diplopia, or migraine. If examination reveals papilledema or retinal vascular lesions, estrogens should be permanently discontinued.
Anaphylactic Reaction And AngioedemaCases of anaphylaxis, which developed within minutes to hours after taking Duavive (Estrogens conjugated) and require emergency medical management, have been reported in the postmarketing setting. Skin (hives, pruritis, swollen lips-tongue-face) and either respiratory tract (respiratory compromise) or gastrointestinal tract (abdominal pain, vomiting) involvement has been noted.
Angioedema involving the tongue, larynx, face, hands, and feet requiring medical intervention has occurred postmarketing in patients taking Duavive (Estrogens conjugated). If angioedema involves the tongue, glottis, or larynx, airway obstruction may occur. Patients who develop an anaphylactic reaction with or without angioedema after treatment with Duavive (Estrogens conjugated) should not receive Duavive (Estrogens conjugated) again.
Addition Of A Progestin When A Woman Has Not Had A HysterectomyStudies of the addition of a progestin for 10 or more days of a cycle of estrogen administration or daily with estrogen in a continuous regimen, have reported a lowered incidence of endometrial hyperplasia than would be induced by estrogen treatment alone. Endometrial hyperplasia may be a precursor to endometrial cancer.
There are, however, possible risks that may be associated with the use of progestins with estrogens compared to estrogen-alone regimens. These include an increased risk of breast cancer.
Elevated Blood PressureIn a small number of case reports, substantial increases in blood pressure have been attributed to idiosyncratic reactions to estrogens. In a large, randomized, placebo-controlled clinical trial, a generalized effect of estrogen therapy on blood pressure was not seen.
HypertriglyceridemiaIn women with pre-existing hypertriglyceridemia, estrogen therapy may be associated with elevations of plasma triglycerides leading to pancreatitis. Consider discontinuation of treatment if pancreatitis occurs.
Hepatic Impairment And/Or Past History Of Cholestatic JaundiceEstrogens may be poorly metabolized in patients with impaired liver function. For women with a history of cholestatic jaundice associated with past estrogen use or with pregnancy, caution should be exercised, and in the case of recurrence, medication should be discontinued.
HypothyroidismEstrogen administration leads to increased thyroid-binding globulin (TBG) levels. Women with normal thyroid function can compensate for the increased TBG by making more thyroid hormone, thus maintaining free T4 and T3 serum concentrations in the normal range. Women dependent on thyroid hormone replacement therapy who are also receiving estrogens may require increased doses of their thyroid replacement therapy. These women should have their thyroid function monitored in order to maintain their free thyroid hormone levels in an acceptable range.
Fluid RetentionEstrogens may cause some degree of fluid retention. Women with conditions that might be influenced by this factor, such as cardiac or renal dysfunction, warrant careful observation when estrogen alone is prescribed.
HypocalcemiaEstrogen therapy should be used with caution in individuals with hypoparathyroidism as estrogen-induced hypocalcemia may occur.
Hereditary AngioedemaExogenous estrogens may exacerbate symptoms of angioedema in women with hereditary angioedema.
Exacerbation Of EndometriosisA few cases of malignant transformation of residual endometrial implants have been reported in women treated post-hysterectomy with estrogen-alone therapy. For women known to have residual endometriosis post-hysterectomy, the addition of progestin should be considered.
Exacerbation Of Other ConditionsEstrogen therapy may cause an exacerbation of asthma, diabetes mellitus, epilepsy, migraine, porphyria, systemic lupus erythematosus, and hepatic hemangiomas and should be used with caution in women with these conditions.
Laboratory TestsSerum follicle stimulating hormone (FSH) and estradiol levels have not been shown to be useful in the management of moderate to severe vasomotor symptoms and moderate to severe symptoms of vulvar and vaginal atrophy.
Laboratory parameters may be useful in guiding dosage for the treatment of hypoestrogenism due to hypogonadism, castration and primary ovarian failure.
Drug-Laboratory Test InteractionsAccelerated prothrombin time, partial thromboplastin time, and platelet aggregation time; increased platelet count; increased factors II, VII antigen, VIII antigen, VIII coagulant activity, IX, X, XII, VII-X complex, II-VII-X complex, and beta-thromboglobulin; decreased levels of antifactor Xa and antithrombin III, decreased antithrombin III activity; increased levels of fibrinogen and fibrinogen activity; increased plasminogen antigen and activity.
Increased thyroid-binding globulin (TBG) levels leading to increased circulating total thyroid hormone levels 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. Women on thyroid replacement therapy may require higher doses of thyroid hormone.
Other binding proteins may be elevated in serum, for example, corticosteroid binding globulin (CBG), sex hormone-binding globulin (SHBG), leading to increased total circulating corticosteroids and sex steroids, respectively. Free hormone concentrations, such as testosterone and estradiol, may be decreased. Other plasma proteins may be increased (angiotensinogen/renin substrate, alpha-1-antitrypsin, ceruloplasmin).
Increased plasma high-density lipoprotein (HDL) and HDL2 cholesterol subfraction concentrations, reduced low-density lipoprotein (LDL) cholesterol concentrations, increased triglyceride levels.
Impaired glucose tolerance.
Patient Counseling InformationSee FDA-approved patient labeling (PATIENT INFORMATION).
Vaginal BleedingInform postmenopausal women of the importance of reporting vaginal bleeding to their healthcare provider as soon as possible.
Possible Serious Adverse Reactions With EstrogensInform postmenopausal women of possible serious adverse reactions of estrogen therapy including Cardiovascular Disorders, Malignant Neoplasms, and Probable Dementia.
Possible Less Serious But Common Adverse Reactions With EstrogensInform postmenopausal women of possible less serious but common adverse reactions of estrogen therapy such as headache, breast pain and tenderness, nausea and vomiting.
Nonclinical Toxicology Carcinogenesis, Mutagenesis, Impairment Of FertilityLong-term continuous administration of natural and synthetic estrogens in certain animal species increases the frequency of carcinomas of the breast, uterus, cervix, vagina, testis, and liver.
Use In Specific Populations PregnancyDuavive (Estrogens conjugated) should not be used during pregnancy. There appears to be little or no increased risk of birth defects in children born to women who have used estrogens and progestins as an oral contraceptive inadvertently during early pregnancy.
Nursing MothersDuavive (Estrogens conjugated) should not be used during lactation. Estrogen administration to nursing women has been shown to decrease the quantity and quality of the breast milk. Detectable amounts of estrogens have been identified in the breast milk of mothers receiving estrogen-alone therapy. Caution should be exercised when Duavive (Estrogens conjugated) is administered to a nursing woman.
Pediatric UseEstrogen therapy has been used for the induction of puberty in adolescents with some forms of pubertal delay. Safety and effectiveness in pediatric patients have not otherwise been established.
Large and repeated doses of estrogen over an extended time period have been shown to accelerate epiphyseal closure, which could result in short stature if treatment is initiated before the completion of physiologic puberty in normally developing children. If estrogen is administered to patients whose bone growth is not complete, periodic monitoring of bone maturation and effects on epiphyseal centers is recommended during estrogen administration.
Estrogen treatment of prepubertal girls also induces premature breast development and vaginal cornification, and may induce vaginal bleeding. In boys, estrogen treatment may modify the normal pubertal process and induce gynecomastia.
Geriatric UseThere have not been sufficient numbers of geriatric patients involved in studies utilizing Duavive (Estrogens conjugated) to determine whether those over 65 years of age differ from younger subjects in their response to Duavive (Estrogens conjugated).
The Women's Health Initiative StudyIn the WHI estrogen-alone substudy (daily CE 0.625 mg-alone versus placebo), there was a higher relative risk of stroke in women greater than 65 years of age.
In the WHI estrogen plus progestin substudy (daily CE [0.625 mg] plus MPA [2.5 mg]), there was a higher relative risk of nonfatal stroke and invasive breast cancer in women greater than 65 years of age.
The Women's Health Initiative Memory StudyIn the WHIMS ancillary studies of postmenopausal women 65 to 79 years of age, there was an increased risk of developing probable dementia in women receiving estrogen-alone or estrogen plus progestin when compared to placebo.
Since both ancillary studies were conducted in women 65 to 79 years of age, it is unknown whether these findings apply to younger postmenopausal women8.
Renal ImpairmentThe effect of renal impairment on the pharmacokinetics of Duavive (Estrogens conjugated) has not been studied.
Hepatic ImpairmentThe effect of hepatic impairment on the pharmacokinetics of Duavive (Estrogens conjugated) has not been studied.
REFERENCES
1. Rossouw JE, et al. Postmenopausal Hormone Therapy and Risk of Cardiovascular Disease by Age and Years Since Menopause. JAMA. 2007;297:1465-1477.
2. Hsia J, et al. Conjugated Equine Estrogens and Coronary Heart Disease. Arch Int Med. 2006;166:357-365.
3. Curb JD, et al. Venous Thrombosis and Conjugated Equine Estrogen in Women Without a Uterus. Arch Int Med. 2006;166:772-780.
4. Cushman M, et al. Estrogen Plus Progestin and Risk of Venous Thrombosis. JAMA. 2004;292:1573-1580.
5. Stefanick ML, et al. Effects of Conjugated Equine Estrogens on Breast Cancer and Mammography Screening in Postmenopausal Women With Hysterectomy. JAMA. 2006;295:1647-1657.
6. Chlebowski RT, et al. Influence of Estrogen Plus Progestin on Breast Cancer and Mammography in Healthy Postmenopausal Women. JAMA. 2003;289:3234-3253.
7. Anderson GL, et al. Effects of Estrogen Plus Progestin on Gynecologic Cancers and Associated Diagnostic Procedures. JAMA. 2003;290:1739-1748.
8. Shumaker SA, et al. Conjugated Equine Estrogens and Incidence of Probable Dementia and Mild Cognitive Impairment in Postmenopausal Women. JAMA. 2004;291:29472958.
No effects known.
Any unused medicinal product or waste material should be disposed of in accordance with local requirements.
17β-estradiol is expected to pose a risk to the aquatic environment, especially to fish populations.
