1. Name Of The Medicinal Product
Vagifem 10 micrograms vaginal tablets.
2. Qualitative And Quantitative Composition
Each vaginal tablet contains:
Estradiol hemihydrate equivalent to estradiol 10 micrograms.
For a full list of excipients, see section 6.1.
3. Pharmaceutical Form
Vaginal tablet.
White, film-coated, biconvex tablet, engraved with NOVO 278 on one side. Diameter 6 mm.
4. Clinical Particulars
4.1 Therapeutic Indications
Treatment of vaginal atrophy due to oestrogen deficiency in postmenopausal women (see section 5.1).
The experience treating women older than 65 years is limited.
4.2 Posology And Method Of Administration
Vagifem is administered intravaginally using the applicator.
Initial dose: One vaginal tablet daily for two weeks.
Maintenance dose: One vaginal tablet twice a week.
Treatment may be started on any convenient day.
If a dose is forgotten, it should be taken as soon as the patient remembers. A double dose should be avoided.
For initiation and continuation of treatment of postmenopausal symptoms, the lowest effective dose for the shortest duration (see also section 4.4) should be used.
A switch to the higher dose product Vagifem 25 micrograms should be considered if the response after three months is insufficient for satisfactory symptom relief.
Vagifem may be used in women with or without an intact uterus.
During treatment, especially during the first two weeks of daily administration, minimal systemic absorption may occur but as plasma estradiol levels usually do not exceed normal postmenopausal levels the addition of a progestagen is not recommended.
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 idiopathic or current venous thromboembolism (deep venous thrombosis, pulmonary embolism)
• 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 Use
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.
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 mammography should be carried out in accordance with currently accepted screening practices, modified to the clinical needs of the individual.
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 systemic oestrogen treatment, in particular:
• Leiomyoma (uterine fibroids) or endometriosis
• A history of, or 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.
Due to the local administration of low dose estradiol in Vagifem, 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 contra-indication 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
Endometrial hyperplasia
Women with 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.
The risk of endometrial cancer after treatment with oral unopposed oestrogens is dependent on both duration of treatment and on oestrogen dose. The dose of estradiol in Vagifem is very low and treatment is local. A minor degree of systemic absorption may occur in some patients, especially during the first two weeks of once daily administration (see section 5.2). No systemic effect is expected during the local oestrogen treatment with Vagifem, and the addition of a progestagen is not recommended.
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 on 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.
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.
Breast cancer
Systemic oestrogen or oestrogen-progestagen treatment may increase the risk of breast cancer. Relative risk of breast cancer with conjugated equine oestrogens or estradiol was greater when a progestagen was added, either sequentially or continuously, and regardless of type of progestagen. A large randomised clinical trial (WHI trial) showed no increase in breast cancer incidence in hysterectomised postmenopausal women treated with conjugated equine oestrogen alone.
Venous thromboembolism
Systemic HRT is associated with a higher relative risk of developing venous thromboembolism (VTE), i.e. deep vein thrombosis or pulmonary embolism.
In the oestrogen alone sub-study of WHI, the risk of VTE (DVT and pulmonary embolism (PE)) was reported to be increased for women receiving daily conjugated equine oestrogens (CEE) compared to placebo (30 versus 22 per 10,000 women-years). The occurrence of such an event is more likely in the first year of treatment than later.
Generally recognised risk factors for VTE include a personal history or family history, severe obesity (BMI>30 kg/m2) and systemic lupus erythematosus (SLE). The risk of VTE may be temporarily increased with prolonged immobilisation, major trauma or major surgery. Where prolonged immobilisation is liable to follow elective surgery, particularly abdominal or orthopaedic surgery to the lower limbs, consideration should be given to temporarily stopping HRT 4 to 6 weeks prior to surgery, if possible. Treatment should not be restarted until the woman is completely mobilised.
If VTE develops after initiating therapy, the drug should be discontinued. Patients should be told to contact their doctors immediately when they experience a potential thromboembolic symptom (e.g., painful swelling of a leg, sudden pain in the chest, dyspnea). Those women already on anticoagulant treatment require careful consideration of the benefit-risk of use of HRT.
Coronary artery disease (CAD)
There is no evidence from randomised controlled trials that oestrogens or combined oestrogen-progestagen protect against coronary artery disease.
Stroke
In the WHI estrogen alone sub-study, a statistically significant increased risk of stroke was reported in women receiving daily conjugated oestrogens (CE 0.625 mg) compared to placebo (45 versus 33 per 10,000 women-years). The increase in risk was demonstrated after the first year of treatment and persisted.
Ovarian cancer
Use of systemic oestrogen alone and oestrogen plus progestagen therapies for at least 5-10 years has been associated with a slightly increased risk of ovarian cancer in some epidemiological studies.
Other conditions
Oestrogens may cause fluid retention, and therefore patients with cardiac or renal dysfunction should be carefully observed during the first weeks of treatment.
There is no conclusive evidence for improvement of cognitive function. There is some evidence from the WHI trial of increased risk of probable dementia in women who start using continuous combined CEE and MPA after the age of 65. It is unknown whether the findings apply to younger post-menopausal women or other HRT products.
Intravaginal applicator may cause minor local trauma, especially in women with serious vaginal atrophy.
4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction
Due to a local administration of the very low dose of estradiol in Vagifem, systemic interactions of clinical relevance are not expected.
4.6 Pregnancy And Lactation
Vagifem is not indicated during pregnancy. If pregnancy occurs during medication with Vagifem, treatment should be withdrawn immediately. The results of most epidemiological studies to date relevant to inadvertent foetal exposure to oestrogens indicate no teratogenic or foetotoxic effect.
Lactation
Vagifem is not indicated during lactation.
4.7 Effects On Ability To Drive And Use Machines
No effects known.
4.8 Undesirable Effects
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.
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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 (incl. cysts and polyps): breast cancer, endometrial cancer
• Immune system disorders: generalized 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 systemic oestrogen treatment:
• 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 (see section 4.4).
4.9 Overdose
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.
5. Pharmacological Properties
5.1 Pharmacodynamic Properties
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 dependant 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-month double-blind, randomized, parallel group, placebo-controlled multicenter 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, normalization 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, multicenter 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.
5.2 Pharmacokinetic Properties
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 randomized 1:1 to receive either 10 micrograms or 25 micrograms Vagifem. Plasma levels of estradiol (E2), oestrone (E1) and oestrone sulphate (E1S) were determined. 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:
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The levels of oestrone and oestrone sulphate after 12 weeks of Vagifem 10 micrograms administration did not exceed baseline levels, i.e., no accumulation of oestrone or oestrone sulphate 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 oestriol, which is the major urinary metabolite. In postmenopausal women, a significant portion of the circulating oestrogens exist as sulphate conjugates, especially oestrone sulphate, which serves as a circulating reservoir for the formation of more active oestrogens.
Elimination
Estradiol, oestrone and oestriol 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.
5.3 Preclinical Safety Data
17β-Estradiol is a well-known substance. Nonclinical studies provided no additional data of relevance to clinical safety beyond those already included in other sections of the SPC.
6. Pharmaceutical Particulars
6.1 List Of Excipients
Tablet core:
Hypromellose
Lactose monohydrate
Maize starch
Magnesium stearate
Film-coating:
Hypromellose
Macrogol 6000
6.2 Incompatibilities
Not applicable.
6.3 Shelf Life
3 years.
6.4 Special Precautions For Storage
Do not refrigerate.
6.5 Nature And Contents Of Container
Each tablet is contained in a disposable single-use polyethylene/polypropylene applicator. The applicators are packed separately in PVC/aluminium foil blisters.
18 packs contain 3 blister cards of 6 applicators with inset tablets
24 packs contain 4 blister cards of 6 applicators with inset tablets
Not all pack sizes may be marketed.
6.6 Special Precautions For Disposal And Other Handling
Any unused product or waste material should be disposed of in accordance with local requirements.
7. Marketing Authorisation Holder
Novo Nordisk A/S
Novo Allé
DK-2880 Bagsværd
Denmark
The registered office in the UK is:-
Novo Nordisk Ltd
Broadfield Park
Brighton Road
Crawley
West Sussex
RH11 9AT
Tel: 01293 613555
8. Marketing Authorisation Number(S)
PL 04668/0237
9. Date Of First Authorisation/Renewal Of The Authorisation
Date of first authorisation: 17th February 2010
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