Vagifem^® 25 micrograms film-coated vaginal tablets

One vaginal tablet contains:

Estradiol hemihydrate equivalent to estradiol 25 micrograms.

Excipients:

For a full list of excipients, see section 6.1

Film-coated vaginal tablet inset in disposable applicator.

Hormone replacement therapy for the treatment of vaginal atrophy due to oestrogen deficiency.

The experience of treating women older than 65 years is limited.

4.2.1 Dosage

Vagifem^® is administered intravaginally using the applicator. An initial dose of one tablet daily for two weeks will usually improve vaginal atrophy and associated symptoms; a maintenance dose of two tablets per week should then be instituted.

Treatment may be started on any convenient day.

If a dose is forgotten, it should be administered 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.

Vagifem^® may be used in women with or without an intact uterus.

The addition of a progestogen is not recommended during treatment with Vagifem^® (but see section 4.4)

Not intended for children or males.

Use in the elderly: there are no special dosage requirements.

4.2.2 Administration

The applicator is inserted into the vagina up to the end of the smooth part of the applicator (approximately 9 cms). The tablet is released by pressing the plunger. The applicator is then withdrawn and disposed of.

Known, past or suspected breast cancer.

Known, past or suspected oestrogen-dependent malignant tumours (eg 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 history of liver disease as long as liver function tests have failed to return to normal.

Known hypersensitivity to the active substance or to any of the excipients.

Porphyria.

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 annually and HRT should only be continued as long as the benefit outweighs the risk.

Medical examination/follow-up

Before initiating or reinstituting HRT, a complete personal and family medical history should be taken. Physical (including pelvic and breast) examination should be guided by this and by the contra-indications 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.

Vaginal infections should be treated before initiation of Vagifem^® therapy.

Due to the intermittent administration of low dose estradiol in Vagifem^®, low systemic exposure of estradiol is expected (see section 5.2), however being an 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 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

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

The risk of endometrial hyperplasia and carcinoma is increased when systemic oestrogens are administered for prolonged periods of time. The endometrial safety of long-term or repeated use of topical vaginal oestrogens is uncertain. Therefore, if repeated, treatment should be reviewed at least annually, with special consideration given to any symptoms of endometrial hyperplasia or carcinoma.

If bleeding or spotting appears at any time on therapy, the reason should be investigated, which may include endometrial biopsy to exclude endometrial malignancy.

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 local low dose preparation and therefore the occurrence of the below mentioned conditions is less likely than that with systemic oestrogen treatment.

Breast cancer

A randomised placebo-controlled trial, the Women's Health Initiative study (WHI), and epidemiological studies, including the Million Women Study (MWS), have reported an increased risk of breast cancer in women taking estrogens, estrogen-progestagen combinations or tibolone for HRT for several years (see section 4.8). For all HRT, an excess risk becomes apparent within a few years of use and increases with duration of intake but returns to baseline within a few (at most five) years after stopping treatment.

In the MWS, the relative risk of breast cancer with conjugated equine estrogens (CEE) or estradiol (E2) was greater when a progestagen was added, either sequentially or continuously, and regardless of type of progestagen. There was no evidence of a difference in risk between the different routes of administration.

In the WHI study, the continuous combined conjugated equine estrogen and medroxyprogesterone acetate (CEE + MPA) product used was associated with breast cancers that were slightly larger in size and more frequently had local lymph node metastases compared to placebo. HRT, especially estrogen-progestagen combined treatment, increases the density of mammographic images which may adversely affect the radiological detection of breast cancer.

Venous thromboembolism

Systemic HRT is associated with a higher relative risk of developing venous thromboembolism (VTE), i.e. deep vein thrombosis or pulmonary embolism. One randomised controlled trial and epidemiological studies found a two- to threefold higher risk for users compared with non-users. For non-users it is estimated that the number of cases of VTE that will occur over a 5 year period is about 3 per 1000 women aged 50-59 years and 8 per 1000 women aged between 60-69 years. It is estimated that in healthy women who use HRT for 5 years, the number of additional cases of VTE over a 5 year period will be between 2 and 6 (best estimate = 4) per 1000 women aged 50-59 years and between 5 and 15 (best estimate = 9) per 1000 women aged 60-69 years. The occurrence of such an event is more likely in the first year of HRT 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). There is no consensus about the possible role of varicose veins in VTE.

Patients with a history of VTE or known thrombophilic states have an increased risk of VTE. HRT may add to this risk. Personal or strong family history of thromboembolism, or recurrent spontaneous abortion, should be investigated in order to exclude a thrombophilic predisposition. Until a thorough evaluation of thrombophilic factors has been made or anticoagulant treatment initiated, use of HRT in such patients should be viewed as contraindicated. Those women already on anticoagulant treatment require careful consideration of the benefit-risk of use of HRT.

The risk of VTE may be temporarily increased with prolonged immobilisation, major trauma or major surgery. As in all postoperative patients, scrupulous attention should be given to prophylactic measures to prevent VTE following 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 earlier, 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 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 cardiovascular benefit with continuous combined conjugated estrogens and medroxyprogesterone acetate (MPA). Two large clinical trials (WHI and HERS i.e. Heart and Estrogen/progestin Replacement Study) showed a possible increased risk of cardiovascular morbidity in the first year of use and no overall benefit. For other HRT products there are only limited data from randomised controlled trials examining effects in cardiovascular morbidity or mortality. Therefore, it is uncertain whether these findings also extend to other HRT products.

Stroke

One large randomised clinical trial (WHI-trial) found, as a secondary outcome, an increased risk of ischaemic stroke in healthy women during treatment with continuous combined conjugated oestrogens and medroxyprogesterone acetate (MPA). For women who do not use HRT, it is estimated that the number of cases of stroke that will occur over a 5 year period is about 3 per 1000 women aged 50-59 years and 11 per 1000 women aged 60-69 years. It is estimated that for women who use conjugated oestrogens and MPA for 5 years, the number of additional cases will be between 0 and 3 (best estimate = 1) per 1000 users aged 50-59 years and between 1 and 9 (best estimate = 4) per 1000 users aged 60-69 years. It is unknown whether the increased risk also extends to other HRT products.

Ovarian cancer

Long-term (at least 5 -10 years) use of oestrogen-only HRT products in hysterectomised women has been associated with an increased risk of ovarian cancer in some epidemiological studies. It is uncertain whether long-term use of combined HRT confers a different risk than oestrogen-only products.

Other conditions

Oestrogens may cause fluid retention, and therefore patients with cardiac or renal dysfunction should be carefully observed. Patients with terminal renal insufficiency should be closely observed, since the level of circulating active ingredient in Vagifem^® may be increased.

Systemic oestrogens have been reported to increase thyroid binding globulin (TBG), leading to increased circulating total thyroid hormone as measured by protein-bound iodine (PBI), T4 levels (by column or by radio-immunoassay) or T3 levels (by radio-immunoassay). T3 resin uptake is decreased, reflecting the elevated TBG. Free T4 and free T3 concentrations are unaltered. Other binding proteins may be elevated in serum, i.e. corticoid binding globulin (CBG), sex-hormone-binding globulin (SHBG), leading to increased circulating corticosteroids and sex steroids respectively. Free or biologically active hormone concentrations are unchanged. Other plasma proteins may be increased (angiotensinogen/renin substrate, alpha-1-antitrypsin, ceruloplasmin). The systemic exposure of estradiol with intermittent administration of low dose estradiol in Vagifem^® (see section 5.2) may result in less pronounced effects on plasma binding proteins than with oral hormones

Women with pre-existing hypertriglyceridaemia should be followed closely during oestrogen replacement or hormone replacement therapy, since rare cases of large increases in plasma triglycerides leading to pancreatitis have been reported with oestrogen therapy in this condition.

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.

None reported.

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 effects.

Vagifem^® is not indicated during lactation.

No effects known.

More than 640 patients have been treated with Vagifem^® in clinical trials, including over 200 patients treated for between 28 and 64 weeks. Well known oestrogen-related adverse effects which occurred with a higher frequency in the treated group as compared with the placebo group are presented as “Common (>1/100, <1/10)"

The spontaneous reporting rate on Vagifem^® corresponds to approximately 1 case per 10,000 patient years. Adverse events for which an increased frequency has not been observed in clinical trials, but which have been spontaneously reported and which on an overall judgement are considered possibly related to Vagifem^® treatment are therefore presented as “Very rare (<1/10,000)"

Post marketing experience is subject to under-reporting especially with regard to trivial and well-known adverse drug reactions. The presented frequencies should be interpreted in that light.

The most commonly reported adverse drug reactions are: vaginal discharge and vaginal discomfort. Oestrogen-related adverse events such as breast pain, peripheral oedema and postmenopausal bleedings are most likely to present at the beginning of Vagifem^® treatment.

Breast cancer

According to evidence from a large number of epidemiological studies and one randomised placebo-controlled trial, the Women's Health Initiative (WHI), the overall risk of breast cancer increases with increasing duration of HRT use in current or recent HRT users.

For oestrogen-only HRT, estimates of relative risk (RR) from a reanalysis of original data from 51 epidemiological studies (in which>80% of HRT use was oestrogen-only HRT) and from the epidemiological Million Women Study (MWS) are similar at 1.35 (95%CI 1.21 – 1.49) and 1.30 (95%CI 1.21 – 1.40), respectively.

For oestrogen plus progestagen combined HRT, several epidemiological studies have reported an overall higher risk for breast cancer than with oestrogens alone.

The MWS reported that, compared to never users, the use of various types of oestrogen-progestagen combined HRT was associated with a higher risk of breast cancer (RR = 2.00, 95%CI: 1.88 – 2.12) than use of oestrogens alone (RR = 1.30, 95%CI: 1.21 – 1.40) or use of tibolone (RR=1.45; 95%CI 1.25-1.68).

The WHI trial reported a risk estimate of 1.24 (95%CI 1.01 – 1.54) after 5.6 years of use of oestrogen-progestagen combined HRT (CEE + MPA) in all users compared with placebo.

The absolute risks calculated from the MWS and the WHI trial are presented below:

The MWS has estimated, from the known average incidence of breast cancer in developed countries, that:

• For women not using HRT, about 32 in every 1000 are expected to have breast cancer diagnosed between the ages of 50 and 64 years.

• For 1000 current or recent users of HRT, the number of additional cases during the corresponding period will be

o For users of oestrogen-only replacement therapy

o For users of oestrogen plus progestagen combined HRT,

The WHI trial estimated that after 5.6 years of follow-up of women between the ages of 50 and 79 years, an additional 8 cases of invasive breast cancer would be due to oestrogen-progestagen combined HRT (CEE + MPA) per 10,000 women years.

According to calculations from the trial data, it is estimated that:

o about 16 cases of invasive breast cancer would be diagnosed in 5 years.

o between 0 and 9 (best estimate = 4) for 5 years' use.

The number of additional cases of breast cancer in women who use HRT is broadly similar for women who start HRT irrespective of age at start of use (between the ages of 45-65) (see section 4.4).

The following adverse reactions have been reported in association with other oestrogen treatment:

- Myocardial infarction, stroke

- Gallbladder disease

- Skin and subcutaneous disorders: chloasma, erythema multiforme, erythema nodosum, vascular purpura, pruritus

- Risk of development of endometrial cancer (see section 4.4), endometrial hyperplasia or increase in size of uterine fibroids*

- Probable dementia (see section 4.4).

* In non-hysterectomised women.

Symptoms that may occur in the case of an acute overdose of oestrogen are nausea and vomiting. If necessary a symptomatic treatment should be instituted.

Pharmacotherapeutic group: ATC code G03C A03

Natural and semisynthetic oestrogens, plain (for vaginal use).

The active ingredient in Vagifem^® is synthetic 17β-estradiol which is chemically and biologically identical to endogenous human estradiol.

17β-estradiol is the principal and most active of the naturally occurring human oestrogens. It has pharmacological actions in common with all oestrogenic compounds. The action on the vagina is to increase maturation of vaginal epithelial cells and increase cervical secretory activity.

Estrogen drug products are well absorbed through the skin, mucous membranes, and the gastrointestinal tract. After treatment with Vagifem^®, marginal elevations of plasma estradiol and conjugated oestrogens as well as suppression of pituitary gonadotrophins have been observed. The vaginal delivery of estrogens circumvents first-pass metabolism.

A single-centre randomised, double-blind two period cross-over study was performed to evaluate the pharmacokinetics of Vagifem^®. Peak levels were approximately 175 pmol/L (48pg/ml) following a single dose of Vagifem^®. After 14 days of treatment, only marginal absorption of estradiol could be detected, with mean levels in the postmenopausal range.

Another study in younger patients, mean age 52 years, showed that vaginal administration of Vagifem^® over a 12 week course demonstrated a mean C_max of estradiol of 50 pg/ml and that there was no significant accumulation of estradiol as measured by the AUC_0-24 (see table 1 below). The average estradiol concentrations at each time point were within the normal postmenopausal range.

Table 1: Mean (± standard deviation) pharmacokinetic parameters for estradiol

The levels of oestrone seen during 12 weeks of Vagifem^® administration do not show any accumulation of oestrone, and the observed values are within the postmenopausal range.

Oestrogen metabolites are primarily excreted in the urine as glucuronides and sulphates.

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 25 µg E2 tablet . Subjects were randomized 1:1 to receive either 25 µg E2 (Vagifem) or 10 µg E2. Plasma levels of oestradiol (E2), oestrone (E1) and oestrone sulfate (E1S) were determined at Day -1 (pre-dose), Day 1 (after 1st dosing), Day 14 (after 14 days of once-daily dosing), Day 82 (pre-dose after 10 weeks twice-weekly treatment) and Day 83 (post-dose after 10 weeks twice-weekly treatment). The primary bioavailability endpoint of the clinical trial was AUC(0-24) for plasma E2 levels (see Table 1): this parameter indicated higher systemic oestradiol levels for Vagifem 25 µg as compared to baseline on treatment days 1, 14 and 83. However, average plasma E2 levels (Cave(0-24)) at all time points overall remained below 20 pg/ml. The data from day 82 indicate that in the long term, systemic oestradiol levels do not accumulate during twice weekly maintenance therapy (see Table 2).

Table 2 Values of PK parameters from plasma Oestradiol (E2) concentrations:

Study VAG-1850

The levels of oestrone seen during 12 weeks of Vagifem 25 μg administration do not show any accumulation of oestrone.

Estrogen metabolites are primarily excreted in the urine as glucuronides and sulfates.

As 17β-estradiol is a well known substance in humans, described in the pharmacotoxicological literature, no further studies have been performed.

Tablet core:

Hypromellose

Lactose monohydrate

Maize starch

Magnesium stearate

Film-coating:

Hypromellose

Macrogol 6000

None known

36 months

Store in a dry place, protect from light. Store below 25ºC. Do not refrigerate.

Laminated bubble strips containing 5 applicators with inset tablet. Packed in cartons containing 3 strips (15 tablets and applicators).

No special requirements

Novo Nordisk A/S

Novo Alle

DK-2880 Bagsvaerd

Denmark

The registered office in the UK is:-

Novo Nordisk Limited

BroadfieldPark

Crawley

West Sussex

RH11 9RT

Tel: (01293) 613555

PL 4668/0026

First authorised August 1990

Authorisation renewed 10/03/2009

06/10/2010