Vagifem 10 micrograms vaginal tablets

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Section 4.8

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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 10 micrograms and are considered possibly related to treatment. The frequencies for the below mentioned reporting rate of these spontaneous adverse drug reactions cannot be interpreted because these reactions are reported voluntarily from a population of uncertain size: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 vein thrombosis

•       Gastrointestinal disorders: diarrhoea

•       Skin and subcutaneous tissue disorders: pruritus, rash, urticaria, rash erythematous, rash pruritic, genital pruritus

•       Reproductive system and breast disorders: endometrial hyperplasia, vaginal irritation, vaginal pain, vaginismus, vaginal ulceration vulvovaginal pain¹, pruritus genital

•       General disorders and administration site conditions: application site reaction², drug ineffective, injury associated with device³

•       Investigations: weight increased, blood oestrogen increased.

¹ Including Vulvovaginal burning sensation

² Local allergic reactions including Vulvovaginal erythema, Genital erythema, Vulvovaginal rash, Genital rash

³ Minor local trauma caused by intravaginal applicator

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2.         What you need to know before you use Vagifem

Warnings and precautions

Tell your doctor if you have or have ever had any of the following problems, before you start the treatment, as these may return or become worse during treatment with Vagifem. If so, you should see your doctor more often for check-ups. 

•       hereditary and acquired angioedema.

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Stop using Vagifem and see a doctor immediately

If you notice any of the following when using HRT:

•       Swollen face, tongue and/or throat and/or difficulty swallowing or hives, together with difficulty breathing which are suggestive of an angioedema

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3.         How to use Vagifem

General information about treating symptoms of the menopause

     For OTC-products

•       When using medicines for any menopausal symptoms, it is recommended to use the lowest dose that works, and to use the medicine for as short a time as it is needed.

         For prescription only products

•       Your doctor will aim to prescribe the lowest dose of Vagifem to treat your symptom for as short as necessary. Speak to your doctor if you think this dose is too strong or not strong enough.

•       Treatment should only be continued if the benefit is greater than the risk. Talk to your doctor about this.

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Reporting of side effects

Malta:

ADR Reporting

Website: www.medicinesauthority.gov.mt/adrportal

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Other sources of information

Detailed information on this medicine is available on the website of: HPRA

2       QUALITATIVE AND QUANTITATIVE COMPOSITION

Editorial change from:

Each vaginal tablet contains: Estradiol hemihydrate equivalent to estradiol 10 micrograms.

to

Each vaginal tablet contains: estradiol hemihydrate equivalent to estradiol 10 micrograms.

4.4    Special warnings and precautions for use

Other conditions

Addition of:

Exogenous oestrogens may induce or exacerbate symptoms of hereditary and acquired angioedema.

Lo-call phone number (1850) removed from Section 6.

Date of revision updated to 07/2022.

Section 4.6 heading updated to

Fertility, pregnancy and lactation

Section 4.4

Epidemiological evidence from a large meta-analysis suggests no increase in risk of breast cancer in women with no history of breast cancer taking low dose vaginally applied oestrogens. It is unknown if low dose vaginal oestrogens stimulate recurrence of breast cancer. The overall evidence suggests an increased risk of breast cancer in women taking combined oestrogen-progestagen and possibly also oestrogen-only systemic HRT, that is dependent on the duration of taking HRT.

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.

Section 4.8

Breast cancer risk

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 (see section 4.4).

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

US WHI studies – additional risk of breast cancer after 5 years’ use

* WHI study in women with no uterus, which did not show an increase in risk of breast cancer.

Section 4.8 - how to report a side effect:

Reporting details for the HPRA shortened to 'HPRA Pharmacovigilance, Website: www.hpra.ie'

As this is a renewal, these are the following changes. The suspected adverse reaction reporting information (address updated from IMB to HPRA) in section 4.8 of this SmPC has also been updated, section 9 Date of lastest renewal is added and in section 10 Date of revision of the text has been updated.

In section 4.8 (Undesirable effects ) 

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 HPRA Pharmacovigilance, Earlsfort Terrace , IRL - Dublin 2; Tel: +353 1 6764971; Fax: +353 1 6762517. Website: www.hpra.ie; E-mail: medsafety@hpra.ie.

In section 9:

DATE OF FIRAT AUTHORISATION/RENEWAL OF THE AUTHORISATION
Date of lastest renewal: 06 January 2015 under Section 9 of the SmPC.

In section 10:

DATE OF REVISION OF THE TEXT

Changes outlined below.
... indicates unchanged sections that have been omitted.

2          QUALITATIVE AND QUANTITATIVE COMPOSITION

Each vaginal tablet contains:

Estradiol hemihydrate equivalent to estradiol 10  micrograms.

For thea full list of excipients, see section 6.1.

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4.2       Posology and method of administration

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Vagifem is a local vaginal therapy and in women with an intact uterus, progestagen treatment is not necessary (however see sSection 4.4, ‘Special warnings and precautions for use’, ‘Eendometrial hyperplasia and carcinoma’).

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4.4       Special warnings and precautions for use

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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 (C_{ave (0-24)}) at all evaluated days remained within the normal postmenopausal range in all subjects (see section 5.2).

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 duringon therapy, the reason should be investigated, which may include endometrial biopsy to exclude endometrial malignancy.

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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 (see section 4.8).

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 (see section 4.3).

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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 (see section 4.8).

A relationship between ischaemic stroke and low dose local vaginal oestrogen therapy is uncertain.

Other conditions

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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.

4.8       Undesirable effects

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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 (see section 4.4).

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. In the Million Women Study the use of five years of combined (sequential or continuous) HRT did not increase risk of endometrial cancer (RR of 1.0 (0.8-1.2)).

Please also see section 4.4.

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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

Pharmacovigilance Section

Irish Medicines Board

Kevin O’Malley House

Earlsfort Centre

Earlsfort Terrace

IRL - Dublin 2

Tel: +353 1 6764971

Fax: +353 1 6762517

Website: www.imb.ie

e-mail: imbpharmacovigilance@imb.ie

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6.6       Special precautions for disposal and other handling

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.

10        DATE OF REVISION OF THE TEXT