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Blissel

Document: Blissel vaginal gel ENG SmPC change

SUMMARY OF PRODUCT CHARACTERISTICS


1 NAME OF THE MEDICINAL PRODUCT


Blissel 50 micrograms/g vaginal gel


2 QUALITATIVE AND QUANTITATIVE COMPOSITION


1 g vaginal gel contains 50 micrograms estriol.

Excipients: 1 g vaginal gel contains 1.60 mg of sodium methyl parahydroxybenzoate and 0.20 mg of sodium propyl parahydroxybenzoate.


For the full list of excipients, see section 6.1.


3 PHARMACEUTICAL FORM


Vaginal gel

Gel homogeneous, colourless, clear to slightly translucent.


4 CLINICAL PARTICULARS


4.1 Therapeutic indications


Local treatment of vaginal dryness in postmenopausal women with vaginal atrophy.


4.2 Posology and method of administration


Blissel 50 micrograms/g vaginal gel is an estrogen-only product for vaginal use.

Blissel has to be introduced into the vagina using a dose-marked applicator, following carefully “Instructions for use” included in the information leaflet.

One applicator-dose (applicator filled to the mark) delivers a dose of 1 g vaginal gel containing 50 micrograms estriol.

For initiation and continuation of treatment of post-menopausal symptoms, the lowest effective dose for the shortest duration should be used (see also section 4.4.)

Initial treatment: One applicator-dose of vaginal gel per day for 3 weeks (suitably at bedtime).

As maintenance treatment one applicator-dose of vaginal gel twice a week (suitably at bedtime) is recommended. An evaluation of treatment continuation after 12 weeks should be carried out by the physician.


A missed dose should be administered as soon as remembered, unless it is more than 12 hours overdue. In the latter case the missed dose should be skipped and the next dose should be administered at the normal time.


4.3 Contraindications



4.4 Special warnings and precautions for use


For the treatment of postmenopausal symptoms, local estrogen therapy should only be initiated for symptoms that adversely affect quality of life. As with all estrogen-based products, a careful appraisal of the risks and benefits should be undertaken at least annually. Therapy should only be continued as long as the benefit outweighs the risk.


Blissel 50 micrograms/g vaginal gel must not be combined with estrogen preparations for systemic treatment, as there are no studies of safety and risks with estrogen concentrations attained in combination treatment.


Intravaginal applicator may cause minor local trauma, especially in women with serious vaginal atrophy.


Warning about excipients


Blissel 50 micrograms/g vaginal gel contains sodium methyl parahydroxibenzoate (E 219) and sodium propyl parahydroxibenzoate (E 217). May cause allergic reactions (possibly delayed).


Medical examination/follow-up of treatment


Before estriol treatment is initiated or reinstituted, a complete personal and family medical history should be taken. A general medical and gynaecological examination (including pelvic and breast examination) shall be performed, with consideration taken of the patient’s own history of disease and of contraindications and warnings in connection with the treatment.

During treatment, periodic check-ups are recommended with a frequency and nature adapted to the individual woman. Women should be advised of which changes in their breasts should be reported to their doctor or nurse.

Investigations, including mammography, are recommended to be carried out in accordance with currently accepted screening practices, modified to the clinical needs of the individual.

In case of vaginal infections, these should be treated before starting therapy with Blissel 50 micrograms/g vaginal gel.


Conditions which require extra 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 treatment with Blissel 50 micrograms/g vaginal gel, in particular:



Reasons for immediate withdrawal of treatment


Therapy should be discontinued in case a contraindication is discovered and in the following situations:



Endometrial hyperplasia


The risk of endometrial hyperplasia and carcinoma in peroral treatment solely with estrogenis dependent on both the duration of treatment and the dose of estrogen.An increased risk of endometrial hyperplasia or uterine cancer has not been attributed to treatment with estriol by vaginal use. However, if continued treatment is required, periodical revisions are recommended, with special consideration given to any symptoms suggestive of endometrial hyperplasia or endometrial malignancy.


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


Unopposed estrogen stimulation may lead to premalignant 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, uterine and ovarian cancer


Systemic treatment with estrogens may increase the risk of certain types of cancer, in particular uterine, ovarian and breast cancer. Blissel 50 micrograms/g vaginal gel administered locally that contains a low dose of estriol is not expected to increase the risk of cancer.


Venous thromboembolic disorder, stroke and coronary artery disease


Hormone replacement treatment with preparations with systemic effect is associated with an increased risk of venous thromboembolism (VTE), stroke and coronary artery disease. Blissel 50 micrograms/g vaginal gel, which contains a low dose of estriol for local treatment, is not expected to give an elevated risk of VTE, stroke and coronary artery disease.


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. Closely supervision is recommended in these patients.

Other conditions


Estrogens with systemic effects may cause fluid retention or increase of plasma tryglicerides, for which reason, patients with heart diseases or impaired renal function or with preexisting hypertriglyceridemia, respectively, should be carefully observed during the first weeks of treatment. Blissel 50 micrograms/g vaginal gel contains a low dose of estriol for local treatment, therefore systemic effects are not expected.


Patients suffering from severe renal insufficiency /should be carefully observed, as it may be expected that the level of circulating estriol is increased.


4.5 Interaction with other medicinal products and other forms of interaction


No interaction studies between Blissel 50 micrograms/g vaginal gel and other medicines have been performed. As Blissel is administered locally at a low dose, no clinically relevant interactions are expected.


4.6 Fertility, pregnancy and lactation


Pregnancy

Blissel 50 micrograms/g vaginal gel is not indicated during pregnancy.

If pregnancy occurs during treatment with Blissel 50 micrograms/g vaginal gel, treatment shall be withdrawn immediately.

For estriol no clinical data on exposed pregnancies are available.

The results of most epidemiological studies to date relevant to inadvertent foetal exposure to estrogens indicate no teratogenic or foetotoxic effects.


Breastfeeding

Blissel 50 micrograms/g vaginal is not indicated during lactation.


4.7 Effects on ability to drive and use machines


Blissel 50 micrograms/g vaginal gel has no influence on the ability to drive and use machines.


4.8 Undesirable effects


Undesirable effects from estriol are usually reported in 3-10% of those patients who are treated. They are often transient and of mild intensity.


At the beginning of treatment, when the mucous membrane in the vagina is still atrophic, local irritation may occur in the form of a sensation of heat and/or itching.


The undesirable effects found in the clinical studies performed with Blissel 50 micrograms/g vaginal gel have been classified according to frequency of appearance:


Organ System Class

Common ( 1/100 to <1/10)

Uncommon (1/1,000 to <1/100)

Rare (1/10,000 to <1/1000)

Reproductive system and breast disorders

Pruritus genital.



Pelvic pain, genital rash.

General disorders and administration site conditions

Application site pruritus


Application site irritation

Infections and infestations

Candidiasis

Nervous system disorders

Headache

Skin and subcutaneous tissue disorders

Pruritus


Prurigo

Blissel is a locally administered vaginal gel with a very low dose of estriol and self-limiting systemic exposure (shown to be almost negligible after repeated administration), and as such is highly unlikely to produce the more severe effects associated with oral estrogen replacement therapy. However, other very rare adverse reactions have been reported with higher dose systemic estrogen/progestin therapy. These are:


- Estrogen-dependent neoplasms benign and malignant, e.g. endometrial cancer and breast cancer (see also section 4.3 Contraindications and 4.4. Special warnings and precautions for use)


- Venous thromboembolism, i.e. deep leg or pelvic venous thrombosis and pulmonary embolism, is more frequent among hormone replacement therapy users than among non-users. For further information, see section 4.3 Contraindications and 4.4. Special warnings and precautions for use


- Myocardial infarction and stroke


- Gall bladder disease


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


- Probable dementia


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 national reporting system listed in Appendix V


4.9 Overdose


Toxicity for estriol is very low. Overdose of Blissel 50 micrograms/g vaginal gel with vaginal application is very unlikely. Symptoms that may occur in the case of a high dose is accidentally ingested are nausea, vomiting and vaginal bleeding in females. There is no known specific antidote. If necessary, a symptomatic treatment should be instituted.


5 PHARMACOLOGICAL PROPERTIES


5.1 Pharmacodynamic properties


Pharmacotherapeutic group: Estrogens, ATC code: G03CA04.


Blissel 50 micrograms/g vaginal gel contains synthetic estriol, which is chemically and biologically identical to human estriol.Estriol exerts their pharmacological and biological effects through its action on estrogen receptors (ER). Estriol has a high relative binding affinity for estrogen receptors in the bladder and vaginal tissue and a relatively low binding affinity to endometrial and breast tissue estrogen receptors. For this reason, the estriol binding to the endometrial estrogen receptor is too short to induce true proliferation when estriol is given once daily, while its binding to the vaginal estrogen receptor is sufficient to exert a full vaginotrophic effect despite of using very low dose of estriol.


In postmenopausal women, the decrease of estrogen levels result in genital areas becoming dry, itchy and more easily irritated. Local vaginal estriol works directly onthe estrogen-sensitive tissues of the lower genito-urinary tract,relieving the symptoms of vaginal atrophy. Estriol induces normalization of the vaginal, cervical and urethral epithelium and thus helps to restore the normal microflora and the physiological pH in the vagina. Moreover, estriol increases the resistance of the vaginal epithelial cells to infection and inflammation and decreases the incidence of urogenital complaints.


Estriol can be used in the treatment of vaginal symptoms and complaints (vaginal dryness, itching, discomfort and painful intercourse) due to estrogen deficiency related to menopause (whether naturally or surgically induced).


In a randomized clinical trial versus placebo, intravaginal application of a low dose of estriol (50 micrograms per application) produces a significant improvement in maturation value of vaginal epithelium, vaginal pH and vaginal atrophy signs such as fragility, dryness and pallor of the mucosa and flattening of folds. In the responder analysis by symptom (secondary endpoint), statistical significance was reached for vaginal dryness, but not for dyspareunia, vaginal pruritus, burning and dysuria, after 12 weeks of treatment.


5.2 Pharmacokinetic properties


After single administration of Blissel 50 microgram/g vaginal gel, estriol is readily absorbed and peak estriol plasma concentrations of 106±63 pg/mL were reached at 2 (range 0.5 – 4) h. After the peak, estriol plasma concentrations decrease mono-exponentially with an average half-life of 1.65 ± 0.82 h.


After 21 days of repeated treatment with Blissel, the absorption declines significantly and systemic exposure to estriol is almost negligible. Estriol levels were below the limit of quantitation for all subjects investigated 24 h post-dose.

Nearly all (90%) estriol is bound to albumin in the plasma and estriol is hardly bound to sex hormone-binding globulin (SHBG). The metabolism of estriol consists mainly of conjugation and deconjugation during enterohepatic circulation. Estriol, is mainly excreted by the urine in the conjugated form. Only a small fraction (≤2%) is excreted via the faeces, mainly as unconjugated estriol.


5.3 Preclinical safety data


The toxicological properties of estriol are well known. There is no preclinical data of relevance to the assessment of safety beyond that which has already been considered in other sections of the summary of product characteristics.


6 PHARMACEUTICAL PARTICULARS


6.1 List of excipients


Glycerol (E422)

Sodium methyl parahydroxybenzoate (E 219)

Sodium propyl parahydroxybenzoate (E 217)

Polycarbophil

Carbopol

Sodium hydroxide (for pH-adjustment)

Hydrochloric acid (for pH-adjustment)

Purified water.


6.2 Incompatibilities


Not applicable.


6.3 Shelf life


2 years.


6.4 Special precautions for storage


Store below 25ºC.


6.5 Nature and contents of container


Not all pack sizes may be marketed


Aluminium tubes of 10 and 30 g.

In the case of 10g pack size the tube of 10g is packaged in an outer cardboard box together with the patient information leaflet and may be provided in two presentations:

1 sealed blister containing 10 disposable cannula with a filling mark and 1 reusable plunger or

1 sealed bag containing 1 reusable cannula with a filling mark and 1 reusable plunger.


In the case of 30g pack size, the tube is also packaged in an outer cardboard box together with the patient information leaflet and may be provided in two presentations:


6.6 Special precautions for disposal


No special requirements.

Any unused medicinal product or waste material should be disposed of in accordance with local requirements.


7 MARKETING AUTHORISATION HOLDER


Italfarmaco S.A.

San Rafael 3

28108 Alcobendas (Madrid)

Spain


8 MARKETING AUTHORISATION NUMBER(S)


43094


9 DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION


Date of first authorisation: 2010-07-28

Date of latest renewal: 2015-07-29


10 DATE OF REVISION OF THE TEXT


2015-05-12