Instructions Blissel vaginal gel 50 mcg/g tube 10 g with disposable cannulas
Composition
active ingredient: estriol;
1 g of vaginal gel contains 50 mcg of estriol;
Excipients: polycarbophil, carbopol 971P, glycerin, sodium methyl parahydroxybenzoate (E 219), sodium propyl parahydroxybenzoate (E 217), hydrochloric acid, sodium hydroxide, purified water.
Dosage form
Vaginal gel.
Main physicochemical properties: homogeneous, colorless, transparent to slightly translucent gel, without visible and tangible particles.
Pharmacotherapeutic group
Sex hormones and drugs used in pathologies of the reproductive system. Natural and semi-synthetic estrogens. Estriol.
ATX code G03C A04.
Pharmacological properties
Pharmacodynamics
Treatment of vaginal symptoms of estrogen deficiency: Vaginal application of estrogen alleviates symptoms of vaginal atrophy in postmenopausal women caused by estrogen deficiency.
Clinical efficacy and safety
The efficacy of Blissel, vaginal gel, 50 mcg/g, was investigated in a multicenter, randomized, double-blind, placebo-controlled study in postmenopausal women with symptoms and signs of vulvovaginal atrophy.
Intravaginal administration of low-dose estriol (50 micrograms per application) resulted in significant improvements in vaginal epithelial maturation, vaginal pH, and reduced signs of vaginal atrophy such as fragility/fragility, dryness and pallor of the mucosa, and flattening of the mucosal folds. In the analysis of responders by symptoms (secondary endpoint), statistical significance was achieved for vaginal dryness, but not for dyspareunia (p = 0.095), vaginal itching, burning, and dysuria after 12 weeks of treatment.
Pharmacokinetics
After a single administration of Blissel, vaginal gel, 50 mcg/g, estriol is readily absorbed and peak plasma estriol concentrations are 106 ± 63 pg/mL after 2 (range 0.5–4) hours.
After 21 days of daily treatment with Blissel, vaginal gel, 50 mcg/g, the mean peak plasma estriol concentration (± standard deviation) was 22.80 (±15.78) pg/mL. After reaching the peak, plasma estriol concentration declines monoexponentially with a mean half-life of 1.65 ± 0.82 hours, with no accumulation.
The systemic exposure to estriol during the use of the drug Blissel, vaginal gel, 50 mcg/g, twice a week has not been studied.
In plasma, almost all (90%) of estriol is bound to albumin and has little interaction with sex hormone binding globulin. The metabolism of estriol consists mainly of conjugation and deconjugation during enterohepatic circulation. Estriol is mainly excreted in the urine in conjugated form. Only a small proportion (≤ 2%) is excreted in the feces, mainly as unconjugated estriol.
Preclinical safety data
The toxicity profile of estriol is well known. There are no additional preclinical safety data beyond those already discussed in other sections.
Indication
For the treatment of symptoms of vaginal atrophy associated with estrogen deficiency in postmenopausal women.
Contraindication
· Established, past or suspected breast cancer.
· Established or suspected estrogen-dependent malignant tumors (e.g. endometrial cancer).
· Vaginal bleeding of unknown etiology.
· Untreated endometrial hyperplasia.
Previous idiopathic or existing venous thromboembolism (deep vein thrombosis, pulmonary embolism).
Active or recent arterial thromboembolism (e.g. angina pectoris, myocardial infarction).
· Established thrombophilic disorders (e.g. protein C, protein S or antithrombin deficiency) (see "Special instructions").
· Acute liver disease or a history of liver disease until function tests return to normal values.
· Hypersensitivity to the active substance or to any of the excipients.
· Porphyria.
Interaction with other medicinal products and other types of interactions
No drug interaction studies have been conducted between Blissel, vaginal gel, 50 mcg/g, and other drugs. Due to the topical application and minimal systemic absorption, it is unlikely that any clinically significant drug interactions with Blissel will occur. However, the possibility of interactions with other topical vaginal drugs should be considered.
Application features
For the treatment of postmenopausal symptoms, topical estrogen therapy should only be initiated if symptoms occur that negatively affect quality of life.
In all cases, the risks and benefits should be carefully assessed at least once a year, and hormone replacement therapy (HRT) should only be used as long as the benefits of treatment outweigh the risks.
The intravaginal applicator, which consists of a disposable cannula and a reusable plunger, may cause minor local damage, especially in women with severe vaginal atrophy.
Medical examination/follow-up treatment
Before initiating or reinstituting/reintroducing estriol, a complete personal and family medical history should be taken. A physical examination (including pelvic and breast examination) should be performed taking into account the patient's medical history, contraindications and precautions for use of the medicinal product. Periodic medical examinations are recommended during treatment, the frequency and nature of which depend on the individual. Women should be informed of any changes in their breasts that they should report to their doctor or nurse (see Breast Cancer).
It is recommended that screening, including mammography, be performed in accordance with current screening practices, adjusted to the clinical needs of the individual patient. If vaginal infections are present, they should be treated before starting therapy with Blissel, vaginal gel, 50 mcg/g.
Conditions that require medical attention
If the following conditions are present or if they have been observed previously and/or worsened during pregnancy or previous hormonal therapy, the patient's condition should be closely monitored, as these conditions may recur or worsen during treatment with the vaginal gel:
- leiomyoma (uterine fibroid) or endometriosis;
- risk factors for the development of thromboembolic disorders (see "Venous thromboembolism");
- risk factors for estrogen-dependent tumors, such as a family history of breast cancer in first-degree relatives;
- hypertension;
- liver disease (e.g. hepatoadenoma);
- diabetes mellitus with or without diabetic angiopathy;
- gallstone disease;
- migraine or severe headache;
- systemic lupus erythematosus (SLE);
- history of endometrial hyperplasia (see "Endometrial hyperplasia and carcinoma");
- epilepsy;
- asthma;
- otosclerosis.
Reasons for immediate discontinuation of treatment
Therapy should be discontinued immediately if any of the contraindications are detected, as well as in the following situations:
- jaundice or deterioration of liver function;
- significant increase in blood pressure;
- a new attack of migraine-type headache;
- pregnancy.
Blissel, vaginal gel, 50 mcg/g, is a local medicine with a low dose of estriol, therefore the occurrence of the conditions mentioned below is less likely than with systemic estrogen treatment.
Endometrial hyperplasia and carcinoma
• In women with an intact uterus, the risk of endometrial hyperplasia and carcinoma is increased if systemic estrogens are administered alone for a prolonged period.
• Progestogen-containing medicinal products are not recommended for use with vaginal estrogen-containing medicinal products where systemic estrogen exposure remains within the normal postmenopausal range.
• The safety of long-term (more than one year) or repeated use of vaginal estrogen-containing products for the endometrium is unknown. Therefore, if a repeat course of treatment is required, the need for treatment should be reviewed at least annually.
• If breakthrough bleeding or spotting occurs during therapy, the cause should be investigated, which may include endometrial biopsy to exclude endometrial malignancy.
• Uncontrolled estrogen stimulation may lead to precancerous transformation of residual endometriosis. Therefore, caution should be exercised when prescribing this drug to women who have undergone hysterectomy for endometriosis, especially if they have residual endometriosis.
The following risks are associated with systemic HRT and are less relevant to vaginal estrogen-containing medicinal products where systemic estrogen exposure remains within the normal postmenopausal range. However, these risks should be considered with prolonged or repeated use of this medicinal product.
Breast cancer
Epidemiological evidence from a large meta-analysis suggests that there is no increased risk of breast cancer with the use of low-dose estrogen-containing vaginal products in women without a history of breast cancer. It is not known whether the use of low-dose estrogen-containing vaginal products increases the risk of breast cancer recurrence.
Ovarian cancer
Ovarian cancer is much less common than breast cancer. Epidemiological evidence from a large meta-analysis suggests a slightly increased risk in women taking estrogen-only HRT, which becomes apparent within 5 years of use and decreases over time after stopping therapy.
Venous thromboembolism (VTE)
• Patients with established medical conditions associated with thrombophilic disorders are at increased risk of VTE, and HRT may increase this risk. Therefore, HRT is contraindicated in such patients (see Contraindications).
• Well-known risk factors for VTE include estrogen use, advanced age, major surgery, prolonged immobilization, obesity (body mass index > 30 kg/m2), pregnancy, postpartum period, systemic lupus erythematosus (SLE), and cancer. There is no consensus on the role of varicose veins in the development of VTE.
Coronary heart disease (CHD)
Hormone replacement therapy with systemic drugs is associated with an increased risk of coronary heart disease.
Ischemic stroke
Systemic hormone replacement therapy is associated with an increased risk of ischemic stroke. However, since the baseline absolute risk of ischemic stroke is strongly age-dependent, the overall risk of stroke in women taking HRT increases with age (see Adverse Reactions).
Other states
Systemic estrogens may cause fluid retention or increase plasma triglyceride levels, so patients with cardiovascular disease, renal failure, or a history of pre-existing hypertriglyceridemia should be closely monitored during the first weeks of treatment. Blissel, vaginal gel, 50 mcg/g, contains a low dose of estriol and is intended for topical use, so systemic effects are not expected. Patients with severe renal failure should be closely monitored as they are likely to have increased blood estriol levels.
Exogenous estrogens may induce or exacerbate symptoms of hereditary and acquired angioedema.
Excipient warnings
The drug Blissel, vaginal gel, 50 mcg/g, contains sodium methyl parahydroxybenzoate (E 219) and sodium propyl parahydroxybenzoate (E 217), which may cause allergic reactions (possibly delayed).
Use during pregnancy or breastfeeding
Fertility
There are no data on the effect of the drug on fertility.
Pregnancy
The drug is not used during pregnancy. If a woman becomes pregnant during treatment, therapy should be stopped immediately.
There are no clinical data on the effects of estriol on the course of pregnancy.
To date, the results of most epidemiological studies regarding the unintended effects of estrogens on the fetus do not indicate the presence of teratogenic or fetotoxic effects.
Breastfeeding period
The medicine is not used during breastfeeding.
Ability to influence reaction speed when driving vehicles or other mechanisms
The drug Blissel, vaginal gel, 50 mcg/g, does not affect the ability to drive or use other mechanisms.
Method of administration and doses
For intravaginal use.
The medicine is inserted into the vagina using an applicator consisting of a disposable cannula with a filling mark and a reusable plunger, carefully following the “Instructions for Use” below. It is advisable to insert it before going to bed.
One dose (filled to the cannula mark) contains 1 g of gel, corresponding to 50 mcg of estriol.
Treatment can be started at any time after the onset of vaginal atrophy.
Initial treatment: One dose of vaginal gel per day for 3 weeks.
As maintenance treatment. One dose of vaginal gel twice a week is recommended. The need for continued treatment after 12 weeks should be assessed by a physician.
For initial and continued treatment of postmenopausal symptoms, the lowest effective dose should be used for the shortest duration possible (see Precautions).
It is not recommended to use progestogen-containing medicinal products together with vaginal oestrogen-containing medicinal products where systemic oestrogen exposure remains within the normal postmenopausal range (see section 4.4).
If a dose is missed, it should be taken as soon as it is remembered, provided that no more than 12 hours have passed since the scheduled dose. If more than 12 hours have passed, the missed dose should not be taken and treatment should be continued as usual.
Instructions for use
| Tube with cap | Reusable piston |
| Disposable cannula | |
| Filling mark | |
| 1. Remove the cap from the tube, turn it over and use the sharp protrusion on it to open the tube (pierce the seal on the tube). |
| 2. Remove one disposable cannula and reusable plunger from the package. Insert the plunger into the cannula until it stops. Screw the cannula onto the neck of the tube. |
| 3. Squeeze the tube, filling the applicator with gel until the piston stops at the fill mark. |
| 4. Unscrew the cannula from the tube and close the tube with a cap. |
5. To insert the gel, lie on your back with your knees bent and spread apart, carefully insert the open end of the applicator deep into the vagina and slowly press the plunger until it is completely empty, then pull it out. | | 6. Remove the plunger from the cannula, discard the cannula, and rinse the plunger with clean warm water so that it can be used for subsequent applications. |
Children.
The medicine is not used in children.
Overdose
The toxicity of estriol is very low, so an overdose with Blissel, vaginal gel, 50 mcg/g, intravaginally is unlikely. Symptoms that may occur in the event of accidental ingestion of a high dose include nausea, vomiting and vaginal bleeding in women. There is no specific antidote known. If necessary, symptomatic treatment should be given.
Adverse reactions
Adverse reactions are typically reported in 3-10% of patients receiving treatment.
At the beginning of treatment, when the vaginal mucosa is still atrophic, local irritation in the form of a sensation of heat and/or itching may occur.
Adverse reactions identified in clinical studies of the drug Blissel, vaginal gel, 50 mcg/g, are classified according to the frequency of occurrence:
| System organ class | Often (≥1/100 to | Infrequently (≥1/1000 to | Rarely (≥1/10000 to |
| Reproductive system and breast disorders | Genital itching | Pelvic pain, genital rash | |
| General disorders and administration site conditions | Itching at the application site | Application site irritation | |
| Infections and infestations | Candidiasis | | |
| Nervous system disorders | Headache | | |
| Skin and subcutaneous tissue disorders | Itch | Prurigo (itching) | |
Blissel, vaginal gel, 50 mcg/g, is a medicinal product for topical use containing estriol in a very low dose and, accordingly, has limited systemic effect (practically negligible after multiple administration). Therefore, it is unlikely that the use of the medicinal product will cause more serious adverse reactions than those associated with oral estrogen replacement therapy.
Effects associated with systemic HRT that are specific to this class of drugs
The risks listed below are associated with systemic HRT and to a lesser extent with estrogen preparations, which when used vaginally keep systemic estrogen exposure within the normal postmenopausal range.
Ovarian cancer
The use of systemic HRT has been associated with a slightly increased risk of being diagnosed with ovarian cancer (see “Special warnings and precautions for use”).
A meta-analysis of 52 epidemiological studies found an increased risk of ovarian cancer in women using systemic HRT compared with women who had never used HRT (RR 1.43, 95% CI 1.31-1.56). In women aged 50 to 54 years who had used HRT in the past 5 years, this resulted in approximately 1 additional case per 2000 patients. In women aged 50 to 54 years who had not used HRT, approximately 2 women in 2000 would be diagnosed with ovarian cancer over a 5-year period.
Risk of developing venous thromboembolism (VTE)
When using HRT, the relative risk of VTE, i.e. deep vein thrombosis or pulmonary embolism, increases by 1.3-3 times (see "Special instructions"). The results of the Women's Health Initiative (WHI) studies are presented below.
WHI study: additional risk of VTE over 5 years of use
| Age group (years) | Number of cases per 1000 women in the placebo group over 5 years | Hazard ratio and 95% CI | Additional cases per 1000 people receiving HRT |
| Oral estrogen-only HRT* | | | |
| 50−59 | 7 | 1.2 (0.6−2.4) | 1 (-3−10) |
*Study in women with a removed uterus.
Risk of developing ischemic stroke
The use of systemic HRT is associated with a 1.5-fold increased relative risk of ischemic stroke. The risk of hemorrhagic stroke is not increased during HRT.
This relative risk does not depend on the age of the patient or the duration of use of the drug, but because the initial risk is largely age-dependent, the overall risk of stroke increases with increasing age in HRT users (see "Special warnings and precautions for use").
Combined WHI studies: additional risk of ischemic stroke* over 5 years of use
| Age group (years) | Number of cases per 1000 women in the placebo group over 5 years | Hazard ratio and 95% CI | Additional cases per 1000 people receiving HRT |
| 50−59 | 8 | 1.3 (1.1−1.6) | 3 (1−5) |
*Differentiation between ischemic and hemorrhagic stroke was not performed.
Other adverse reactions have also occurred with systemic estrogen/progestogen treatment:
· Gallbladder disease.
Skin and subcutaneous tissue disorders: chloasma, erythema multiforme, erythema nodosum, hemorrhagic purpura.
Reporting of suspected adverse reactions.
Reporting adverse reactions after the registration of a medicinal product is important. This allows monitoring of the benefit/risk ratio when using this medicinal product. Medical and pharmaceutical professionals, as well as patients or their legal representatives, should report all cases of suspected adverse reactions and lack of efficacy of the medicinal product via the Automated Information System for Pharmacovigilance at the link: https://aisf.dec.gov.ua.
Expiration date
2 years.
Storage conditions
Store in original packaging at a temperature not exceeding 25 ° C. Keep out of the reach of children.
Packaging
10 g of vaginal gel in an aluminum tube with a cap, 1 aluminum tube with a cap complete with 1 blister containing 10 disposable cannulas and 1 reusable piston, in a cardboard pack.
Vacation category
According to the recipe.
Producer
ITALPHARMACO, S.A.
Location of the manufacturer and address of its place of business
S/San Rafael 3, Pol. Ind. Alcobendas, Alcobendas, Madrid, 28108, Spain.
