COLPOTROPHINE 1% Cream Tube/30g

Cream.

Promestriene.....................................................................................................................................................1,00 g

For 100 g of cream.

Excipients with known effect: Methyl parahydroxybenzoate sodium (E 219), Propyl parahydroxybenzoate sodium (E 217).

Excipients:

Symptomatic treatment of vulvovaginal atrophy related to oestrogen deficiency in postmenopausal women.

Dosage

During the first week of treatment, 1 vulvar application per day as a thin layer, followed by gentle massage. Then, until regression of symptoms (on average after 3 weeks): one application every 2 days.

For initiating and continuing treatment of postmenopausal symptoms, the minimum effective dose should be used for the shortest duration possible (see also section Warnings and precautions).

For oestrogen-containing products for vaginal administration where systemic oestrogen exposure remains within normal postmenopausal values, adding a progestogen is not recommended.

Maintenance courses may be necessary.

• Known or suspected breast cancer or history of breast cancer;
• Known or suspected oestrogen-dependent malignant tumours (for example endometrial cancer);
• Undiagnosed cause of uterine bleeding;
• Untreated endometrial hyperplasia;
• History or presence of venous thromboembolism (deep venous thrombosis, pulmonary embolism);
• Known thrombophilia (for example protein S, protein C or antithrombin deficiency, see section Warnings and precautions) ;
• Active or recent arterial thromboembolic disease (for example angina, myocardial infarction);
• Acute liver disease or history of liver disease until liver function tests return to normal;
• Porphyria;
• Breast-feeding (see section Fertility, pregnancy and breastfeeding) ;
• In association with spermicidal products and when using latex male condoms (see section Interactions) ;
• Hypersensitivity to the active substance or to any of the excipients listed in section Composition.

Special warnings

For the treatment of postmenopausal symptoms, HRT should only be initiated if the symptoms negatively affect quality of life. In all cases, a careful assessment of the benefit/risk ratio should be carried out at least once a year, and HRT should only be continued as long as the benefit outweighs the risk.

Data on the risks associated with HRT in the treatment of premature menopause are limited. However, given the low absolute risk level in young women, the benefit-risk balance in these women may be more favourable than in older women.

Clinical examinations/monitoring

Before starting or resuming an HRT, a complete personal and family history must be taken. The clinical examination (including a pelvic and breast examination) must be guided by this and by the contraindications and precautions for use. During treatment, regular check-ups are recommended, the frequency and nature of which must be individually adapted to each patient. Patients must be informed of the types of breast changes that should be reported to their doctor or nurse (see "Breast cancer" below). Examinations, including appropriate imaging modalities, for example mammography, must be carried out in accordance with current screening practices and adapted to the patient's clinical needs.

Situations requiring monitoring

If any of the situations below are present, have a history of, and/or worsen during a previous pregnancy or hormonal treatment, the patient must be closely monitored. It should be taken into account that these situations may recur or worsen during treatment with COLPOTROPHINE 1 PERCENT, cream, in particular:

• leiomyoma (uterine fibroids) or endometriosis;
• risk factors for thromboembolic diseases (see below);
• risk factors for estrogen-dependent cancers, for example breast cancer in a first-degree relative;
• arterial hypertension;
• hepatic conditions (for example hepatocellular adenoma);
• diabetes with or without vasculopathy;
• cholelithiasis;
• migraine or (severe) headaches;
• systemic lupus erythematosus;
• history of endometrial hyperplasia (see below);
• epilepsy;
• asthma;
• otosclerosis.

Reasons for immediate discontinuation of treatment

Treatment must be discontinued if a contraindication is discovered and in the following situations:

• jaundice or deterioration of liver function;
• significant increase in blood pressure;
• onset of migraine-type headaches;
• pregnancy.

Endometrial hyperplasia and cancer

In women without a hysterectomy, the risk of endometrial hyperplasia and cancer is increased when estrogens alone are administered systemically for long periods.

For estrogen-based products for vaginal administration for which systemic estrogen exposure remains within normal post-menopausal values, adding a progestogen is not recommended. 

The safety with regard to endometrial hyperplasia or cancer of long-term (more than one year) or repeated vaginal estrogen treatment has not been established with certainty. Therefore, if treatment is repeated, it must be reassessed at least once a year.

Stimulation by estrogens alone may lead to premalignant or malignant transformation in residual endometriotic foci. Therefore, caution is recommended when using this medicinal product in women who have undergone hysterectomy due to endometriosis, particularly if known residual endometriosis is present.

If metrorrhagia or spotting occurs at any time during treatment, the cause must be investigated, and investigations may include an endometrial biopsy to exclude the presence of endometrial cancer. 

The following risks have been associated with systemic HRT and apply to a lesser extent to estrogen-based products for vaginal administration for which systemic estrogen exposure remains within normal post-menopausal values. However, they must be taken into account in cases of long-term or repeated use of this medicinal product.

Breast cancer

Epidemiological data from a large meta-analysis suggest no increased risk of breast cancer in women with no history of breast cancer taking low-dose vaginal estrogens. It has not been established whether low-dose vaginal estrogens promote recurrence of breast cancer.

Ovarian cancer

Ovarian cancer is much rarer than breast cancer.

Epidemiological data from a large meta-analysis appear to indicate a slight increase in risk in women using estrogen-only systemic HRT, which becomes apparent after 5 years of use and decreases over time after treatment is stopped.

Thrombo-venous embolism

Systemic HRT is associated with a 1,3 to 3-fold increase in the risk of developing venous thromboembolism (VTE), i.e. deep vein thrombosis or pulmonary embolism. This type of event is more likely to occur during the first year of treatment (see section Adverse effects).

The risk of VTE is increased in patients with known thrombophilia, and HRT may increase this risk. It is therefore contraindicated in these patients (see section Contraindications).

Generally recognised risk factors for VTE are: estrogen treatment, advanced age, major surgery, prolonged immobilisation, obesity (BMI > 30 kg/m2), pregnancy/postpartum period, systemic lupus erythematosus (SLE) and cancer. There is no consensus on the possible role of varicose veins in VTE.

As in all postoperative patients, prophylactic measures should be considered to prevent VTE after surgery. If a planned surgical procedure is to be followed by a prolonged period of immobilisation, it is recommended to interrupt HRT 4 to 6 weeks before the procedure. Treatment should only be resumed once the patient is fully mobile.

In women with no personal history of VTE but whose first-degree relative has a history of thrombosis at a young age, screening may be offered after careful counselling about its limitations (screening can only identify certain thrombophilic abnormalities).

If a thrombophilic abnormality associated with thrombosis in family members is identified, or if the abnormality is "severe" (for example antithrombin, protein S or protein C deficiency, or a combination of deficiencies), HRT is contraindicated.

The benefit-risk ratio of using HRT in women already receiving regular anticoagulant treatment should be carefully evaluated.

If VTE occurs after initiation of treatment, treatment must be stopped. Patients should be informed that they must contact their doctor immediately if they notice a possible symptom of thromboembolism (for example painful swelling of a leg, sudden chest pain, dyspnoea). 

Coronary heart disease (CHD)

Estrogens alone

Data from randomised studies have not shown an increased risk of CHD in hysterectomised women using estrogen-only systemic treatment.

Ischaemic stroke

Systemic estrogen-only treatments are associated with an increase of up to 1,5-fold in the risk of ischaemic stroke. The relative risk does not change with age or time since menopause. However, since the baseline risk of stroke is highly age-dependent, the overall risk in women using HRT will increase with age (see section Adverse effects).

Other situations

Estrogens may cause fluid retention, so patients with cardiac or renal insufficiency must therefore be closely monitored.

Patients with pre-existing hypertriglyceridaemia must be closely monitored during estrogen replacement therapy or any hormone replacement therapy, as rare cases of marked increases in plasma triglyceride levels leading to pancreatitis have been reported with estrogen treatment in this situation.

Estrogens increase TBG (thyroxine-binding globulin) levels, resulting in increased circulating total thyroid hormone levels, measured by protein-bound iodine (PBI), T4 levels (by column chromatography or radioimmunoassay) or T3 (by radioimmunoassay). T3 resin uptake is decreased, reflecting the increase in TBG. Free T4 and T3 concentrations are unchanged. Serum levels of other binding proteins, such as CBG (corticosteroid-binding globulin) or SHBG (sex hormone-binding protein) may be elevated, resulting in increased circulating corticoids and sex steroids respectively. Free or biologically active hormone levels are unchanged. Levels of other plasma proteins may be increased (angiotensinogen/renin substrate, alpha-1-antitrypsin, ceruloplasmin).

The use of HRT does not improve cognitive function. Some data indicate an increased risk of probable dementia in women who start using continuous combined or estrogen-only HRT after the age of 65 years.

This medicine contains sodium methyl parahydroxybenzoate (E219) and sodium propyl parahydroxybenzoate (E217), and may cause allergic reactions (possibly delayed).

Contraindicated combinations

Latex male condoms

Risk of condom rupture when used with fatty substances or lubricants containing mineral oils.

Combinations not recommended

Spermicides

Any local vaginal treatment may inactivate a local spermicidal contraceptive.

Associations to be taken into account

Due to vulvar administration and minimal systemic absorption, clinically relevant interactions of COLPOTROPHINE 1 PER CENT, cream with other medicinal products are unlikely. However, the possibility of interactions with other local treatments administered by vulvar application or vaginal route should be considered. 

Pregnancy

COLPOTROPHINE 1 PER CENT, cream is not indicated during pregnancy. If pregnancy occurs during treatment with COLPOTROPHINE 1 PER CENT, cream, the latter must be stopped immediately.

Data from most epidemiological studies conducted to date regarding accidental fetal exposure to estrogens have not demonstrated teratogenic or fetotoxic effects.

Consequently, the discovery of a pregnancy under estrogens does not justify its interruption.

Breast-feeding

COLPOTROPHINE 1 PER CENT, cream is contraindicated during breastfeeding.

No effect on the ability to drive vehicles and use machines has been reported.

Table of undesirable effectsthe

The following undesirable effects may occur during treatment with COLPOTROPHINE 1 PER CENT, cream:

System organ class	Common undesirable effects (≥1/100, <1/10)	Uncommon undesirable effects (≥1/1 000, <1/100)	Rare undesirable effects (≥1/10 000, <1/1 000)	Very rare undesirable effects (<1/10 000)	Frequency not known
Immune system disorders				Hypersensitivity (e.g. skin rash, eczema, anaphylactic reaction)
General disorders and administration site conditions				Irritation
Disorders of the reproductive system and breast				Vulvovaginal pruritus	Vaginal bleeding, vulvovaginal burning sensation, vulvovaginal discomfort, vulvovaginal pain, vaginal discharge

Class effects associated with systemic HRT

The following risks have been associated with systemic HRT and apply to a lesser extent to estrogen-based products for vaginal administration for which systemic estrogen exposure remains within normal post-menopausal values.

Ovarian cancer

The use of systemic HRT has been associated with a slight increase in the risk of ovarian cancer (see section Warnings and precautions).

A meta-analysis of 52 epidemiological studies showed an increased risk of ovarian cancer in women using systemic HRT compared with those who had never used it (RR 1,43, CI at 95 %: 1,31; 1,56). For women aged 50 to 54 years using HRT for 5 years, this results in approximately one additional case per 2 000 users. Among women aged 50 to 54 years who do not use HRT, ovarian cancer will be diagnosed in approximately 2 women out of 2 000 over a period of 5 years.

Risk of thrombo-venous embolism

Systemic HRT is associated with an increase of 1,3 to 3 times in the relative risk of developing venous thromboembolism (VTE), i.e. deep vein thrombosis or pulmonary embolism. This type of event is more likely to occur during the first year of HRT use (see section Warnings and precautions). The results of the WHI studies are presented below:

WHI studies – Additional risk of VTE per 5 years of use

Age range (years)	Incidence per 1 000 women in the placebo group over 5 years	Relative risk and CI at 95 %#	Number of additional cases for 1 000 users of HRT
Estrogen-only HRT*
50-59	7	1,2 (0,6-2,4)	1 (-3 ; 10)

 * Study in hysterectomised women.

Risk of ischaemic stroke

• Use of systemic HRT is associated with an increase of up to 1,5 times in the relative risk of ischaemic stroke. The risk of haemorrhagic stroke is not increased during HRT use.
• This relative risk does not depend on age or duration of use, but since the baseline risk of stroke is strongly age-dependent, the overall risk in women using HRT will increase with age (see section Warnings and precautions).

Combined WHI studies – Additional risk of ischaemic stroke* per 5 years of use

Age range (years)	Incidence per 1 000 women in the placebo group over 5 years	Relative risk and CI at 95 %	Number of additional cases for 1 000 users of HRT per 5 years
50-59	8	1,3 (1,1 ; 1,6)	3 (1-5)

*no distinction was made between ischaemic and haemorrhagic stroke.

 

Other adverse effects have been reported with the use of systemic estroprogestogen therapy:

• Biliary disorders;
• Skin and subcutaneous tissue disorders: chloasma, erythema multiforme, erythema nodosum, vascular purpura;
• Risk of dementia if treatment is started after the age of 65 years (see section Warnings and precautions).

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: National Agency for the Safety of Medicines and Health Products (ANSM) and the network of Regional Pharmacovigilance Centres - Website: https://signalement.social-sante.gouv.fr/

Given the route of administration and the very low systemic passage of promestriene (cf. section Pharmacokinetics), systemic overdose is unlikely.

However, excessive use could lead to an exacerbation of local adverse effects such as vulvar irritation, pruritus and burning.

Pharmacotherapeutic class: natural and semi-synthetic estrogens for local use, not combined, ATC code: G03CA

Promestriene treats vaginal symptoms due to estrogen deficiency: estrogens applied vaginally relieve the symptoms of vulvovaginal atrophy linked to estrogen deficiency in postmenopausal women. After vaginal application, no systemic hormonal effect has ever been detected, particularly on estrogen-sensitive organs located away from the vagina.

After cutaneous application, less than 1% of promestriene passes into the general circulation.

2 years.

Store at a temperature not exceeding 25°C.

No special requirements.

List II

Marketing authorisation (AMM)

CIP 3400931994107 (T/30g).

Price:

4,29 euros (T/30g).

Social security reimbursement at 30%.