Colpotrophin

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT COLPOTROPHINE® (COLPOTROPHINE®)

Composition:

Active substance: promestriene;

1 capsule contains 10 mg of promestriene;

Excipients: sodium methylparahydroxybenzoate (E 219), sodium propylparahydroxybenzoate (E 217), white soft paraffin, hydrogenated polyisobutene, sorbitan sesquioleate, colloidal anhydrous silicon dioxide, purified water, gelatin, glycerin, dimethicone.

Pharmaceutical form. Vaginal soft capsules.

Main physicochemical characteristics: oval, soft, pale-yellow capsules.

Pharmacotherapeutic group. Natural and semisynthetic estrogens. ATC code G03C A09.

Pharmacological properties.

Pharmacodynamics.

Promestriene is a synthetic estrogen-like agent intended for local use, exerting a local estrogenic effect on the mucous membrane of the lower parts of the urogenital tract and restoring their trophicity. When administered intravaginally, it does not produce systemic effects; therefore, it does not affect the endometrium, mammary glands, or pituitary gland.

Promestriene exerts a local estrogenic influence on the vaginal mucosa, promoting proliferation of the vaginal epithelium.

Pharmacokinetics.

Upon intravaginal administration, the tablet interacts with vaginal secretions, disintegrates, and releases its components. Promestriene does not accumulate in tissues; less than 1% of promestriene is absorbed, and its half-life elimination period is 24 hours. Following intravaginal administration, promestriene does not produce resorptive effects, and systemic hormonal effects are absent.

Clinical characteristics.

Indications.

Vaginal atrophy due to estrogen deficiency. Delayed healing of the vagina, cervix, and vulva following childbirth, surgery, or physical therapy.

Contraindications.

• Hypersensitivity to promestriene or to any component of the medicinal product.
• Breastfeeding period.
• Concomitant use with spermicidal agents or latex condoms.
• Breast cancer (confirmed, suspected, or in history).
• Diagnosed or suspected estrogen-dependent tumors (e.g., endometrial cancer).
• Untreated endometrial hyperplasia.
• Genital bleeding of unknown etiology.
• Venous thromboembolism, including in history (deep vein thrombosis, pulmonary embolism).
• Severe nephropathy.
• Heart disease.
• Thrombophlebitis.
• Diagnosed thrombophilic disorders (e.g., antithrombin deficiency, protein C deficiency, protein S deficiency; see section "Special precautions").
• Acute or recently experienced arterial thromboembolism (e.g., angina pectoris, myocardial infarction).
• Acute (or in history) liver disease until liver function tests return to normal range.
• Established or suspected pregnancy.
• Porphyria.

Interaction with other medicinal products and other forms of interaction.

Since systemic absorption of promestriene following vaginal administration is minimal, any clinically significant interaction with other medicinal products is unlikely. However, interactions with other vaginally administered drugs should be considered.

Spermicides

All vaginal medicinal products may inactivate topical spermicidal contraceptives.

Latex condoms

There is a risk of condom damage during use of Colpotrophin due to the effect of oily substances and lubricants containing mineral oils.

Special precautions for use.

During treatment, patients should remain under medical supervision.

In case of metrorrhagia, the cause should be determined and supportive therapy initiated.

Despite its oily nature, the liquid contained in the capsules is an emulsion and can be easily washed off with water.

Unless otherwise prescribed by a physician, daily vaginal douching is not necessary; external washing with water and soap is sufficient.

In some cases, the use of hygiene wipes may be appropriate.

When treating postmenopausal symptoms, local estrogen therapy is indicated only when these symptoms negatively affect quality of life. In each case, the benefit-risk ratio must be carefully evaluated at least once a year. Therapy should be continued only if the expected benefit outweighs the potential risks.

Data on risks associated with HRT (hormone replacement therapy) in premature menopause are limited. Due to the low absolute risk in younger women, the benefit-risk ratio may be more favorable for younger women compared to older women.

Medical examination

Before initiating or resuming local estrogen therapy, a detailed personal and family medical history should be obtained. Together with examination findings (including breast and pelvic organs), contraindications and existing risk factors should be considered. During treatment, women are recommended to undergo periodic medical examinations and check-ups, the frequency and nature of which are individual. The patient should be informed about the necessity to report any changes in the breasts to the physician (see section "Breast cancer"). Medical examinations, including mammography, should be performed according to current diagnostic guidelines and individual clinical needs of the patient.

Promestriene should be prescribed with caution in women with a family history of breast cancer or fibrocystic mastopathy.

A Papanicolaou test should be performed to confirm or rule out dysplasia.

Conditions requiring monitoring

Careful monitoring is required in patients with any of the following conditions, either currently present or in medical history, or if they worsen during pregnancy or previous hormonal therapy. These conditions may appear or worsen during promestriene treatment, namely:

• Leiomyoma (uterine fibroids) or endometriosis.
• Risk factors for thromboembolic disorders (see below).
• Risk factors for estrogen-dependent tumors, e.g., breast cancer in close relatives.
• Arterial hypertension.
• Liver function disorders (e.g., hepatic adenoma).
• Diabetes mellitus with or without vascular complications (in diabetic patients, appropriate preventive measures should be taken, as estrogens may reduce glucose tolerance).
• Cholelithiasis.
• Migraine or severe headache.
• Systemic lupus erythematosus.
• History of endometrial hyperplasia (see below).
• Epilepsy.
• Bronchial asthma.
• Otosclerosis.
• Heart disease.
• Nephropathy.
• Current or past severe depression.

Systemic absorption of promestriene during local vaginal administration is minimal (see section "Pharmacological properties"), therefore recurrence or worsening of the above-mentioned conditions is less likely than during systemic estrogen therapy.

Reasons for immediate discontinuation of treatment

Treatment must be discontinued if any contraindication is detected or if any of the following conditions occur:

• Jaundice or liver function disorders, cholestatic jaundice, especially in patients with a history of jaundice.
• Marked increase in blood pressure.
• New onset of migraine.
• Pregnancy.
• First signs of thrombotic or embolic disorders.
• First signs of hypercalcemia in women with breast cancer.

The following risks are associated with systemic hormone replacement therapy (HRT) and are less relevant to vaginal estrogen preparations, whose systemic exposure remains within postmenopausal normal ranges. However, these risks should be considered in cases of repeated or prolonged use of this medicinal product.

Endometrial hyperplasia and carcinoma

In women with intact uterus, the risk of endometrial hyperplasia and carcinoma increases when systemic estrogens are used as monotherapy over a prolonged period.

Progesterogens should not be added to vaginal estrogen preparations in which systemic estrogen exposure remains within postmenopausal normal levels.

The endometrial safety of long-term (more than one year) or repeated use of local vaginal estrogens has not been established. Therefore, treatment should be reviewed at least annually when repeated administration is considered.

Estrogen stimulation may lead to malignant or premalignant transformations in residual endometriosis foci. Therefore, cautious use of this drug is recommended in women after hysterectomy due to endometriosis, especially if residual endometriosis is diagnosed.

If vaginal bleeding or spotting occurs during therapy, the cause should be investigated, e.g., by endometrial biopsy, to exclude endometrial malignancy.

The following risks have been associated with systemic HRT and are less relevant to local estrogen application when systemic estrogen exposure remains within postmenopausal normal levels. However, such risks should be considered in case of prolonged or repeated use of Colpotrophin.

Endometrial, ovarian, and breast cancer

Systemic estrogen therapy increases the risk of certain cancers, particularly of the uterus, ovaries, and breast. With promestriene, whose systemic absorption during local vaginal administration is minimal, an increased cancer risk is not expected.

Breast cancer

Overall data indicate an increased risk of breast cancer in women receiving combined estrogen-progestogen or estrogen-only systemic HRT, with risk depending on the duration of HRT.

The risk of breast cancer increases during several years of HRT use but returns to baseline levels within several (up to five) years after stopping treatment.

Ovarian cancer

Ovarian cancer occurs much less frequently than breast cancer.

Epidemiological data from a large meta-analysis indicate a slightly increased risk in women receiving estrogen-only systemic HRT. This risk becomes evident after 5 years of use and decreases over time after stopping therapy.

Vein thromboembolism

Systemic HRT is associated with a 1.3–3-fold increased risk of developing venous thromboembolism (VTE), i.e., deep vein thrombosis or pulmonary embolism. Thrombosis is more likely during the first year of HRT than later.

Patients with thrombophilic conditions have an increased risk of VTE, and HRT further increases this risk. Therefore, HRT is contraindicated in such patients (see section "Contraindications").

Risk factors for venous thromboembolism include: use of systemic estrogens, advanced age, major surgery, prolonged immobilization, obesity (BMI > 30 kg/m²), pregnancy/postpartum period, systemic lupus erythematosus, and cancer. There is no consensus on the possible role of varicose veins in the development of venous thromboembolism.

As for all postoperative patients, preventive measures should be taken to avoid VTE after surgery. It is recommended to temporarily discontinue HRT 4–6 weeks before elective surgery if prolonged immobilization is expected afterward. Treatment should not be resumed until full mobility is restored.

Women without VTE history but with close relatives who experienced thrombosis at a young age may be offered screening. Patients should be informed that only part of thrombophilic defects can be detected by screening.

If a thrombophilic defect associated with thrombosis in family members is detected, or if the defect is severe (e.g., antithrombin, protein S or protein C deficiency, or a combination of defects), HRT is contraindicated.

For women already receiving long-term anticoagulant therapy, the benefit-risk ratio of HRT should be carefully assessed.

If VTE develops after starting therapy, Colpotrophin should be discontinued. Patients should be informed to seek immediate medical attention if possible thromboembolic symptoms occur (such as painful leg swelling, sudden chest pain, or dyspnea).

Ischemic heart disease (IHD)

Estrogen monotherapy

Randomized controlled trials have not shown an increased risk of IHD in women after hysterectomy who received systemic estrogen monotherapy.

Ischemic stroke

Systemic estrogen monotherapy is associated with a 1.5-fold increased risk of ischemic stroke. The relative risk does not change with age or time since menopause. However, since the baseline risk of stroke increases significantly with age, the overall risk of stroke in women receiving HRT increases with age.

Other situations

Estrogens may cause fluid retention; therefore, careful monitoring is required in patients with cardiac or renal dysfunction.

Women with hypertriglyceridemia should be closely monitored during estrogen replacement therapy or hormone replacement therapy, as rare cases of significant increase in plasma triglyceride levels have been reported during estrogen therapy in such patients, leading to pancreatitis.

Estrogens increase levels of thyroxine-binding globulin (TBG), resulting in increased total circulating thyroid hormone. Free T4 and T3 concentrations remain unchanged. Levels of other binding proteins in serum, namely corticosteroid-binding globulin (CBG) and sex hormone-binding globulin (SHBG), may also be increased, leading to higher circulating levels of corticosteroids and sex steroids. The concentration of free or biologically active hormone remains unchanged. Levels of other plasma proteins may increase (renin substrate/angiotensin, alpha-1-antitrypsin, ceruloplasmin).

Systemic absorption of promestriene during local vaginal administration is minimal (see section "Pharmacological properties"), so no significant effect on plasma protein binding is expected.

In case of concomitant vaginal infection, specific or anti-inflammatory agents are recommended.

Use of the medicinal product, especially prolonged use, may cause sensitization reactions. In such cases, treatment should be discontinued and appropriate therapy initiated.

To avoid prolonged stimulation of target organs, it is advisable to administer Colpotrophin in cycles, alternating with adequate washout periods. In case of long-term therapy, precise tests should be performed every 6 months (including endometrial biopsy).

Local estrogen-containing products may cause discharge, vulvovaginal candidiasis, cervical changes; exacerbation of endometriosis, mastodynia, breast enlargement or nipple discharge, cholestatic jaundice, exacerbation of previous allergic rash or pruritus.

HRT does not improve cognitive function. There is some evidence of an increased risk of dementia if long-term combined HRT or estrogen monotherapy is initiated in women over 65 years of age.

This medicinal product contains sodium methylparaben (E 219) and sodium propylparaben (E 217), which may cause allergic reactions (sometimes appearing some time after starting use).

The onset of metrorrhagia requires thorough investigation, including biopsy, to exclude the presence of a malignant uterine tumor.

Use during pregnancy or breastfeeding.

Colpotrophin is contraindicated during pregnancy. If pregnancy occurs during promestriene use, treatment must be discontinued immediately.

Results of most recent epidemiological studies on the effects of estrogens on the fetus do not indicate teratogenic or fetotoxic effects.

Breastfeeding

Promestriene is contraindicated during breastfeeding.

Women who are breastfeeding must decide whether to discontinue breastfeeding or to discontinue the drug.

Ability to affect reaction speed when driving or operating machinery.

Colpotrophin does not affect the ability to drive or operate machinery.

Administration and Dosage.

Insert 1 capsule (previously moistened) deeply into the vagina for 20 days. If necessary, treatment may be prolonged (menopause, castration, use of estrogen-progestin containing contraceptives).

Children. Not to be used.

Overdose.

Products containing estrogens may exert anabolic effects and cause salt and water retention as well as hyperglycemia.

Due to the route of administration and very low absorption of promestriene (see section "Pharmacological Properties"), systemic overdose is unlikely. However, excessive use may exacerbate local adverse effects such as irritation, itching, and vulvar burning.

Adverse reactions

The frequency of adverse reactions is classified as follows: very common (≥ 1/10), common (≥ 1/100 to <1/10), uncommon (≥ 1/1,000 to <1/100), rare (≥ 1/10,000 to <1/1,000), very rare (<1/10,000), frequency not known (cannot be estimated from the available data).

Immune system disorders

Rare: hypersensitivity (including rash, eczema, anaphylactic reactions).

Skin and subcutaneous tissue disorders

Frequency not known: mild vulvovaginal burning with erythema, especially after prolonged use in the most sensitive patients.

Reproductive system and breast disorders

Rare: vulvovaginal pruritus; frequency not known: vulvovaginal pain, discomfort and burning sensation, vaginal discharge.

General disorders at the site of administration

Frequency not known: irritation at the application site.

Effects associated with systemic HRT, specific to this class of drugs

The risks listed below have been associated with systemic HRT and, to a lesser extent, apply to estrogen products for vaginal use, in which systemic estrogen exposure remains within the normal postmenopausal range.

Risk of breast cancer

The risk of developing breast cancer was almost doubled in women who received combined estrogen-progestagen therapy for more than 5 years.

The risk is considerably lower in women receiving estrogen monotherapy compared to those taking estrogen-progestagen combinations.

The level of risk depends on the duration of treatment (see section "Special precautions for use").

Below are the results from the largest randomized placebo-controlled trial (the WHI study) and the largest epidemiological study (MWS).

Table 1

Million Women Study: risk of breast cancer after 5 years of treatment

Age (years)	Additional cases per 1000 women not using HRT over a 5-year period*	Relative risk and 95% confidence interval#	Additional cases per 1000 women using HRT for more than 5 years (95% confidence interval)
Estrogen-only HRT
50–65	9–12	1.2	1–2 (0–3)

*Based on baseline disease incidence rates in developed countries.

#Overall risk coefficient. The risk coefficient is not a constant value; it increases with increasing duration of use.

Note. Since baseline breast cancer incidence rates differ across each EU country, the number of additional breast cancer cases varies proportionally in each EU country.

Table 2

WHI study in the USA: additional risk of developing breast cancer after 5 years of treatment

Age (years)	Number of cases per 1000 women in the placebo group over a 5-year period	Relative risk and 95% confidence interval	Additional cases per 1000 women using estrogen-only HRT for more than 5 years (95% confidence interval)
Estrogen-only therapy
50–79	21	0.8 (0.7–1.0)	4 (–6 — 0)*

*WHI study in women with hysterectomy, which did not show an increased risk of breast cancer.

Ovarian cancer

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

A meta-analysis of 52 epidemiological studies showed an increased risk of ovarian cancer in women who were currently using systemic HRT compared to women who had never used HRT (relative risk (RR) 1.43, 95% confidence interval (CI) 1.31–1.56). In women aged 50–54 years using HRT for 5 years, the risk of ovarian cancer increases by approximately 1 case per 2000 women. In women aged 50–54 years not using HRT, approximately 2 out of 2000 women will be diagnosed with ovarian cancer over 5 years.

Risk of venous thromboembolism

The relative risk of venous thromboembolism (VTE), such as deep vein thrombosis or pulmonary embolism, is increased by 1.3–3 times with the use of systemic HRT. The occurrence of thrombosis is most likely during the first year of hormone therapy (see section "Special precautions"). The data from the WHI study are presented below.

Table 3

WHI study: additional risk of developing VTE over 5 years of treatment

Age (years)	Number of cases per 1000 women in the placebo group over a 5-year period	Risk ratio and 95% confidence interval	Additional cases per 1000 women receiving HRT
Oral estrogen-only therapy*
50–59	7	1.2 (0.6–2.4)	1 (–3 — 10)

*Study in women with hysterectomy.

Risk of ischemic stroke

Systemic HRT use is associated with a 1.5-fold increase in relative risk of developing ischemic stroke. The risk of hemorrhagic stroke is not increased during HRT use. This relative risk is independent of age or duration of treatment. However, since the baseline risk largely depends on age, the overall risk of stroke increases with advancing age in women using HRT (see section "Special precautions").

Table 4

Combined WHI studies: additional risk of developing ischemic stroke* over 5 years of treatment

Age (years)	Number of cases per 1000 women in the placebo group over a 5-year period	Relative risk and 95% confidence interval	Additional cases per 1000 individuals using HRT for more than 5 years
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 been reported during estrogen-based therapy (risk assessments were based on systemic administration, and it is unknown how they can be extrapolated to local treatment):

• benign and malignant estrogen-related neoplasms, such as endometrial cancer and breast cancer (see also sections "Contraindications" and "Special precautions");
• venous embolism, i.e. deep vein thrombosis in the leg or pelvis, and pulmonary embolism; more frequently observed in patients receiving hormone replacement therapy. See sections "Contraindications" and "Special precautions";
• myocardial infarction and stroke;
• gallbladder disease;
• skin and subcutaneous tissue disorders: chloasma, erythema multiforme, nodular erythema, vasculitic purpura;
• dementia in women aged 65 years and older (see section "Special precautions").

Treatment must be discontinued immediately upon the first signs of thrombotic or embolic disorders, hypertension, hypercalcemia in women with breast cancer, or cholestatic jaundice in patients with a history of gestational jaundice.

Topical estrogen-containing products may cause discharge, vulvovaginal candidiasis, cervical changes; exacerbation of endometriosis, mastodynia, breast enlargement or nipple discharge, cholestatic jaundice, or worsening of previous allergic rash or pruritus.

Shelf life. 5 years.

Storage conditions. Store at a temperature not exceeding 25 °C in a place inaccessible to children.

Packaging.

10 capsules per blister, 1 blister per cardboard box.

Prescription status. Prescription only.

Manufacturer.

Lafal Industries.

Manufacturer's address and site of operations.

248 Avenue de la Victoire, Rousset, 13106, France.