Colpotrophin

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

Composition:

Active substance: promestriene;

1 g of cream contains 10 mg of promestriene;

Excipients: sodium methylparaben (E 219), sodium propylparaben (E 217), mixture of mono- and diglycerides of saturated fatty acids, polyglycolized ether of saturated fatty alcohols, decyloleate, medium-chain triglycerides, glycerol, purified water.

Pharmaceutical form. Vaginal cream.

Main physicochemical properties: homogeneous white cream with a characteristic odor.

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

Pharmacological properties.

Pharmacodynamics.

The medicinal product is intended for intravaginal use. Promestriene has a local estrogenic effect on the vaginal mucosa, improving its trophicity. Promestriene protects and restores the vaginal epithelium, promoting its proliferation. When administered intravaginally, it does not exert systemic effects and therefore does not affect the endometrium, mammary glands, or pituitary gland.

Pharmacokinetics.

Upon intravaginal administration, the drug interacts with vaginal secretions, undergoes breakdown, and its components are released. Promestriene does not accumulate in tissues; less than 1% of promestriene is absorbed, and its half-life elimination period is 24 hours. After 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.
• Breast cancer: confirmed, suspected, or history of.
• Established or suspected estrogen-dependent malignant neoplasms (e.g., endometrial cancer).
• Untreated endometrial hyperplasia.
• Genital bleeding of unknown etiology.
• Severe nephropathy and heart disease.
• Acute liver disease or history of liver disease until liver function tests return to normal limits.
• Thrombophlebitis.
• History of venous thromboembolism (deep vein thrombosis, pulmonary embolism).
• Thrombophilic disorders (e.g., antithrombin deficiency, protein C deficiency, protein S deficiency; see section "Special precautions").
• Active or recent arterial thromboembolic disease (e.g., angina pectoris, myocardial infarction).
• Confirmed or suspected pregnancy.
• Breastfeeding.
• 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 drugs administered vaginally should be considered.

Spermicides

All vaginal products may inactivate local spermicidal contraceptives.

Special precautions for use.

During treatment, patients should remain under medical supervision.

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

For treatment of postmenopausal symptoms, local estrogen therapy is indicated only when these symptoms negatively affect quality of life. The benefit-risk ratio must be carefully evaluated at least once a year. Therapy should be continued only if the expected benefits outweigh potential risks.

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

Medical examination

Before initiating or resuming local estrogen therapy, a detailed personal and family medical history should be obtained. Contraindications and existing risk factors should be considered along with examination findings (including breast and pelvic examination). Periodic medical examinations and check-ups should be performed during treatment, with frequency and nature individualized for each patient. Women should be informed about the necessity to report any changes in their breasts to their physician. Medical examinations, including mammography, should be performed according to current diagnostic guidelines and individual clinical needs.

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

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

Conditions requiring monitoring

Careful monitoring is required in the presence of any of the following conditions, either currently or in the patient's history, or if they worsen during pregnancy or previous hormonal therapy. These conditions may appear or worsen during promestriene treatment:

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

Systemic absorption of promestriene during local vaginal administration is minimal (see section "Pharmacological properties"), so recurrence or worsening of the above conditions is less likely compared to 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 impairment, cholestatic jaundice, particularly 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 risks listed below are associated with systemic hormone replacement therapy (HRT) and are less relevant to vaginal estrogen preparations, where 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 an intact uterus, the risk of endometrial hyperplasia and carcinoma increases when systemic estrogens are used as monotherapy over a prolonged period.

Progesteragen should not be added to vaginal estrogen preparations in which systemic estrogen exposure remains within normal postmenopausal 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, this product should be used cautiously in women who have undergone hysterectomy due to endometriosis, especially if residual endometriosis has been diagnosed.

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

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

Breast, uterine, and ovarian cancer

Systemic estrogen therapy increases the risk of certain cancers, including those of the uterus, ovaries, and breast. With promestriene, where 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-progestagen or estrogen-only systemic HRT, 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 discontinuation of treatment.

Ovarian cancer

Ovarian cancer is significantly rarer 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 apparent after 5 years of use and decreases over time after therapy cessation.

Venous thromboembolism

Systemic HRT is associated with a 1.3–3-fold increased risk of venous thromboembolism (VTE), i.e., deep vein thrombosis or pulmonary embolism. Thrombosis is more likely to occur 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 prevent 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 a history of VTE but with close relatives who experienced thrombosis at a young age may be offered screening. Patients should be informed that only a portion of thrombophilic defects can be detected by screening.

If a thrombophilic defect associated with thrombosis in family members is identified, or if the defect is severe (e.g., antithrombin deficiency, protein S or protein C deficiency, or combined 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, Colpotrophine 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 is highly age-dependent, the overall risk of stroke in women receiving HRT increases with age.

Other conditions

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 increases in plasma triglyceride levels have been reported during estrogen therapy in such patients, potentially leading to pancreatitis.

Estrogens increase levels of thyroxine-binding globulin (TBG), leading to increased total circulating thyroid hormone. Free T4 and T3 concentrations remain unchanged. Levels of other binding proteins in serum, such as corticosteroid-binding globulin (CBG) and sex hormone-binding globulin (SHBG), may also be elevated, resulting in increased circulating corticosteroids and sex steroids. Concentrations of free or biologically active hormone remain unchanged. Levels of other plasma proteins may increase (renin/angiotensin substrate, 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 phenomena. In such cases, treatment should be discontinued and appropriate therapy initiated.

To avoid prolonged stimulation of effector organs, it is advisable to administer Colpotrophine in cycles, alternating with adequate washout periods. In case of prolonged therapy, precise testing should be performed every 6 months (including endometrial biopsy).

Local estrogen-containing products may cause discharge, vulvovaginal candidiasis, cervical changes, endometriosis exacerbation, mastodynia, breast enlargement or nipple discharge, cholestatic jaundice, or 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 (which sometimes appear after a delay following initiation of use).

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

Use during pregnancy or breastfeeding.

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

Results from 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, taking into account the benefits of breastfeeding for the infant and the benefits of the drug for the mother.

Ability to influence reaction speed when driving vehicles or operating machinery.

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

Method of administration and dosage.

Apply the cream once or twice daily every 2–3 days.

Children.

Do not use.

Overdose.

Products containing estrogens may exert anabolic effects, cause fluid and salt retention, and hyperglycemia.

Considering the route of administration and the 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 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 site of administration.

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 preparations for vaginal use, in which systemic estrogen exposure remains within the postmenopausal range.

Risk of breast cancer

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

The risk is significantly lower in patients receiving estrogen monotherapy compared to women receiving estrogen-progestagen combinations.

The level of risk depends on the duration of treatment (see section "Special instructions 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*	Risk ratio 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 ratio. The risk ratio is not a fixed value; it increases with longer duration of use.

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

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	Risk ratio and 95% confidence interval	Additional cases per 1000 women using estrogen-only HRT for over 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, in which no increased risk of breast cancer development was observed.

Ovarian cancer

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

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

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 during systemic HRT use. The occurrence of thrombosis is most likely during the first year of hormone therapy (see section "Special precautions for use"). WHI study data are provided below.

Table 3

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

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

*Study in women with hysterectomy.

Risk of ischemic stroke

The use of systemic HRT is associated with a 1.5-fold increase in the relative risk of developing ischemic stroke. The risk of hemorrhagic stroke is not increased during HRT use. This relative risk does not depend on age or duration of treatment. However, because the baseline risk is largely age-dependent, 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 women using HRT for over 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 these risks can be extrapolated to local treatment):

• benign and malignant neoplasms associated with estrogen, such as endometrial cancer and breast cancer (see also sections "Contraindications" and "Special precautions for use");
• venous embolism, i.e., deep vein thrombosis in the leg or pelvis, and pulmonary embolism; more commonly observed in patients receiving hormone replacement therapy. See sections "Contraindications" and "Special precautions for use";
• 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 for use").

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

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

Shelf life. 5 years.

Storage conditions. The medicinal product does not require special storage conditions. Keep out of reach of children.

Packaging.

15 g of cream in a tube, 1 tube per box.

Prescription status. Prescription only.

Manufacturer.

Laboratoires CHAMINEO.

Manufacturer's address and location of business activity.

Rue de Moné 93, 37210 Vouvray, France.