ESTIMA Gé 200 mg Soft capsule oral/vaginal Blister/45

Progesterone..........................................................................................................................................200,00 mg

For one soft capsule

Excipients: peanut oil, soya lecithin.

Oral use

Disorders related to progesterone insufficiency, in particular:

• premenstrual syndrome,

• menstrual irregularities due to dysovulation or anovulation,

• benign mastopathies,

• premenopause,

• hormone replacement therapy for menopause (in addition to estrogen therapy).

Vaginal route

• substitution with progesterone during complete deficiencies in ovariectomized women (oocyte donations),

• luteal phase support during in vitro fertilization (IVF) cycles,

• luteal phase support during spontaneous or induced cycles, in cases of hypofertility or primary or secondary infertility, notably due to dysovulation,

• in cases of threatened miscarriage or prevention of recurrent miscarriage due to luteal insufficiency, up to the 12th week of pregnancy.

In all other indications for progesterone, the vaginal route represents an alternative to the oral route in cases of:

• side effects due to progesterone (drowsiness after oral absorption).

In all therapeutic indications, it is important to strictly adhere to the recommended dosages.

Whatever the indication and route of administration (oral or vaginal), the dose must not exceed 200 mg per dose

Oral use

In progesterone insufficiency, the average dose is 200 to 300 mg of micronized progesterone per day.

It is recommended to take the medicine away from meals, preferably in the evening at bedtime.

• In luteal insufficiency (premenstrual syndrome, benign mastopathy, menstrual irregularities, premenopause), the usual therapeutic regimen is 200 to 300 mg per day:

• i.e. 200 mg in 1 dose taken in the evening at bedtime,
• or 300 mg in 2 doses,

10 days per cycle, usually from the 17th to the 26th day inclusive.

• In hormone replacement therapy for menopause, estrogen therapy alone is not recommended (risk of endometrial hyperplasia): progesterone should be added at a dose of 200 mg per day:

• in two doses of 100 mg each,
• or in a single dose of 200 mg in the evening at bedtime, i.e. 12 to 14 days per month, or the last two weeks of each therapeutic sequence.

This treatment will be followed by an interruption of all replacement therapy for about one week, during which a withdrawal bleed is usually observed.

For these indications, use the vaginal route, at the same doses as the oral route, in case of side effects due to progesterone (drowsiness after oral absorption).

Vaginal route

Each capsule must be inserted deeply into the vagina.

• Progesterone substitution during complete deficiencies in ovariprive women (egg donations)

The therapeutic regimen (in addition to appropriate estrogen treatment) is as follows:

• 100 mg of micronized progesterone per day on days 13 and 14 of the transfer cycle, then,
• 200 mg of micronized progesterone per day from day 15 to day 25 of the cycle, divided into one or two doses per day, then,
• from day 26 of the cycle and in case of early pregnancy, this dose may reach a maximum of 600 mg/day divided into 3 doses.

This dosage will be continued until day 60th and at the latest until week 12th of pregnancy.

• Luteal phase support during IVF cycles:

The recommended dose is 400 to 600 mg/day, in two to three doses per day, from the day of hCG injection until week 12th of pregnancy.

• Luteal phase support during spontaneous or induced cycles, in case of subfertility or primary or secondary infertility, particularly due to dysovulation: the recommended dose is 200 to 300 mg/day, in two doses, from day 17 of the cycle for 10 days.

Treatment will be resumed promptly in case of absence of menstrual return and pregnancy diagnosis, until week 12 of pregnancy.

• Threatened early miscarriage or prevention of recurrent miscarriage due to luteal insufficiency: the recommended dosage is 200 to 400 mg/day in two doses, until the 12th week of pregnancy.

This medicine is contraindicated in cases of severe impairment of liver function.

This medicine contains peanut oil; it is contraindicated in cases of allergy to peanut or soy.

This medicine contains soya lecithin; it is contraindicated in cases of allergy to peanut or soy.

Warnings :

More than half of early spontaneous miscarriages are due to genetic accidents. In addition, infectious phenomena and mechanical disorders may be responsible for early miscarriages. The administration of progesterone would then have the sole effect of delaying the expulsion of a dead egg (or the interruption of a non-viable pregnancy).

• the use of progesterone must be reserved for cases where the secretion of the corpus luteum is insufficient.

• treatment under the recommended conditions of use is not contraceptive.

• the use of ESTIMA during pregnancy is reserved for the first trimester and for the vaginal route. ESTIMA is not a treatment for the threat of premature delivery.

Cases of cytolytic-type liver involvement and cases of gestational cholestasis have been exceptionally reported during administration of micronized progesterone during the 2 and 3 trimesters of pregnancy.

Numerous epidemiological studies involving more than a thousand patients do not find an association between progesterone and foetal malformations.

Attention is drawn, particularly to vehicle drivers and machine operators, to the risks of drowsiness and/or dizziness associated with the use of this medicine by the oral route.

Oral use

• Drowsiness or transient dizziness occurring 1 to 3 hours after ingestion of the product. In this case,

• reduce the dosage per dose,
• or modify the timing of doses (for example, for a dosage of 200 mg/day, take the 200 mg in the evening at bedtime as a single dose, away from meals),
• or adopt the vaginal route.

• Shortening of the menstrual cycle or intercurrent bleeding.

Delay the start of treatment later in the cycle (for example start on the 19th day of the cycle instead of the 17th).

These effects most often indicate an overdose.

Due to the presence of peanut oil and soya lecithin, risk of hypersensitivity reaction (anaphylactic shock, urticaria).

Vaginal route

• No local intolerance (burning, pruritus or greasy discharge) was observed during the various clinical studies.

• No general side effects, in particular drowsiness or dizziness, have been reported during clinical studies at the recommended dosages.

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

Pharmacotherapeutic class: PROGESTOGEN, ATC code: G03DA04.

(G: Genito-urinary system and sex hormones)

The properties of ESTIMA are comparable to those of natural progesterone, in particular: progestogenic, antioestrogenic, weakly antiandrogenic, antialdosterone.

Oral use

Absorption

Micronised progesterone is absorbed via the digestive tract.

Elevation of progesteronemia begins from the first hour, and the highest plasma levels are observed 1 to 3 hours after intake.

Pharmacokinetic studies performed in volunteers showed that after simultaneous ingestion of two ESTIMA 100 mg capsules, progesteronemia rises on average from 0,13 ng/ml to 4,25 ng/ml after 1 hour, 11,75 ng/ml at 2 hours, 8,37 ng/ml at 4 hours, 2,00 ng/ml at 6 hours and 1,64 ng/ml at 8 hours.

Given the tissue retention time of the hormone, it appears necessary, in order to obtain impregnation throughout the nychthemeron, to divide the dosage into two intakes spaced approximately 12 hours apart.

There are marked individual variations; however, the same individual retains the same pharmacokinetic characteristics several months apart, which allows good individual adaptation of the dosage.

Metabolism

In plasma, the main metabolites are the 20α - hydroxy, Δ4 α pregnanolone and the 5α - dihydroprogesterone.

Urinary elimination occurs for 95% in the form of glycoconjugated metabolites, the main one being the 3 α, 5 β - pregnanediol (pregnandiol). These plasma and urinary metabolites are identical to those found during physiological secretion of the ovarian corpus luteum.

Vaginal route

Absorption

After vaginal insertion, absorption of progesterone through the vaginal mucosa is rapid, as shown by the rise in plasma progesterone levels from the first hour following administration.

The maximum plasma concentration of progesterone is reached 2 to 6 hours after application and is maintained at an average concentration over 24 hours of 9,7 ng/ml after administration of 100 mg morning and evening. This recommended average dosage therefore induces physiological and stable plasma progesterone concentrations, similar to those observed during the luteal phase of a normo-ovulatory menstrual cycle. The small inter-individual variations in progesterone levels allow the expected effect to be precisely predicted with a standard dosage.

At doses above 200 mg/day, the progesterone concentrations obtained are comparable to those described during the first trimester of pregnancy.

Metabolism

In plasma, the concentration of the 5β-pregnanolone is not increased.

Urinary elimination occurs mainly in the form of 3α, 5β-pregnanediol (pregnandiol), as shown by the progressive increase in its concentration (up to reaching the maximum concentration of 142 ng/ml at the 6th hour).

3 years.

To be stored at a temperature not exceeding 30°C

No special requirements.

• Premenopause (Plq/15, Plq/45)
• Hypofertility due to luteal insufficiency (Plq/15, Plq/45)
• Benign mastopathy (Plq/15, Plq/45)
• Menopause, treatment associated with oestrogen therapy (of the) (Plq/15, Plq/45)
• Premenstrual syndrome (Plq/15, Plq/45)
• Menstrual irregularity (Plq/15, Plq/45)
• Gynaecological disorders due to luteal insufficiency (Plq/15, Plq/45)
• Luteal phase supplementation during ART (Plq/15, Plq/45)