SEIDIGESTAN^®

Name: Seidigestan^®
Presentation: 100 mg, 30 soft capsules. Seidigestan^® 200 mg 15 and 60 soft capsules.
Active substance: Progesterone.

In disorders linked to a progesterone deficiency: Irregular menstrual cycle due to ovulation disorders. Premenstrual syndrome. Pre-menopause. In the menopause as a complement to oestrogen therapy in women with an intact uterus.

MORE INFORMATION:

See the full range Hormonal treatments (with prescription)

1 - NAME OF THE MEDICINAL PRODUCT

- - Seidigestan® 100 mg soft capsules
    Seidigestan® 200 mg soft capsules

2 - QUALITATIVE AND QUANTITATIVE COMPOSITION.

Each capsule contains:

Seidigestan® 100 mg: 100 mg of progesterone
Seidigestan® 200 mg: 200 mg of progesterone

For the full list of excipients, see section 6.1.

3 - PHARMACEUTICAL FORM

Soft capsule

Seidigestan® 100 mg: spherical cream-coloured capsules
Seidigestan® 200 mg: ovoid cream-coloured capsules

4 - CLINICAL PARTICULARS.

4.1 Therapeutic indications

Seidigestan® 100 and Seidigestan® 200 are indicated in:

Oral administration:

- - - - Disorders linked to a progesterone deficiency
        
        Irregular menstrual cycle due to ovulation disorders
        
        Premenstrual syndrome
        
        Pre-menopause

In the menopause: as a complement to oestrogen therapy in women with an intact uterus.

Vaginal administration:

This route of administration is used particularly in the following cases:

- - - - Progesterone replacement during the course of complete deficiencies in ovarian hormone deprived women (egg transplantation)
      - Supplementation in the luteal phase during the course of in vitro fertilisation (IVF) cycles
      - Supplementation in the luteal phase during the course of spontaneous or induced cycles in case of hypofertility or primary or secondary infertility due to ovulatory dysfunction
      - Threatened miscarriage or prevention of repeated miscarriages due to luteal phase defect

1. 1. 2 Posology and method of administration

Posology

The dose regimen should be established according to each patient’s plasma hormone levels.

Method of administration

Oral administration:

Take the capsules with a glass of water, away from mealtimes. The average recommended dose is 200 to 300 mg of progesterone daily, i.e., 200 mg in the evening at bedtime or 100 mg in the morning and 200 mg in the evening at bedtime.

- - - - In the case of cycle irregularities, treatment should be used ten days per cycle, usually from the 17th to the 26th day, inclusive, at a daily dose of 200-300 mg of progesterone.
        
        As a complement to oestrogen therapy in women with an intact uterus, progesterone will be added for the last two weeks of each monthly sequence of oestrogen, the daily dose of progesterone being 200 mg. This is followed by a one-week break during which no hormone replacement therapy is administered and during which a withdrawal bleed is usually observed. Another possible low-dose treatment regimen (100 mg of progesterone daily) consists of a single dose of one capsule of Seidigestan® in the evening for the duration of the oestrogen treatment (21 to 25 days/month). This treatment achieves amenorrhoea in most patients.

Vaginal administration:

Insert the capsules deep into the vagina by pushing them in with the finger. The following regimens are normally used:

- - - - Progesterone replacement during the course of complete deficiencies in ovarian hormone deprived women (egg transplantation). As a complement to appropriate oestrogen therapy: 100 mg of progesterone/day on the 13th and 14th day of the transfer cycle. Then 200 mg/day (100 mg of progesterone in the morning + 100 mg of progesterone in the evening) from the 15th to the 25th day of the cycle. From the 26th day and if pregnancy is established, the dose is increased by 100 mg progesterone/day each week, reaching a maximum dose of 600 mg of progesterone/day, administered in three doses. This dose is maintained up to the 60th day.
        
        Supplementation in the luteal phase during the course of in vitro fertilisation (IVF) cycles. The recommended dose is 400 to 600 mg of progesterone/day, from the day hCG is injected up to the 12th week of pregnancy.
        
        Supplementation in the luteal phase during the course of spontaneous or induced cycles in case of hypofertility or primary or secondary infertility due to ovulatory dysfunction. The recommended dose is 200 to 300 mg of progesterone/day from the 17th day of the cycle, for 10 days; it should be resumed as soon as possible if menstruation does not occur and pregnancy is diagnosed.
        
        Threatened miscarriage or prevention of repeated miscarriages due to luteal phase defect. The recommended dose is 200 to 400 mg of progesterone/day in two applications.

4.3 Contraindications

- - - - Hypersensitivity to progesterone or to any of the excipients listed in section 6.1.
      - Undiagnosed vaginal bleeding
      - History of thromboembolic disorders
      - Oral administration: Impaired hepatic function

4.4. Special warnings and precautions for use

- - - - In case of drowsiness, it is recommended that the capsules should preferably be taken in the evening at bedtime.
      - The use of progesterone in cases of threatened miscarriage or prevention of repeated miscarriages should be reserved for cases where there is insufficient secretion from the corpus luteum. More than half of early miscarriages are due to genetic disorders. Other infectious or mechanical processes may be the cause of miscarriage. In these cases, the administration of progesterone would only have the effect of delaying the expulsion of a dead embryo or delaying the termination of a non-viable pregnancy.
      - The use of Seidigestan® 100 or Seidigestan® 200 during pregnancy should be reserved for the first trimester and it should only be used vaginally. There is a risk of undesirable effects on the liver during the 2nd and 3rd trimester of pregnancy.
      - Treatment under the recommended conditions of use does not confer contraceptive protection.

4.5. Interaction with other medicinal products and other forms of interaction

No significant clinical interaction has been observed in the studies conducted.

Seidigestan® 100 or Seidigestan® 200 with food and drink:

Based on the studies carried out, it can be deduced that ingestion of food after taking the capsules increases the bioavailability of natural micronised progesterone. Therefore, the medication should be taken at the same time, away from mealtimes, avoiding variations in the administration schedule from one day to another.

4.6. Fertility, pregnancy and lactation

Pregnancy

Progesterone is the hormone that increases during pregnancy, so its administration during pregnancy does not induce adverse effects.

Breast-feeding

Progesterone is excreted in breast milk; therefore, its administration in breast-feeding women is not recommended.

4.7 Effects on ability to drive and use machines

A risk of drowsiness and/or dizziness has been reported in relation to the use of oral progesterone. Patients who drive vehicles and use dangerous machinery are warned about this possibility.

4.8. Undesirable effects

The most common adverse reactions are:

Oral administration

- - - - Drowsiness or transient dizziness. It occurs 1 to 3 hours after taking the product. In this case, reduce the quantity of the dose or change the time of administration: 200 mg of progesterone in the evening.
        
        Shortening of the menstrual cycle or breakthrough bleeding. Delay the start of treatment in each cycle (e.g., start on the 19th day instead of the 17th).
        
        All of these effects may be related to an overdose.

Vaginal administration

There are no general side effects such as drowsiness or transient dizziness at the recommended dose.

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 Spanish Pharmacovigilance System of Medicines for Human Use: www.notificaRAM.es.

4.9 Overdose

The therapeutic dose used in women (average: 6 mg/kg/day of micronised progesterone for a woman who weighs 50 kg) is 50 times lower than the toxic dose (acute toxicity). Therefore, 150 capsules of Seidigestan® 100 or 75 capsules of Seidigestan® 200 would have to be taken to reach the toxic dose, an amount that is not supplied in a normal pack.

In the event of overdose or massive ingestion, various effects can occur, such as menstrual disorders, including amenorrhoea, and also sedation and hepatic abnormalities. These effects are reversible and disappear when the medicinal product is discontinued.

5 - PHARMACOLOGICAL PROPERTIES

5.1 Pharmacodynamic properties

Pharmacotherapeutic group: G03DA04 – Progesterone

- - - - Anti-oestrogenic
      - Slightly anti-androgenic
      - Anti-aldosterone
      - Gestagenic

5.2 Pharmacokinetic properties

For oral administration

- - - - Absorption:

Micronised progesterone is absorbed in the digestive tract.

Progesteronaemia begins to increase within the first hour and the highest plasma levels are observed between the first and third hour after ingestion.

Pharmacokinetic studies conducted in volunteers show that after ingestion of 200 mg of progesterone, the mean plasma levels of progesterone are as follows: between 0.13 ng/ml and 4.25 ng/ml one hour after ingestion, 11.75 ng/ml after 2 hours, 8.37 ng/ml after 4 hours, 2 ng/ml after 6 hours and 1.64 ng/ml after 8 hours.

There are considerable variations between individuals, but the same individual maintains the same pharmacokinetic characteristics over several months. This makes it possible to adjust the dose on an individual basis.

- - - - Metabolism:

Progesterone undergoes hepatic first-pass metabolism. It is partly metabolised in the liver cells, which progesterone enters via the portal system after oral administration. The pharmacologically active major metabolites are:

20a Dihydroxyprogesterone

17a Hydroxyprogesterone

5a Pregnanolone

5b Pregnanolone

Desoxycorticosterone

5a and 5b pregnanolone are responsible for the tranquillising effect of progesterone.

10% of progesterone is transformed into 20a dihydroxyprogesterone, which accounts for 25 to 50% of its progestational activity.

The majority of progesterone and its metabolites are excreted in the urine (95%) as pregnanediol glucuronide and pregnanolone. A small proportion of these metabolites are also eliminated by biliary and faecal excretion.

For vaginal administration

- - - - Absorption:

After vaginal administration, progesterone is rapidly absorbed through the vaginal mucosa, as shown by the increase in plasma progesterone levels from the first hour after administration.

The maximum plasma concentration of progesterone is reached 2 to 6 hours after application and remains at a mean concentration of 9.7 ng/ml for 24 hours after administration of 100 mg of progesterone in the morning and evening. This recommended average dose therefore induces physiological and stable plasma concentrations of progesterone that are similar to those observed during the luteal phase of a normo-ovulatory menstrual cycle. Slight inter-individual variations in the progesterone level make it possible to accurately predict the discount with a standard dose.

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

- - - - Metabolism:

The plasma concentration of 5b-pregnanolone is not increased.

Urinary elimination is primarily in the form of 3a, 5b-pregnanediol, as shown by the progressive increase in its concentration up to the maximum concentration of 142 ng/ml after 6 hours.

5.3 Preclinical safety data

The LD50 of micronised progesterone in female rats is equivalent to 50 times the dose recommended for clinical use in menopausal women (300 mg/day, i.e., 6 mg/kg/day of micronised progesterone for a woman who weighs 50 kg).

All single and repeated oral dose toxicity studies confirm that micronised progesterone is absorbed orally. It induces effects related to the intrinsic properties of the hormone, in addition to specific adverse reactions such as sedation and moderate hepatic impairment.

When administered vaginally, it does not have these side effects.

6 - PHARMACEUTICAL PARTICULARS.

6.1 List of excipients

Sunflower oil

Soy lecithin

Jelly

Glycerol (E 422)

Titanium dioxide (E 171)

6.2 Incompatibilities

They have not been described.

6.3 Shelf life

3 years

6.4 Special precautions for storage

No special storage conditions are required.

6.5 Nature and contents of container

Seidigestan® 100 mg: cardboard box with 30 capsules (2 blisters) or 60 capsules (4 blisters)
Seidigestan® 200 mg: cardboard box with 15 capsules (1 blister) or 60 capsules (4 blisters)