PROGEFFIK - PACKAGE LEAFLET - LEAFLETS

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Progeffik - Package Leaflet

Indications Contraindications Precautions for use Interactions Warnings Dosage and method of use Overdose Undesirable Effects Shelf life and Storage Composition and pharmaceutical form

Active ingredients: Progesterone

Progeffik 100 mg soft capsules for oral and vaginal use
Progeffik 200 mg soft capsules for oral and vaginal use

Indications Why is Progeffik used? What is it for?

Progeffik belongs to the pharmaceutical category of sex hormones and modulators of the genital system (progestins).

Oral use

Progeffik is used for disorders due to progestin insufficiency, in particular:

premenstrual syndrome (the symptoms that precede menstruation);
alterations in the menstrual cycle due to alterations in ovulation or anovulation (menstrual cycle in which the ovary fails to release an oocyte); - benign mastopathies (breast lumps);
premenopause (the period preceding the definitive cessation of the menstrual cycle);
menopausal hormone replacement therapy (in combination with estrogen therapy).

Vaginal use (represents an "alternative to" oral use) Progeffik is used as:

supplement in the luteal phase (the last phase of the menstrual cycle, after ovulation) during spontaneous or induced cycles, in case of hypofertility (lower than normal reproductive capacity) or primary (the inability to conceive) or secondary ( the inability to conceive again after having completed a pregnancy), due in particular to primary ovarian failure (the ovaries are unable to respond to normal stimulation) or secondary (the ovaries are normal but are not stimulated enough) with changes in ovulation;
supplement in the luteal phase during in-vitro fertilization cycles or other assisted reproduction techniques, limited to ovariectomized women (who have undergone surgical removal of the ovary);
in case of threat of abortion or in the prevention of repeated abortions due to luteal insufficiency (inadequate production of progesterone by the ovary in the second phase of the menstrual cycle), up to the 12th week of amenorrhea (absence of menstruation);

In all other indications of progesterone, vaginal use represents an alternative to oral use in the case of:

secondary effects due to progesterone (sleepiness after oral intake);
contraindications to oral use in case of liver disease (liver disease).

Contraindications When Progeffik should not be used

Do not take Progeffik

if you are allergic to progesterone, chemically closely related substances or any of the other ingredients of this medicine (listed in section 6), if you are allergic to peanuts or soya;
if you suffer from severe hepatic insufficiency (impaired liver function);
if you have vaginal bleeding of an unknown nature;
in case of internal or incomplete abortion;
if you have or have suffered in the past from thromboembolism (blockage of blood vessels caused by blood clots);
if you have or are suspected of having breast or genital cancer;
if you suffer from thrombophlebitis (inflammation of the superficial veins);
if you have brain haemorrhage (rupture of a blood vessel in the area of the brain).

Precautions for use What you need to know before taking Progeffik

Talk to your doctor or pharmacist before taking this medicine.

The treatment, at the recommended doses for use, is not a contraceptive. Training

Get a thorough general and gynecological examination (pelvic and breast examination), including a Pap smear, before starting treatment.

As some progestogens can cause some degree of retention, your doctor will need to closely monitor your condition to closely monitor conditions that may be affected by this factor:

if you suffer from epilepsy (disease leading to convulsions);
if you suffer from migraine (one-sided headache);
if you suffer from asthma;
if you suffer or have suffered in the past from heart failure (the inability of the heart to pump the adequate amount of blood necessary for the body's needs)
if you have or have suffered in the past from kidney failure (reduced kidney function);

Especially talk to your doctor if:

you have vaginal bleeding, because in cases of metrorrhagia (bleeding from the uterus, outside the menstrual period) of an unknown nature, your doctor will first identify the causes;
have a history of mental depression; in this case your doctor will need to carefully monitor your condition.
you suffer from diabetes mellitus, as progestogens can cause or worsen states of water retention (water) and reduce glucose tolerance.

If you have to perform a histological examination (the analysis of the tissue taken with the biopsy), please inform your doctor that you are being treated with Progeffik.

In case of combination of Progeffik with estrogen, as part of hormone replacement therapy (HRT), pay attention if during the treatment you notice symptoms of partial or total loss of vision or double vision; stop treatment at the first symptoms of thrombotic disorders (formation of blood clots) affecting the peripheral, cerebral or pulmonary vessels.

Your doctor will only prescribe Progeffik if you have luteal insufficiency, as this medicine is not a treatment for all cases of premature miscarriage. The only effect of the administration of progesterone in the case of spontaneous abortions due to genetic diseases would be to delay the evacuation of a lifeless oocyte or the termination of a pregnancy that cannot be completed in any case.

Limited to use in menopausal disorders in association with hormone replacement therapy (HRT)

As part of the treatment of menopause symptoms, you start hormone replacement therapy (HRT) only for symptoms that compromise your quality of life. of the benefits of treatment, continuing HRT only until the benefit obtained outweighs the risk.

Before starting or resuming HRT, your doctor will ask you about your personal and family medical history (medical history) and will undergo a thorough general and gynecological examination (including pelvic and breast examination), based on the medical history , contraindications and warnings for use.

During your HRT treatment, your doctor will undergo periodic check-ups, the nature and frequency of which will be adapted according to individual clinical needs, for an accurate assessment of the risks and benefits in relation to the continuation of therapy. Get tested in accordance with your current follow-up programs, including mammography, and report any changes to your doctor.

You will be closely monitored if you have a family history of cancer or if you have or have suffered from:

recurrent cholestasis (blockage of biliary excretion) or persistent itching during pregnancy;
changes in liver function (liver);
kidney or heart failure;
breast lumps of an undetermined nature;
an ear disease that occurs with deafness (otospongiosis);
diabetes mellitus;
multiple sclerosis;
immune system disease (systemic lupus erythematosus).

Use of Progeffik in combination with hormone replacement therapy (HRT) in menopause

Taking hormone replacement therapy (HRT) slightly to moderate increases the likelihood of being diagnosed with breast cancer if you are postmenopausal.

The risk of breast cancer may indeed increase with the duration of treatment. This risk appears to return to baseline five years after stopping HRT. In women between the ages of fifty and seventy who do not use HRT, about 45 in 1000 babies are diagnosed with breast cancer, with an increase related to age. In women who use HRT, for at least five years , the number of cases of breast cancer diagnosed increases between 2 and 12 out of 1000, depending on the age at which the patient begins treatment and the duration of the treatment.

Your doctor will discuss with you the increased likelihood of being diagnosed with breast cancer, weighing it against the benefits of HRT.

Interactions Which drugs or foods can modify the effect of Progeffik

Tell your doctor or pharmacist if you are taking, have recently taken or might take any other medicines, including medicines obtained without a prescription.

Progesterone can cause amenorrhea (absence or cessation of menstruation) and galactorrhea (secretion of breast milk outside of the breastfeeding period), interfering with the action of bromocriptine (a substance used to correct hormonal imbalances). Do not take the two medicines. in the same amount of time.

Warnings It is important to know that:

Pregnancy and breastfeeding

If you are pregnant or breast-feeding, think you may be pregnant or are planning to have a baby, ask your doctor or pharmacist for advice before taking this medicine.

Pregnancy

Progeffik can be used during pregnancy, preferably vaginally, and under medical supervision. Administration of micronized progesterone during the second and third trimester of pregnancy can cause cholestatic jaundice (yellowing of the skin, whites of the eyes and mucous membranes caused by blockage of biliary excretion) or hepato-cellular (liver cell) disease.

Feeding time

Do not take Progeffik while breastfeeding as progesterone is excreted in breast milk.

Driving and using machines

Exercise caution when driving and operating machinery, as this medicine can cause drowsiness and dizziness.

Progeffik contains peanut oil and soy lecithin

Do not take this medicine if you are allergic to peanuts or soy.

Dosage and method of use How to use Progeffik: Dosage

Always take this medicine exactly as your doctor or pharmacist has told you.

If in doubt, consult your doctor or pharmacist.

Absolutely respect the recommended doses.

The dose should not exceed 200 mg for each administration, regardless of the indication and route of administration (oral or vaginal).

Oral use

In progestogenic insufficiency, the average daily dose is 200 mg -300 mg of micronized progesterone divided into two doses. Take this medicine between meals.

In luteal insufficiency (premenstrual syndrome, benign mastopathies, cycle alterations, premenopause), the average daily dose is 200 mg-300 mg of progesterone:

o 200 mg in a single administration in the evening before bedtime (1 capsule of 200 mg or 2 of 100 mg)
o 300 mg in two doses: 1 capsule of 100 mg + 1 capsule of 200 mg (or 2 of 100 mg) for a therapeutic cycle of 10 days, usually from the 17th to the 26th day inclusive of the cycle.

In menopausal hormone replacement therapy, estrogen therapy alone is not recommended (risk of endometrial hyperplasia [thickening of the uterine lining]). Progesterone should be administered at a dose of 200 mg per day:

or in two doses of 100 mg each
or in a single administration of 200 mg in the evening before bedtime (1 capsule of 200 mg or 2 of 100 mg)

for 12 - 14 days per month, or during the last two weeks of each therapeutic cycle.

HRT should be stopped for about a week during which you may experience vaginal bleeding.

For these indications, if you suffer from liver disease (liver disease) and progesterone side effects (sleepiness after oral intake), vaginal use should be used as an alternative to oral use with the same doses.

Vaginal use

Insert each capsule deeply into the vagina.

Supplement in the luteal phase during spontaneous or induced cycles, in case of primary or secondary hypofertility or infertility, particularly in the case of altered ovulation: the recommended daily dose is 200 mg (in two doses of 100 mg each), or 300 mg in two doses: 1 capsule of 100 mg + 1 capsule of 200 mg (or 2 of 100 mg), starting from the 17th day of the cycle for 10 consecutive days. Resume treatment as soon as possible in the case of amenorrhea and confirmed pregnancy, up to the 12th week of pregnancy.

Threat of miscarriage or prevention of repeated miscarriages due to luteal insufficiency: the recommended daily dose is 200 mg (in two doses of 100 mg each), or 400 mg (in two doses of 200 mg each: 1 capsule of 200 mg each) or 2 of 100 mg) up to the 12th week of pregnancy.

Overdose What to do if you have taken too much Progeffik

If you take more Progeffik than you should

If you accidentally swallow / take too much Progeffik, notify your doctor immediately or go to the nearest hospital.

If you have any further questions on the use of this medicine, ask your doctor or pharmacist.

Side Effects What are the side effects of Progeffik

Like all medicines, this medicine can cause side effects, although not everybody gets them. The following list shows the side effects that have been associated with the use of Progeffik:

System and organ classification Side effects Nervous system Drowsiness and dizziness* . **, headache**. Disorders of the skin and sotocutaneous tissue Skin reactions (urticaria, skin rash with or without itching) **, Chloasma **. Disorders of the reproductive and mammary systems Reduced menstrual cycle or metrorrhagia *** Intermenstrual bleeding **, menstrual flow disturbances **, amenorrhea **, cervical mucus alteration **, breast pain **. Psychiatric disorders Depression**, Insomnia **, Nnervousness **. Disorders of metabolism and nutrition Weight modification (increase or decrease) **. Hepatobiliary disorders Coleostatic jaundice **.

* Somnolence and dizziness may occasionally occur in some patients after oral administration of Progeffik. In this case the dose should be reduced or readjusted (for example, with one 200 mg capsule or 2 100 mg capsules in a single administration away from meals before bedtime for 12-14 days each cycle). vaginal administration.

** The following undesirable effects have been reported following the administration of progestogens in general.

*** In these cases it is advisable to postpone the start of treatment for a few days (for example, start treatment on the 19th day of the cycle instead of the 17th day).

Compliance with the instructions contained in the package leaflet reduces the risk of undesirable effects.

Reporting of side effects

If you get any side effects, talk to your doctor or pharmacist. This includes any possible side effects not listed in this leaflet. You can also report side effects directly via the national reporting system, http://www.agenziafarmaco.gov.it/it/responsabili. By reporting side effects you can help provide more information on the safety of this medicine.

Expiry and Retention

Keep this medicine out of the sight and reach of children. Store at a temperature below 30 ° C

Do not use this medicine after the expiry date which is stated on the package. The expiry date refers to the last day of that month. The expiry date refers to the product in intact packaging, correctly stored.

Do not throw any medicines via wastewater or household waste. Ask your pharmacist how to throw away medicines you no longer use. This will help protect the environment.

Composition and pharmaceutical form

What Progeffik contains

100 mg soft capsule:

The active ingredient is micronized progesterone. Each capsule contains 100 mg micronized progesterone.
The other ingredients are: peanut oil, soy lecithin (E322).
The components of the capsule are: gelatin, glycerol, titanium dioxide (E171). 200 mg soft capsule:
The active ingredient is micronized progesterone. Each capsule contains 200 mg micronized progesterone.
The other ingredients are: peanut oil, soy lecithin (E322).
The components of the capsule are: gelatin, glycerol, titanium dioxide (E171).

Description of Progeffik's appearance and content

Soft capsules for oral or vaginal use.

Progeffik 100 mg: pack of 30 capsules.

Progeffik 200 mg: pack of 15 capsules.

Source Package Leaflet: AIFA (Italian Medicines Agency). Content published in January 2016. The information present may not be up-to-date.
To have access to the most up-to-date version, it is advisable to access the AIFA (Italian Medicines Agency) website. Disclaimer and useful information.

Further information on Progeffik can be found in the "Summary of Characteristics" tab. 01.0 NAME OF THE MEDICINAL PRODUCT 02.0 QUALITATIVE AND QUANTITATIVE COMPOSITION 03.0 PHARMACEUTICAL FORM 04.0 CLINICAL PARTICULARS 04.1 Therapeutic indications 04.2 Posology and method of administration 04.3 Contraindications 04.4 Special warnings and appropriate precautions for use 04.5 Interactions with other medicinal products and other forms of interaction 04.6 Pregnancy and lactation 04.7 Effects on ability to drive and use machines 04.8 Undesirable effects 04.9 Overdose 05.0 PHARMACOLOGICAL PROPERTIES 05.1 Pharmacodynamic properties 05.2 Pharmacokinetic properties 05.3 Preclinical safety data 06.0 PHARMACEUTICAL PARTICULARS 06.1 Excipients 06.2 Incompatibilities 06.3 Shelf life 06.4 Special precautions for storage 06.5 Nature of the primary packaging and contents of the package 06.6 Instructions for use and handling 07.0 MARKETING AUTHORIZATION HOLDER 08.0 MARKETING AUTHORIZATION NUMBER CIO 09.0 DATE OF FIRST AUTHORIZATION OR RENEWAL OF THE AUTHORIZATION 10.0 DATE OF REVISION OF THE TEXT 11.0 FOR RADIO DRUGS, FULL DATA ON INTERNAL RADIATION DOSIMETRY 12.0 FOR RADIO DRUGS, FURTHER DETAILED INSTRUCTIONS ON PREPARATION AND QUALITY CONTROL

01.0 NAME OF THE MEDICINAL PRODUCT

PROGEFFIK SOFT CAPSULES FOR ORAL AND VAGINAL USE

02.0 QUALITATIVE AND QUANTITATIVE COMPOSITION

Each 100 mg soft capsule contains:

Active principle: Micronized progesterone 100 mg

Excipients: Peanut oil, soy lecithin (E322)

Each 200 mg soft capsule contains:

Active principle: Micronized progesterone 200 mg

Excipients: Peanut oil, soy lecithin (E322)

For the full list of excipients, see section 6.1

03.0 PHARMACEUTICAL FORM

Soft capsules for oral or vaginal use.

04.0 CLINICAL INFORMATION

04.1 Therapeutic indications

Oral use:

Disorders due to progestogen insufficiency, in particular:

- premenstrual syndrome;

- alterations in the menstrual cycle due to changes in ovulation or anovulation;

- benign mastopathies;

- premenopause;

- menopausal hormone replacement therapy (in association with estrogen therapy).

Vaginal use (represents an "alternative to" oral use):

- supplement in the luteal phase during spontaneous or induced cycles, in case of hypofertility or primary or secondary sterility, due in particular to primary or secondary ovarian failure with alterations in ovulation;

- supplement in the luteal phase during in-vitro fertilization cycles or other assisted reproduction techniques, limited to ovariectomized women;

- in case of threat of abortion or in the prevention of repeated abortions due to luteal insufficiency, up to the 12th week of amenorrhea;

- in all other indications of progesterone, vaginal use represents an alternative to oral use in the case of:

• secondary effects due to progesterone (sleepiness after oral intake);

• contraindications to oral use (liver disease).

04.2 Posology and method of administration

The recommended posologies must be absolutely respected.

The dose should not exceed 200 mg for each administration, regardless of the indication and route of administration (oral or vaginal).

Oral use

In progestogenic insufficiency, the average daily dose is 200-300 mg of micronized progesterone divided into two doses.

It is recommended to take the drug between meals.

In luteal insufficiency (premenstrual syndrome, benign mastopathies, cycle alterations, premenopause), the average daily dose is 200-300 mg of progesterone:

- or 200 mg in a single dose in the evening before bedtime (1 capsule of 200 or 2 of 100)

- or 300 mg in two doses: 1 capsule of 100 + 1 capsule of 200 (or 2 of 100)

for a therapeutic cycle of 10 days, usually from the 17th to the 26th day inclusive.

In menopausal hormone replacement therapy, estrogen monotherapy is not recommended (risk of endometrial hyperplasia). Progesterone should be administered at a dose of 200 mg per day:

- or in two doses of 100 mg each

- or in a single administration of 200 mg in the evening before bedtime (1 capsule of 200 or 2 of 100)

for 12 - 14 days per month, or during the last two weeks of each therapeutic cycle.

HRT should be stopped for about a week during which vaginal bleeding may occur.

For these indications, in the case of liver disease and side effects due to progesterone (drowsiness after oral intake), vaginal use should be used as an alternative to oral use with the same dosage.

Vaginal use

Each capsule must be inserted deep into the vagina.

Supplement in the luteal phase during spontaneous or induced cycles, in case of primary or secondary hypofertility or infertility, particularly in the case of altered ovulation: the recommended daily dose is 200 mg (in two doses of 100 mg each), or 300 mg in two doses: 1 capsule of 100 + 1 capsule of 200 (or 2 of 100), starting from the 17th day of the cycle for 10 consecutive days. Treatment should be resumed as soon as possible in the case of amenorrhea and pregnancy ascertained, up to the 12th week of pregnancy.

04.3 Contraindications

Hypersensitivity to the active substance or to any of the excipients or to closely related substances from a chemical point of view.

Severe hepatic insufficiency, vaginal bleeding of an unknown nature, internal or incomplete abortion, current or previous thromboembolism, suspected or known breast or genital carcinoma, thrombophlebitis, cerebral haemorrhage.

Progeffik contains peanut oil and soy lecithin, in case of allergy to peanut or soy do not take the medicine. Refined peanut oil may contain peanut proteins. The monograph of the European Pharmacopoeia does not provide for an assay for residual proteins.

04.4 Special warnings and appropriate precautions for use

Before starting the treatment it is advisable to carry out a thorough general and gynecological examination (pelvic and breast examination) including a Pap test. If Progeffik is combined with estrogen as part of hormone replacement therapy (HRT), care should be taken if symptoms of total or partial loss of vision or double vision appear during treatment; stop treatment at the first symptoms of thrombotic disorders affecting the peripheral, cerebral or pulmonary vessels.

Since some progestogens can cause some degree of retention, conditions that could be affected by this factor, such as epilepsy, migraine, asthma, heart or kidney failure, should be monitored. Patients with a history of mental depression require careful observation during treatment with Progeffik. In diabetics, progestogens can cause or worsen water retention and reduce glucose tolerance.

Patients with a family history of cancer and those who suffer or have suffered from the following conditions should be closely monitored:

• recurrent cholestasis or persistent itching during pregnancy

• changes in liver function

• kidney or heart failure

• breast lumps of an undetermined nature

• epilepsy

• asthma

• otospongiosis

• diabetes mellitus

• multiple sclerosis

• systemic lupus erythematosus

Progestogenic treatment in premenopausal patients can mask the onset of climacteric. If a histological examination is to be performed, it should be noted that the patient is being treated with Progeffik. In case of vaginal bleeding, the non-functional causes should be taken into account. In cases of unexplained metrorrhagia, appropriate diagnostic measures are recommended.

Abnormal endocrine tests or liver function tests may occur following the administration of progesterone. Over half of the miscarriages are due to genetic complications. Furthermore, infectious diseases and uterine defects of a structural and functional nature can induce premature abortions. Therefore the only effect of the administration of progesterone in this case would be to delay the elimination of a lifeless egg or the termination of a pregnancy that however, it cannot be completed. The use of progesterone should therefore be limited to cases of luteal insufficiency.

The treatment, at the recommended dosage for use, is not contraceptive.

Use of Progeffik in menopause in association with hormone replacement therapy

When treating symptoms of menopause, HRT should only be started for symptoms that impair quality of life. In any case, a careful evaluation of the risks and benefits of treatment should be performed at least annually, and HRT should only be continued as long as the benefit obtained outweighs the risk.

Before initiating or resuming HRT, a complete personal and family medical history should be taken, together with a thorough general and gynecological examination (including pelvic and breast examination), based on the medical history, contraindications and warnings for use. During treatment, periodic checks are recommended, the nature and frequency of which must be individually adapted. Patients should be advised to report any changes to their physician. Investigations, including mammography, should be performed in accordance with current screening programs, modified according to individual clinical needs. In women treated with hormone replacement therapy, a "careful risk / benefit assessment must be carried out over time.

Currently available clinical data (deriving from the evaluation of data from fifty-one epidemiological studies) suggest that in postmenopausal women undergoing or undergoing hormone replacement therapy, there is a mild to moderate increase in the likelihood of cancer diagnosis. mammary. This may be due to either an early diagnosis in treated patients, a real effect of HRT, or a combination of both.

The likelihood of breast cancer being diagnosed increases with duration of treatment and appears to return to baseline five years after stopping HRT. Breast cancer diagnosed in patients who are using or have recently used HRT would appear to be less invasive in nature than that found in untreated women.

In women between the ages of fifty and seventy who do not use HRT, about 45: 1000 people are diagnosed with breast cancer, with an increase related to age. It has been estimated that in women who use HRT for at least five years, the number of additional cases of breast cancer diagnoses will be between 2: 1000 and 12: 1000 subjects, this in relation to the age at which patients start treatment and the duration of the same.

It is important that the physician discusses the increased likelihood of breast cancer being diagnosed with the patient who is a candidate for long-term therapy, evaluating it in relation to the benefits of HRT.

04.5 Interactions with other medicinal products and other forms of interaction

Progesterone can cause amenorrhea and galactorrhea by interfering with the action of bromocriptine. Do not use at the same time.

04.6 Pregnancy and lactation

Progeffik can be used during pregnancy, preferably vaginally, and under medical supervision.

The administration of micronized progesterone during the second and third trimester of pregnancy can cause jaundice cholestatic hepato-cellular diseases.

Progesterone is excreted in breast milk so its use during breastfeeding is not recommended.

04.7 Effects on ability to drive and use machines

As this medicine may cause drowsiness and dizziness, caution should be exercised when driving or operating machinery.

04.8 Undesirable effects

The table shows the main adverse reactions in patients treated with Progeffik grouped by system organ class (SOCs).

System Organ Class (SOC) Nervous system Drowsiness and dizziness* . **, headache**. Disorders of the skin and sotocutaneous tissue Skin reactions (urticaria, skin rash with or without itching) **, Chloasma **. Disorders of the reproductive and mammary systems Reduced menstrual cycle or metrorrhagia *** Intermenstrual bleeding **, menstrual flow disturbances **, amenorrhea **, cervical mucus alteration **, breast pain **. Psychiatric disorders Depression**, Insomnia **, Nnervousness **. Disorders of metabolism and nutrition Weight modification (increase or decrease) **. Hepatobiliary disorders Coleostatic jaundice **.

** The following undesirable effects have been reported following the administration of progestogens in general.

*** In these cases it is advisable to postpone the start of treatment for a few days (for example, start treatment on the 19th day of the cycle instead of the 17th day).

04.9 Overdose

In case of overdose (which can manifest itself as drowsiness and dizziness, shortening of the menstrual cycle or bleeding) it is advisable to interrupt the administration of the drug and institute symptomatic therapy.

05.0 PHARMACOLOGICAL PROPERTIES

05.1 Pharmacodynamic properties

Pharmacotherapeutic group: genitourinary system and sex hormones: progestogens ATC code G03DA04.

05.2 Pharmacokinetic properties

Oral use

* Absorption

Micronized progesterone is absorbed in the digestive tract. The level of progesterone in plasma increases uniformly during the first hour of treatment and the highest plasma values were observed 1 to 3 hours after intake.

Pharmacokinetic studies conducted on volunteers show that, after the simultaneous administration of 2 capsules of 100 mg, plasma progesterone increases to a mean value of 0.13 - 4.25 ng / ml after one "hour, of 11.75 ng. / ml after 2 hours, 8.37 ng / ml after 4 hours, 2.00 ng / ml after 6 hours and 1.64 ng / ml after 8 hours.

In consideration of the retention time of this hormone in the tissues, it is considered necessary to divide the dose into two administrations at intervals of about 12 hours to ensure the action of the drug over 24 hours.

Although with modest individual variations, the pharmacokinetic characteristics of an individual are maintained after many months, thus allowing a good individual adaptation of the dosage.

* Metabolism

In plasma, the main metabolites are 20 a-hydroxy-D 4 a-pregnanolone and 5 a dihydroprogesterone.

95% of the metabolites are excreted in the urine in the form of glucuronide conjugates, mainly 3a, 5b pregnanediol. The plasma and urinary metabolites are similar to those found during physiological secretion of the corpus luteum.

Vaginal use

* Absorption

The absorption after vaginal introduction of progesterone is rapid, as evidenced by the high plasma levels of progesterone reached 1 hour after application.

The maximum plasma concentration of progesterone, after administration of 100 mg twice daily, is reached between 2 and 6 hours after application and remains at a mean concentration of 9.7 ng / ml after 24 hours if administered. at a dose of 100 mg twice a day.

This posology determines physiological plasma concentrations of progesterone at equilibrium similar to those observed in the luteal phase of a normal ovulatory cycle.

Weak interindividual variations in progesterone levels allow predicting expected reactions with a standard posology.

At daily doses above 200 mg, progesterone concentrations are comparable to those described in the first trimester of pregnancy.

* Metabolism

The plasma concentration of 5b-pregnanolone does not increase.

Urinary elimination is mainly observed in the form of 3a, 5b pregnanediol as evidenced by the progressive increase in its concentration (up to a maximum concentration of 142 ng / ml after 6 hours).

05.3 Preclinical safety data

Progesterone is a physiological hormone, used for many years in the clinic in various pharmaceutical forms, well documented in the scientific literature.

There is no information, deriving from preclinical data, of relevant importance for the physician that has not already been reported in the other sections of the SmPC.