Prolyuta soft capsules 100 mg blister No. 30

Instructions for Prolyuta soft capsules 100 mg blister No. 30

Composition

active ingredient: progesterone;

1 capsule contains 100 mg or 200 mg of micronized progesterone;

Excipients: grape seed oil, soy lecithin, gelatin, glycerin, titanium dioxide (E 171).

Dosage form

Soft capsules.

Main physicochemical properties:

100 mg capsules: soft gelatin capsules, oval in shape, almost white in color, approximately 12 mm long and approximately 8 mm wide;

200 mg capsules: soft gelatin capsules, oval in shape, almost white in color, approximately 16 mm long and approximately 9.6 mm wide.

Pharmacotherapeutic group

Hormones of the sex glands and drugs used in pathologies of the genital area. Progestogens. ATX code G03D A04.

Pharmacological properties

Pharmacodynamics.

The pharmacological properties of the drug are due to progesterone, one of the hormones of the corpus luteum, which contributes to the formation of a normal secretory endometrium in women. Causes the transition of the uterine mucosa from the proliferation phase to the secretory phase, and after fertilization promotes its transition to the state necessary for the development of a fertilized egg. Reduces the excitability and contractility of the muscles of the uterus and fallopian tubes. Does not have androgenic activity. Blocks the secretion of hypothalamic factors for the release of luteinizing hormone (LH) and follicle-stimulating hormone (FSH), inhibits the formation of gonadotropic hormones by the pituitary gland and ovulation.

Pharmacokinetics.

Oral use.

An increase in the level of progesterone in the plasma is observed from the first hour after absorption of the drug in the digestive tract. The highest level of progesterone in the blood plasma is observed 1-3 hours after taking the drug (after 1 hour - 4.25 ng/ml, after 2 hours - 11.75 ng/ml, after 4 hours - 8.37 ng/ml, after 6 hours - 2 ng/ml and 1.64 ng/ml after 8 hours). The main metabolites of progesterone in the plasma are 20-alphahydroxydelta-4-alphapregnanolone and 5-alphadihydroprogesterone. The drug is excreted in the urine in the form of glucuronic metabolites, the main of which is 3-alpha, 5-betapregnanenediol (pregnanediol). These metabolites are identical to those formed during physiological secretion of the corpus luteum.

Intravaginal use.

After vaginal administration, progesterone is rapidly absorbed by the mucous membrane. The increase in plasma progesterone levels begins within the first hour, with peak plasma levels achieved 1–3 hours after administration.

At an average dose (100 mg of progesterone per night), the drug allows you to achieve and maintain a physiological and stable level of plasma progesterone (average 9.7 ng/ml), similar to that in the luteal phase of the menstrual cycle with normal ovulation. Thus, the drug stimulates adequate maturation of the endometrium, promotes embryo implantation.

At higher doses (above 200 mg per day), which are increased gradually, the vaginal route of administration allows achieving plasma progesterone levels similar to those during the first trimester of pregnancy.

The metabolites in plasma and urine are identical to those found during physiological secretion of the corpus luteum of the ovary. In plasma, these are mainly 20-alphahydroxydelta-4-alphapregnanolone and 5-alphadihydroprogesterone. Urinary excretion is 95% in the form of glucuronic metabolites, the main component of which is 3-alpha, 5-betapregnanenediol (pregnanediol).

Indication

Disorders associated with progesterone deficiency.

Oral use.

Gynecological:

– disorders associated with progesterone deficiency, namely:

· premenstrual syndrome,

· menstrual cycle disorders (dysovulation, anovulation),

· fibrocystic mastopathy,

· premenopausal period;

– for hormone replacement therapy in menopause (in combination with estrogen therapy);

– infertility due to luteal insufficiency.

Obstetric:

– for the prevention of habitual miscarriage or threatened miscarriage due to luteal insufficiency;

– the threat of premature birth.

Intravaginal use.

– Reduced ability to fertilize in primary or secondary infertility with partial or complete luteal insufficiency (dysovulation, luteal phase support during preparation for in vitro fertilization, egg donation program).

– For the prevention of habitual miscarriage or the threat of spontaneous miscarriage in case of luteal insufficiency.

– For the prevention of preterm birth in women with a short cervix or in women with a history of premature spontaneous birth.

– Impossibility or limitation of oral administration of the drug.

Contraindication

When used in combination with estrogens, the drug is contraindicated in patients with any of the following conditions:

– Hypersensitivity to the active substances, soy lecithin, peanuts or any of the excipients.

– Confirmed, previously diagnosed or suspected breast cancer.

– Confirmed or suspected estrogen-dependent malignant tumors (e.g. genital tract carcinoma).

– Undiagnosed vaginal bleeding.

– Thrombophilic diseases.

– Acute liver disease or history of liver disease if liver function tests have not returned to normal.

– Porphyria.

– Cerebral hemorrhage.

– Breastfeeding (see section “Use during pregnancy or breastfeeding”).

Interaction with other medicinal products and other types of interactions

Enzyme inducers: Drugs that induce hepatic CYP450-3A4, such as barbiturates, antiepileptics (phenytoin, carbamazepine), rifampicin, phenylbutazone, bromocriptine, spironolactone, griseofulvin, some antibiotics (ampicillins, tetracyclines), and herbal products containing St. John's wort (Hypericum perforatum), may increase the metabolism and excretion of progesterone.

Enzyme inhibitors: Ketoconazole and other CYP450-3A4 inhibitors, such as ritonavir and nelfinavir, may increase the bioavailability of progesterone. Progesterone metabolism by human liver microsomes was inhibited by ketoconazole (IC50

Immunosuppressants: Progesterone may increase the plasma concentration of cyclosporine.

Antisteroid drugs: Aminoglutethimide markedly reduces plasma concentrations of medroxyprogesterone acetate and megestrol, possibly due to an inducing effect on hepatic enzymes.

Anticoagulants. Progesterone may enhance or reduce the anticoagulant effect of coumarins. Progesterone blocks the anticoagulant effect of phenindione.

Diabetic medications: For women receiving concomitant progesterone treatment, dosage adjustments of the antidiabetic agent may be required.

Emergency contraception: Concomitant use of ulipristal acetate with progesterone may result in reduced efficacy of progesterone.

Diazepam. Progesterone may increase the plasma concentration of diazepam. Tizanidine. Progesterone may increase the plasma concentration of tizanidine. Terbinafine. There have been isolated reports of breakthrough bleeding when terbinafine is used concomitantly with progesterone.

Laboratory tests: Progesterone may affect the results of laboratory tests of liver function and/or endocrine system.

Application features

Warning:

· Hormone replacement therapy (HRT) in menopause should only be initiated for symptoms that negatively impact quality of life. In all cases, a careful risk-benefit assessment should be performed at least annually, and HRT should only be continued as long as the benefits outweigh the risks.

· Evidence regarding the risks associated with HRT in the case of premature menopause is limited.

However, due to the low absolute risk in young women, the benefit-risk ratio for these women may be more favorable than for older women.

The drug PROLUTA is not suitable for:

· with confirmed pregnancy (see section "Interaction with other medicinal products and other types of interactions");

· in the treatment of premature birth;

as a contraceptive.

Precautions.

Medical examination/checkup.

Before starting or reinstituting HRT, a complete personal and family medical history should be taken. A physical examination (including pelvic and breast) should be performed taking this into account, as well as the contraindications and warnings for use. Periodic examinations are recommended during treatment, the frequency and nature of which are adapted to the individual woman. Women should be informed that any changes in their breasts should be reported to their doctor or nurse (see “Breast cancer” below). Investigations, including appropriate imaging tools such as mammography, should be carried out in accordance with current screening practice, modified according to the clinical needs of the patient. Conditions requiring surveillance.

If any of the following conditions are present, have occurred previously and/or have worsened during pregnancy or previous hormonal treatment, the patient should be closely monitored. It should be taken into account that these conditions may recur or worsen during use of the medicinal product, in particular:

· Leiomyoma (uterine fibroids) or endometriosis.

· The existence of risk factors for thromboembolic diseases (see below).

· The existence of risk factors for estrogen-dependent tumors, such as 1st degree heredity for breast cancer.

Hypertension.

Liver disorders (e.g. liver adenoma).

· Diabetes mellitus, with or without vascular damage.

· Gallstone disease.

· Migraine or (severe) headache.

· Systemic lupus erythematosus.

· History of endometrial hyperplasia (see below).

Epilepsy.

Asthma.

· Otosclerosis.

Depression.

· Photosensitivity.

Reasons for immediate discontinuation of therapy.

Therapy should be discontinued if contraindications are identified and in the following cases:

· Jaundice or deterioration of liver function.

· Significant increase in blood pressure.

· New attack of migraine-type headache.

Pregnancy.

· Sudden or gradual, partial or complete loss of vision.

· Proptosis or diplopia.

· Swelling of the papilla.

· Damage to retinal vessels.

In women with an intact uterus, the risk of endometrial hyperplasia and carcinoma is increased when estrogens are used alone for long periods. The increased risk of endometrial cancer among those taking estrogen alone varies and is 2- to 12-fold compared with those not taking estrogen, depending on the duration of treatment and the dose of estrogen (see section "Adverse Reactions"). After stopping treatment, the risk may remain elevated for at least 10 years.

The addition of progesterone for at least 12 days per month (or 28-day cycle) or continuous combined estrogen-progestogen therapy in non-hysterectomized women avoids the excess risk associated with estrogen-only HRT. Breakthrough bleeding and spotting may occur during the first months of treatment. If breakthrough bleeding does not stop, a lower dose of the drug for 25 days per cycle may be considered (see section "Method of administration and dosage").

If breakthrough bleeding or spotting occurs some time after therapy or continues after treatment has been discontinued, the cause should be investigated, including an endometrial biopsy to rule out endometrial malignancy.

Breast cancer.

Overall evidence suggests an increased risk of breast cancer in women taking combined estrogen-progestogen and possibly also estrogen HRT, which depends on the duration of HRT use.

Combined estrogen-progestin therapy.

• A randomised placebo-controlled trial (the Women's Health Initiative [WHI]) and epidemiological studies support an increased risk of breast cancer in women taking combined oestrogen-progestagen HRT, which becomes apparent after approximately 3 years (see section 4.8).

The increased risk becomes apparent within a few years of use but returns to baseline within a few (maximum five) years after stopping treatment. HRT, especially combined estrogen-progestogen therapy, increases the density of mammographic images, which may adversely affect the radiographic detection of breast cancer.

Ovarian cancer.

Ovarian cancer is much less common than breast cancer. Epidemiological evidence from a large meta-analysis suggests a slightly increased risk in women taking oestrogen-only or combined oestrogen-progestagen HRT, which becomes apparent within 5 years of use and decreases over time after discontinuation. Some other studies, including the WHI trial, suggest that the use of combined HRT is associated with a similar or slightly lower risk (see Adverse Reactions).

Venous thromboembolism.

HRT is associated with a 1.3- to 3-fold increased risk of venous thromboembolism (VTE), i.e. deep vein thrombosis or pulmonary embolism. This is more likely to occur during the first year of HRT than later (see section 4.8).

Patients with thrombophilic states are at increased risk of VTE, and HRT increases this risk. Therefore, HRT is contraindicated in such patients (see section 4.3). Generally recognised risk factors for VTE include estrogen use, older age, major surgery, prolonged immobilisation, obesity (body mass index [BMI] > 30 kg/m2), pregnancy/postpartum period, systemic lupus erythematosus (SLE) and cancer. There is no consensus on the possible role of varicose veins in VTE. As in all post-operative patients, prophylactic measures to prevent VTE should be considered after surgery. If prolonged immobilisation is planned after elective surgery, it is recommended that HRT be temporarily discontinued 4–6 weeks in advance. Treatment should not be resumed until the woman is fully ambulatory. Women without a personal history of VTE but with a first-degree relative who has had thrombosis at a young age may be offered screening after careful counselling about its limitations (screening only detects a subset of thrombophilic defects). If a thrombophilic defect is detected in the presence of thrombosis in family members or if the defect is severe (e.g., antithrombin, protein S, or protein C deficiency, or a combination of defects), HRT is contraindicated. Women already on continuous anticoagulant therapy require a careful benefit-risk assessment of HRT.

If VTE develops after initiation of therapy, the drug should be discontinued. Patients should be advised to seek immediate medical attention if they are aware of potential symptoms of thromboembolism (e.g., painful swelling of a leg, sudden chest pain, shortness of breath).

Coronary heart disease (CHD).

Randomized controlled trials have found no evidence of protection against myocardial infarction in women with or without coronary heart disease who received combined estrogen-progestogen or estrogen-only HRT.

Combined estrogen-progestin therapy.

• The relative risk of coronary heart disease is slightly increased with combined estrogen-progestogen HRT. Since the baseline absolute risk of coronary heart disease is strongly age-dependent, the number of additional cases of coronary heart disease due to estrogen+progestogen use is very low in healthy postmenopausal women, but increases with age.

Combined estrogen-progestogen therapy and estrogen-only therapy increase the risk of ischemic stroke by almost 1.5 times. The relative risk does not change with age or with time after menopause. However, since the baseline risk of stroke is strongly age-dependent, the overall risk of stroke in women using HRT will increase with age (see section 4.8).

Cognitive functions.

HRT does not improve cognitive function. There is some evidence of an increased risk of dementia in women who start using continuous combined or estrogen-only HRT after the age of 65.

Important information about excipients. The medicinal product contains soya lecithin and may cause hypersensitivity reactions (urticaria and anaphylactic shock in hypersensitive patients). As there may be a link between soya allergy and peanut allergy, patients with peanut allergy should avoid the medicinal product.

Use during pregnancy or breastfeeding

The use of the drug is not contraindicated during pregnancy, including the first weeks (see section "Indications" [obstetric indications]).

No adverse effects on the fetus were observed during the use of progesterone.

When using the drug in the II and III trimesters of pregnancy, liver function should be monitored.

The passage of progesterone into breast milk has not been studied in detail. Therefore, its administration to nursing mothers should be avoided.

There is evidence of the possible development of hypospadias when progestogens are used during pregnancy to prevent habitual miscarriage or threatened miscarriage due to luteal insufficiency, which the patient should be informed about.

Ability to influence reaction speed when driving vehicles or other mechanisms

Attention to drivers and machine operators: drowsiness and dizziness are possible when taking the medicine orally. Taking the capsules before bedtime can help to avoid these unpleasant effects. Cases of drowsiness and dizziness have only been observed with oral administration of the medicine.

Method of administration and doses

The duration of treatment depends on the nature of the disease.

Oral use.

In most cases, the average daily dose is 200-300 mg in 1 or 2 doses (200 mg in the evening before bedtime and 100 mg in the morning, if necessary).

– In case of luteal phase insufficiency (premenstrual syndrome, menstrual cycle disorders, premenopause, fibrocystic breast disease): take for 10 days (usually from the 17th to the 26th day of the cycle, inclusive).

– In menopausal hormone replacement therapy: since estrogen therapy alone is not recommended, progesterone should be used as a supplement to it for the last 2 weeks of each therapeutic course, which follow a one-week maintenance of any replacement therapy, during which withdrawal bleeding may occur.

– In case of threat of preterm labor: take 400 mg of progesterone every 6−8 hours until symptoms disappear. The effective dose and frequency of administration should be selected individually, depending on the clinical manifestations of the threat of preterm labor. After the symptoms disappear, the dose of progesterone should be gradually reduced to a maintenance dose (for example, 200 mg 3 times a day). At this dose, the drug can be used up to 36 weeks of pregnancy. The use of progesterone after 36 weeks of pregnancy is not recommended.

Intravaginal use.

The capsules should be inserted deep into the vagina while lying on your back.

Before each use of the medicine, hands must be washed thoroughly; it is necessary that no detergent remains on the hands.

The average dose is 200 mg of progesterone per day - 1 capsule of 200 mg or 2 capsules of 100 mg (divided into 2 doses, morning and evening), which are inserted deep into the vagina, if necessary using an applicator. The dose can be increased depending on the patient's response.

– In case of partial luteal phase insufficiency (dysovulation, menstrual cycle disorders), the daily dose is 200 mg for 10 days (usually from the 17th to the 26th day of the cycle).

– In case of complete luteal phase deficiency [complete absence of progesterone in women with non-functioning (absent) ovaries (egg donation)]: the dose of progesterone is 100 mg on the 13th and 14th days of the transfer cycle. From the 15th to the 25th day of the cycle, the dose of progesterone is 200 mg, divided into two doses (morning and evening). Starting from the 26th day, in case of early diagnosis of pregnancy, the dose is gradually increased every week by 100 mg of progesterone per day, reaching a maximum of 600 mg of progesterone per day, divided into three doses. This dosage should be followed until the 60th day.

– Luteal phase support during an in vitro fertilization cycle: treatment is carried out starting from the evening of the embryo transfer day, at the rate of 600 mg per day in 3 doses (200 mg once every 8 hours).

– In case of threatened miscarriage or for the prevention of habitual miscarriages due to luteal insufficiency: 200−400 mg per day (100−200 mg in one dose every 12 hours) up to 12 weeks of pregnancy.

– Prevention of preterm birth in women with a short cervix or in women with a history of spontaneous preterm birth: the dose is 200 mg per day and is administered in the evening before bedtime from the 22nd to the 36th week of pregnancy.

There are no clinical data on the use of the drug in children.

Overdose

Symptoms: Overdose may be manifested by symptoms of adverse reactions, including drowsiness, dizziness, euphoria, dysmenorrhea, decreased cycle length, metrorrhagia. For some individuals, the usual dose may be excessive due to the presence or secondary occurrence of unstable endogenous progesterone secretion, hypersensitivity to the drug, or very low concomitant blood estradiol levels.

Treatment: In case of overdose:

– reduce the dose of progesterone or prescribe progesterone in the evening before bedtime for 10 days per cycle in case of drowsiness or transient dizziness;

– postpone the start of treatment to a later date in the cycle (for example, day 19 instead of day 17) in case of its shortening or bleeding;

– to check whether the estradiol level is sufficient in a patient receiving hormone replacement therapy in premenopause.

Adverse reactions

All adverse reactions are listed by system organ class and frequency: very common (≥ 1/10), common (≥ 1/100 -

The following phenomena were observed with oral administration:

Adverse reactions such as changes in libido, breast discomfort, premenstrual symptoms, hyperthermia, insomnia, alopecia, hirsutism, venous thromboembolism, pulmonary embolism, fluid retention, weight changes, gastrointestinal disorders, and anaphylactic reactions may also occur.

Drowsiness and/or transient dizziness are most commonly observed in cases of concomitant hypoestrogenism. Reducing the dose of the drug or increasing the dose of estrogen immediately eliminates these phenomena without reducing the therapeutic effect.

If the treatment course begins too early in the menstrual cycle, especially before the 15th day, cycle shortening or spotting may occur.

When using the drug vaginally, hypersensitivity reactions are possible, including burning, itching, hyperemia, and the appearance of oily discharge.

Reporting of suspected adverse reactions.

Reporting adverse reactions after registration of a medicinal product is of great importance. This allows monitoring of the benefit/risk ratio when using this medicinal product. Medical and pharmaceutical professionals, as well as patients or their legal representatives, should report all cases of suspected adverse reactions and lack of efficacy of a medicinal product via the Automated Information System for Pharmacovigilance at the link: https://aisf.dec.gov.ua

Expiration date

2 years.

Storage conditions

Store in original packaging at a temperature not exceeding 30 ° C. Keep out of the reach of children.

Packaging

100 mg capsules: 15 capsules in a blister; 2 blisters in a cardboard box. 200 mg capsules: 14 capsules in a blister; 1 blister in a cardboard box.

Vacation category

According to the recipe.

Producer

LABORATORIOS LEON PHARMA S.A.

Location of the manufacturer and address of its place of business

Calle La Vallina s/n, Polígono Industrial Navategera, Villaquilambre, 24193, Spain