Prolyuta

INSTRUCTION FOR MEDICAL USE OF THE MEDICINAL PRODUCT PROLUTA (PROLUTA)

Composition:

Active substance: progesterone;

1 capsule contains micronized progesterone 100 mg or 200 mg;

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

Pharmaceutical form. Soft capsules.

Main physico-chemical properties:

100 mg capsules: soft gelatin capsules of oval shape, nearly white, approximately 12 mm in length and 8 mm in width;

200 mg capsules: soft gelatin capsules of oval shape, nearly white, approximately 16 mm in length and 9.6 mm in width.

Pharmacotherapeutic group. Gonad hormones and drugs used in disorders of the reproductive system. Progestogens. ATC code G03D A04.

Pharmacological properties.

Pharmacodynamics.

The pharmacological properties of the medicinal product are determined by progesterone—one of the hormones of the corpus luteum—which promotes the formation of normal secretory endometrium in women. It induces the transition of the uterine mucosa from the proliferative phase to the secretory phase, and after fertilization, facilitates its transformation into a state necessary for the development of the fertilized ovum. It reduces excitability and contractility of the uterine musculature and fallopian tubes. It has no androgenic activity. It blocks the secretion of hypothalamic luteinizing hormone (LH) and follicle-stimulating hormone (FSH) releasing factors, suppresses the pituitary gland's production of gonadotropic hormones and ovulation.

Pharmacokinetics.

Oral administration.

Increased plasma levels of progesterone are observed starting from the first hour after absorption of the medicinal product in the gastrointestinal tract. The highest plasma progesterone concentration occurs 1–3 hours after administration (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 plasma are 20-alpha-hydroxy-delta-4-alpha-pregnanolone and 5-alpha-dihydroprogesterone. The drug is excreted in urine as glucuronic metabolites, the main one being 3-alpha, 5-beta-pregnandiol (pregnanediol). These metabolites are identical to those formed during physiological secretion by the corpus luteum.

Intravaginal administration.

After vaginal administration, progesterone is rapidly absorbed through the mucous membrane. Increased plasma progesterone levels begin within the first hour, with peak plasma concentrations reached within 1–3 hours after administration.

With a standard dose (100 mg of progesterone per night), the medicinal product enables achieving and maintaining a physiological and stable plasma progesterone level (on average 9.7 ng/mL), similar to that observed during the luteal phase of a menstrual cycle with normal ovulation. Thus, the medicinal product promotes adequate endometrial maturation and supports embryo implantation.

With higher doses (above 200 mg per day), progressively increased, the vaginal route of administration allows achieving plasma progesterone levels comparable to those observed during the first trimester of pregnancy.

Metabolites in plasma and urine are identical to those detected during physiological secretion by the ovarian corpus luteum. In plasma, these are mainly 20-alpha-hydroxy-delta-4-alpha-pregnanolone and 5-alpha-dihydroprogesterone. Urinary excretion occurs in 95% as glucuronic metabolites, the main component being 3-alpha, 5-beta-pregnandiol (pregnanediol).

Clinical Characteristics.

Indications.

Disorders associated with progesterone deficiency.

Oral administration.

Gynecological:

• Disorders associated with progesterone deficiency, namely:

  • Premenstrual syndrome,
  • Menstrual cycle disorders (dysovulation, anovulation),
  • Fibrocystic mastopathy,
  • Perimenopausal period;

• Hormone replacement therapy in menopause (in combination with estrogen therapy);

• Infertility due to luteal phase deficiency.

Obstetrical:

• Prevention of habitual or threatened miscarriage in the setting of luteal phase deficiency;
• Threatened preterm labor.

Intravaginal administration.

• Reduced fertility in primary or secondary infertility due to partial or complete luteal phase deficiency (dysovulation, luteal phase support during preparation for in vitro fertilization, oocyte donation programs).
• Prevention of habitual or threatened spontaneous abortion due to luteal phase deficiency.
• Prevention of preterm birth in women with a short cervix or with a history of spontaneous preterm birth.
• Inability or limitations to oral administration of the drug.

Contraindications.

• Hypersensitivity to any component of the drug.
• Severe hepatic dysfunction.
• Suspected or confirmed neoplasia of the breast or genital organs.
• Undiagnosed vaginal bleeding.
• Failed or incomplete abortion.
• Thrombophlebitis. Thromboembolic disorders.
• Intracranial hemorrhage.
• Porphyria.

Interaction with other medicinal products and other forms of interactions.

When administering estrogen therapy for menopausal hormone therapy, it is recommended to initiate progesterone treatment no later than day 12 of the cycle.

If progesterone is used in combination with beta-adrenomimetics for the treatment of threatened preterm labor, the doses of the latter may be reduced.

Concomitant use of other drugs may alter progesterone metabolism, leading to increased or decreased plasma concentrations of progesterone and, consequently, to changes in drug effects.

Potent inducers of hepatic enzymes, namely: barbiturates, antiepileptic agents (phenytoin), rifampicin, phenylbutazone, spironolactone, griseofulvin – cause enhanced hepatic metabolism.

Some antibiotics (ampicillins, tetracyclines) may alter intestinal microflora, resulting in changes to the enterohepatic steroid cycle.

It is known that such drug interactions are individual and may significantly vary among different patient groups; therefore, it is impossible to reliably predict any clinical manifestations of such interactions. All progestins may reduce glucose tolerance, which may necessitate an increase in the daily dose of insulin and other antidiabetic agents in patients with diabetes mellitus.

Progesterone bioavailability may be decreased by smoking and increased by alcohol consumption.

Special precautions for use.

Treatment at recommended doses does not have contraceptive effect.

If treatment is initiated very early in the menstrual cycle, particularly before day 15 of the cycle, shortened cycles or breakthrough bleeding may occur.

Do not administer the drug in cases of uterine bleeding without first determining the cause, including endometrial examination.

Use with caution in patients with fluid retention (e.g., hypertension, cardiovascular, renal diseases), in patients with epilepsy, migraine, bronchial asthma, in patients with a history of depression, diabetes mellitus, hepatic dysfunction, or photosensitivity.

Prior to initiating treatment, patients with a family history of neoplasms, or with recurrent cholestasis, persistent pruritus during pregnancy, hepatic dysfunction, cardiac or renal insufficiency, fibrocystic mastopathy, epilepsy, asthma, otosclerosis, diabetes mellitus, multiple sclerosis, or systemic lupus erythematosus should be carefully examined.

Due to the thromboembolic and metabolic risk, which cannot be completely excluded, discontinue the drug if any of the following occur:

• Visual disturbances such as loss of vision, diplopia, retinal vascular lesions, proptosis, or optic disc edema;
• Venous thromboembolic or thrombotic complications, regardless of the site;
• Severe headache or migraine.

In case of amenorrhea during treatment, pregnancy should be confirmed or excluded, as it may be the cause of amenorrhea.
Vaginal administration of the drug may result in oily discharge, related to the pharmaceutical formulation.

More than half of early spontaneous abortions are caused by genetic abnormalities. In addition, infectious conditions and mechanical disturbances may also lead to early miscarriages; the only justified indication for progesterone administration would be delayed expulsion of a nonviable gestational sac. Therefore, progesterone should be prescribed only when progesterone secretion is insufficient, as determined by a physician.

Prior to initiating treatment, the patient should undergo a thorough medical and gynecological examination, including vaginal and mammological examination and Pap smear, taking into account the patient's history, contraindications, and precautions. Regular medical check-ups are recommended during treatment. Women receiving hormone replacement therapy (HRT) should be carefully counseled regarding all potential risks and benefits associated with such therapy.

In postmenopausal women receiving or who have previously received hormone replacement therapy (HRT), there is a slight to moderate increase in the likelihood of breast cancer diagnosis. This may be due to earlier disease detection, a true effect of HRT, or a combination of both. The risk of breast cancer diagnosis increases with duration of treatment and returns to baseline levels within five years after discontinuation of HRT. Breast cancer diagnosed in women receiving or who recently received HRT tends to be less invasive than in women who have not undergone HRT. The physician should discuss the increased risk of breast cancer with patients considering long-term hormone therapy, carefully weighing the benefits of HRT.

The drug should not be taken with food and should be administered before bedtime. Concurrent food intake increases the bioavailability of the drug.

Important information about excipients. The medicinal product contains soy lecithin and may cause hypersensitivity reactions (urticaria and anaphylactic shock in hypersensitive patients). Since a cross-reactivity between soy allergy and peanut allergy may exist, patients with peanut allergy should avoid using this medicinal product.

Use during pregnancy or breastfeeding.

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

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

Liver function monitoring is required when the drug is used during the second and third trimesters of pregnancy.

Excretion of progesterone into breast milk has not been thoroughly studied. Therefore, its use in breastfeeding mothers should be avoided.

There are data suggesting a possible risk of hypospadias following the use of progestogens during pregnancy for prevention of recurrent miscarriage or threatened miscarriage due to luteal phase deficiency; patients should be informed about this potential risk.

Ability to influence the speed of reactions while driving or operating machinery

For drivers and machine operators: drowsiness and dizziness may occur following oral administration of the drug. Administration of capsules before bedtime may help avoid these adverse effects. Cases of drowsiness and dizziness have been reported only with oral administration of the drug.

Dosage and Administration

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

Oral administration.

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

• In luteal phase deficiency (premenstrual syndrome, menstrual cycle disorders, perimenopause, fibrocystic mastopathy): take for 10 consecutive days (usually from day 17 to day 26 of the cycle, inclusive).
• In hormone replacement therapy during menopause: since estrogen therapy alone is not recommended, progesterone should be used as an add-on treatment during the last 2 weeks of each therapeutic cycle, following a one-week supportive therapy period, during which withdrawal bleeding may occur.
• In threatened preterm labor: administer 400 mg of progesterone every 6–8 hours until symptoms resolve. The effective dose and frequency should be individually adjusted based on clinical signs of threatened preterm labor. After symptom resolution, the progesterone dose should be gradually reduced to a maintenance level (e.g., 200 mg three times daily). The drug may be used at this dose until week 36 of pregnancy. Progesterone administration beyond 36 weeks of pregnancy is not recommended.

Vaginal administration.

Capsules should be inserted deeply into the vagina while lying on the back.

Before each administration, hands must be thoroughly washed, ensuring no residual soap remains on the skin.

The average daily dose is 200 mg of progesterone — 1 capsule of 200 mg or 2 capsules of 100 mg (divided into two doses, morning and evening), inserted deeply into the vagina, with or without an applicator if needed. The dose may be increased depending on the patient's response.

• In partial luteal phase deficiency (dysovulation, menstrual cycle disorders): the daily dose is 200 mg for 10 days (usually from day 17 to day 26 of the cycle).
• In complete luteal phase deficiency [complete absence of progesterone in women with non-functioning (absent) ovaries (oocyte donation)]: the progesterone dose is 100 mg on days 13 and 14 of the transfer cycle. From day 15 to day 25 of the cycle, the dose is 200 mg daily, divided into two doses (morning and evening). Starting from day 26, in case of early pregnancy diagnosis, the dose should be gradually increased by 100 mg per day each week, up to a maximum of 600 mg per day, divided into three doses. This dosage should be maintained until day 60.
• Luteal phase support during in vitro fertilization (IVF) cycles: treatment begins on the evening of embryo transfer, at a dose of 600 mg per day divided into three doses (200 mg every 8 hours).
• In threatened miscarriage or for prevention of recurrent miscarriages due to luteal insufficiency: 200–400 mg per day (100–200 mg per dose every 12 hours) up to 12 weeks of gestation.
• Prevention of preterm birth in women with a short cervix or with a history of spontaneous preterm birth: the dose is 200 mg per day administered in the evening before bedtime from week 22 to week 36 of pregnancy.

Children.

Clinical data on the use of the drug in children are lacking.

Overdose.

Symptoms. Overdose may manifest as an exaggeration of adverse reactions, including drowsiness, dizziness, euphoria, dysmenorrhea, shortened cycle duration, and metrorrhagia. In some individuals, the standard dose may be excessive due to existing or secondary unstable endogenous progesterone secretion, increased sensitivity to the drug, or very low concomitant serum estradiol levels.

Treatment. In case of overdose:

• reduce the progesterone dose or administer the dose in the evening before bedtime for 10 days per cycle if drowsiness or transient dizziness occurs;
• delay the start of treatment to a later point in the cycle (e.g., day 19 instead of day 17) if cycle shortening or bleeding occurs;
• assess whether the patient receiving hormone replacement therapy in perimenopause has adequate estradiol levels.

Adverse reactions.

All adverse reactions are listed by system organ class and frequency: very common (≥ 1/10), common (≥ 1/100 — < 1/10), uncommon (≥ 1/1000 — < 1/100), rare (≥ 1/10000 — < 1/1000), very rare (< 1/10000), frequency not known (cannot be estimated from available data).

With oral administration, the following events have been observed:

Other adverse reactions that may occur include changes in libido, breast discomfort, premenstrual symptoms, hyperthermia, insomnia, alopecia, hirsutism, venous thromboembolism, pulmonary artery embolism, fluid retention, change in body weight, gastrointestinal disorders, and anaphylactic reactions.

Somnolence and/or transient dizziness are most commonly observed in cases of concomitant hypoestrogenism. Reducing the dose of the drug or increasing the estrogen dose promptly resolves these symptoms without diminishing the therapeutic effect.

If treatment is initiated very early in the menstrual cycle, especially before day 15, cycle shortening or breakthrough bleeding may occur.

Vaginal administration of the drug may cause hypersensitivity reactions, including burning, itching, hyperemia, and the appearance of oily discharge.

Reporting suspected adverse reactions

Reporting suspected adverse reactions after drug registration is of great importance. It enables continuous monitoring of the benefit-risk balance of the drug. Healthcare and pharmaceutical professionals, as well as patients or their legal representatives, should report all suspected adverse reactions and lack of drug efficacy via the Automated Pharmacovigilance Information System at the following link: https://aisf.dec.gov.ua

Shelf life. 2 years.

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

Packaging. 100 mg capsules: 15 capsules per blister; 2 blisters per cardboard box. 200 mg capsules: 14 capsules per blister; 1 blister per cardboard box.

Prescription status. Prescription only.

Manufacturer. LABORATORIOS LEON FARMA S.A.

Manufacturer's address and location of business activity.
Calle La Valentina s/n, Polígono Industrial Navatejera, Villacarralambre, 24193, Spain