Utrogestan

INSTRUCTION FOR MEDICAL USE OF THE MEDICINAL PRODUCT UTROGESTAN®

Composition:

Active substance: progesterone;

1 capsule contains micronized progesterone 100 mg or 200 mg;

Excipients: sunflower oil, soy lecithin, gelatin, glycerin, titanium dioxide (E 171), purified water.

Pharmaceutical form. Capsules.

Main physicochemical properties:

100 mg capsules: round, soft, gelatin capsules of slightly yellowish color, containing a whitish oily suspension;

200 mg capsules: oval, soft, gelatin capsules of slightly yellowish color, containing a whitish oily suspension.

Pharmacotherapeutic group.

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

Pharmacological Properties

Pharmacodynamics.

The pharmacological properties of the drug 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 exerts an inhibitory effect on the secretion of hypothalamic releasing factors LH and FSH, suppresses the pituitary gland's production of gonadotropic hormones, and inhibits ovulation.

Pharmacokinetics.

Oral administration

An increase in plasma progesterone levels is observed within the first hour after absorption of the drug in the gastrointestinal tract. The highest plasma progesterone levels occur 1–3 hours after drug 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 after 8 hours – 1.64 ng/mL). 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 glucuronide 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.

An increase in progesterone levels in plasma begins within the first hour, with peak plasma concentrations reached 1–3 hours after administration.

With a medium dose (100 mg of progesterone per night), Utrogestan® enables achieving and maintaining a physiological and stable plasma progesterone level (on average around 9.7 ng/mL), similar to that observed during the luteal phase of a menstrual cycle with normal ovulation. Thus, Utrogestan® 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 similar to those observed during the first trimester of pregnancy.

Metabolism. The metabolites in plasma and urine are identical to those observed during physiological secretion by the ovarian corpus luteum: in plasma, the main metabolites are 20-alpha-hydroxy-delta-4-alpha-pregnanolone and 5-alpha-dihydroprogesterone. Urinary excretion occurs in 95% as glucuronide 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,

• premenopausal period;

• hormone replacement therapy during menopause (in combination with estrogen therapy);

• infertility due to luteal phase deficiency.

Obstetrical:

• prevention of habitual or threatened miscarriage associated with luteal phase deficiency;
• prevention of 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 limitation of oral administration of the drug.

Contraindications.

• Hypersensitivity to any component of the drug.
• Severe liver function disorders.
• Suspected or confirmed neoplasia of the breast or genital organs.
• Undiagnosed vaginal bleeding.
• Incomplete or failed abortion.
• Thrombophlebitis. Thromboembolic disorders.
• Cerebral hemorrhage.
• Porphyria.

Interaction with other medicinal products and other types of interactions.

In hormone replacement therapy for menopause with estrogens, it is recommended to administer progesterone no later than day 12 of the cycle.

If Utrogestan® is used in combination with beta-adrenergic agonists for the treatment of preterm labor, the doses of the latter may be reduced.

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

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 differ among various patient groups; therefore, it is impossible to predict clinical manifestations of such interactions with certainty. 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 reduced by smoking and increased by alcohol consumption.

Special precautions.

Treatment at the recommended doses does not have a 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 evaluation of the endometrium.

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

Prior to initiating treatment, patients with a family history of tumors, 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 thoroughly examined.

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

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

In case amenorrhea occurs 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 form of the preparation.

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 embryo. Therefore, progesterone should be prescribed only when there is proven insufficient progesterone secretion.

Before initiating treatment, the patient should undergo a thorough medical and gynecological examination, including a bimanual and mammological examination and a Pap smear, taking into account the patient's medical history, contraindications, and precautions. Regular physician visits are recommended during treatment. Women receiving hormone replacement therapy should carefully evaluate all risks and benefits associated with the 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 related to earlier disease detection, actual benefit from HRT, or a combination of both. The risk of breast cancer diagnosis increases with longer duration of treatment and returns to baseline levels within five years after discontinuation of HRT. Breast cancer diagnosed in women receiving or recently receiving 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 who are to receive long-term hormone therapy, 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.

Utrogestan contains soy lecithin and may cause hypersensitivity reactions (urticaria and anaphylactic shock).

Use during pregnancy or breastfeeding.

The use of Utrogestan® is not contraindicated during pregnancy, including the first weeks (see section "Indications" (Obstetrical indications)).

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

When the drug is used during the second and third trimesters of pregnancy, liver function should be monitored.

Excretion of progesterone into breast milk has not been thoroughly studied. Therefore, the drug should be avoided during breastfeeding.

There are data suggesting a possible risk of hypospadias development when progestogens are used during pregnancy for prevention of habitual or threatened miscarriage due to luteal phase deficiency; patients should be informed of this potential risk.

Ability to affect reaction speed when driving or operating machinery.

Drivers and machine operators: drowsiness and dizziness may occur related to the internal (oral) administration of the drug.

Administration of the capsules before bedtime may help avoid these adverse effects.

Cases of drowsiness and dizziness have been observed 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 daily dose is 200–300 mg administered in 1 or 2 doses (200 mg in the evening before bedtime and 100 mg in the morning, if necessary).

• Luteal phase deficiency (premenstrual syndrome, menstrual cycle disorders, perimenopause, fibrocystic mastopathy): administer for 10 days (usually from day 17 to day 26 of the cycle, inclusive).
• Hormone replacement therapy during menopause: since estrogen therapy alone is not recommended, progesterone must be used as an adjunct for the last 2 weeks of each treatment cycle, following a one-week support period of any hormone replacement therapy, during which withdrawal bleeding may occur.
• Threatened preterm labor: administer 400 mg of Utrogestan® every 6–8 hours until symptoms disappear. The effective dose and frequency of administration should be individually adjusted according to clinical signs of preterm labor. After symptoms resolve, the dose of Utrogestan® should be gradually reduced to a maintenance dose (e.g., 200 mg three times daily). This dose may be continued until 36 weeks of gestation.

Use of progesterone after 36 weeks of pregnancy is not recommended.

Vaginal Administration

Insert capsules deeply into the vagina while lying on the back.

Hands must be thoroughly washed before each application; ensure no soap residue 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 two doses in the morning and evening, inserted deeply into the vagina, using an applicator if necessary). The dose may be increased depending on the patient's response.

• 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).
• 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 progesterone dose is 200 mg, 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 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 gestation.

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

Overdose.

Symptoms of overdose may include adverse reactions such as drowsiness, dizziness, euphoria, dysmenorrhea, shortened cycle duration, and metrorrhagia.

In some individuals, the usual 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.

In such cases, the following measures should be taken:

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

Adverse Reactions.

The following phenomena were observed with oral administration:

The following adverse reactions may also be observed: changes in libido, breast discomfort, premenstrual symptoms, hyperthermia, insomnia, alopecia, hirsutism, venous thromboembolism, pulmonary artery embolism, fluid retention, changes in body weight, gastrointestinal disorders, and anaphylactic reactions.

Somnolence and/or transient dizziness are particularly observed in cases of concomitant hypoestrogenism. Reducing the dose of the drug or increasing the estrogen dose promptly eliminates these symptoms without reducing 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 oily vaginal discharge.

Reporting of suspected adverse reactions

Reporting of suspected adverse reactions after drug authorization is important. It allows continuous monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals are requested to report any suspected adverse reactions via the national reporting system.

Shelf life. 3 years.

Storage conditions.

Store in a place inaccessible to children, at a temperature not exceeding 25 °C.

Packaging.

100 mg capsules – 15 soft capsules in a blister; 2 blisters in a cardboard box.

200 mg capsules – 7 soft capsules in a blister; 2 blisters in a cardboard box.

Prescription status. Prescription only.

Manufacturer.

Sydnea Pharma, S.L.

Manufacturer's address and location of operations.

Polígono Industrial Emiliano Revilla Sans. Avenida de Agreda, 31, Olvega, 42110 (Soria), Spain.

Marketing Authorization Holder. Besen Healthcare S.A.

Address of the Marketing Authorization Holder and/or its representative.

Rue Washington 80, 1050 Ixelles, Belgium.