Utrogestan^® (Capsules) Instructions for Use

ATC Code

G03DA04 (Progesterone)

Active Substance

Progesterone (Rec.INN registered by WHO)

Clinical-Pharmacological Group

Gestagen

Pharmacotherapeutic Group

Sex hormones and modulators of the genital system; gestagens; pregn-4-ene derivatives

Pharmacological Action

Mechanism of action, pharmacodynamic effects

The active substance of the drug Utrogestan^® is Progesterone, identical to the natural hormone of the corpus luteum of the ovary.

By binding to receptors on the surface of target organ cells, it penetrates the nucleus where, activating DNA, it stimulates RNA synthesis.

It promotes the transition of the uterine mucosa from the proliferation phase, induced by the follicular hormone estradiol, into the secretory phase, and after fertilization, into the state necessary for the development of the fertilized egg.

It reduces the excitability and contractility of the uterine and fallopian tube muscles.

It promotes the formation of a normal endometrium.

It stimulates the development of the terminal elements of the mammary gland and induces lactation.

By stimulating protein lipase, it increases fat reserves; increases glucose utilization; by increasing the concentration of basal and stimulated insulin, it promotes the accumulation of glycogen in the liver; increases the production of pituitary gonadotropic hormones; reduces azotemia, increases nitrogen excretion by the kidneys.

Pharmacokinetics

Absorption and Distribution

When taken orally

Micronized Progesterone is well absorbed in the gastrointestinal tract.

The plasma concentration of progesterone gradually increases during the first hour, with C_max observed 1-3 hours after administration.

The plasma concentration of progesterone increases from 0.13 ng/ml to 4.25 ng/ml after 1 hour, to 11.75 ng/ml after 2 hours, and is 8.37 ng/ml after 3 hours, 2 ng/ml after 6 hours, and 1.64 ng/ml after 8 hours after administration.

When administered intravaginally

Absorption occurs rapidly, a high plasma concentration of progesterone is observed 1 hour after administration.

C_max of progesterone in plasma is reached 2-6 hours after administration.

When administering 100 mg twice daily, the average plasma concentration remains at 9.7 ng/ml for 24 hours.

When administered in doses greater than 200 mg/day, the progesterone concentration corresponds to the first trimester of pregnancy.

Plasma protein binding is 90%.

Progesterone accumulates in the uterus.

Metabolism

When taken orally

The main metabolites determined in plasma are 20-alpha-hydroxy-delta-4-alpha-pregnanolone and 5-alpha-dihydroprogesterone.

When administered intravaginally

It is metabolized to form mainly 3-alpha, 5-beta-pregnanediol.

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

Excretion

When taken orally

It is excreted by the kidneys in the form of metabolites, 95% of which are glucuronoconjugated metabolites, mainly 3-alpha, 5-beta-pregnanediol (pregnanediol).

The indicated metabolites, which are determined in plasma and urine, are similar to substances formed during the physiological secretion of the corpus luteum.

When administered intravaginally

It is excreted by the kidneys in the form of metabolites, the main part being 3-alpha, 5-beta-pregnanediol (pregnanediol).

This is confirmed by a constant increase in its concentration (C_max=142 ng/ml after 6 hours).

Indications

The drug Utrogestan^® is indicated for the treatment of progesterone-deficient conditions in adult women.

For oral use

• Threatened abortion or prevention of habitual abortion due to progesterone insufficiency;
• Infertility due to luteal insufficiency;
• Premenstrual syndrome;
• Menstrual cycle disorders due to impaired ovulation or anovulation;
• Fibrocystic mastopathy;
• Menopausal transition period;
• Menopausal hormone therapy (MHT) in peri- and postmenopause (in combination with estrogen-containing drugs).

For intravaginal use

• HRT (hormone replacement therapy) in case of progesterone deficiency with non-functioning (absent) ovaries (egg donation);
• Prevention of preterm birth in women at risk (with shortened cervix and/or history of preterm birth and/or premature rupture of membranes);
• Luteal phase support during preparation for in vitro fertilization;
• Luteal phase support in a spontaneous or induced menstrual cycle;
• Premature menopause;
• MHT (in combination with estrogen-containing drugs);
• Infertility due to luteal insufficiency;
• Threatened abortion or prevention of habitual abortion due to progesterone insufficiency.

ICD codes

Dosage Regimen

Capsules

Dosage regimen for oral use

In most cases of progesterone insufficiency, the daily dose of Utrogestan^® is 200-300 mg, divided into 2 doses (200 mg in the evening before bedtime and 100 mg in the morning, if necessary).

For threatened abortion or prevention of habitual abortion due to progesterone insufficiency 200-600 mg daily in the first and second trimesters of pregnancy.

Further use of Utrogestan^® is possible as prescribed by the attending physician based on the assessment of the pregnant woman’s clinical data.

For luteal phase insufficiency (premenstrual syndrome, fibrocystic mastopathy, dysmenorrhea, menopausal transition period) the daily dose is 200 or 400 mg, taken for 10 days (usually from the 17th to the 26th day of the cycle).

For MHT in perimenopause against the background of estrogen intake, Utrogestan^® is used at 200 mg/day for 12 days.

For MHT in postmenopause in a continuous regimen, Utrogestan^® is used at a dose of 100-200 mg from the first day of taking estrogen-containing drugs.

The dose is selected individually.

Dosage regimen for intravaginal use

Prevention of preterm birth in women at risk (with shortened cervix and/or history of preterm birth and/or premature rupture of membranes) the usual dose is 200 mg before bedtime, from the 22nd to the 34th week of pregnancy.

Complete absence of progesterone in women with non-functioning (absent) ovaries (egg donation) against the background of estrogen therapy, 100 mg/day on the 13th and 14th days of the cycle, then 100 mg twice daily from the 15th to the 25th day of the cycle, from the 26th day, and in case of confirmed pregnancy, the dose increases by 100 mg/day each week, reaching a maximum of 600 mg/day, divided into 3 doses.

This dose can be used for up to 60 days.

Luteal phase support during the in vitro fertilization cycle it is recommended to use from 200 to 600 mg/day, starting from the day of chorionic gonadotropin injection throughout the first and second trimesters of pregnancy.

Luteal phase support in a spontaneous or induced menstrual cycle for infertility associated with corpus luteum dysfunction it is recommended to use 200-300 mg/day, starting from the 17th day of the cycle for 10 days; in case of delayed menstruation and diagnosed pregnancy, treatment should be continued.

In cases of threatened abortion or for the prevention of habitual abortion occurring against the background of progesterone insufficiency 200-400 mg/day in 2 divided doses daily in the first and second trimesters of pregnancy.

Children

Efficacy and safety in children under 18 years of age have not been established.

No data available.

Method of administration

For oral use

The drug is taken orally in the evening before bedtime, with water.

For intravaginal use

The capsules are inserted deep into the vagina.

Adverse Reactions

Tabulated summary of adverse reactions

The adverse reactions (AR) listed below, noted with the oral route of administration of the drug, are distributed by frequency of occurrence according to the following gradation: common (≥1/100, but <1/10), uncommon (≥1/1000, but <1/100), rare (≥1/10000, but <1/1000), very rare (<1/10000).

With intravaginal use

There have been isolated reports of local intolerance reactions to the components of the drug (in particular, soy lecithin) in the form of hyperemia of the vaginal mucosa, burning, itching, oily discharge.

Systemic ARs with intravaginal use of the drug in recommended doses, in particular, drowsiness or dizziness (observed with oral administration of the drug), were not noted.

Description of selected adverse reactions

Drowsiness, transient dizziness are possible, as a rule, 1-3 hours after oral administration of the drug.

These ARs can be reduced by lowering the dose, using the drug before bedtime, or switching to the vaginal route of administration.

These ARs are usually the first signs of overdose.

Drowsiness and/or transient dizziness are observed, in particular, in the case of concomitant hypoestrogenism.

Reducing the dose or restoring higher estrogenization immediately eliminates these phenomena without reducing the therapeutic effect of progesterone.

If the course of treatment is started too early (in the first half of the menstrual cycle, especially before the 15th day), shortening of the menstrual cycle or acyclic bleeding is possible.

Recorded changes in the menstrual cycle, amenorrhea or acyclic bleeding are characteristic of all gestagens.

Use in clinical practice

When used in clinical practice, the following ARs have been noted with oral progesterone use: insomnia; premenstrual syndrome; breast tenderness; vaginal discharge; joint pain; hyperthermia; increased night sweats; fluid retention; change in body weight; acute pancreatitis; alopecia, hirsutism; changes in libido; thrombosis and thromboembolic complications (during MHT in combination with estrogen-containing drugs); increased blood pressure.

The drug contains soy lecithin, which may cause hypersensitivity reactions (urticaria and anaphylactic shock).

Reporting of suspected adverse reactions

It is important to report suspected adverse reactions after drug registration to ensure continuous monitoring of the benefit-risk balance of the drug.

Healthcare professionals are encouraged to report any suspected adverse drug reactions through the national adverse reaction reporting system of the member states of the Eurasian Economic Union.

Contraindications

• Hypersensitivity to progesterone or any of the excipients included in the drug;
• Deep vein thrombosis, thrombophlebitis;
• Thromboembolic disorders (pulmonary embolism, myocardial infarction, stroke); intracranial hemorrhage or a history of these conditions/diseases;
• Vaginal bleeding of unknown origin;
• Incomplete abortion;
• Porphyria;
• Established or suspected malignant neoplasms of the breast and genitals;
• Severe liver diseases (including cholestatic jaundice, hepatitis, Dubin-Johnson syndrome, Rotor syndrome, malignant liver tumors) currently or in history;
• Breastfeeding period.

Use in Pregnancy and Lactation

Pregnancy

The drug should be used with caution in the second and third trimesters of pregnancy due to the risk of cholestasis.

Breastfeeding period

Progesterone passes into breast milk, therefore the use of the drug is contraindicated during breastfeeding.

Use in Hepatic Impairment

Contraindicated in severe liver diseases (including cholestatic jaundice, hepatitis, Dubin-Johnson syndrome, Rotor syndrome, malignant liver tumors) currently or in history.

Use with caution in mild to moderate hepatic impairment.

Use in Renal Impairment

Use with caution in chronic renal failure.

Pediatric Use

Contraindicated for use under 18 years of age (efficacy and safety have not been established).

Special Precautions

The drug Utrogestan^® should not be used for contraception.

The drug should not be taken with food, as food intake increases the bioavailability of progesterone.

Utrogestan^® should be used with caution in patients with diseases and conditions that may be aggravated by fluid retention (arterial hypertension, cardiovascular diseases, chronic renal failure, epilepsy, migraine, bronchial asthma); in patients with diabetes mellitus; mild to moderate hepatic impairment; photosensitivity.

Patients with a history of depression should be monitored, and in case of severe depression, the drug should be discontinued.

Patients with concomitant cardiovascular diseases or a history thereof should be periodically monitored by a physician.

Use of Utrogestan^® after the first trimester of pregnancy may cause cholestasis.

The drug should be used with caution in the second and third trimesters of pregnancy.

With long-term treatment with progesterone, regular medical examinations are necessary (including liver function tests); treatment should be discontinued in case of deviations from normal liver function test results or cholestatic jaundice.

When using progesterone, a decrease in glucose tolerance and an increased need for insulin and other hypoglycemic drugs in patients with diabetes mellitus is possible.

If amenorrhea occurs during treatment, pregnancy must be excluded.

If the course of treatment is started too early at the beginning of the menstrual cycle, especially before the 15th day of the cycle, shortening of the cycle and/or acyclic bleeding is possible.

In case of acyclic bleeding, the drug should not be used until their cause is clarified, including histological examination of the endometrium.

In patients with a history of chloasma or a tendency to develop it, it is recommended to avoid UV radiation.

More than 50% of cases of spontaneous abortion in early pregnancy are due to genetic disorders.

In addition, the cause of spontaneous abortion in early pregnancy can be infectious processes and mechanical damage.

The use of Utrogestan^® in these cases may only delay the rejection and evacuation of a non-viable ovum.

The use of Utrogestan^® to prevent threatened abortion is justified only in cases of progesterone deficiency.

When conducting MHT with estrogens in the perimenopausal period, it is recommended to use Utrogestan^® for at least 12 days of the menstrual cycle.

For continuous MHT in postmenopause, it is recommended to use the drug from the first day of taking estrogens.

When conducting MHT, the risk of venous thromboembolism (deep vein thrombosis or pulmonary embolism), the risk of ischemic stroke, and coronary artery disease increases.

Due to the risk of thromboembolic complications, the use of the drug should be discontinued in case of occurrence: visual disturbances, such as loss of vision, exophthalmos, double vision, vascular lesions of the retina; migraine; venous thromboembolism or thrombotic complications, regardless of their location.

If there is a history of thrombophlebitis, the patient should be under close supervision.

When using Utrogestan^® with estrogen-containing drugs, it is necessary to refer to their instructions for use regarding the risks of venous thromboembolism.

The results of the Women’s Health Initiative Study (WHI) indicate a slight increase in the risk of breast cancer with long-term, more than 5 years, combined use of estrogen-containing drugs with synthetic gestagens.

It is unknown whether there is an increased risk of breast cancer in postmenopausal women when conducting MHT with estrogen-containing drugs in combination with progesterone.

The WHI study results also revealed an increased risk of dementia when starting MHT after the age of 65.

Before starting MHT and regularly during its implementation, a woman should be examined to identify contraindications to its implementation.

If clinically indicated, a breast examination and gynecological examination should be performed.

The use of progesterone may affect the results of some laboratory tests, including liver function parameters, thyroid function parameters; coagulation parameters; pregnanediol concentration.

Excipients

The drug Utrogestan^® contains soya lecithin, which may cause hypersensitivity reactions (urticaria and anaphylactic shock).

Effect on ability to drive vehicles and operate machinery

When the drug is used orally, caution should be exercised when driving vehicles and engaging in other potentially hazardous activities that require increased concentration and speed of psychomotor reactions.

Overdose

Symptoms drowsiness, transient dizziness, euphoria, shortening of the menstrual cycle, dysmenorrhea. In some patients, the average therapeutic dose may be excessive due to existing or emerging unstable endogenous progesterone secretion, particular sensitivity to the drug, or too low estradiol concentration.

Treatment in case of drowsiness or dizziness, it is necessary to reduce the daily dose or prescribe the drug at bedtime for 10 days of the menstrual cycle. In case of shortening of the menstrual cycle or “spotting” bleeding, it is recommended to postpone the start of treatment to a later day of the cycle (for example, to the 19th instead of the 17th).

In perimenopause and during MHT in postmenopause, it is necessary to ensure that the estradiol concentration is optimal.

Drug Interactions

With oral use

Progesterone enhances the effect of diuretics, antihypertensive drugs, immunosuppressants, anticoagulants.

Reduces the lactogenic effect of oxytocin.

Concomitant use with inducers of hepatic microsomal enzymes CYP3A4, such as barbiturates, antiepileptic drugs (phenytoin, carbamazepine), rifampicin, phenylbutazone, spironolactone, griseofulvin, is accompanied by an acceleration of progesterone metabolism in the liver.

Concomitant administration of progesterone with some antibiotics (penicillins, tetracyclines) may lead to a decrease in its effectiveness due to disruption of the enterohepatic recirculation of sex hormones as a result of changes in the intestinal microflora. The severity of these interactions may vary among patients, so predicting the clinical effects of the listed interactions is difficult.

Ketoconazole may increase the bioavailability of progesterone.

Progesterone may increase the concentration of ketoconazole and cyclosporine.

Progesterone may reduce the effectiveness of bromocriptine.

Progesterone may cause a decrease in glucose tolerance, thereby increasing the need for insulin or other hypoglycemic drugs in patients with diabetes mellitus.

The bioavailability of progesterone may decrease with smoking and increase with alcohol consumption.

With intravaginal use

The interaction of progesterone with other drugs during intravaginal use has not been evaluated. The simultaneous use of other intravaginally applied drugs should be avoided to prevent impairment of the release and absorption of progesterone.

Storage Conditions

The drug should be stored out of the reach of children at a temperature not exceeding 25°C (77°F).

Shelf Life

The shelf life is 4 years. Do not use after the expiration date.

Dispensing Status

The drug is dispensed by prescription.

Important Safety Information

This information is for educational purposes only and does not replace professional medical advice. Always consult your doctor before use. Dosage and side effects may vary. Use only as prescribed.