Prajisun^® (Capsules, Gel) 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

A gestagen, a corpus luteum hormone. 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 to the secretory phase, and after fertilization, to the state necessary for the development of the fertilized egg.

It reduces the excitability and contractility of the uterine and fallopian tube muscles and stimulates the development of the terminal elements of the mammary gland.

By stimulating protein lipase, it increases fat reserves, increases glucose utilization by increasing the concentration of basal and stimulated insulin, promotes the accumulation of glycogen in the liver, and increases aldosterone production.

In small doses, it accelerates, and in large doses, it suppresses the production of pituitary gonadotropic hormones; reduces azotemia, increases nitrogen excretion in the urine. It activates the growth of the secretory section of the mammary gland acini and induces lactation. It promotes the development of a normal endometrium.

Pharmacokinetics

When taken orally

Absorption

Micronized Progesterone is well absorbed from the gastrointestinal tract. The plasma progesterone concentration gradually increases during the first hour, with C_max observed 1-3 hours after administration. After a 200 mg dose, the plasma progesterone concentration increases from 0.13 ng/ml to 4.25 ng/ml after 1 hour and is 11.75 ng/ml after 2 hours, 8.37 ng/ml after 3 hours, 2 ng/ml after 6 hours, and 1.64 ng/ml after 8 hours.

Metabolism

It is metabolized in the liver with the participation of the isoenzyme CYP2C19. The main metabolites detected in plasma are 20-alpha-hydroxy-delta-4-alpha-pregnanolone and 5-alpha-dihydroprogesterone.

Excretion

It is excreted by the kidneys in the form of metabolites. 95% of them are glucuronoconjugated metabolites, mainly 3-alpha, 5-beta-pregnanediol (pregnanediol). These metabolites, detected in plasma and urine, are similar to substances formed during the physiological secretion of the corpus luteum.

With vaginal administration

Absorption

Absorption occurs rapidly; Progesterone accumulates in the uterus; a high plasma progesterone concentration is observed 1 hour after administration. C_max of progesterone in plasma is reached 2-6 hours after administration. When the drug is administered at 100 mg 3 times/day, the average concentration is maintained for 24 hours. When administered in doses greater than 200 mg/day, the progesterone concentration corresponds to the first trimester of pregnancy.

Metabolism

It is metabolized to form mainly 3-alpha, 5-beta-pregnanediol. The concentration of 5-beta-pregnanediol in plasma does not increase.

Excretion

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

Disorders associated with progesterone deficiency.

Oral route of administration

• Infertility due to luteal phase deficiency;
• Premenstrual syndrome;
• Menstrual cycle disorders due to impaired ovulation or anovulation;
• Fibrocystic mastopathy;
• Premenopause;
• Hormone replacement therapy for peri- and postmenopause (in combination with estrogen-containing drugs).

Vaginal route of administration

• 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 a 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;
• Hormone replacement therapy (in combination with estrogenic drugs);
• Infertility due to luteal insufficiency;
• Prevention of habitual and threatened abortion due to progestin deficiency.

ICD codes

Dosage Regimen

Capsules

The duration of treatment is determined by the nature and characteristics of the disease.

Oral route of administration

The drug is taken orally after meals with water.

In most cases of progesterone deficiency, the daily dose of Prajisun^® is 200-300 mg, divided into 2 doses (morning and evening).

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

For hormone replacement therapy in perimenopause against the background of estrogen intake, Prajisun^® is used at 200 mg/day for 12 days.

For hormone replacement therapy in postmenopause in a continuous regimen, Prajisun^® is used at a dose of 100-200 mg from the first day of estrogen intake.

The dose selection is individualized.

Vaginal route of administration

The capsules are inserted deep into the vagina.

Absolute progesterone deficiency in women with non-functioning (absent) ovaries (egg donation): against the background of estrogen therapy, 200 mg/day on the 13th and 14th days of the cycle, then 100 mg 2 times/day 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.

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

Luteal phase support during preparation for in vitro fertilization: it is recommended to take 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 take 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 abortions occurring against the background of progesterone deficiency: 200-400 mg daily in 2 divided doses in the first and second trimesters of pregnancy.

Gel

For the treatment of infertility due to luteal insufficiency, 90 mg of progesterone (1 applicator) is administered intravaginally daily, starting from the day of confirmed ovulation or from days 18 to 21 of the cycle for 10 days.

For luteal phase support in the process of using assisted reproductive technologies (ART): starting from the day of embryo transfer, the gel is used at a dose of 90 mg of progesterone (1 applicator) and administered intravaginally daily. Upon the onset of pregnancy, the use of the drug is continued for 12 weeks or for 10-12 weeks from the day of pregnancy confirmation.

Secondary amenorrhea, dysfunctional uterine bleeding due to progesterone deficiency: 90 mg of progesterone (1 applicator) is administered intravaginally every other day from the 15th to the 25th day of the cycle. If necessary, the dose can be reduced or increased.

Hormone replacement therapy in postmenopause (in combination with estrogenic drugs): 90 mg of progesterone (1 applicator) is administered 2 times a week.

Rules for self-administration of Prajisun^®

Prajisun^® is inserted into the vagina. For hygienic reasons and for ease of use, Prajisun^® is packaged in a disposable applicator, which is discarded after use.

1. Open the package with the applicator and remove the applicator from it.
2. Unscrew the cap.
3. Hold the applicator firmly between the thumb and middle finger with the index finger on the plunger.
4. Lie on your back with your knees slightly bent. Gently insert the applicator into the vagina.
5. Press the plunger of the applicator firmly with your index finger so that the gel from the applicator enters the vagina.

Note

Although some of the gel remains in the applicator, the patient receives the full required dose. Progesterone will be absorbed slowly and over a long period. Now you can discard the applicator with the remaining gel.

Adverse Reactions

With oral administration

The adverse events listed below, noted with oral use of the drug, are distributed by frequency of occurrence according to the following gradation: common (>1/100, <1/10), uncommon (>1/1000, <1/100), rare (>1/10,000, <1/1000), very rare (<1/10,000).

Reproductive system and breast disorders common – amenorrhea, menstrual cycle disorders, acyclic bleeding; uncommon – mastodynia.

Psychiatric disorders very rare – depression.

Nervous system disorders common – headache; uncommon – drowsiness, transient dizziness.

Gastrointestinal disorders common – abdominal bloating; uncommon – vomiting, diarrhea, constipation; rare – nausea.

Hepatobiliary disorders uncommon – cholestatic jaundice.

Immune system disorders very rare – urticaria.

Skin and subcutaneous tissue disorders uncommon – itching, acne; very rare – chloasma.

Drowsiness, transient dizziness are possible, usually 1-3 hours after taking the drug. These side effects can be reduced by lowering the dose, taking the drug before bedtime, or switching to the intravaginal route of administration.

These undesirable effects 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 of the cycle), shortening of the menstrual cycle or acyclic bleeding is possible.

Reported changes in the menstrual cycle, amenorrhea or acyclic bleeding are characteristic of all progestogens.

Use in clinical practice

During post-marketing use, the following adverse events have been noted with oral use of progesterone: 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 (when conducting HRT in combination with estrogen-containing drugs); increased blood pressure.

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

With vaginal administration

Isolated cases 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 have been reported.

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

Contraindications

For oral and vaginal use

• 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 genital organs;
• Age under 18 years (efficacy and safety not established);
• Period of lactation (breastfeeding);
• Hypersensitivity to progesterone or any of the auxiliary components of the drug.

For oral use (additionally)

• Severe liver diseases (including cholestatic jaundice, hepatitis, Dubin-Johnson syndrome, Rotor syndrome, malignant liver tumors) currently or in history;

With caution the drug should be used in diseases of the cardiovascular system, arterial hypertension, chronic renal failure, diabetes mellitus, bronchial asthma, epilepsy, migraine, depression, in the second trimester of pregnancy.

Use in Pregnancy and Lactation

During pregnancy, the drug can only be used intravaginally.

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

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

Use in Hepatic Impairment

Oral administration is contraindicated in severe liver diseases (including cholestatic jaundice, hepatitis, hepatocellular carcinoma, Dubin-Johnson syndrome, Rotor syndrome) currently or in history.

Use in Renal Impairment

The drug should be prescribed with caution in chronic renal failure.

Pediatric Use

The use of the drug is contraindicated under the age of 18 years (efficacy and safety not established).

Geriatric Use

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

Special Precautions

Prajisun^® should not be used for contraceptive purposes.

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

Prajisun^® 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 liver dysfunction, 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 of them should also be periodically monitored by a doctor.

The use of Prajisun^® after the first trimester of pregnancy may cause the development of cholestasis.

With long-term treatment with progesterone, regular medical examinations are necessary (including liver function tests); treatment must 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 very early at the beginning of the menstrual cycle, especially before the 15th day of the cycle, shortening of the menstrual cycle and/or acyclic bleeding is possible. In case of acyclic bleeding, the drug should not be used until the cause is clarified, including a histological examination of the endometrium.

Patients with a history of chloasma or a tendency to develop it are advised to avoid UV radiation.

More than 50% of cases of early spontaneous abortions are due to genetic disorders. In addition, the cause of early spontaneous abortions can be infectious processes and mechanical damage. The use of Prajisun^® in these cases can only lead to a delay in the rejection and evacuation of a non-viable ovum. The prescription of Prajisun^® for the prevention and/or treatment of threatened miscarriage is justified only in cases of progesterone deficiency.

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

When conducting estrogen HRT during perimenopause, it is recommended to use Prajisun^® for at least 12 days of the menstrual cycle. For continuous HRT in postmenopause, it is recommended to use the drug from the first day of estrogen intake.

When conducting hormone replacement therapy (HRT), the risk of developing venous thromboembolism (deep vein thrombosis or pulmonary embolism), the risk of developing ischemic stroke, and ischemic heart disease increases.

Due to the risk of thromboembolic complications, the drug should be discontinued if the following occur: visual disturbances, such as vision loss, exophthalmos, double vision, retinal vascular lesions; migraine; venous thromboembolism or thrombotic complications, regardless of their location. Patients with a history of thrombophlebitis should be under close observation.

When using Prajisun^® with estrogen-containing drugs, it is necessary to refer to their prescribing information regarding the risks of venous thromboembolism.

Results from the Women’s Health Initiative (WHI) clinical study 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 progestins. It is unknown whether there is an increased risk of breast cancer in postmenopausal women receiving hormone replacement therapy (HRT) with estrogen-containing drugs in combination with progesterone.

Results from the WHI study also revealed an increased risk of dementia when initiating HRT after the age of 65.

Before starting HRT and regularly during its course, a woman should be examined to identify contraindications. If clinically indicated, a breast examination and gynecological check-up should be performed.

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

Effect on the ability to drive vehicles and operate machinery

When taken orally, caution should be exercised when driving vehicles, operating machinery, 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 normal menstrual cycle, dysmenorrhea.

For 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 and dizziness, it is necessary to reduce the dose or prescribe taking the drug before bedtime for 10 days of the menstrual cycle;
• In case of a shortened 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 day instead of the 17th);
• In perimenopause and during HRT in postmenopause, it is necessary to ensure that the estradiol concentration is optimal.

Symptomatic treatment is administered if necessary.

Drug Interactions

For oral use

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

It reduces the lactogenic effect of oxytocin.

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

Concomitant administration of progesterone with certain antibiotics (penicillins, tetracyclines) may lead to a decrease in its effectiveness due to disruption of the enterohepatic recirculation of sex hormones caused by changes in the intestinal microflora.

The severity of these interactions may vary among different patients, making it difficult to predict the clinical effects of the listed interactions.

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, consequently increasing the need for insulin or other hypoglycemic drugs in patients with diabetes mellitus.

The bioavailability of progesterone may be reduced in smoking patients and with excessive alcohol consumption.

For intravaginal use

Interactions for intravaginal use have not been evaluated.

Concomitant use of other intravaginal medications should be avoided to prevent interference with the release and absorption of progesterone.

Storage Conditions

The drug should be stored in a place protected from light, out of the reach of children, at a temperature not exceeding 25°C (77°F).

Shelf Life

The shelf life is 2 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.