Pharmacological properties

Pharmacodynamics. progesterone in medicament of lutein is synthetic received hormone of a yellow body of an ovary. in physiological conditions progesterone is formed in the luteinized granular cages of a yellow body of an ovary, in a sincytium of fibers of a placenta approximately on the 14-18th week of pregnancy, in puchkovy and mesh layers of bark of adrenal glands and also in central nervous system. the yellow body of an ovary produces progesterone in ii a phase of a menstrual cycle in quantity which increases from 5 to 55 mg/days in the 20-22nd day of a cycle and decreases till 27th day of a cycle. progesterone discharge a yellow body occurs pulsatsionno.

In the woman's organism through the specific receptors which are in a uterus, mammary glands, central nervous system and a hypophysis. The receptor of the person for progesterone has two isoforms: PR-A and PR-B (PR-progesterone). PR-A can serve as both inhibitor, and the transcription activator that does possible various fabric action. The most important effects of influence of progesterone on reproductive organs are: simplification of an ovulation by proteolysis of a wall of a graafov of a bubble; secretory changes of endometrium that does possible oospore implantation; braking of an excess hypertrophy of endometrium under the influence of estrogen; cyclic changes in an epithelium of uterine tubes, neck of the uterus and vagina. Progesterone affects synergistically with estrogen a mammary gland, stimulating growth of bubbles of gland and epithelium of channels and also participating in an expression of the receptors necessary for a lactation. Progesterone — the hormone necessary for incubation of pregnancy throughout all its term: brakes the immunological answer of a uterus to fruit antigens, is substrate for products gliko- and fruit mineralokortikoid, initiates childbirth, eliminates sokratitelny activity of a pregnant uterus.

Other metabolic effects of effect of progesterone are: fervescence, breath stimulation, decrease in concentration of amino acids in blood plasma, the increase in concentration of a glucagon and reduction of expressiveness of hypoglycemic effect of insulin, increase in discharge of calcium and phosphorus, anti-androgenic action consisting in blocking of activity 5-α-редуктазы which turns testosterone into dihydrotestosterone, and receptors of androgens, diuretic action by blocking of action of Aldosteronum in distal tubules of nephron.

Predecessor of progesterone is XC, synthesized from acetyl coenzyme A (atsetil-KoA) and also coming from LDL (LDL). In an internal cover of mitochondrions of XC under the influence of LG (lyutropin) turns in pregnenolon — the direct predecessor of progesterone.

Pharmacokinetics. Progesterone mainly in a liver is metabolized (about 90% of hormone are exposed to effect of the first passing). Metabolites in the form of pregnandiols and pregnanol turn in a liver into glyukuronata and sulfates. Progesterone metabolites which are allocated through biliary tract can change further in reactions of a reduction, dehydroxylation and also an epimerization. Metabolites are removed generally in biliary and uric tract. Metabolites which are removed through biliary tract can turn further in a liver or be removed with a stake.

About 96-99% of progesterone about 50-54% — albumine and 43–48% — with transcortinum (the globulin connecting CBG corticosteroids) contact proteins of blood plasma. Progesterone is well soaked up at reception under language. After sublingual reception of 100 mg of progesterone the concentration of hormone in blood plasma reaches the maximum level approximately in 1–4 h, and after reception of 200 mg — approximately in 2–6 h. The t _½ progesterone accepted sublingual (as well as orally), makes about 6-7 h

After sublingual reception of 100 mg of progesterone the concentration of hormone in blood plasma increases on average up to 13.5 ng/ml.

It is considered p that the concentration of progesterone necessary for secretory change of endometrium defined in the middle of a lyuteinovy phase of a cycle has to make about 12-15 ng/ml. However often concentration of progesterone in blood plasma does not correlate with a histologic condition of endometrium. To define insufficiency of a lyuteinovy phase, besides establishment of concentration of progesterone in blood plasma, it is necessary to confirm by a histopathological research endometrium maturing delay at least for 3 days concerning the calculated day of a cycle. Significantly also reduction of duration of a lyuteinovy phase to less than 10 days.

Indication

Treatment of endogenous deficiency of progesterone in the form of violations of a menstrual cycle, secondary amenorrhea, anovulatory cycles, a premenstrual syndrome, functional uterine bleedings. at artificial fertilization, the infertility connected with lyuteinovy insufficiency, a usual abortion and threat of a misbirth at deficiency of progesterone, insufficiency of a yellow body, a secondary amenorrhea, prevention of a hypertrophy of endometrium at the women accepting estrogen (for example at replacement hormonal therapy — zgt).

Dose of a lyuteina in each case by

individually depending on indications and therapeutic effect.

At violations of a menstrual cycle and a premenstrual syndrome are applied on 50 mg of progesterone by 3–4 times a day sublingual. Treatment lasts 3–6 cycles in a row.

To prevention of a hypertrophy of endometrium (at ZGT) in combination with estrogen most often are applied on 50 mg of progesterone by 3–4 times a day sublingual. At the prolonged faltering schemes medicament is used under language for the last 12–14 days of a 28-day cycle.

At the prolonged continuous schemes progesterone is applied daily without breaks.

Dose of progesterone has to depend on a dose of estrogen so that to protect endometrium from proliferative effect of estrogen.

When performing progesteronovy test at a secondary amenorrhea progesterone are accepted in a dose on 50 mg by 3–4 times a day sublingual. The periods have to appear for 7–10 days after the end of treatment.

At treatment of functional uterine bleedings are applied on 50 mg of progesterone by 3–4 times a day sublingual from the 15th to the 25th day of a cycle. It is necessary to continue treatment 2–3 months in a row.

At a usual miscarriage and threat of a misbirth, the anovulatory and induced cycles are applied on 100 mg of progesterone by 3–4 times a day sublingual.

use of progesterone needs to be begun with

in case of a usual miscarriage during a cycle in which pregnancy, or is planned earlier (pregravidarny preparation in 3–4 months). Treatment needs to be continued continuously approximately till 18-20th week of pregnancy.

In programs of fertilization in vitro (extracorporal) are applied on 100–150 mg of progesterone by 3–4 times a day sublingual.

Contraindication

Hypersensitivity to medicine components. feeding period breast. the suspected or confirmed neoplasia of mammary glands or genitals. bleeding from a genital tract of unspecified genesis. heavy abnormal liver functions. cholestatic jaundice. a syndrome of the rotor and a syndrome a cudgel — Johnson. clotting disease of veins (thrombophlebitis of deep veins, pulmonary embolism). the available or postponed thromboembolic violations of arteries (stenocardia, a myocardial infarction). abortions and also existence of the remains after an abortion in a cavity of the uterus. porphyria, cerebral hemorrhage.

Side effects

At application of a lyuteina, the containing progesterone identical to endogenous hormone, side effects arose seldom, except for the symptoms developing in case of overdose.

were Noted by violations from the following systems and bodies:

from central nervous system: drowsiness, violation of concentration of attention, feeling of fear, depressions, headache and dizziness, insomnia.

from a reproductive system: abnormal bleedings from a uterus, a dysmenorrhea, a krovomazaniye, an amenorrhea, premenstrual symptoms, the alternating bleedings, a mastodynia, changes of a libido, discomfort in mammary glands.

from skin and its appendages: erubescence, eels, allergic reactions, urticaria, itch, alopecia, hirsutism, anaphylactic reactions, hloazma.

from digestive system: nausea, dryness in a mouth, an odontorrhagia, cholestatic jaundice, gastrointestinal violations, vomiting, diarrhea, a lock.

from the vascular system: thromboses, venous thrombembolia, embolism of a pulmonary artery.

Other violations: liquid delay, hyperthermia.

Progesterone can cause fluctuations of body weight.

Drowsiness and/or passing dizziness arise in case of the accompanying gipoestrogeniya. The dose decline of medicine or increase in a dose of estrogen eliminates these phenomena at once, without reducing therapeutic effect.

at the beginning of a monthly cycle, till 15th day, can note reduction of a cycle or bleeding.

Special instructions

Prior to treatment needs to perform gynecologic examination and a palpation of mammary glands. in case of uterine bleedings prior to treatment it is necessary to carry out diagnostics for the purpose of an exception of the organic cause of bleeding. patients at whom in the past noted a depression have to be under special observation as progesterone can cause strengthening of a depression. in case of development of the expressed depression it is necessary to cancel medicine.

Use of medicine for patients of premenopausal age can hide the beginning of a menopause.

In a heavy abnormal liver function should not use drug. Patients with diseases of a liver have to be under observation of the doctor during treatment Lyuteina in the form of sublingual tablets.

At persons with diabetes or violation of tolerance to glucose progesterone can reduce tolerance to glucose. Lutein has no contraceptive effect. In case of use of progesterone for other reasons which are not connected with infertility it is necessary to apply contraceptive means at the same time. It is necessary to warn patients about need to surely inform the doctor at identification of any changes in a mammary gland.

is Especially carefully applied at patients after the postponed thromboembolic violations: the available or postponed arterial or venous thromboembolic violations, including thrombophlebitis of deep veins, a pulmonary embolism, stenocardia, a myocardial infarction.

at the beginning of a monthly cycle, can note reduction of a cycle or bleeding.

in case of uterine bleedings not to appoint medicine without specification of the reason, in particular at endometrium inspection.

With care should be applied at patients with a liquid delay (for example AG, diseases of a cardiovascular system, kidneys, epilepsy, migraine, OH), diabetes, photosensitivity.

Before prescribing of medicine should examine carefully patients with existence of new growths in the family anamnesis and with a recurrent cholestasia or constant feeling of an itch during pregnancy, an abnormal liver function, a heart or renal failure, fibrotsistny mastopathy, epilepsy, OH, an otosclerosis, diabetes, multiple sclerosis, a system lupus erythematosus.

Because of risk of development of tromboembolic and metabolic episodes which cannot be excluded completely should stop administration of medicament at emergence:

• visual violations, such as loss of sight, doubling in eyes, vascular damages of a retina, a ptosis, a papilledema;
• tromboembolic venous or trombotichesky episodes, irrespective of the site of defeat;
• expressed headache, migraines.

in case of an amenorrhea in the course of treatment should confirm or exclude pregnancy which can become the amenorrhea reason.

More than a half of early misbirths is caused by genetic complications. Besides infectious manifestations and mechanical violations can be the cause of early abortions; the delay of exile of a dead fruit would be the only justification of prescribing of progesterone in that case. Therefore, prescribing of progesterone according to the recommendation of the doctor has to be provided for cases when secretion of progesterone is insufficient.

Before an initiation of treatment the patient has to undergo careful medical and gynecologic examination, including intra vaginal and mammology inspection, Papanikolau's smear, taking into account the given anamnesises, contraindications and precautionary measures at application. During treatment it is recommended to have regular examinations at the doctor.

At women who receive ZGT should estimate carefully the ratio risk/advantage connected with therapy.

At patients with post-menopausal symptoms which receive or were received by ZGT, there is a weak or moderate increase in probability of diagnosing of a breast cancer. It can be connected with early diagnostics or the actual advantage of ZGT and also their combination. The risk of developing of a breast cancer increases with increase in duration of treatment and is restored to initial values in 5 years after the termination of reception of ZGT. The breast cancer which is diagnosed for the patients who are receiving or recently receiving ZGT is less invasive, than that, arising at the women who were not receiving ZGT. The doctor has to discuss higher probability of development of a breast cancer with patients who will receive long-term hormonal therapy, estimating advantages of ZGT.

Drug cannot be taken with food. The medicament is recommended to be taken before going to bed. The concomitant use of food increases bioavailability of medicine.

contains lactose therefore it is not necessary to use medicament at patients with hereditary forms of intolerance of a galactose, insufficiency of lactase (Lapp type) or a syndrome of violation of absorption of glucose galactose.

Period of pregnancy and feeding by a breast. Drug of Lutein can be used in the I trimester of pregnancy. There is hypospadias given about possible risk of development at use of progestogens during pregnancy for prevention of a usual abortion or threat of an abortion against the background of lyuteinovy insufficiency what the patient has to be informed on.

Progesterone gets into breast milk therefore use of medicine during feeding by a breast contraindicated.

Children. It is not recommended to apply at children.

Ability to influence speed of response at control of vehicles or work with other mechanisms. Special researches of influence of progesterone on ability to steer vehicles and to work with mechanisms were not conducted, but considering that at use of progesterone are in rare instances possible dizziness, drowsiness, violation of concentration of attention, the driver or the operator working with mechanisms has to be warned about it. Use of tablets before going to bed allows to avoid these undesirable effects.

Interaction

Metabolism of progesterone can accelerate at simultaneous use of the substances enhancing activity of enzyme of cytochrome r450 such as antiepileptic, antibacterial agents, collecting herbs. in the researches in vitro it is revealed that the medicines reducing activity of cytochrome r450 (for example ketokonazol), can slow down progesterone metabolism. the clinical value of this interaction is unknown. use of progesterone can increase concentration of cyclosporine in blood plasma.

Some antibiotics (for example ampicillin, tetracyclines) can cause changes of intestinal microflora, change of a hepatic steroid cycle is a consequence of what.

Powerful inductors of liver enzymes, namely barbiturates, antiepileptic medicines (Phenytoinum), rifampicin, phenylbutazone, Spironolactonum, griseofulvin, not Virapinum, efavirents, carbamazepine, cause the increased metabolism at the hepatic level. Ritonavir and nelfinavir are known as strong inhibitors of cytochrome, show enzyme - the inducing properties at simultaneous application with steroid hormones.

All progestins can reduce tolerance to glucose that can demand increase in a daily dose of insulin and other antidiabetic means from patients with diabetes.

because of smoking and is increased at alcohol intake.

did not confirm interactions of progesterone with other medicines which would have clinical value.

Overdose

Symptoms of overdose can be shown by symptomatology of side reactions, including drowsiness, dizziness, euphoria, a dysmenorrhea, reduction of duration of a menstrual cycle, a metrorrhagia, a depression.

At some persons excessive because of the existing or secondary unstable endogenous secretion of progesterone, hypersensitivity to medicament or very low accompanying oestradiol level in blood. In such cases it is enough:

• to lower a dose of progesterone or to appoint intake of progesterone in the evening before going to bed within 10 days for a cycle at drowsiness or tranzitorny dizziness;
• to transfer an initiation of treatment to later term in a cycle (for example for the 19th day instead of the 17th) in case of its reduction or bloody discharges;
to check
• whether oestradiol level at the patient receiving ZGT during the premenopauzalny period is sufficient.

Treatment: symptoms, as a rule, disappear independently after medicament withdrawal.

in case of overdose should stop administration of medicament and to perform symptomatic treatment.

Storage conditions

In original packing at a temperature not above 25 °C.