Progesterone

Package leaflet (information for patients)

Tradename
Progesterone

Dosage form
Solution for injection 25 mg / ml.

Description
Transparent liquid of light yellow color with a weak odor.

Structure
1 ml of solution contains:
Active ingredient: Progesterone 25mg.
Auxiliary components: ethyl oleate.

Pharmacotherapeutic group
Progestogen

Pharmacological properties
A hormone 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 into the nucleus, where it activates DNA and stimulates RNA synthesis.
Promotes the transition of the uterine mucosa from the proliferation phase caused by the follicular hormone estradiol into the secretory phase. After fertilization, it promotes the transition to a state necessary for the development of a fertilized egg. Reduces the excitability and contractility of the muscles of the uterus and fallopian tubes. Promotes the formation of a normal endometrium. Stimulates the development of the end elements of the mammary gland, induces lactation.
By stimulating protein lipase, it increases fat stores, 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 urinary nitrogen excretion.
Pharmacokinetics
After oral administration, it is well absorbed from the gastrointestinal tract. The concentration of progesterone in the blood plasma gradually increases during the first hour, Cmax in the blood plasma is observed 1-3 hours after administration. The concentration of progesterone in blood plasma 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 - 8 hours after administration. The main metabolites that are detected in blood plasma are 20-alpha-hydroxy-delta-4-alpha-pregnanolone and 5-alpha-dihydroprogesterone. It is excreted in the urine in the form of metabolites, 95% of them are conjugates with glucuronic acid, mainly 3-alpha, 5-beta-pregnanediol (pregnandione). These metabolites, which are determined in blood plasma and urine, are similar to those formed during physiological secretion of the corpus luteum.
With intravaginal administration, absorption occurs quickly, a high concentration of progesterone is observed 1 hour after administration. Cmax of progesterone in blood plasma is achieved 2-6 hours after administration. With the introduction of 100 mg 2 times / day, the average concentration remains at the level of 9.7 ng / ml for 24 hours. When administered in doses of more than 200 mg / day, the concentration of progesterone corresponds to the first trimester of pregnancy. Plasma protein binding is 90%. Progesterone builds up in the uterus. Metabolized to form predominantly 3-alpha, 5-beta-pregnanediol. The concentration of 5-beta-pregnanolone in blood plasma does not increase. It is excreted in the urine in the form of metabolites, the main part is 3-alpha, 5-beta-pregnanediol (pregnandione). This is confirmed by a constant increase in its concentration (Cmax 142 ng / ml after 6 h).
After i / m administration, it is absorbed quickly and almost completely. After i / m administration of 10 mg of progesterone, Cmax in plasma is reached within about 8 hours and remains above the basal level for about 24 hours. Progesterone actively binds to plasma proteins, mainly albumin (50-54%) and corticosteroid binding globulin (43-48%). It is metabolized in the liver with the formation of metabolites - pregnandiol and pregnanolone, which are conjugated with glucuronic and sulfuric acids. The isoenzyme CYP2C19 is involved in metabolism. Progesterone metabolites are excreted by the kidneys - 50-60%, through the intestines - more than 10%. The amount of metabolites excreted by the kidneys varies depending on the phase of the corpus luteum. T1 / 2 - a few minutes.

Indications for use
Progesterone deficiency states in women.
Inside: threatening abortion or prevention of habitual abortion due to progesterone deficiency; infertility due to luteal insufficiency; premenstrual syndrome; menstrual irregularities due to impaired ovulation or anovulation; fibrocystic breast disease; the period of the menopausal transition; menopausal (replacement) hormone therapy (MHT) in peri- and postmenopausal women (in combination with estrogen- containing drugs).
Vaginally: MHT in case of progesterone deficiency with non-functioning (absent) ovaries (egg donation); prevention (prophylaxis) of premature birth in women at risk (with shortening of the cervix and / or a history of preterm labor and / or premature rupture of membranes); support of the luteal phase during preparation for in vitro fertilization; support of the luteal phase in a spontaneous or induced menstrual cycle; premature menopause; MHT (in combination with estrogen-containing drugs); infertility due to luteal insufficiency; threatening abortion or prevention of habitual abortion due to progesterone deficiency.
For i / m administration: infertility due to insufficiency of the corpus luteum.

Method of administration and dosage
Before use, the ampoule with the drug is slightly warmed up in a water bath (up to 30-40 ° C). In case of precipitation of crystals, the ampoule is heated in a boiling water bath until they are completely dissolved. The drug is administered intramuscularly or subcutaneously.
For bleeding associated with ovarian dysfunction - 5-15 mg daily for 6-8 days. If after 6-8 days of treatment the bleeding has not stopped, further administration of progesterone is inappropriate. If bleeding stops, treatment should not be interrupted earlier than 6 days.
With hypogenitalism and amenorrhea, 5 mg daily or 10 mg every other day for 6-8 days is administered (immediately after the use of estrogen drugs).
For the prevention and treatment of threatened miscarriage caused by insufficient function of the corpus luteum - 10-25 mg daily or a line a day until the risk of miscarriage is completely eliminated. With habitual miscarriage, the drug is administered up to 4 months of pregnancy. In case of algodismenorrhea (dysmenorrhea) to reduce or eliminate pain, the drug is started 6-8 days before menstruation, 5-10 mg daily for 6-8 days. The course of treatment can be repeated several times. The highest single and daily intramuscular dose is 25 mg (2.5 ml of 1% solution or 1 ml of 2.5% solution). Progesterone treatment for algodismenorrhea associated with underdevelopment of the uterus can be combined with the preliminary appointment of estrogen drugs.

Side effects
From the nervous system: drowsiness, headache, depression, apathy, dysphoria. From the digestive system: cholestatic hepatitis, nausea, vomiting, loss of appetite, calculous cholecystitis.
On the part of the genitourinary system: decreased libido, reduced menstrual cycle, intermediate bleeding, genital itching, vaginal discharge, vaginal mycosis.
On the part of the senses: visual impairment,
On the part of the CVS: increased blood pressure, edema, thromboembolism (including pulmonary artery and cerebral vessels), thrombophlebitis, retinal vein thrombosis.
From the endocrine system: galactorrhea, alopecia, weight gain, breast enlargement, pain and tension; hirsutism., acne, chloasma. Allergic reactions.
Local reactions: soreness at the injection site.
Excessive amounts of progestogens can cause virilization of the female fetus (up to the uncertainty of gender).

Contraindication
Liver disease, abnormal liver function, breast and genital cancer, a tendency to thrombosis, active venous or arterial thromboembolism, severe thrombophlebitis or a history of these conditions, pregnancy after 36 weeks, ectopic pregnancy or abortion that did not take place (in history), vaginal bleeding of unknown origin, condition after abortion, porphyria; pregnancy 2-3 trimester.

Overdose
Symptoms: hepatotoxicity and intoxication. During intoxication, sweating, nausea, and vomiting may occur. These symptoms can be eliminated by reducing the dose.
Treatment: in case of signs of poisoning, induce vomiting or gastric lavage, prescribe activated charcoal and a laxative, and consult a doctor.
Intoxication and hepatotoxicity are more likely in elderly patients and especially in young children (therapeutic overdose or accidental intoxication can be very dangerous for them).

Precautions
Not used for contraceptive purposes.
Food intake increases the bioavailability of progesterone.
Should be taken with caution in patients with diseases and conditions that can be aggravated by fluid retention (arterial hypertension, cardiovascular disease, chronic renal failure, epilepsy, migraine, bronchial asthma); in patients with diabetes mellitus; impaired liver function of mild to moderate severity; photosensitivity.
Patients with a history of depression should be monitored and progesterone should be discontinued if severe depression develops.
Patients with concomitant cardiovascular diseases or a history of them should also be observed periodically by a doctor.
The use of progesterone after the first trimester of pregnancy can cause the development of cholestasis.
Long-term progesterone treatment requires regular medical examinations (including liver function tests); treatment should be canceled in case of deviations from the normal parameters of liver function tests or cholestatic jaundice.
With the use of progesterone, it is possible to reduce glucose tolerance and increase the need for insulin and other hypoglycemic drugs in patients with diabetes mellitus.
If amenorrhea occurs during treatment, pregnancy should be excluded.
If the course of treatment begins 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 are possible. In the case of acyclic bleeding, progesterone should not be used until their cause is clarified, including a histological examination of the endometrium.

Interaction with other medicinal products
Progesterone enhances the effect of diuretics, antihypertensive drugs, immunosuppressants, anticoagulants.
Reduces the lactogenic effect of oxytocin.
Simultaneous use with drugs-inducers of microsomal liver enzymes CYP3A4, such as barbiturates, antiepileptic drugs (phenytoin), rifampicin, phenylbutazone, spironolactone, griseofulvin, is accompanied by an acceleration of the metabolism of pro gesterone in the liver.
The simultaneous administration of progesterone with some antibiotics (penicillins, tetracyclines) can lead to a decrease in its effectiveness due to a violation of the intestinal-hepatic recirculation of sex hormones due to changes in the intestinal microflora.
The severity of these interactions may vary in different patients; therefore, the prediction of the clinical effects of the listed interactions is difficult.
Ketoconazole may increase the bioavailability of progesterone.
Progesterone can increase the concentration of ketoconazole and cyclosporine.
Progesterone can reduce the effectiveness of bromocriptine.
Progesterone can cause a decrease in glucose tolerance, as a result of which - an increase in the need for insulin or other hypoglycemic drugs in patients with diabetes mellitus.
The bioavailability of progesterone can be reduced in patients who smoke and with excessive alcohol consumption.
The simultaneous use of other drugs used intravaginally should be avoided in order to avoid impaired release and absorption of progesterone.

Special instructions
If there is a history of chloasma or a tendency to develop it, patients are advised to avoid UV exposure.
More than 50% of spontaneous abortions in early pregnancy are due to genetic disorders. In addition, infectious processes and mechanical damage can be the cause of spontaneous abortions in early pregnancy. The use of progesterone in these cases can only lead to a delay in the rejection and evacuation of an unviable ovum.
The use of progesterone to prevent threatening abortion is justified only in cases of progesterone deficiency.
With MHT, the risk of developing venous thromboembolism (deep vein thrombosis or pulmonary embolism), the risk of ischemic stroke and coronary heart disease increases.
Due to the risk of thromboembolic complications, progesterone should be discontinued in the event of: visual disturbances such as vision loss, exophthalmos, double vision, vascular retinal lesions; migraine; venous thromboembolism or thrombotic complications, regardless of their location.
If there is a history of thrombophlebitis, the patient should be closely monitored.
Before starting MHT and regularly during its implementation, a woman should be examined to identify contraindications to its implementation. In the presence of clinical indications, an examination of the mammary glands and a gynecological examination should be carried out.
The use of progesterone can interfere with the results of some laboratory tests, including indicators of liver function, thyroid gland; coagulation parameters ; concentration of pregnandiol.
Influence on the ability to drive vehicles and mechanisms
During treatment, care must be taken when driving vehicles, mechanisms or engaging in activities that require an increased concentration of attention and speed of psychomotor reactions.

Pregnancy and elbowing
This drug should not be used during pregnancy and lactation.
During pregnancy, the drug can cause virilization in female fetuses.
During breastfeeding, it is not known how anabolic steroids are excreted in breast milk. In accordance with the adverse reactions that may occur in infants, it is necessary to decide whether to stop breastfeeding or stop taking the drug.

Influence on the ability to drive vehicles and work with mechanisms
Does not affect.

Storage conditions
Store in a dry, dark place at a temperature not exceeding 25 ° C, out of the reach of children.

Shelf life
3 years. Do not use after the expiration date printed on the package.

Vacation conditions
On prescription.

Packaging
The solution is in 1 ml glass ampoules. Each ampoule is fixed in a plastic clip for 5 ampoules. 5 ampoules are packed in a cardboard box in a fixer together with an enclosed leaflet.