active ingredient: 1 bottle contains 500 mg acetate medroxyprogesterone
1 ml suspension contains 150 mg of medroxyprogesterone acetate
Auxiliary substances: Polysorbate 80, methylparaben (E 218), propylparaben (E 216), polyethylene glycol 3350, sodium chloride, sodium hydroxide, concentrated hydrochloric acid, water for injection.
Suspension for injection.
Basic physico-chemical properties: white suspension.
Gestagen. Code ATX G03DA02.
Medroxyprogesterone acetate is a synthetic progestin, which in its structure resembles the endogenous hormone progesterone. There was such a pharmacological effect on the endocrine system:
the inhibition of the synthesis of pituitary gonadotropins (FSH and LH)
decrease in the levels of ACTH and hydrocortisone in the blood
the decrease in the level of circulating testosterone;
reduction of circulating estrogen levels (due to inhibition of follicle stimulating hormone synthesis and enzyme induction of reductase in the liver, which leads to an increase in testosterone clearance and, consequently, to a decrease in androgen conversion into estrogens).
All this leads to a number of pharmacological effects described above.
Medroxyprogesterone acetate with its parenteral use by women in the recommended dose inhibits the secretion of gonadotropins, which, for its part, prevents the maturation of the follicle and the onset of ovulation and leads to the thinning of the endometrium.
Medroxyprogesterone acetate with its oral or parenteral use in recommended doses by women with a sufficient level of endogenous estrogen leads to the conversion of proliferative endometrium in secretory. Its androgenic and anabolic effects are noted, but it is obvious that this drug does not have significant estrogenic activity. While parenteral use of medroxyprogesterone acetate inhibits the formation of gonadotropins, which, for its part, prevents the maturation of the follicle and the onset of ovulation. Available data to date indicate that this does not occur with a daily single intake of the usual recommended oral daily dose.
Medroxyprogesterone acetate has an antitumor activity. When using patient medroxyprogesterone acetate at high doses (via oral or intramuscular routes of administration), it is effective in palliative treatment of malignant hormone-dependent tumors.
The study of mineral density of bone tissue.
The changes of mineral bone density in adult women.
In a controlled clinical trial in adult women who received injections of acetate medroxyprogesterone (intramuscularly at a dose of 150 mg) for a period of up to 5 years for the purpose of contraception, there was a decrease in the mineral density of bone and hip tissue by an average of 5-6% compared to the absence of significant changes in the mineral density of bone tissue in the control group. The decrease in mineral density of bone tissue was more pronounced in the first two years of the drug and less in subsequent years. After 1, 2, 3, 4 and 5 years of application, the average values of changes in the mineral density of bone of the lumbar spine were respectively -2,86%, -4,11%, -4,89%, -4,93% and -5, 38%. The average decrease in bone mineral density of the hip as a whole and the neck of the hip was about the same.
After the termination of injections of medroxyprogesterone acetate (intramuscularly at a dose of 150 mg), there was a gradual recovery of bone mineral density to the initial level during the 2-year period after treatment. 2 years after the termination of treatment, the deficit of bone mineral density in the spine and hip decreased to about 2.1%. A longer treatment was associated with a slower rate of recovery of bone mineral density (see section "Features of application").
The changes of mineral bone density in adolescent girls (aged 12-18 years).
An open non-randomized clinical study of injections of acetate medroxyprogesterone (intramuscularly at a dose of 150 mg every 3 months for a period of up to 240 weeks [4.6 years]) in adolescent girls (aged 12-18 years) for the purpose of contraception also showed a significant decrease in the mineral density of bone of the initial level indicator. Among the girls who received ? 4 injections over a 60-week period, the average decrease in bone mineral density of the lumbar spine was -2.1% for 240 weeks, the average decrease for the hip as a whole and the femoral neck was respectively -6.4% and -5.4%. Based on an average of the changes, further follow-up after treatment showed that the mineral bone density of the lumbar spine was restored to baseline levels 1 year after treatment cessation, and mineral bone density of the hip after 3 years after stopping treatment. In contrast, the average increase in bone mineral density after 240 weeks was 6.4%, 1.7% and 1.9% for the lumbar spine, hip as a whole, and femoral neck, respectively, in patients who were not compared and did not receive treatment (see section "Features of application").
Study "women's health Initiative".
Study "women's health Initiative" study of conjugated equine estrogens (0,625 mg)/medroxyprogesterone acetate (2.5 mg) to assess the risks and benefits of this combination therapy in comparison with placebo to prevent the development of certain chronic diseases were involved 16608 women in postmenopausal period aged 50-79 years with intact uterus at baseline. The primary end point was the incidence of coronary heart disease (non-lethal myocardial infarction and fatal outcome associated with coronary heart disease), and invasive breast cancer was considered as the primary undesirable result. The study was stopped early in the follow up period, which averaged 5.2 years (planned duration 8.5 years) because, in accordance with a predetermined criterion of the termination of the study, an increased risk of developing breast cancer and cardiovascular events outweighed the stated benefits to be included to the total index (see section "Peculiarities of use").
Combination therapy with horse-conjugated estrogens/medroxyprogesterone acetate caused a significant decrease in the frequency of fractures due to osteoporosis (23%) and the total frequency of fractures (24%).
The study of the "Million women".
The study "Millions of women" was a prospective cohort study conducted in the UK involving 1084110 women aged 50-64 years, of whom 828 923 some time after menopause were included in the primary analysis, the risk of developing breast cancer in conjunction with hormonal therapy. In total, 50% of the studied population used hormonal therapy at some point in time. Women who received hormonal therapy at the initial level, used drugs containing only estrogen (41%) or a combination of estrogen and progestin (50%). The average duration of follow up period was 2.6 years for analyses of the incidence of cancer and 4.1 years for analyses of mortality (see Section "Peculiarities of use").
The study of the effect of estrogen/progestin substitution therapy on the heart (study of HERS and HERS II) was a 2-randomized prospective studies on secondary prevention, which studied the long-term effects of oral continuous combination therapy with horse estrogen conjugated/medroxyprogesterone acetate (0.625 mg horse estrogen conjugated and 2.5 mg medroxyprogesterone acetate) in women with ischemic heart disease in the periodical section (see section "Especially use of"). This study included 2,763 women with an intact uterus with an average age of 66.7 years in the postmenopausal period. The average duration of follow up period was 4.1 years for research HERS and 2.7 additional years (total of 6.8 years) for HERS AI research (see Section "Peculiarities of use").
Memory research in the framework of the "women's health Initiative".
The study of memory in the framework of the "Initiative on women's health", which was podolyany "Initiative on women's health" included 4532 predominantly healthy women aged 65 to 79 years in postmenopause and evaluated the influence of therapy anywhereanytime equine estrogen/medroxyprogesterone acetate (0,625 mg conjugated equine estrogens and 2.5 mg medroxyprogesterone acetate) or only anywhereanytime horse estrogens (0,625 mg) on the incidence of development of dementia compared with placebo. The average duration of follow-up follow-up was 4.05 years for the group of the use of conjugated equine estrogens/medroxyprogesterone acetate (see Section "Peculiarities of use").
Absorption. After the introduction of medroxyprogesterone acetate is slowly released, which ensures its low but constant blood levels. Immediately after administration of medroxyprogesterone acetate at a dose of 150 mg/ml, its plasma levels were 1.7 ± 0.3 nmol/l.after 2 weeks, these levels were 6.8 ± 0.8 nmol/l. after administration, the average time to reach peak concentrations was about 4-20 days. The concentration of medroxyprogesterone acetate in serum gradually decreases and remains at a relatively constant level (about 1 ng/ml) for 2-3 months. The levels of the drug in the blood can be determined within 7-9 months after injection.
Distribution. Medroxyprogesterone acetate is approximately 90 to 95% bound to protein. The volume of distribution is 20 ± 3 liters. Medroxyprogesterone acetate crosses the blood-brain and placental barrier (see Section "Use during pregnancy or breastfeeding"). In breast milk of women who were breast-fed and received intramuscular injections of medroxyprogesterone acetate at a dose of 150 mg, was determined low levels of medroxyprogesterone acetate (see Section "Use during pregnancy or breastfeeding").
Metabolism. Medroxyprogesterone acetate is metabolized in the liver.
Conclusion. The half-life after a single administration of the drug is about 6 weeks. Medroxyprogesterone acetate predominantly in the feces through biliary secretion. About 30% of intramuscularly administered dose is excreted in the urine after 4 days.
Gynecology treatment of endometriosis.
recurrent and/or metastatic breast cancer;
recurrent and/or metastatic endometrial cancer
recurrent and/or metastatic kidney cancer
metastatic cancer of the prostate.
The use of medroxyprogesterone acetate is contraindicated in patients with such conditions:
established or probable pregnancy;
undiagnosed vaginal bleeding;
severe impairment of liver function
known hypersensitivity to medroxyprogesterone acetate or other components of the drug.
Additional contraindications for use with contraception and for the treatment of endometriosis in dosages according to the indications:
known or suspected malignant neoplasm of breast;
confirmed or suspected hormone-dependent malignant tumor of the genital organs.
Interaction with other medicinal products and other forms of interaction
Aminoglutetimid while the use of high doses of medroxyprogesterone acetate inside can significantly reduce the concentration of medroxyprogesterone acetate in serum. Patients receiving high-dose medroxyprogesterone acetate inside, should be warned of the possibility of reducing its efficiency with simultaneous use of aminoglutethimide.
Medroxyprogesterone acetate can enhance or reduce the effects of coumarin derivatives. Medroxyprogesterone acetate is the antagonist of the anticoagulant activity fenindion.
Medroxyprogesterone acetate in vitro is metabolized by hydroxylation via CYP3A4. Studies of specific interactions with other drugs to assess the clinical effects of CYP3A4 inductors or inhibitors on medroxyprogesterone acetate have not been conducted, so the clinical effects of CYP3A4 inductors or inhibitors are unknown.
The cases of interaction with other drugs has been reported rarely (including oral anticoagulants), but the reasons for this interaction were identified. It is necessary to take into account the possibility of interaction in patients, for the treatment of which other drugs are simultaneously used.
In the case of sudden bleeding from the vagina during therapy medroxyprogesterone acetate should determine the cause of bleeding.
The use of medroxyprogesterone acetate can lead to some fluid retention in the body, so use the drug in patients with comorbidities that may worsen as a result of such fluid retention, should be careful.
When using medroxyprogesterone acetate should carefully monitor the condition of patients in the past received treatment for clinical depression.
The use of medroxyprogesterone acetate in some patients is accompanied by a decrease in glucose tolerance, so during the use of the drug, it is necessary to carefully monitor the condition of patients with diabetes.
The study of the effect of the acetate medroxyprogesterone on lipid metabolism did not reveal a clear interaction. Both increases and decreases in total cholesterol, triglycerides, and low density lipoprotein (LDL) cholesterol were observed during the studies. The use of Depo-provera is associated with a decrease of 15-20% in the cholesterol level of high-density lipoproteins (HDL) in serum, which can protect a woman from cardiovascular disorders. The clinical consequences of this observation are unknown. For the use of the drug should consider the possibility of an increased risk of coronary heart disease.
Physicians must carefully consider the use of Depo-provera for patients who have recently had trophoblastic disease, while the levels of human chorionic gonadotropin returned to normal.
The use of Depo-provera may affect the results of some laboratory tests, including glucose tolerance test, test with metyrapone, functional liver tests (may be increased), tests for thyroid function (iodine binding level of proteins may be increased and the level of absorption of TC may decrease). Coagulation for prothrombin (factor II) and factors VII, VIII, IX and X may increase.
When sending samples of endometrium or endocervical tissue to the study, the laboratory assistant should be warned that the patient used medroxyprogesterone acetate.
The physician/laboratory assistant should be informed that the use of medroxyprogesterone acetate can lead to a decrease in the level of endocrine biomarkers:
steroids in blood plasma/urine (e.g. cortisol, estrogens, pregnanediol, progesterone, testosterone)
gonadotropins in blood plasma/urine (e.g. luteinizing hormone and follicle-stimulating hormone)
globulin that binds sex hormones.
In case of sudden partial or complete loss of vision or sudden appearance of proptosis, diplopia or migraine, do not use the drug again for the examination of the patient. If the examination reveals lesions of the retina vessels or swelling of the optic nerve disc, the drug should be discontinued.
Although it was found that the use of medroxyprogesterone acetate leads to the development of thrombotic or thromboembolic complications, it is not recommended to use the drug in patients with a history of venous thromboembolism. Discontinue use of medroxyprogesterone acetate in the case of developing venous thromboembolism during its application.
The loss of mineral density of bone tissue.
The use of injections of medroxyprogesterone acetate reduces the level of estrogen in serum in women in premenopause and is associated with a significant loss of bone mineral density as a result of adjusting the metabolism of this tissue to reduce estrogen levels. The loss of bone mineral density becomes particularly important in adolescence and early adulthood - in the critical period of bone growth. Bone loss increases with increasing duration of use of the drug, and may not be fully reversible. It is not known that the use of medroxyprogesterone acetate in young women will reduce the peak of bone mass and increase the risk of bone fractures due to osteoporosis in adulthood. Both in adult women and adolescent girls, the reduction of bone mineral density is partially restored after the withdrawal of injections of medroxyprogesterone acetate and the increase in estrogen production by the ovaries.
Changes in bone mineral density in adult women after 6 months of endometriosis treatment.
During 2 clinical trials with the participation of 573 adult women with endometriosis compared the effect on mineral density of bone tissue of 6-month use of medroxyprogesterone acetate subcutaneous with the effect of 6-monthly applications leuprolide. After the end of treatment, the patients were further observed for the next 12 months.
The proportion of patients with a decrease in mineral density of bone tissue at the level of 5% or higher were statistically significantly more in the application group leuprolide than the use of medroxyprogesterone acetate subcutaneously in each time interval.
The proportion of patients with a decrease in mineral bone density at 5% or above the baseline level after 6-month use of medroxyprogesterone acetate subcutaneously or leuprolide and 6 months after discontinuation of treatment (study 268 and 270 combined).
Indicator mineral density of bone denisekatipunera acetate subcutaneously n/n * (%)Leuprolide n/n * (%)value **
The end of treatment (6 months of therapy)
позвоночник12/208 (5.8%)85/229 (37.1%)<0.001
Thigh in General 1/207 (0.5%)25/227 (11.0%)<0.001
Visit in 12 months (6 months without treatment)
позвоночник8/166 (4.8%)32/178 (18.0%)<0.001
Hip целом3/166 (1.8%)25/178 (14,0%)<0.001
* N - the number of patients with a decrease in bone mineral density at 3 5%; N-the total number of patients.
In the UK, a retrospective cohort study was conducted to assess the effect of injections of medroxyprogesterone acetate on the incidence of bone fractures in 312,395 women who used this drug or other contraceptive drugs. The frequency of fractures was compared in women taking medroxyprogesterone acetate, and women who used other contraceptives (without indications for their use of medroxyprogesterone acetate). The ratio of risks of occurrence of any fracture in the course of further observations (average 5.5 years) was 1.41 (95% confidence interval: 1.35; 1.47). Among the subgroups for which data were obtained for the periods before and after the first reported contraceptive use (N = 166 367), a comparison was made for the follow-up period as well as for the 6-month period before the first reported contraceptive use. When comparing between women who used medroxyprogesterone acetate and women who did not use it, the ratio of the risks of any fracture to treatment (the ratio of risks of occurrence 1,28; 95% confidence interval 1,07; 1,53) was comparable with the ratio of the risk of fractures after treatment (the ratio of risks 1,37; 95% confidence interval: 1,29; 1,45). The overall results prove the fact that the high incidence of fractures was observed in this study among women who used medroxyprogesterone acetate, is primarily the result of other factors and not a consequence of the introduction of medroxyprogesterone acetate. Injections of medroxyprogesterone acetate should be used as a long-term (e.g. more than 2 years) method of birth control or endometrial treatment only when other methods of birth control or endometrial treatment are not suitable. If a woman requires the use of medroxyprogesterone acetate for a long time, it is necessary to assess the mineral density of her bone tissue. When interpreting the results of the study of bone mineral density in adolescent girls should take into account the age of the patient and the degree of maturity of the skeleton.
According to the results of the analysis of the risk/benefit ratio of the use of injections of acetate medroxyprogesterone, it is necessary to consider the possibility of using other methods of birth control or endometrial treatment for women who have the following risk factors for osteoporosis
chronic alcohol and/or Smoking;
chronic use of drugs that can reduce bone mass such as anticonvulsants or corticosteroids;
low body mass index or eating disorders such as nervous anorexia or bulimia;
disease associated with metabolic disorders of bone tissue;
numerous cases of osteoporosis in the family history.
All patients are advised to consume calcium and vitamin D in sufficient quantities.
The majority of women who use the suspension of medroxyprogesterone acetate for injection, there are violations of the nature of menstrual bleeding (eg irregular or unpredictable bleeding/spotting, rarely - intensive or prolonged bleeding). With the continuation of the use of the suspension of medroxyprogesterone acetate for injections in fewer and fewer women there are irregular bleeding and an increasing number of women - amenorrhea.
As part of the long-term observation type case - control in the application of the medroxyprogesterone acetate suspension for injection noted a slight increase or no increase in the overall risk of breast cancer and no increase in the overall risk of ovarian, liver or cervical cancer, as well as a long-term protective effect-reducing the risk of endometrial cancer.
The suspension of medroxyprogesterone acetate for injection has a long contraceptive effect. Median contraception period after the last injection of the drug for those who became pregnant is 10 months with a range of 4-31 months and does not depend on the duration of use.
During the treatment of medroxyprogesterone acetate women were prone to increase body weight.
In the case of jaundice should consider not re-use this drug.
Patients must be informed that the suspension of medroxyprogesterone acetate does not protect against HIV infection (AIDS) and other sexually transmitted diseases.
While several epidemiological studies in women who received injections of depo progestogen, there was no increase in risk of developing breast cancer compared to women who did not receive them. However, women who are currently receiving injections of depo-progestogen, or received them only a few years ago, there was an increase in the relative risk (for example 2.0 in a single study). Based on these data, it is impossible to conclude that there is an increase in the frequency of diagnosis of breast cancer in women who are currently receiving such treatment, a consequence of closer monitoring of such women, the biological effect of injectable Progestogens or a combination of these factors.
Estrogens in combination with or without progestins should be used for the prevention of cardiovascular disease. In several randomized prospective studies long-term effects (see Section "Method of application and dosage") of combined regimens of estrogen/progestin in women in postmenopause reported a higher risk of developing cardiovascular events such as myocardial infarction, coronary heart disease, stroke and venous thromboembolism.
Coronary artery disease
Randomized controlled studies do not indicate the benefits of continuous combined use of conjugated estrogen and medroxyprogesterone acetate for the cardiovascular system. 2 large clinical studies "women's health Initiative" study of conjugated equine estrogens and medroxyprogesterone acetate, and studies of the effects of replacement therapy with estrogen/progestin on the heart (see Section "Pharmacological") demonstrated the possibility of increasing the risk of cardiovascular disease in the first year of treatment and the lack of common benefits of this therapy.
In the study, "the women's health Initiative" study of conjugated equine estrogens and medroxyprogesterone acetate in women taking conjugated equine estrogens/medroxyprogesterone acetate, there was an increase in the risk of complications of ischemic heart disease (defined as nonfatal myocardial infarction and death related to coronary heart disease) compared to women receiving placebo (37 vs. 30 per 10,000 patient-years). Increased risk of venous thromboembolism was observed in the first year and remained during the entire period of observation (see section "dosage and Administration").
In the course of the clinical study "women's health Initiative" on the study of conjugated horse estrogen and medroxyprogesterone acetate in women taking conjugated horse estrogen/medroxyprogesterone acetate, there was an increase in the risk of stroke compared with those in women receiving placebo (29 compared with 21 per 10,000 patients-years). Increased risk was observed in the first year and maintained throughout the period of observation (see section "dosage and Administration").
Venous thromboembolism/pulmonary embolism.
Hormone therapy is associated with a higher relative risk of developing venous thromboembolism, ie deep vein thrombosis or pulmonary embolism. In the course of the clinical study "women's health Initiative" on the study of conjugated horsepower estrogen and medroxyprogesterone acetate in women taking conjugated horsepower estrogens/medroxyprogesterone acetate was observed twice the incidence of venous thromboembolism, including deep vein thrombosis and pulmonary embolism, compared to women who received a placebo. The increased risk was observed in the first year and remained during the entire observation period (see section "specific applications").
A study of memory in the framework of the" women's health initiative "(see section" Pharmacological"), which was an additional study of the" women's health Initiative " for the study of conjugated horsepower estrogens and medroxyprogesterone acetate, demonstrated an increased risk of possible dementia in women aged 65 years and over during postmenopause. In addition, the use of conjugated horse estrogens/medroxyprogesterone acetate did not prevent the development of mild cognitive impairment in these women. It is not recommended to use hormonal therapy to prevent dementia or mild cognitive impairment in women aged 65 years.
In some epidemiological studies, the current use of only estrogens or estrogens in combination with progestins by women during postmenopause for five years or more has been associated with an increased risk of ovarian cancer. The use of only estrogens or estrogens in combination with progestins in the past was not accompanied by an increased risk of ovarian cancer. Other studies have not demonstrated the existence of significant relationship between these factors. In the study, "the women's health Initiative" study of conjugated equine estrogens and medroxyprogesterone acetate was reported that estrogen combined with a progestin increased the risk of ovarian cancer, but this risk was not statistically significant. In one study, women who received hormone replacement therapy had increased risk of fatal ovarian cancer.
Recommendations for the collection of history and medical examination.
Before beginning any hormone therapy you should collect a full medical and family history. During medical examinations in preparation for treatment and periodic medical examinations should pay special attention to the measurement of blood pressure, examination of the chest, abdomen and pelvic organs (with cytological examination of the cervix).
After taking single or multiple doses of medroxyprogesterone acetate in the form of injections may be observed prolonged anovulation with amenorrhea and/or irregular menstruation.
Medroxyprogesterone acetate can cause the development cushingoid symptoms.
Some patients who use medroxyprogesterone acetate may inhibit adrenal function. Medroxyprogesterone acetate can reduce the level of ACTH and hydrocortisone in the blood.
The physician/laboratory personnel must be informed of the fact that, in addition to the endocrine biomarkers, the list of which is provided in the section "peculiarities of use", the use of medroxyprogesterone acetate in Oncology indications may also cause partial adrenal insufficiency (decrease in the response of the pituitary-adrenal system) during the tests with metyrapone. Thus, the assessment of the adrenal cortex ability to respond to ACTH should be carried out for the use of meth.
After taking single or multiple doses of medroxyprogesterone acetate in the form of injections may be observed prolonged anovulation with amenorrhea and/or irregular menstruation.
Parenteral dosage forms in high doses (for example, when applying for cancer indications to women during premenopause).
The decrease in mineral density of bone tissue.
Studies of the effect on the mineral density of bone oral forms of medroxyprogesterone acetate or parenteral forms of medroxyprogesterone acetate in high doses (for example, when used for cancer indications) was not carried out. An assessment of bone mineral density may be appropriate in some patients taking medroxyprogesterone acetate for a long time (see above - bone mineral density loss).
In 1 ml of this drug contains less than 1 mmol of sodium-in fact, " without sodium."
Application during pregnancy and lactation
Medroxyprogesterone acetate is contraindicated in pregnant women.
Some reports suggest, under certain conditions, a link between progestagen exposure in the uterus in the first trimester of pregnancy and pathology of the genital organs in the fetus. Children born as a result of unplanned pregnancies that occur 1-2 months after the injection of medroxyprogesterone acetate may have an increased risk of birth with low birth weight, which in turn is associated with an increased risk of death in the neonatal period. This risk is low, because pregnancy when using medroxyprogesterone acetate is infrequent. Full information about other dosage forms of medroxyprogesterone acetate is missing.
If the patient became pregnant while using this drug, it should be informed about the existence of a possible threat to the fetus.
Use in lactation period.
Medroxyprogesterone acetate and its metabolites penetrate into breast milk. The arguments in favor of the fact that this can pose a threat to the baby, no.
The ability to influence the reaction rate when driving motor transport or operating other mechanisms
There was no systematic study of the effect of acetate medroxyprogesterone on the ability to drive vehicles or operate other automated systems.
Method of application and doses
Prior to use suspension for in