INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT DEPO-PROVERA® (DEPO-PROVERA®)

Composition:

Active ingredient: medroxyprogesterone acetate.

One vial contains 500 mg of medroxyprogesterone acetate;
1 ml of suspension contains 150 mg of medroxyprogesterone acetate;

Excipients: polysorbate 80, methylparaben (E 218), propylparaben (E 216), polyethylene glycol 3350, sodium chloride, sodium hydroxide, concentrated hydrochloric acid, water for injections.

Pharmaceutical form. Injectable suspension.

Main physicochemical properties: white-colored suspension.

Pharmacotherapeutic group. Progestogens. ATC code G03D A02.

Pharmacological properties.

Pharmacodynamics.

Mechanism of action.

Medroxyprogesterone acetate is a synthetic progestin structurally similar to the endogenous hormone progesterone. The following pharmacological effects on the endocrine system have been observed:

• suppression of pituitary gonadotropin synthesis (follicle-stimulating hormone and luteinizing hormone);
• reduction in blood levels of adrenocorticotropic hormone and hydrocortisone;
• reduction in circulating testosterone levels;
• reduction in circulating estrogen levels (due to suppression of follicle-stimulating hormone synthesis and enzyme induction of reductase in the liver, leading to increased testosterone clearance and, consequently, reduced conversion of androgens into estrogens).

These effects collectively result in a number of pharmacological actions described below.

Contraception.

When administered parenterally to women at the recommended dose, medroxyprogesterone acetate suppresses the secretion of gonadotropins, thereby preventing follicular maturation and ovulation, and causes thickening of cervical mucus, which hinders sperm entry into the uterus.

Gynecology.

When administered orally or parenterally at recommended doses to women with sufficient endogenous estrogen levels, medroxyprogesterone acetate transforms the proliferative endometrium into the secretory phase. Androgenic and anabolic effects have been noted; however, this medicinal product evidently lacks significant estrogenic activity. When administered parenterally, medroxyprogesterone acetate suppresses gonadotropin production, thereby preventing follicular maturation and ovulation. Current data indicate that this does not occur with daily single oral administration of the usual recommended oral daily dose.

Oncology.

Medroxyprogesterone acetate exhibits antitumor activity. When used in high doses (orally or intramuscularly), medroxyprogesterone acetate is effective in palliative treatment of malignant hormone-dependent neoplasms.

Clinical studies.

• Bone mineral density studies.

Changes in bone mineral density in adult women.

A study comparing changes in bone mineral density in women receiving subcutaneous (s.c.) depot medroxyprogesterone acetate (DMPA) versus women receiving intramuscular (i.m.) medroxyprogesterone acetate injections demonstrated similar levels of bone mineral density loss in both groups after two years of treatment. The mean percentage changes in bone mineral density in the s.c. DMPA group are presented in Table 1.

Table 1. Mean percentage change in bone mineral density in adult women using DMPA, by skeletal site, compared to baseline levels

Treatment period	Lumbar spine		Hip joint		Femoral neck
	N	Mean % change (95% CI)	N	Mean % change (95% CI)	N	Mean % change (95% CI)
1st year	166	-2.7 (from -3.1 to -2.3)	166	-1.7 (from -2.1 to -1.3)	166	-1.9 (from -2.5 to -1.4)
2nd year	106	-4.1 (from -4.6 to -3.5)	106	-3.5 (from -4.2 to -2.7)	106	-3.5 (from -4.3 to -2.6)

CI – confidence interval

In another controlled clinical study involving adult women who received intramuscular DMPA injections for up to 5 years, an average decrease in bone mineral density (BMD) of 5–6% at the spine and hip was demonstrated, compared with no significant changes in BMD in the control group. The reduction in BMD was more pronounced during the first 2 years of use and diminished in subsequent years. On average, changes in lumbar spine BMD were -2.9%, -4.1%, -4.9%, -4.9%, and -5.4% after 1, 2, 3, 4, and 5 years, respectively. Mean decreases in total hip and femoral neck BMD were similar. Additional information is presented in Table 2.

After discontinuation of intramuscular DMPA injections, BMD increased toward baseline values during the post-treatment period. Longer duration of treatment was associated with a slower rate of BMD recovery.

In the same clinical study, a limited number of women who had used DMPA intramuscularly (depot medroxyprogesterone acetate intramuscular injections) for 5 years were followed for an additional 2 years after stopping DMPA. Bone mineral density (BMD) values increased toward baseline levels over the 2-year post-treatment period. Two years after discontinuation of DMPA injections, mean BMD values had increased at all 3 skeletal sites, although a deficit remained (see Table 2 below).

Table 2. Mean percentage change in bone mineral density compared to baseline in adult women by skeletal site after 5 years of treatment with 150 mg medroxyprogesterone acetate intramuscularly and after 2 years following discontinuation or 7 years of observation (control group)

Study Period	Spine		Total Femur		Femoral Neck
	DMPA	Control	DMPA	Control	DMPA	Control
5 years* n# SD## LSM§ CI§§ 95%	33 -5.4 % 3.57 -6.65; -4.11	105 0.4 % 3.27 -0.20; 1.06	21 -5.2 % 3.60 -6.80; -3.52	65 0.2 % 3.18 -0.60; 0.98	34 -6.1 % 4.68 -7.75; -4.49	106 -0.3 % 5.22 -1.27; 0.73
7 years** n# SD## LSM§ CI§§ 95%	12 -3.1 % 3.15 -5.13; -1.13	60 0.5 % 3.65 -0.39; 1.49	7 -1.34 % 4.95 -5.92; 3.23	39 0.94 % 3.81 -0.29; -3.73	13 -5.4 % 2.73 -7.03; -3.73	63 -0.1 % 5.88 -1.51; 1.45

* The treatment group consisted of women who received intramuscular DMPA injections for 5 years, and the control group consisted of women who did not use hormonal contraceptives during this period.

** The treatment group consisted of women who received intramuscular DMPA injections for 5 years and were followed for an additional 2 years after the end of therapy, and the control group consisted of women who did not use hormonal contraceptives for 7 years.

n – number of participants

##SZ – mean % change

§ SSV – standard standard deviation

§§CI – confidence interval

Changes in bone mineral density in adolescent girls (12–18 years).

Results from an open, non-randomized clinical study of intramuscular DMPA injections (150 mg intramuscularly every 12 weeks for up to 240 weeks (4.6 years), with subsequent post-treatment monitoring) in adolescent girls (12–18 years) also demonstrated that intramuscular administration of medroxyprogesterone acetate is associated with a significant decrease in bone mineral density compared to baseline levels. In patients who received ≥4 injections during a 60-week period, the mean decrease in bone mineral density at the lumbar spine was -2.1% after 240 weeks (4.6 years); the mean decrease at the femur and femoral neck was -6.4% and -5.4%, respectively (see Table 3). In contrast, a non-comparable group of untreated adolescent girls with baseline bone density values differing from those in DMPA-treated patients showed a mean increase in bone mineral density after 240 weeks at the lumbar spine, femur, and femoral neck of 6.4%, 1.7%, and 1.9%, respectively.

Table 3. Mean percentage change in bone mineral density (with 95% confidence interval) compared to baseline in adolescent girls who received ≥4 injections per 60-week period, by skeletal site

Treatment Duration	DMPA IM
	N	Mean % change value ( 95% confidence interval)
Total hip BMD 60 weeks (1.2 years) 120 weeks (2.3 years) 180 weeks (3.5 years) 240 weeks (4.6 years)	113 73 45 28	-2.8 [-3.27; -2.12] -5.4 [-6.16; -4.64] -6.4 [-7.38; -5.37] -6.4 [-8.56; -4.24]
Femoral neck BMD 60 weeks 120 weeks 180 weeks 240 weeks	113 73 45 28	-2.9 [-3.72; -2.15] -5.3 [-6.23; -4.37] -6.0 [-7.31; -4.59] -5.4 [-7.81; -3.00]
Lumbar spine BMD 60 weeks 120 weeks 180 weeks 240 weeks	114 73 44 27	-2.5 [-2.95; -1.98] -2.7 [-3.57; -1.91] -2.7 [-3.99; -1.35] -2.1 [-4.16; -0.07]

Results of post-therapeutic follow-up in adolescent girls who received at least 1 injection of DMPA during the study and in whom BMD was measured at least once after discontinuation of intramuscular DMPA are presented in Table 4. The mean number of injections received by patients in this cohort during the treatment phase was 9. At the time of the last DMPA injection, the percent change in BMD from baseline in this cohort was -2.7%, -4.1%, and -3.9% at the lumbar spine, total hip, and femoral neck, respectively. After discontinuation of intramuscular DMPA injections, mean BMD values recovered to baseline levels: at 1.2 years for the lumbar spine, at 4.6 years for the total hip, and by at least 4.6 years for the femoral neck region. However, it is important to note that many patients discontinued the study prematurely. Thus, these results are based on data from a small number of patients, and some patients still had reduced BMD at the total hip at 240 weeks. Longer duration of treatment and smoking were associated with slower recovery (see Table 4).

Table 4. Percent change in bone mineral density from baseline in adolescent girls after discontinuation of DMPA

Week after stopping DMPA	N	Mean number of injections	Mean % change (SE) from baseline to end of study	95% CI	Mean % change (SE) at visit after stopping DMPA compared to baseline level	95% CI
Total hip BMD
0 24 60 120 180 240	98 74 71 52 39 25	9 9 8 10 7 9	-4.1 (0.43) -4.1 (0.53) -3.6 (0.46) -4.3 (0.64) -4.1 (0.72) -3.4 (0.67)	[-4.95; -3.25] [-5.15; -3.04] [-4.48; -2.66] [-5.56; -2.98] [-5.55; -2.63] [-4.73; -1.98]	Not applicable 0 (0.61) -2.8 (0.56) -1.7 (0.72) 1.2 (0.85) 0.1 (0.98)	[-5.25; -2.80] [-3.97; -1.72] [-3.14; -0.26] [-2.96; -0.46] [-1.95; -2.11]
Femoral neck BMD
0 24 60 120 180 240	98 74 71 52 39 25	9 9 8 10 7 9	-3.9 (0.50) -3.8 (0.60) -3.3 (0.56) -3.8 (0.74) -3.9 (0.85) -3.4 (0.80)	[-4.92; -2.92] [-5.01; -2.62] [-4.41; -2.18] [-5.25; -2.28] [-5.62; -2.17] [-5.07; -1.78]	Not applicable -4.0 (0.71) -3.6 (0.70) -1.8 (0.82) -1.0 (0.98) -0.7 (1.19)	[-5.40; -2.55] [-4.99; -2.18] [-3.43; -0.13] [-3.00; 0.97] [-3.20; 1.72]
Lumbar spine BMD
0 24 60 120 180 240	98 74 70 52 39 25	9 9 8 10 7 9	-2.7 (0.39) -2.6 (0.43) -2.8 (0.43) -2.7 (0.61) -3.0 (0.67) -2.6 (0.80)	[-3.45; -1.19] [-3.42; -1.69] [-3.66; -1.96] [-3.96; -1.50] [-4.35; -1.66] [-4.28; -0.99]	Not applicable -2.5 (0.51) -0.2 (0.60) 2.24 (0.73) 2.8 (0.79) 4.5 (1.03)	[-3.52; -1.48] [-1.41; 1.01] [0.74; 3.67] [1.16; 4.35] [2.35; 6.61]

⸹ - standard error

⸹⸹ - confidence interval

Association between fracture rate and use of intramuscular DMPA (150 mg) in women of reproductive age

A large retrospective cohort study using data from the General Practice Research Database (GPRD) included 41,876 women who used DMPA for contraception and contained data from 6–24 months prior to the first DMPA injection and an average follow-up period of 5.5 years after the first DMPA injection. The risk of fractures was higher overall in the DMPA cohort compared to subjects who did not use the drug, both before and after DMPA use. The risk of fractures after the first injection was compared to the period before the first injection: relative risk 1.01 (95% CI: 0.92, 1.11), indicating that DMPA did not increase the risk of bone fractures.

The maximum observation period in this study was 15 years; therefore, potential effects of Depo-Provera® beyond 15 years of follow-up cannot be determined. It is important to note that this study does not allow conclusions regarding whether DMPA affects the incidence of fractures at a later age, i.e., after menopause.

• Women's Health Initiative Study.

The Women's Health Initiative study evaluated combined conjugated estrogens (0.625 mg)/medroxyprogesterone acetate (2.5 mg) to assess the risks and benefits of this combined therapy compared to placebo in preventing certain chronic diseases. The study involved 16,608 postmenopausal women aged 50–79 years with an intact uterus at baseline. The primary endpoint was the incidence of coronary heart disease (non-fatal myocardial infarction and coronary heart disease-related death), and invasive breast cancer was considered a primary adverse outcome. The study was terminated prematurely during a follow-up period averaging 5.2 years (planned duration 8.5 years) because, according to a pre-specified stopping rule, the increased risks of breast cancer and cardiovascular events outweighed the benefits included in the "global index" (see section "Special precautions for use").

Combined therapy with conjugated estrogens/medroxyprogesterone acetate resulted in a significant reduction in osteoporotic fractures (23%) and overall fracture rate (24%).

• Million Women Study.

The Million Women Study was a prospective cohort study conducted in the United Kingdom involving 1,084,110 women aged 50–64 years, of whom 828,923 were included in the main analysis of breast cancer risk associated with hormone therapy after menopause. Overall, 50% of the study population used hormone therapy at some point. Women receiving hormone therapy at baseline used medications containing either estrogen alone (41%) or a combination of estrogen and progestin (50%). The average follow-up duration was 2.6 years for cancer incidence analysis and 4.1 years for mortality analysis (see section "Special precautions for use").

• Heart and Estrogen/progestin Replacement Study (HERS and HERS II).

The Heart and Estrogen/progestin Replacement Studies (HERS and HERS II) were two randomized, prospective trials of secondary prevention that investigated the long-term effects of oral continuous combined therapy with conjugated estrogens/medroxyprogesterone acetate (0.625 mg conjugated estrogens and 2.5 mg medroxyprogesterone acetate) in postmenopausal women with coronary heart disease (see section "Special precautions for use"). The study included 2,763 women with an intact uterus, with a mean age of 66.7 years, in the postmenopausal period. The average follow-up duration was 4.1 years for HERS and an additional 2.7 years (total 6.8 years) for HERS II (see section "Special precautions for use").

• Memory Study within the Women's Health Initiative.

The Memory Study within the Women's Health Initiative, a substudy of the Women's Health Initiative, included 4,532 predominantly healthy postmenopausal women aged 65–79 years and evaluated the effect of conjugated estrogens/medroxyprogesterone acetate (0.625 mg conjugated estrogens and 2.5 mg medroxyprogesterone acetate) or conjugated estrogens alone (0.625 mg) on the incidence of possible dementia compared to placebo. The average follow-up duration was 4.05 years for the conjugated estrogens/medroxyprogesterone acetate group (see section "Special precautions for use").

Pharmacokinetics.

Absorption. After intramuscular administration, medroxyprogesterone acetate is slowly released, providing low but sustained blood levels. Immediately after intramuscular injection of medroxyprogesterone acetate at a dose of 150 mg/mL, plasma levels were 1.7±0.3 nmol/L. After 2 weeks, these levels reached 6.8±0.8 nmol/L. Following intramuscular administration, the mean time to peak concentration was approximately 4–20 days. The serum concentration of medroxyprogesterone acetate gradually decreases and remains at a relatively constant level (approximately 1 ng/mL) for 2–3 months. Drug levels in blood can be detected for 7–9 months after intramuscular administration.

Distribution. Medroxyprogesterone acetate is approximately 90–95% protein-bound. The volume of distribution is 20±3 liters. Medroxyprogesterone acetate crosses the blood-brain and placental barriers (see section "Use in pregnancy or lactation"). Low levels of medroxyprogesterone acetate were detected in the breast milk of lactating women who received intramuscular injections of medroxyprogesterone acetate at a dose of 150 mg (see section "Use in pregnancy or lactation").

Biotransformation. Medroxyprogesterone acetate is metabolized in the liver.

Elimination. The elimination half-life after a single intramuscular dose is approximately 6 weeks. Medroxyprogesterone acetate is primarily excreted in feces via biliary secretion. Approximately 30% of the intramuscularly administered dose is excreted in urine within 4 days.

Clinical characteristics.

Indications.

Contraception.

Gynecology:

• treatment of endometriosis;
• treatment of vasomotor symptoms during menopause.

Oncology:

• recurrent and/or metastatic breast cancer;
• recurrent and/or metastatic endometrial cancer;
• recurrent and/or metastatic renal cancer;
• metastatic prostate cancer.

Contraindications.

Use of medroxyprogesterone acetate is contraindicated in patients with the following conditions:

• established or suspected pregnancy;
• undiagnosed vaginal bleeding;
• severe impairment of liver function;
• known hypersensitivity to the active substance (medroxyprogesterone acetate) or to any of the excipients;
• active thrombophlebitis, current or history of thromboembolic disorders, cerebrovascular disease.

Additional contraindication when the drug is used in gynecology:

• known or suspected malignant neoplasm of the breast;

Additional contraindication when the drug is used for contraception:

• known or suspected hormone-dependent malignant neoplasm of the breast or genital organs.

Interaction with other medicinal products and other forms of interaction.

Aminoglutethimide, when used concomitantly with high oral doses of medroxyprogesterone acetate, may significantly reduce serum concentrations of medroxyprogesterone acetate. Patients receiving high oral doses of medroxyprogesterone acetate should be advised of the potential for reduced efficacy when aminoglutethimide is used concomitantly.

Medroxyprogesterone acetate may potentiate or diminish the effects of coumarin derivatives. Medroxyprogesterone acetate is an antagonist of the anticoagulant activity of phenindione.

Medroxyprogesterone acetate is metabolized in vitro primarily via hydroxylation by CYP3A4. Specific interaction studies evaluating the clinical effects of CYP3A4 inducers or inhibitors on medroxyprogesterone acetate have not been conducted; therefore, the clinical effects of CYP3A4 inducers or inhibitors are unknown.

Special precautions for use.

In the event of unexpected vaginal bleeding during therapy with medroxyprogesterone acetate, the cause of bleeding should be determined.

The use of medroxyprogesterone acetate may lead to some degree of fluid retention; therefore, the drug should be used with caution in patients with concomitant conditions that may be exacerbated by such fluid retention.

Patients with a history of clinical depression should be carefully monitored during treatment with medroxyprogesterone acetate.

The use of medroxyprogesterone acetate may be associated with decreased glucose tolerance in some patients; therefore, careful monitoring of patients with diabetes mellitus is necessary during treatment.

When submitting samples of endometrial or endocervical tissue for examination, the laboratory personnel should be informed that the patient has been receiving medroxyprogesterone acetate.

The physician/laboratory personnel should be informed that the use of medroxyprogesterone acetate may lead to decreased levels of the following endocrine biomarkers:

• steroids in plasma/urine (e.g. cortisol, estrogen, pregnanediol, progesterone, testosterone);
• gonadotropic hormones in plasma/urine (e.g. luteinizing hormone and follicle-stimulating hormone);
• sex hormone-binding globulin.

The drug should not be re-administered following sudden partial or complete loss of vision, or sudden onset of proptosis, diplopia, or migraine until the patient has been examined. If, during examination, retinal vascular lesions or papilledema are detected, the drug should be discontinued.

Although it has not been established that medroxyprogesterone acetate causes thrombotic or thromboembolic complications, the drug is not recommended for patients with a history of venous thromboembolism. Treatment with medroxyprogesterone acetate should be discontinued if venous thromboembolism develops during therapy.

Contraception/Endometriosis.

Loss of bone mineral density.

Since bone mineral density loss may occur in women of any age receiving long-term treatment with Depo-Provera® (see section "Special precautions for use"), consideration should be given to performing a risk/benefit assessment, including evaluation of bone mineral density loss observed during pregnancy and/or breastfeeding.

However, it should be noted that recovery of fertility (ovulation) may be delayed for up to one year (see section "Special precautions for use").

Administration of medroxyprogesterone acetate injections reduces serum estrogen levels and is associated with statistically significant loss of bone mineral density due to the effect of estrogen deficiency on the bone remodeling system. With increasing duration of Depo-Provera® use, bone loss may be greater; however, after discontinuation of Depo-Provera®, bone mineral density increases along with ovarian estrogen production.

Particular concern exists regarding bone density loss during puberty and adolescence, which is a critical period for bone accretion. It is unknown whether the use of Depo-Provera® injections in younger women reduces peak bone mass and increases the risk of future fractures, for example, after menopause.

Studies evaluating the effect of depot medroxyprogesterone acetate injections on bone mineral density in adolescent girls have shown that its use was associated with a statistically significant decrease in bone density compared to baseline values. After discontinuation of Depo-Provera® in adolescents, recovery of bone mineral density to baseline levels takes 1.2 years for the lumbar spine, 4.6 years for the hip, and 4.6 years for the femoral neck (see section "Pharmacodynamics"). However, in some participants, bone mineral density did not fully recover to baseline levels during follow-up, and the long-term effect in this group is unknown.

Use of Depo-Provera® in adolescent girls is possible only after discussing other contraceptive methods with the patients and determining that other contraceptive methods are unsuitable or unacceptable.

A large observational study in predominantly adult women using contraceptives showed that Depo-Provera® injections do not affect fracture risk in women. Importantly, this study could not determine whether the use of Depo-Provera® injections affects the risk of fractures later in life (see section "Pharmacodynamics").

Changes in bone mineral density in adult women after 6 months of endometriosis treatment.

In two clinical studies involving 573 adult women with endometriosis, the effects of 6-month subcutaneous administration of medroxyprogesterone acetate versus 6-month leuprolide treatment on bone mineral density were compared. Patients were followed for an additional 12 months after completion of treatment.

The proportion of patients with a decrease in bone mineral density of 5% or more was statistically significantly higher in the leuprolide group compared to the subcutaneous medroxyprogesterone acetate group at each time point (see table below).

Proportion of patients with a decrease in bone mineral density of 5% or more from baseline after 6 months of subcutaneous medroxyprogesterone acetate or leuprolide treatment and 6 months after discontinuation of treatment (Studies 268 and 270, combined).

Bone mineral density indicator	Subcutaneous medroxyprogesterone acetate n/N* (%)	Leuprorelin n/N* (%)	p-value**
End of treatment (6 months of therapy)
Spine	12/208 (5.8 %)	85/229 (37.1 %)	<0.001
Total hip	1/207 (0.5 %)	25/227 (11.0 %)	<0.001
12-month visit (6 months off treatment)
Spine	8/166 (4.8 %)	32/178 (18.0 %)	<0.001
Total hip	3/166 (1.8 %)	25/178 (14.0 %)	<0.001

* n – number of patients with a decrease in bone mineral density of ≥ 5%; N – total number of patients.

** chi-square.

For women of all ages, the risks and benefits of treatment should be carefully weighed if they require use of the drug for more than two years. In particular, in the presence of significant lifestyle risk factors and/or medical risk factors that may lead to osteoporosis, women should consider alternative contraceptive methods before using Depo-Provera®:

• chronic alcohol consumption and/or smoking;
• chronic use of medications that may reduce bone mass, such as anticonvulsants or corticosteroids;
• low body mass index or eating disorders, such as anorexia nervosa or bulimia;
• previous fracture resulting from a fall from standing height;
• multiple cases of osteoporosis in family history.

For bone health, it is important for women of any age to receive adequate amounts of calcium and vitamin D (either through supplements or an appropriate diet).

Contraception.

In most women using medroxyprogesterone acetate injectable suspension, menstrual bleeding patterns become irregular (e.g., irregular or unpredictable bleeding/spotting, rarely heavy or prolonged bleeding). With continued use of medroxyprogesterone acetate injectable suspension, irregular bleeding occurs in fewer women over time, while amenorrhea becomes more common.

In long-term case-control observational studies, use of medroxyprogesterone acetate injectable suspension was associated with a slight increase or no increase in overall risk of developing breast cancer, and no increase in overall risk of developing ovarian, liver, or cervical cancer. A prolonged protective effect—reduced risk of endometrial cancer—has been observed.

Medroxyprogesterone acetate suspension for intramuscular injection provides prolonged contraceptive effect. The median time to conception after the last injection among those who became pregnant was 10 months, with a range of 4–31 months, and was independent of duration of use.

During treatment with medroxyprogesterone acetate, women tended to gain body weight.

If jaundice develops, re-administration of this medicinal product should be reconsidered.

Patients should be informed that medroxyprogesterone acetate suspension does not protect against sexually transmitted infections, including HIV (AIDS), but that Depo-Provera® is a sterile injection and, when used according to instructions, will not expose them to the risk of infection with sexually transmitted diseases. Measures to ensure safe sex, including correct use of condoms in all cases, reduce the risk of transmission of STIs, including HIV, through sexual contact.

The benefits and risks of different contraceptive methods should be individually assessed for each woman.

Depressed mood and depression are known adverse reactions associated with hormonal contraceptives (see section "Adverse Reactions**"**). Depression can be severe and is a known risk factor for suicidal behavior and suicide. Women should be advised to contact their physician promptly if mood changes or symptoms of depression occur after initiating treatment.

Gynecology.

Treatment of vasomotor symptoms during menopause / Counteracting endometrial effects of estrogen in menopausal women receiving estrogen therapy (hormone therapy)

Other doses of oral conjugated estrogens combined with medroxyprogesterone acetate and other combinations and dosage forms used in hormone therapy (HT) were not studied in the Women's Health Initiative (WHI) clinical trial (see section "Pharmacological Properties"), and in the absence of comparable data, such risks should be considered similar.

Breast cancer.

In several epidemiological studies, no overall increased risk of breast cancer was observed in women receiving depot progestogen injections compared to women not receiving them. However, an increased relative risk (e.g., 2.0 in one study) was observed in women who were currently receiving depot progestogen injections or had received them only a few years prior. Based on these data, it is not possible to conclude whether the increased frequency of breast cancer diagnosis in women currently receiving such treatment results from more intensive surveillance of these women, a biological effect of injectable progestogens, or a combination of these factors.

Cardiovascular disorders.

Estrogens, with or without progestins, should not be used for the prevention of cardiovascular diseases. In several randomized, prospective long-term studies (see section "Dosage and Administration"), combined estrogen/progestin regimens in postmenopausal women were associated with an increased risk of cardiovascular events such as myocardial infarction, ischemic heart disease, stroke, and venous thromboembolism.

• Coronary artery disease.

Randomized controlled trials do not demonstrate cardiovascular benefit from continuous combined use of conjugated estrogens and medroxyprogesterone acetate. Two large clinical trials—the Women's Health Initiative (WHI) study on conjugated estrogens and medroxyprogesterone acetate, and the Heart and Estrogen/progestin Replacement Study (HERS) (see section "Pharmacodynamics")—demonstrated a possible increased risk of cardiovascular disease during the first year of treatment and no overall benefit from this therapy. In the WHI study of conjugated estrogens and medroxyprogesterone acetate, women receiving conjugated estrogens/medroxyprogesterone acetate had an increased risk of ischemic heart disease complications (defined as non-fatal myocardial infarction and ischemic heart disease-related death) compared to women receiving placebo (37 vs. 30 per 10,000 patient-years). An increased risk of venous thromboembolism was observed during the first year and persisted throughout the observation period (see section "Dosage and Administration").

• Stroke.

In the WHI study of conjugated estrogens and medroxyprogesterone acetate, women receiving conjugated estrogens/medroxyprogesterone acetate had an increased risk of stroke compared to women receiving placebo (29 vs. 21 per 10,000 patient-years). The increased risk was observed during the first year and persisted throughout the observation period (see section "Dosage and Administration").

• Venous thromboembolism/pulmonary embolism.

Hormone therapy is associated with an increased relative risk of venous thromboembolism, i.e., deep vein thrombosis or pulmonary embolism. In the WHI study of conjugated estrogens and medroxyprogesterone acetate, women receiving conjugated estrogens/medroxyprogesterone acetate experienced twice the rate of venous thromboembolism, including deep vein thrombosis and pulmonary embolism, compared to women receiving placebo. The increased risk was observed during the first year and persisted throughout the observation period (see section "Special Warnings and Precautions for Use").

Dementia.

The Memory Study within the Women's Health Initiative (WHIMS) (see section "Pharmacological Properties"), a secondary study of the WHI trial on conjugated estrogens and medroxyprogesterone acetate, demonstrated an increased risk of probable dementia in postmenopausal women aged 65 years and older. Furthermore, use of conjugated estrogens/medroxyprogesterone acetate did not prevent mild cognitive impairment in these women. Hormone therapy is not recommended for the prevention of dementia or mild cognitive impairment in women aged 65 years and older.

Ovarian cancer.

In some epidemiological studies, current use of estrogens alone or in combination with progestins by postmenopausal women for five years or more has been associated with an increased risk of ovarian cancer. Previous use of estrogens alone or in combination with progestins was not associated with an increased risk of ovarian cancer. Other studies have not demonstrated a significant association between these factors. In the WHI study of conjugated estrogens and medroxyprogesterone acetate, estrogen combined with progestin was associated with an increased risk of ovarian cancer, but this risk was not statistically significant. In one study, women receiving hormone replacement therapy had an increased risk of fatal ovarian cancer.

Recommendations for history taking and medical examination.

A complete medical and family history should be taken before initiating any hormone therapy. During pre-treatment and periodic medical examinations, particular attention should be paid to blood pressure measurement, breast, abdominal, and pelvic organ examination (including cervical cytology).

After administration of a single or multiple doses of medroxyprogesterone acetate as injections, prolonged anovulation with amenorrhea and/or irregular menstruation may occur.

Oncology.

Medroxyprogesterone acetate may cause Cushingoid symptoms.

In some patients receiving medroxyprogesterone acetate, adrenal gland function may be suppressed. Medroxyprogesterone acetate may reduce blood levels of adrenocorticotropic hormone and hydrocortisone.

The physician/laboratory personnel should be informed that, in addition to endocrine biomarkers listed in the section "Special Warnings and Precautions for Use," use of medroxyprogesterone acetate for oncological indications may also cause partial adrenal insufficiency (reduced response of the hypothalamic-pituitary-adrenal system) during a metyrapone test. Therefore, assessment of adrenal cortex response to adrenocorticotropic hormone should be performed before administering metyrapone.

After administration of a single or multiple doses of medroxyprogesterone acetate as injections, prolonged anovulation with amenorrhea and/or irregular menstruation may occur.

Decreased bone mineral density.

Studies on the effect on bone mineral density of oral forms of medroxyprogesterone acetate or high-dose parenteral forms of medroxyprogesterone acetate (e.g., when used for oncological indications) have not been conducted. Assessment of bone mineral density may be appropriate for some patients receiving long-term medroxyprogesterone acetate (see above "Loss of bone mineral density").

Information on excipients.

Each 1 mL of Depo-Provera® contains less than 1 mmol of sodium (23 mg), i.e., essentially a sodium-free preparation.

Depo-Provera® contains the excipients propylparaben and methylparaben, which may cause mild skin, eye, and mucous membrane irritation.

Use during pregnancy or breastfeeding.

Medroxyprogesterone acetate is contraindicated in pregnant women.

Some reports suggest that under certain conditions, there may be an association between in utero exposure to progestogens during the first trimester of pregnancy and fetal genital abnormalities.

Infants born from unintended pregnancies occurring 1–2 months after medroxyprogesterone acetate injection may have an increased risk of low birth weight, which in turn is associated with an increased risk of neonatal mortality. This risk is low, as pregnancy during medroxyprogesterone acetate use is rare. Complete information regarding other dosage forms of medroxyprogesterone acetate is lacking.

If a patient becomes pregnant while using this medicinal product, she should be informed of the potential risk to the fetus.

Use during breastfeeding.

Medroxyprogesterone acetate and its metabolites are excreted in breast milk. There is no evidence that this poses any risk to the infant.

Ability to affect reaction speed when driving or operating machinery.

No systematic study of the effect of medroxyprogesterone acetate on the ability to drive or operate machinery has been conducted.

Method of Administration and Dosage

Before administration, the injection suspension must be shaken well.

Contraception

Immediately before use, the suspension for intramuscular injection should be shaken vigorously to ensure administration of a homogeneous suspension.

• Intramuscular administration

The recommended dose of the injectable suspension is 150 mg every 3 months (12–13 weeks). The drug is administered intramuscularly into the gluteal or deltoid muscle. The suspension for intramuscular injection is not intended for subcutaneous administration.

• First injection

The initial intramuscular injection should be administered within the first 5 days of the onset of a normal menstrual cycle, within the first 5 days after childbirth if the patient is not breastfeeding; if the patient is breastfeeding, the injection should be given 6 weeks after childbirth or later.

• Second and subsequent injections

If the interval between intramuscular injections exceeds 13 weeks, pregnancy should be ruled out before administering the next intramuscular injection.

• Transition from other contraceptive methods

When switching from other contraceptive methods, the intramuscular injection should be administered in such a way as to ensure continuous contraceptive coverage based on the mechanism of action of both methods (e.g., patients switching from oral contraceptives should receive the first injection within 7 days after taking the last active tablet).

Gynecology

In combined estrogen/progestin therapy for the treatment of postmenopausal women, the drug should be used at the lowest effective dose and for the shortest duration consistent with the treatment goals and individual patient's health risks. The need for continued therapy should be periodically evaluated.

Regular examinations, tailored in frequency and type to each individual woman, are recommended.

Adding progestin to the treatment regimen is not recommended for women without an intact uterus, except in cases where endometriosis has been previously diagnosed.

Endometriosis

The drug is administered intramuscularly at a dose of 50 mg once weekly or 100 mg every 2 weeks for at least 6 months.

Vasomotor symptoms during menopause

Injections of the drug are administered intramuscularly at a dose of 150 mg every 12 weeks.

Oncology

• Recurrent and/or metastatic breast cancer

The initial dose of medroxyprogesterone acetate is 500–1000 mg daily by intramuscular injection for 28 days. After this period, patients should be switched to a maintenance regimen of 500 mg twice weekly as long as a therapeutic response is observed.

• Recurrent and/or metastatic endometrial or renal cancer

The recommended initial dose is 400–1000 mg weekly by intramuscular injection. If improvement is observed within several weeks or months and the disease stabilizes, maintenance of improvement may be achieved with a lower dose of 400 mg once monthly.

• Metastatic prostate cancer

The initial dose is 500 mg intramuscularly twice weekly for 3 months. The maintenance dose is 500 mg once weekly.

Hepatic impairment

No clinical studies have been conducted on the effect of liver disease on the pharmacokinetics of medroxyprogesterone acetate. However, it should be noted that medroxyprogesterone acetate is almost entirely eliminated by the liver, and steroid hormones may be poorly metabolized in patients with severe hepatic impairment.

Renal impairment

No clinical studies have been conducted to evaluate the effect of kidney disease on the pharmacokinetics of medroxyprogesterone acetate. However, since medroxyprogesterone acetate is almost entirely eliminated by the liver, dosage adjustment is not required in patients with renal impairment.

Pediatric population
Depo-Provera® is not indicated for use before the onset of menstruation (see section "Indications"). Data from studies in adolescent girls (12–18 years of age) are available (see sections "Special precautions for use" and "Pharmacodynamic properties"). Except for the potential impact on bone mineral density, the safety and efficacy of Depo-Provera® in postmenarchal adolescent girls are expected to be the same as in adult women.

Overdose

Treatment of overdose should be symptomatic and supportive.

Adverse Reactions

Very common: ≥ 1/10; common: from ≥1/100 to < 1/10; uncommon: from ≥1/1000 to < 1/100; rare: from ≥1/10000 to < 1/1000; frequency not known (cannot be estimated from available data).

Contraception

Below is a list of adverse reactions observed in clinical trials involving over 4200 women who used DEPO-PROVERA® for contraception for up to 7 years. Reactions are listed by frequency of occurrence. The most frequently reported adverse reactions (> 5%) were: weight gain (69%), weight loss (25%), headache (16%), nervousness (11%), abdominal pain or discomfort (11%), dizziness (6%), and decreased libido (6%).

Benign, malignant and unspecified neoplasms (including cysts and polyps)
Rare: breast cancer.

Blood and lymphatic system disorders
Rare: anaemia, blood disorders.

Immune system disorders
Uncommon: hypersensitivity to the drug.
Rare: anaphylactic reaction, anaphylactoid reaction, angioedema.

Metabolism and nutrition disorders
Uncommon: increased appetite, decreased appetite.

Endocrine disorders
Rare: prolonged anovulation.

Psychiatric disorders
Very common: nervousness.
Common: depression, decreased libido.
Uncommon: insomnia.
Rare: anorgasmia.

Nervous system disorders
Very common: headache.
Common: dizziness.
Uncommon: seizures, somnolence.
Rare: migraine, paralysis, syncope.

Vascular disorders
Uncommon: hot flushes.
Rare: embolism and thrombosis.

Respiratory, thoracic and mediastinal disorders
Uncommon: dyspnoea.
Rare: pulmonary artery embolism.

Gastrointestinal disorders
Very common: abdominal pain, abdominal discomfort.
Common: nausea, abdominal distension.
Rare: rectal bleeding.

Hepatobiliary disorders
Uncommon: liver function abnormalities.
Rare: jaundice.

Skin and subcutaneous tissue disorders
Common: alopecia, acne, rash.
Uncommon: hirsutism, urticaria, pruritus, chloasma.
Rare: acquired lipodystrophy*, scleroderma, dermatitis, ecchymosis, striae.

Musculoskeletal and connective tissue disorders
Common: back pain, limb pain.
Rare: arthralgia, muscle spasms.

Reproductive system and breast disorders
Common: vaginal discharge, breast tenderness, urinary and genital tract infections.
Uncommon: abnormal uterine bleeding (irregular, heavy, light, spotting), galactorrhea, pelvic pain, dyspareunia, lactation suppression.
Rare: vulvovaginal dryness, ovarian cyst, premenstrual syndrome, vaginitis, amenorrhoea, mastalgia, bloody nipple discharge, failure of return of reproductive function, pregnancy-like symptoms.

General disorders and administration site reactions
Common: fluid retention, asthenia.
Rare: fever, increased fatigue, injection site reactions*, persistence of atrophy/depression/indentation at injection site*, nodules/lumps at injection site*, pain/painfulness at injection site*.

Investigations
Very common: weight gain, weight loss.
Rare: decreased bone mineral density, decreased glucose tolerance.

*Adverse reaction identified during the post-marketing period.

Gynaecology

Below is a list of adverse reactions observed during phase 3 clinical trials evaluating the efficacy and safety of DEPO-PROVERA® in gynaecology. The most frequently reported adverse reactions (> 5%) were: abnormal uterine bleeding (19%), headache (12%), and nausea (10%).

Immune system disorders
Common: hypersensitivity to the drug.
Frequency not known: anaphylactic reaction, anaphylactoid reaction, angioedema.

Endocrine disorders
Frequency not known: prolonged anovulation.

Psychiatric disorders
Common: depression, insomnia, nervousness.

Nervous system disorders
Very common: headache.
Common: dizziness.
Frequency not known: somnolence.

Vascular disorders
Frequency not known: embolism and thrombosis.

Gastrointestinal disorders
Very common: nausea.

Hepatobiliary disorders
Frequency not known: jaundice, cholestatic jaundice.

Skin and subcutaneous tissue disorders
Common: alopecia, acne, urticaria, pruritus.
Uncommon: hirsutism.
Frequency not known: acquired lipodystrophy*, rash.

Reproductive system and breast disorders
Very common: abnormal uterine bleeding (irregular, heavy, light, spotting).
Common: cervical discharge, mastalgia, breast tenderness.
Uncommon: galactorrhea.
Frequency not known: amenorrhoea, cervical erosion.

General disorders and administration site reactions
Common: fever, fatigue, injection site reactions*, persistence of atrophy/depression/indentation at injection site*.
Uncommon: oedema, fluid retention, nodules/lumps at injection site*, pain/painfulness at injection site*.

Investigations
Common: weight gain.
Frequency not known: decreased glucose tolerance, weight loss.

*Adverse reaction identified during the post-marketing period.

Oncology

Below is a list of adverse reactions observed during 4 pivotal trials evaluating the efficacy and safety of DEPO-PROVERA® for oncological indications in 1337 women.

Immune system disorders
Uncommon: angioedema.
Rare: hypersensitivity to the drug.
Frequency not known: anaphylactic reaction, anaphylactoid reaction.

Endocrine disorders
Uncommon: corticoid-like effects.
Frequency not known: prolonged anovulation.

Metabolism and nutrition disorders
Common: weight change.
Uncommon: worsening of diabetes mellitus, hypercalcaemia.

Psychiatric disorders
Common: insomnia.
Uncommon: depression, euphoria, libido changes.
Rare: nervousness.
Frequency not known: confusion.

Nervous system disorders
Common: headache, dizziness, tremor.
Rare: cerebral infarction, somnolence.
Frequency not known: difficulty concentrating, adrenocorticoid-like effects.

Eye disorders
Frequency not known: retinal vascular embolism and thrombosis, diabetic cataract, visual disturbances.

Cardiac disorders
Uncommon: congestive heart failure.
Rare: myocardial infarction.
Frequency not known: tachycardia, palpitations.

Vascular disorders
Uncommon: thrombophlebitis.
Rare: embolism and thrombosis.

Respiratory, thoracic and mediastinal disorders
Uncommon: pulmonary artery embolism.

Gastrointestinal disorders
Common: nausea, constipation, vomiting.
Uncommon: diarrhoea, dry mouth.

Hepatic disorders
Rare: jaundice.

Skin and subcutaneous tissue disorders
Common: hyperhidrosis.
Uncommon: acne, hirsutism.
Rare: alopecia, rash.
Frequency not known: acquired lipodystrophy*, urticaria, pruritus.

Musculoskeletal and connective tissue disorders
Rare: muscle spasms.

Renal and urinary disorders
Frequency not known: glucosuria.

Reproductive system and breast disorders
Common: erectile dysfunction.
Uncommon: abnormal uterine bleeding (irregular, heavy, light, spotting), mastalgia.
Frequency not known: amenorrhoea, cervical erosion, cervical discharge, galactorrhea.

General disorders and administration site conditions
Common: oedema/fluid retention, increased fatigue, injection site reactions*.
Uncommon: pain/painfulness at injection site*.
Rare: malaise, increased body temperature.
Frequency not known: persistence of atrophy/depression/indentation at injection site*, nodules/lumps at injection site*.

Investigations
Rare: decreased glucose tolerance, increased blood pressure.
Frequency not known: abnormal liver function test results, increased white blood cell and platelet counts.

*Adverse reaction identified during the post-marketing period.

Post-marketing period

Intramuscular administration

Rare cases of osteoporosis, including osteoporotic fractures, have been reported in patients receiving intramuscular DEPO-PROVERA® during the post-marketing period.

Reporting suspected adverse reactions

Reporting suspected adverse reactions after a medicinal product is authorised is important. It allows continued monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals and patients, or their legal representatives, should report any suspected adverse reactions and lack of efficacy via the Automated Pharmacovigilance Information System at: https://aisf.dec.gov.ua.

Shelf life: 5 years.

Storage conditions: Store at temperatures not exceeding 25 °C in a place inaccessible to children. Do not freeze. Do not refrigerate. Store the vial in an upright position.

Incompatibilities: Unknown.

Packaging: 3.3 ml of suspension in a glass vial, 1 vial per cardboard box.

Prescription status: Prescription only.

Manufacturer:

Pfizer Manufacturing Belgium NV / Pfizer Manufacturing Belgium NV.

Manufacturer's address and location of operations:

Rijksweg 12, Puurs-Sint-Amands, 2870, Belgium / Rijksweg 12, Puurs-Sint-Amands, 2870, Belgium.