Depo-provera®

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

Composition:

Active substance: medroxyprogesterone;

1 ml of suspension contains 150 mg of medroxyprogesterone acetate;

Excipients: polysorbate 80, methylparahydroxybenzoate (E 218), propylparahydroxybenzoate (E 216), macrogol 3350, sodium chloride, water for injections.

Pharmaceutical form. Injection suspension.

Main physicochemical characteristics: white-colored suspension.

Pharmacotherapeutic group. Systemic hormonal contraceptives. Gestagens. ATC code G03A C06.

Pharmacological properties.

Pharmacodynamics.

Medroxyprogesterone acetate exerts antiestrogenic, antiandrogenic, and antigonadotropic effects.

Changes in bone mineral density in adult women

A study comparing changes in bone mineral density in women receiving subcutaneous (SC) depot medroxyprogesterone acetate (DMPA) and women receiving intramuscular (IM) injections of medroxyprogesterone acetate demonstrated similar levels of bone mineral density loss in the two groups after two years of treatment. The mean percentage changes in bone mineral density in the SC DMPA group are shown in Table 1.

Table 1. Mean percentage change (with 95% confidence intervals) in bone mineral density in adult women using DMPA, by skeletal site, compared to baseline levels

CI – confidence interval.

In another controlled clinical study involving adult women who received intramuscular (IM) DMPA injections for up to 5 years, a mean decrease in bone mineral density (BMD) of the spine and femur by 5–6% 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 treatment 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 BMD of the total femur and femoral neck were similar. Additional information is presented in Table 2.

After discontinuation of IM DMPA injections, BMD increased compared to 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 IM DMPA (depot medroxyprogesterone acetate intramuscular injections) for 5 years were followed for an additional 2 years after stopping IM DMPA. Bone mineral density (BMD) values increased toward baseline levels during the 2-year post-treatment period. Two years after stopping 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 (with 95% confidence intervals) 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 2 years after discontinuation or 7 years of observation (control group)

* The treatment group consisted of women who used intramuscular (IM) 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 used intramuscular (IM) 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 throughout the 7-year period.

SD – standard deviation.

CI – confidence interval.

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

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

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

BMD – bone mineral density.
CI – confidence interval.

Results of post-treatment 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 spine, total hip, and femoral neck, respectively. After discontinuation of intramuscular DMPA injections, mean BMD values returned 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 BMD deficits at the total hip site after 240 weeks. Longer duration of treatment and smoking were associated with slower recovery (see Table 4).

Table 4. Mean percent change (with 95% confidence intervals) in bone mineral density compared to baseline in adolescent girls after discontinuation of DMPA

SE – standard error.

CI – confidence interval.

Relationship 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 provided data from 6–24 months prior to the first DMPA administration and an average follow-up period of 5.5 years after the first DMPA injection. Overall, the risk of fractures was higher in the DMPA cohort compared to subjects who did not use the drug, both before and after DMPA use. When comparing fracture risk after the first injection to the period before the first injection, the relative risk was 1.01 (95% CI: 0.92, 1.11), indicating that DMPA did not increase the risk of bone fractures.

The maximum follow-up period in this study was 15 years. Therefore, it is not possible to determine potential effects of DMPA that might occur more than 15 years after administration. It is important to note that this study does not allow determination of whether DMPA affects the incidence of fractures at a later age, i.e., after menopause.

Pharmacokinetics.

Parenteral medroxyprogesterone acetate is a long-acting progestational steroid. The prolonged effect is due to slow absorption of the drug from the injection site. Immediately after injection of 150 mg/mL medroxyprogesterone acetate, plasma levels were 1.7 ± 0.3 nmol/L. After 2 weeks, levels reached 6.8 ± 0.8 nmol/L. Concentrations returned to baseline levels by the end of 12 weeks. At low doses, medroxyprogesterone acetate plasma levels are considered directly dependent on the administered dose. Accumulation in blood serum over time has not been demonstrated. Medroxyprogesterone acetate is excreted in feces or urine. The plasma elimination half-life is approximately 6 weeks after a single intramuscular injection. At least 11 metabolites have been reported. All are excreted in urine, some (but not all) in conjugated form.

Clinical characteristics.

Indications.

Progestogen: for contraception.

Depo-Provera® is indicated for long-term contraception in women. Each injection prevents ovulation and provides contraception for at least 12 weeks (+/- 5 days). However, it should be noted that the return of reproductive function (ovulation) may be delayed for up to one year (see section "Special precautions").

Depo-Provera® is a suitable method for use in women who have been adequately informed about the possibility of menstrual disturbances and the potential delay in the return of full fertility.

Depo-Provera® may also be used for short-term contraception in the following cases:

1. for female partners of men who have undergone vasectomy, for protection until vasectomy becomes effective;
2. for women immunized against rubella, to prevent pregnancy during the period of viral activity;
3. for women awaiting sterilization.

Children (12–18 years)

Depo-Provera® is not indicated for use before the onset of menstruation.

The drug may be used in adolescents, but only if other contraceptive methods are considered unsuitable or unacceptable after discussion with the patient.

Available data on use in adolescent girls (12–18 years) (see section "Special precautions"). Except for the potential loss of bone mineral density, the safety and efficacy of Depo-Provera® in adolescent girls after menarche are expected to be the same as in adult women.

Contraindications.

Depo-Provera® is contraindicated in patients with known hypersensitivity to medroxyprogesterone acetate or to any of the other components of the drug.

The use of the drug as a contraceptive at the dosage indicated below is contraindicated in the presence of confirmed or suspected hormone-dependent malignant tumors of the breast or genital organs.

Depo-Provera® is contraindicated in patients with current or past history of severe liver disease in which liver function tests have not returned to normal.

When used as monotherapy or in combination with estrogens, Depo-Provera® should not be administered to patients with abnormal uterine bleeding until a diagnosis has been established and malignancy of the genital tract has been excluded.

Interaction with other medicinal products and other forms of interaction.

Concomitant use of aminoglutethimide with Depo-Provera® may significantly reduce the bioavailability of the latter.

Cases of interaction with other medicinal products have been rarely reported (including oral anticoagulants), but the reasons for such interactions have not been established. The possibility of interactions should be considered in patients who are concurrently receiving other medicinal products.

The clearance of medroxyprogesterone acetate is approximately equal to hepatic blood flow. Because of this, it is unlikely that drugs which induce hepatic enzymes will significantly affect the kinetics of medroxyprogesterone acetate. Therefore, dose adjustment is not recommended in patients taking drugs known to affect hepatic metabolizing enzymes.

Medroxyprogesterone acetate is primarily metabolized in vitro by hydroxylation via CYP3A4. Specific drug interaction studies on the effect of CYP3A4 inducers or inhibitors on medroxyprogesterone acetate have not been conducted, and thus the clinical effect of CYP3A4 inducers or inhibitors is unknown.

Special precautions for use

Examination of women prior to initiating hormonal contraceptives (and at regular intervals thereafter) should include a review of personal and family medical history for each woman. A medical examination should be performed based on this information, as well as considering contraindications (section "Contraindications") and warnings (section "Special precautions for use") related to this product. The frequency and nature of these examinations should be based on established guidelines and adapted to the individual needs of each woman, but should include blood pressure measurement and, if the physician deems appropriate, examination of the breasts, abdominal and pelvic organs, including a cervical smear.

Bone mineral density loss

Administration of intramuscular DMPA reduces serum estrogen levels and is associated with significant loss of bone mineral density due to the well-known effect of estrogen deficiency on bone remodeling. Bone mass loss increases with prolonged use of the drug; however, after discontinuation of the drug, bone mineral density appears to increase, along with enhanced ovarian estrogen production.

Bone mineral density loss is of particular concern for adolescents and younger women during the critical period of bone mass accrual. It is unknown whether intramuscular DMPA use reduces peak bone mass in younger women or increases the risk of fractures later in life, such as after menopause.

Studies evaluating the effect of intramuscular DMPA on bone mineral density in adolescent girls have shown that its use was associated with a statistically significant decrease in bone mineral density compared to baseline. After discontinuation of intramuscular DMPA in adolescent girls, the return of mean BMD values to baseline levels required 1.2 years for the lumbar spine, 4.6 years for the total hip, and at least 4.6 years for the femoral neck. However, in some study subjects, BMD values did not fully return to baseline levels during follow-up, and the long-term outcome in this group is unknown. Depo-Provera® may be used in adolescents, but only if other contraceptive methods are considered unsuitable or unacceptable after discussion with the patient.

A large observational study of predominantly adult women using contraceptives showed that intramuscular DMPA use did not increase the risk of bone fractures. It is important to note that this study does not allow determination of whether DMPA affects fracture rates at older ages (see section "Pharmacodynamics").

For women of all age groups, the risks and benefits of treatment should be carefully considered if use of the drug is planned for longer 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®.

Significant risk factors for osteoporosis include:

• alcohol abuse 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;
• family history of osteoporosis.

For additional information on changes in bone mineral density in both adults and adolescent girls, see section "Pharmacodynamics". For bone health, it is important for women of all ages to receive adequate calcium and vitamin D (either through supplements or an appropriate diet).

Irregular menstrual bleeding

The use of Depo-Provera® typically causes disruption of the normal menstrual cycle. Bleeding patterns include amenorrhea (experienced by up to 30% of women within the first 3 months, increasing to 55% and 68% at months 12 and 24, respectively); irregular bleeding and spotting; episodes of prolonged bleeding (more than 10 days) (experienced by up to 33% of women during the first 3 months of use, decreasing to 12% at month 12). In isolated cases, severe prolonged bleeding may occur. Evidence suggests that prolonged or severe bleeding requiring treatment may occur in 0.5–4 cases per 100 patient-years of use. If abnormal bleeding persists or becomes severe, appropriate evaluation should be performed to rule out pathology, and treatment initiated if necessary. Excessive or prolonged bleeding may be managed by concomitant administration of a low dose of estrogen (30 micrograms) with oral contraceptives or estrogen replacement therapy, such as conjugated estrogens (0.625–1.25 mg daily). If needed, estrogen therapy may be repeated for 1–2 additional cycles. Long-term concomitant use of estrogen is not recommended.

Recovery of reproductive function

There is no evidence that Depo-Provera® causes permanent infertility. Pregnancy has occurred as early as 14 weeks after the previous injection; however, in clinical studies, the average time to return of ovulation was 5.3 months after the last injection. Women should be informed that there may be a delay in full recovery of reproductive function after use of this product, regardless of duration of use, but 83% of women can expect conception within 12 months after the first "missed" injection (i.e., 15 months after the last administered injection). The average time to conception after the last injection was 10 months (ranging from 4 to 31 months).

Risk of cancer

Long-term observational data from controlled use of Depo-Provera® have shown either a slight or no overall increased risk of breast cancer and have not shown an overall increased risk of ovarian, liver, or cervical cancer; however, these observations have demonstrated a long-term protective effect, consisting of a reduced risk of endometrial cancer in the population of patients using the drug.

Breast cancer is rare in women under the age of 40, regardless of whether they use hormonal contraceptives or not.

Results of some epidemiological studies suggest a small difference in disease risk between women who have never used this contraceptive and those who are currently or recently used it. Any increased risk for patients who are currently or recently using medroxyprogesterone acetate is small compared to the overall risk of developing breast cancer, especially among younger women (see below), and the elevated risk gradually disappears within 10 years after the last dose of the drug. Duration of use is not considered significant.

Possible number of additional cases of breast cancer diagnosed during the 10-year period following discontinuation of progesterogen injections*

* Based on 5 years of use

Meningioma

Cases of meningioma have been reported following long-term use of progestogens, including medroxyprogesterone acetate. If meningioma is diagnosed, use of the medicinal product Depo-Provera® should be discontinued. Depo-Provera® should be prescribed with caution in patients with a history of meningioma.

Weight gain

There is a tendency for weight gain in women during therapy with Depo-Provera®. Studies indicate that during the first 1–2 years of use, average weight gain was 5–8 pounds (approximately 2–4 kg). In women after 4–6 years of therapy, average weight gain was 14–16.5 pounds (approximately 6–7.5 kg). Evidence suggests that weight gain results from increased fat tissue mass and is not secondary to an anabolic effect or fluid retention.

Anaphylaxis

Reports of anaphylactic reactions (anaphylactic reactions, anaphylactic shock, anaphylactoid reactions) have been received.

Thromboembolic disorders

If pulmonary embolism, cerebrovascular disease, or retinal thrombosis occurs in patients during treatment with Depo-Provera®, the drug should not be re-administered.

Psychiatric disorders

Patients with a history of endogenous depression should be closely monitored. Some patients during therapy with Depo-Provera® may experience premenstrual-type depression.

Depressed mood and depression are well-known side effects of hormonal contraceptives (see section "Adverse reactions"). Depression can become severe and is a known risk factor for suicidal behavior and suicide. Women should be advised to consult their physician if mood changes or symptoms of depression occur, including soon after initiation of treatment.

Abscess formation

As with any intramuscular injection, especially if performed incorrectly, there is a risk of abscess formation at the injection site, which may require medical and/or surgical intervention.

Precautions

The presence or development of the following conditions requires special attention and appropriate investigations: migraine or unusual severe headache, acute visual disturbances of any kind, pathological changes in liver function or hormonal balance.

Patients with thromboembolic disease or coronary artery disease should be carefully evaluated before administration of Depo-Provera®.

Reduced glucose tolerance may occur in some patients during treatment with progestogens. The mechanism of this reduction is not well understood. Therefore, careful monitoring is required in patients with diabetes mellitus during progestogen therapy.

Isolated cases of thromboembolism have been reported during use of Depo-Provera®, but a causal relationship has not been established.

Studies on the effect of medroxyprogesterone acetate on lipid metabolism have not shown a clear interaction. During studies, both increases and decreases in total cholesterol, triglycerides, and low-density lipoprotein cholesterol (LDL-C) levels were observed.

Use of Depo-Provera® is associated with a 15–20% reduction in serum high-density lipoprotein cholesterol (HDL-C) levels, which may protect women from cardiovascular disorders. The clinical significance of this observation is unknown. The potential increased risk of ischemic heart disease should be considered before initiating treatment.

Physicians should carefully consider the use of Depo-Provera® in patients with recent trophoblastic disease until human chorionic gonadotropin levels have returned to normal.

Physicians should inform pathologists about the patient's use of Depo-Provera® when endometrial or endocervical tissue is submitted for examination.

Use of Depo-Provera® may affect the results of certain laboratory tests, including gonadotropin levels (decreased), plasma progesterone levels (decreased), urinary pregnanediol levels (decreased), plasma estrogen levels (decreased), plasma cortisol levels (decreased), glucose tolerance test, metyrapone test, liver function tests (may be elevated), thyroid function tests (protein-bound iodine levels may be increased and T3 uptake may be decreased). Coagulation parameters for prothrombin (Factor II) and Factors VII, VIII, IX, and X may increase.

Since bone mineral density loss may occur in women of any age receiving long-term injections of Depo-Provera® (see section "Special precautions"), the risk/benefit ratio should be considered when prescribing this medicinal product, taking into account the reduction in bone mineral density that may occur during pregnancy and/or breastfeeding.

It is very important to provide potential patients with adequate explanations regarding the long-acting nature of the drug, possible adverse effects, and the inability to immediately reverse the effects of each injection, and to make every effort to ensure that each patient receives the necessary information to fully understand these explanations.

Women should be informed that Depo-Provera® does not protect against sexually transmitted infections (STIs), including HIV infection (AIDS). 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. If any of the mentioned diseases or risk factors are present, the benefits of using Depo-Provera® should be weighed against possible risks for each woman and discussed with the patient before initiating treatment. If any of these conditions or risk factors worsen, exacerbate, or develop, the woman should consult her physician. The physician should decide whether to discontinue Depo-Provera®.

Information on excipients

This medicinal product contains less than 1 mmol (23 mg)/dose of sodium, i.e., essentially sodium-free.

The medicinal product contains methylparahydroxybenzoate (E 218) and propylparahydroxybenzoate (E 216), which may cause allergic reactions (possibly delayed), and in rare cases bronchospasm.

Use during pregnancy or breastfeeding

Fertility

Depo-Provera® is indicated for prevention of pregnancy.

A delay in return to fertility (ability to conceive) may occur after discontinuation of Depo-Provera® (see section "Special precautions").

Pregnancy

Depo-Provera® should not be used during pregnancy, either for diagnosis or treatment. Depo-Provera® is contraindicated in pregnancy.

Physicians must test patients for pregnancy before administering the first injection of Depo-Provera® and also verify whether any subsequent injection has been delayed beyond 89 days (12 weeks and 5 days).

Children born following accidental pregnancies occurring 1–2 months after Depo-Provera® injection had a higher risk of low birth weight, which in turn is associated with a higher risk of neonatal mortality. The absolute risk is low because such pregnancies are rare.

In children exposed to medroxyprogesterone acetate in utero and followed up to adolescence, no adverse effects on health have been observed, including on physical, intellectual, sexual, or social development.

Lactation

Medroxyprogesterone acetate and/or its metabolites pass into breast milk. Studies have been conducted on infants exposed to medroxyprogesterone acetate during breastfeeding, assessing effects on development and behavior up to puberty. No adverse reactions were observed. However, due to limited data on the effects of medroxyprogesterone acetate on infants breastfed under six weeks of age, Depo-Provera® should not be administered earlier than six weeks after delivery, when the infant's enzyme system is more developed.

Ability to affect reaction speed when driving or operating machinery

Use of Depo-Provera® may cause headache and dizziness. If these effects occur, patients should be advised to avoid driving or operating machinery.

Dosage and Administration.

To ensure that the administered dose is a homogeneous suspension of Depo-Provera®, the injectable suspension should be shaken vigorously immediately before administration.

Doses should be administered by deep intramuscular injection. It is essential to confirm that the depot injection is delivered into muscle tissue, preferably into the gluteus maximus, although other muscles such as the deltoid may also be used.

The injection site should be cleansed prior to administration using standard procedures.

Adults

First injection: To ensure contraceptive efficacy during the first cycle of use, administer 150 mg of the drug intramuscularly within the first 5 days of a normal menstrual cycle. If the injection is administered according to these instructions, no additional contraceptive methods are required.

Postpartum: To ensure that the patient is not pregnant at the time of first administration, the injection should be given within 5 days postpartum if the woman is not breastfeeding.

Data indicate that women using Depo-Provera® in the immediate postpartum period may experience prolonged and severe bleeding. For this reason, the drug should be used with caution during the postpartum period. Women who choose to initiate the drug immediately after childbirth or after pregnancy termination should be informed about the increased risk of severe or prolonged bleeding. Clinicians should be reminded that ovulation may occur as early as 4 weeks postpartum in non-breastfeeding women.

If the woman is breastfeeding postpartum, the first injection should be administered no earlier than 6 weeks after childbirth, when the newborn's enzyme system is more fully developed. Subsequent injections should be administered at 12-week intervals.

Subsequent doses: Should be administered at 12-week intervals. However, if the injection is given no later than 5 days beyond this interval, additional contraceptive measures (e.g., barrier methods) are not required. (Note: For partners of men who have undergone vasectomy, a second 150 mg intramuscular injection may be required 12 weeks after the first. This may be necessary for a small number of patients whose partners have not reached zero sperm count.) If, for any reason, the time since the previous injection exceeds 89 days (12 weeks and 5 days), pregnancy should be ruled out prior to the next injection, and the patient should use additional contraceptive measures (e.g., barrier methods) for 14 days following the subsequent injection.

Elderly patients: Not applicable.

Transition from other contraceptive methods

Depo-Provera® should be administered in a way that ensures continuous contraceptive protection. Consideration should be given to the mechanism of action of other contraceptive methods (e.g., for patients switching from oral contraceptives, the first injection should be administered within 7 days after taking the last active tablet).

Hepatic impairment

The effect of liver disease on the pharmacokinetics of Depo-Provera® is unknown. Since the drug is primarily eliminated via the liver, metabolism may be impaired in patients with severe hepatic impairment (see section "Contraindications").

Renal impairment

The effect of renal disease on the pharmacokinetics of Depo-Provera® is unknown. Dose adjustment is not required in women with renal impairment, as Depo-Provera® is almost entirely eliminated via hepatic metabolism.

Children

Depo-Provera® should not be used before the onset of menstruation (see section "Indications").

Available data on intramuscular administration of medroxyprogesterone acetate in adolescent girls (12–18 years of age) are provided (see sections "Special precautions" and "Pharmacodynamics"). Except for concerns regarding loss of bone mineral density, the safety and efficacy of Depo-Provera® in adolescent girls after the onset of menstruation are expected to be similar to those in adult women.

Overdose.

No specific measures are required except discontinuation of therapy.

Adverse Reactions

During a large clinical study involving over 4,200 women who used Depo-Provera® for 7 years, the adverse effects listed below were reported.

Adverse reactions occurring most frequently (in more than 5% of patients): weight gain (69%), weight loss (25%), headache (16%), nervousness (11%), abdominal pain or discomfort (11%), dizziness (6%), decreased libido (6%).

Adverse reactions are listed below by frequency categories:

very common (≥1/10), common (from ≥1/100 to <1/10), uncommon (from ≥1/1000 to <1/100), rare (from ≥1/10,000 to <1/1000), very rare (<1/10,000), frequency not known (frequency cannot be estimated from available data).

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

Disorders of the blood and lymphatic system. Rare: anemia, blood system disorders.

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

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

Psychiatric disorders. Very common: nervousness. Common: depression, decreased libido. Uncommon: insomnia. Rare: anorgasmia, emotional disorder, mood disturbance, irritability, anxiety.

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

Ear and labyrinth disorders. Rare: vertigo.

Cardiac disorders. Rare: tachycardia.

Vascular disorders. Uncommon: hot flushes. Rare: embolism and thrombosis, deep vein thrombosis, thrombophlebitis, arterial hypertension, varicose veins.

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

Gastrointestinal disorders. Very common: abdominal pain, abdominal discomfort. Common: nausea, bloating. Rare: rectal bleeding, gastrointestinal disorder.

Hepatobiliary disorders. Uncommon: liver function disorders. Rare: jaundice, pathological levels of liver enzymes.

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

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

Reproductive system and breast disorders. Common: vaginal discharge, breast tenderness, urinary tract infections. Uncommon: abnormal uterine bleeding (irregular, heavy, light, spotting), galactorrhea, pelvic pain, dyspareunia, lactation suppression. Rare: vaginitis, amenorrhea, breast pain, uterine bleeding, menorrhagia, vulvovaginal dryness, mastalgia, ovarian cyst, premenstrual syndrome, endometrial hyperplasia, changes in breast size, bloody nipple discharge, vaginal cyst, breast enlargement, failure to resume reproductive function, sensation of pregnancy-like symptoms.

General disorders and administration site conditions. Common: edema/fluid retention, asthenia. Uncommon: chest pain. Rare: fever, increased fatigue, injection site reactions*, persistence of atrophy/depression/induration at injection site*, nodules/indurations at injection site*, pain/painfulness at injection site*, thirst, dysphonia, facial nerve paralysis, swelling in the axillary region.

Investigations. Very common: increased body weight, decreased body weight. Rare: decreased bone mineral density, impaired glucose tolerance, abnormal cervical smear test results.

*Adverse reaction identified during the post-marketing period.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after a medicinal product is authorized is important. It allows continued monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals, pharmacists, patients, and their legal representatives should report all suspected adverse reactions and lack of efficacy through the Automated Pharmacovigilance Information System at the following link: 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.

Packaging. 1 ml of suspension in a vial or pre-filled syringe. One vial or one syringe per cardboard box.

Prescription status. Prescription only.

Manufacturer.

Pfizer Manufacturing Belgium NV.

Manufacturer's address and place of business.

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