Proginov film-coated tablets 2 mg No. 21

Instructions for Proginova film-coated tablets 2 mg No. 21

Composition

active ingredient: estradiol valerate;

1 film-coated tablet contains 2 mg of estradiol valerate;

excipients: lactose monohydrate; corn starch; povidone K25; talc; magnesium stearate,

sugar coating of the tablet: sucrose, povidone K90, macrogol 6000, calcium carbonate, talc, montan glycol wax.

Dosage form

Film-coated tablets.

Main physicochemical properties: film-coated tablets, white in color.

Pharmacotherapeutic group

Hormones of the sex glands and drugs used in pathologies of the genital area. Estrogens. ATX code G03C A03.

Pharmacological properties

Pharmacodynamics

The active substance, synthetic estradiol (17b-synthesized estradiol), is chemically and biologically identical to endogenous human estradiol. Proginova should be used for hormone replacement therapy (HRT). HRT minimizes the symptoms of estradiol deficiency in women after menopause.

Pharmacokinetics

Estradiol valerate

Adsorption

After oral administration of estradiol valerate, it is completely absorbed. During adsorption and the first pass through the liver, the steroid ester is cleaved into estradiol and valeric acid. At the same time, estradiol is extensively metabolized, for example to estrone, estriol and estrone sulfate. Only about 3% of estradiol becomes bioavailable after oral administration of estradiol valerate. Food intake does not affect the bioavailability of estradiol.

Distribution

The maximum concentration of estradiol in the blood plasma (about 30 pg/ml) is reached 4-9 hours after taking the tablet. Within 24 hours after taking the tablet, the level of estradiol in the blood plasma decreases to a concentration of about 15 pg/ml. Estradiol binds to albumin in a non-specific manner and to sex steroid binding globulin (SSGB) in a specific manner. Only 1-1.5% of estradiol circulates as a free steroid, 30-40% is bound to SSGB.

The apparent volume of distribution of estradiol after a single intravenous administration is approximately 1 l/kg.

Metabolism

After the ester group is removed from exogenously administered estradiol valerate, its further metabolism follows the biotransformation scheme of endogenous estradiol. Estradiol is mainly metabolized in the liver, but also outside it, for example, in the intestine, kidneys, skeletal muscle and target organs. Metabolic processes include the formation of estrone, estriol, catecholestrogens and sulfate and glucuronide conjugates of these compounds, which are significantly less active or have no estrogenic activity.

Excretion from the body

After a single intravenous administration, the total clearance rate of estradiol from blood plasma is highly variable and ranges from 10 to 30 ml/min/kg. A certain part of the estradiol metabolites is excreted in the bile and undergoes the so-called enterohepatic circulation. Estradiol and its metabolites are excreted in the urine as sulfates and glucuronides.

Equilibrium concentration

After multiple administration, plasma estradiol levels are approximately twice as high as after a single dose. The minimum concentration of estradiol is 30 pg/ml, the maximum is 60 pg/ml. Estrones, the less estrogenic metabolites, reach 8-fold higher plasma concentrations, and estrone sulfates reach 150-fold higher plasma concentrations. 2 or 3 days after the end of treatment, the concentration of estradiol and estrone returns to baseline.

Indication

Hormone replacement therapy for symptoms of estrogen deficiency in postmenopausal women.

Contraindication

Hypersensitivity to the active substance or to any of the excipients of the drug.

Breast cancer, currently diagnosed, in history or suspected.

Known or suspected estrogen-dependent malignant tumors (e.g. endometrial cancer).

Genital bleeding of unknown etiology.

Untreated endometrial hyperplasia.

Venous thromboembolic events (e.g. deep vein thrombosis, pulmonary embolism) currently occurring or having occurred in the past.

Arterial thromboembolic events (e.g. angina pectoris, myocardial infarction) currently occurring or having occurred in the past.

Tendency to develop thrombosis (e.g. protein C deficiency, protein S or antithrombin deficiency).

High risk of developing venous or arterial thrombosis.

Acute liver disease or history of such disease (until liver function tests return to normal).

Severe liver disease.

Porphyria.

Liver tumors (benign or malignant) present or in the past.

Severe hypertriglyceridemia.

Interaction with other medicinal products and other types of interactions

Estrogen metabolism may be enhanced by concomitant administration of other substances that induce hepatic metabolizing enzymes (cytochrome P450). These substances include anticonvulsants (e.g. phenobarbital, phenytoin, carbamazepine, oxcarbazepine, topiramate, felbamate, primidone), antimicrobials (e.g. rifampicin, rifabutin, nevirapine, efavirenz), griseofulvin, meprobamate, and phenylbutazone preparations. Maximum enzyme induction may not occur for 2–3 weeks, but may then become persistent and persist for at least 4 weeks after discontinuation of drug therapy.

When taken simultaneously with steroid hormones, ritonavir and nelfinavir have the property of stimulating enzymes, although they are known as strong enzyme inhibitors.

Herbal preparations containing St. John's wort (Hypericum Perforatum) may stimulate estrogen metabolism.

A clinically significant increase in estrogen metabolism may cause a decrease in the effectiveness of these hormones and provoke changes in the frequency of menstrual bleeding.

Strong and moderate CYP3A4 inhibitors, such as azole fungicides (fluconazole, itraconazole, ketoconazole, voriconazole), verapamil, macrolides (clarithromycin, erythromycin), diltiazem, and grapefruit juice, may increase plasma estrogen concentrations.

Estrogens may enhance the effects and side effects of imipramine.

In the case of simultaneous use of cyclosporine against the background of a reduced ability of the liver to excrete cyclosporine, an increase in the plasma concentration of cyclosporine, creatinine and transaminases is possible.

When used concomitantly with sex hormones, HIV protease inhibitors and non-nucleoside reverse transcriptase inhibitors, as well as HCV (hepatitis C virus) inhibitors, may affect plasma estrogen concentrations. In some cases, the cumulative effect of these changes may be clinically significant.

Therefore, when prescribing HIV/HCV drugs simultaneously, it is necessary to familiarize yourself with the information on their use to avoid potential interactions.

Due to changes in the intestinal microflora after simultaneous administration of activated charcoal and/or antibiotics (e.g. ampicillin or tetracycline), a decrease in the concentration of the active substance, and therefore the effectiveness of the drug Proginova, has been observed. More frequent cases of intermenstrual bleeding have been reported.

Substances that form conjugates to a significant extent during passage through the gastrointestinal tract (e.g. paracetamol) may increase the bioavailability of estradiol by competitively inhibiting conjugation systems during adsorption.

In some cases, the need for oral antidiabetic agents or insulin may change due to effects on glucose tolerance and insulin response.

Drinking alcohol during HRT can lead to increased estradiol levels.

Laboratory studies.

The use of sex steroids may affect the results of certain laboratory tests, including biochemical indicators of liver function, thyroid gland, adrenal glands, kidneys, the level of proteins (transporters), for example, hormone-binding globulins, lipids/lipoprotein fractions, indicators of coagulation and fibrinolysis.

Application features

HRT should only be used to treat postmenopausal disorders that have a negative impact on quality of life. The benefit/risk ratio should be carefully weighed for each case of therapy at least once a year. HRT should only be used when the benefits outweigh the risks.

Data on the risks associated with HRT in the treatment of premature menopause are limited. However, due to the low absolute risk in younger women, the benefit-risk ratio is more favourable in these women than in older women.

Medical examination/consultation

Before initiating or reinstituting HRT, a careful history (including family history) and physical examination (including pelvic and breast examination) should be performed, taking into account contraindications and precautions, and such examinations should be repeated periodically. The frequency and nature of these examinations should be based on current medical practice, taking into account the individual characteristics of each woman and should include, among others, mammography. Women should be advised to be alert to any changes in their breasts and to report any changes immediately to their doctor.

If the patient suffers from prolactinoma, regular medical examinations should be performed at short intervals (including regular measurement of prolactin levels).

Situations requiring supervision

It is necessary to carefully monitor the condition of a patient who has a history or currently has one of the following diseases or the indicated conditions existed/worsened during pregnancy or previous hormonal therapy (including Proginova):

leiomyoma (uterine fibroids) or endometriosis;

history of thromboembolism or the presence of relevant risk factors (see below);

risk factors for estrogen-dependent tumors (for example, stage I breast cancer in a female patient);

arterial hypertension;

diabetes (diabetes mellitus) with/without vascular damage;

gallstone disease;

liver disorders (including liver adenoma);

migraine or (severe) headache;

history of endometrial hyperplasia (see below);

fibrocystic mastopathy;

epilepsy;

asthma;

otosclerosis;

Dubin-Johnson or Rotor syndrome;

sickle cell anemia;

idiopathic jaundice of pregnancy and a history of severe pruritus of pregnancy;

severe obesity;

minor chorea;

hereditary angioedema.

Conditions requiring immediate discontinuation of treatment

Treatment should be discontinued if a contraindication appears, as well as in the following cases:

- development of jaundice or liver failure;

- recurrence of cholestatic jaundice or cholestatic pruritus, observed for the first time during pregnancy or with previous use of sex steroids;

- significant increase in blood pressure;

- first appearance of migraine-like headaches;

- frequent and unusually severe headaches that occur for the first time, or other symptoms that may be prodromal signs of cerebrovascular disorders;

- symptoms of thrombosis or suspicion of them;

- visual impairment and other similar disorders;

- pregnancy.

A possible synergistic increase in the risk of thrombosis should be considered in women with multiple risk factors or with one of the risk factors being more pronounced. In such cases, this increased risk may be greater than if only several risk factors are present. HRT should not be prescribed if the benefit/risk ratio is negative.

Endometrial hyperplasia

The risk of endometrial hyperplasia and endometrial cancer is increased with prolonged estrogen monotherapy (see section 4.8). To reduce this risk, estrogens should be combined with progestogens in women who have not had a hysterectomy (see also section 4.8).

During the first months of treatment, light bleeding or occasional spotting may occur.

In case of frequent irregular bleeding that is prolonged or recurrent:

– bleeding that occurs after a course of treatment,

– bleeding that does not stop after the end of treatment,

Their cause should be determined and an endometrial biopsy should be performed to rule out malignant endometrial degeneration.

Uncompensated estrogen stimulation can lead to premalignant or malignant degeneration of residual endometriosis. If hysterectomy was performed for the purpose of surgical treatment of endometriosis, progestogens are recommended as an adjunct to estrogen replacement therapy, especially if residual endometriosis is detected.

After stopping treatment, the risk may remain elevated for at least 10 years.

Breast cancer

Based on the placebo-controlled randomized clinical trial "Women's Health Initiative" (WHI) and epidemiological studies, including the "Million Women Study" (MWS), an increased risk of breast cancer has been found in women who have taken estrogens, a combination of estrogens and progestogens or tibolone as part of HRT for several years (see section "Adverse reactions"). The risk of developing breast cancer in women taking combined estrogen-progestogen therapy is evident after 3 years. After several years of use, all types of HRT show an increased risk, which increases with the duration of treatment; but after several years (maximum 5 years) after stopping treatment, this risk returns to the baseline level corresponding to the individual age category.

In the MWS study, the relative risk of breast cancer with HRT with conjugated equine estrogens or estradiol was higher with the addition of progestogens, and the risk was independent of the type of progestogen and the regimen of HRT (continuous or sequential progestogen). There was no indication of a difference in risk between different modes of administration.

In the WHI study, continuous combination therapy with conjugated equine estrogens and medroxyprogesterone acetate resulted in mammary tumors that were larger and more likely to metastasize to regional lymph nodes than in the placebo group.

HRT, particularly combined estrogen and progestogen treatment, increases image density during mammography examinations, which may in some cases negatively affect the diagnosis of breast cancer.

Venous thromboembolism

HRT is associated with a small increase in the relative risk of venous thromboembolism (VTE) (deep vein thrombosis or pulmonary embolism). In controlled randomized clinical trials and epidemiological studies, a 2- to 3-fold increased risk has been reported in women who have taken the treatment compared with women who have not. It is estimated that in 1000 women not taking these hormonal drugs, there will be about 3 cases of VTE in the age group 50 to 59 years and 8 cases in the age group 60 to 69 years.

According to this estimate, for every 1000 healthy women who use HRT for 5 years, there will be 2 to 6 additional cases (optimal rate = 4) of VTE in the age group 50 to 59 years and 5 to 15 cases (optimal rate = 9) in the age group 60 to 69 years. VTE is more likely to develop during the first year of HRT than later.

appropriate family or personal predisposition;

obesity (BMI > 30 kg/m2);

systemic lupus erythematosus (SLE);

old age;

major surgical interventions;

prolonged immobilization;

pregnancy/postpartum period;

cancer.

HRT is contraindicated if there is a family history of thrombophilic disorders and/or if the disorders are severe (e.g. antithrombin, protein S or protein C deficiency or a combination of these disorders). For women already taking regular anticoagulant therapy, the benefits and risks of HRT should be carefully weighed.

There is currently no consensus on the potential role of varicose veins in the development of VTE.

Patients with a history of VTE or a known predisposition to thrombosis (thrombophilia) are at increased risk of VTE. HRT may increase this risk. A high family or personal tendency to thromboembolism or a history of recurrent spontaneous abortion should be assessed to exclude a predisposition to thrombosis. HRT is contraindicated in such patients until a precise assessment of thrombophilia factors has been carried out or until treatment with anticoagulants is initiated. For women already receiving anticoagulant treatment, the benefit/risk ratio of HRT should be carefully weighed.

The risk of VTE may be temporarily increased by prolonged immobilisation, severe trauma or major surgery. As in all patients in the postoperative period, careful VTE prophylaxis should be undertaken. If prolonged immobilisation is anticipated following surgery, particularly abdominal surgery or orthopaedic surgery of the lower extremities, it should be possible to temporarily discontinue HRT for 4–6 weeks prior to the planned surgery. HRT should not be resumed until the woman has fully recovered from her previous physical activity.

If VTE develops after starting HRT, the drug should be discontinued. Patients should be informed of the need to immediately report to their doctor any suspected symptoms of thromboembolism (such as painful swelling of a lower limb, sudden chest pain, shortness of breath).

Coronary heart disease

Results from one controlled randomized clinical trial have not shown any cardiovascular benefits of continuous HRT with conjugated equine estrogens and MPA. Results from two large clinical trials (the WHI and HERS studies) suggest an increased risk of cardiovascular disease during the first year of use, but no benefits for women's overall health.

There are few data from controlled randomized trials of other drugs used for HRT that have examined the effects on cardiovascular disease or mortality.

Combined estrogen-progestogen therapy

The relative risk of coronary heart disease (CHD) with combined estrogen-progestogen HRT is slightly increased. As the baseline absolute risk of CHD is largely age-dependent, the number of additional cases of CHD attributable to estrogen and progestogen use is very small in healthy women close to the menopause, but will increase with age.

Estrogen monotherapy

Data from randomized controlled trials have not shown an increased risk of CHD in post-hysterectomy women receiving estrogen monotherapy.

Acute cerebrovascular accident

A large randomized clinical trial (WHI trial) found an increased risk of acute cerebrovascular accidents (as a secondary endpoint) in healthy women taking HRT with a combination of conjugated equine estrogens and MPA in a continuous regimen.

It is estimated that there will be about 3 cases of acute cerebrovascular accidents per 1000 women not taking HRT over a 5-year period in the age group 50 to 59 years and 11 cases in the age group 60 to 69 years. For 1000 women taking a combination of conjugated equine estrogens and MPA over a 5-year period, the number of additional cerebrovascular accidents is as follows: in the age group 50 to 59 years - from 0 to 3 cases (optimal rate = 1), and in the age group 60 to 69 years - from 1 to 9 cases (optimal rate = 4).

Ovarian cancer

Long-term use (at least 5–10 years) of estrogens as monotherapy for HRT in women who have undergone hysterectomy has been associated with an increased risk of ovarian cancer in numerous epidemiological studies. It is currently not known whether long-term use of combined estrogen/progestin HRT is not associated with other risks.

Other states

Patients with rare hereditary problems of fructose intolerance, glucose-galactose malabsorption or sucrase-isomaltase deficiency should not take Proginova.

Women with a history of elevated plasma triglycerides require special monitoring during estrogen and estrogen/progestin HRT, as there have been rare cases of significant increases in plasma triglyceride concentrations leading to pancreatitis during estrogen treatment in such circumstances.

Estrogens increase the concentration of thyroxine-binding globulin. This causes an increase in the total concentration of thyroid hormones in the blood plasma (determined by protein-bound iodine, T4 levels (chromatographic or radioimmunoassay) or T3 levels (radioimmunoassay)). Absorption of T3 is reduced, indicating an increase in thyroxine-binding globulin. Concentrations of free T4 and T3 are unchanged. Concentrations of other binding proteins may increase in the blood plasma, such as transcortin and sex hormone-binding globulin, which in turn leads to an increase in the concentration of circulating corticosteroids or sex hormones. Concentrations of other free and biologically active hormones remain unchanged. Levels of other plasma proteins may increase (angiotensinogen/renin substrate, α1-antitrypsin, ceruloplasmin).

There is no conclusive evidence that HRT improves cognitive function. The WHI trial suggests an increased risk of dementia in women taking HRT with a combination of conjugated equine estrogens and MPA continuously after the age of 65. It is not known whether these risks also apply to younger women with postmenopausal syndrome or are related to other HRT drugs.

In women with hereditary angioedema, taking estrogens may cause or worsen the symptoms of angioedema.

Treatment with Proginova does not have a contraceptive effect and does not protect against HIV.

Women with a tendency to chloasma or with a history of chloasma should minimize exposure to sunlight or ultraviolet radiation.

Estrogens are known to contribute to the formation of gallstones in the biliary system. Some women appear to be predisposed to developing gallbladder disease while taking estrogen.

In rare cases, benign and, even more rarely, malignant liver tumors have been observed after the use of hormonal substances that make up Proginova. In some cases, these tumors have led to life-threatening bleeding in the abdominal cavity.

No association has been established between HRT and the development of hypertension. Slight increases in blood pressure have been reported in women taking HRT, but clinically significant increases have been rare. However, if persistently high blood pressure values are recorded in isolated cases during HRT, discontinuation of HRT should be considered.

Close observation is necessary in patients with mild hepatic impairment, including hyperbilirubinemia, such as Dubin-Johnson syndrome or Rotor syndrome, and periodic monitoring of liver function tests is necessary. In case of deterioration of liver function tests, HRT should be discontinued.

Although HRT may affect peripheral insulin resistance and glucose tolerance, in general, no change in therapy is necessary for diabetic patients receiving HRT. However, careful monitoring of the health of women with diabetes is necessary during HRT.

Some patients may experience undesirable effects of estrogen stimulation, such as abnormal uterine bleeding, while taking HRT. Frequent or persistent uterine bleeding during treatment is an indication for a comprehensive evaluation of the endometrium.

Fibroid tumors of the uterus (fibroids) may increase in size under the influence of estrogens. If this occurs, treatment should be discontinued.

If recurrence of endometriosis occurs during treatment, it is recommended to discontinue therapy.

Patients with prolactinoma require close medical supervision (including periodic determination of prolactin levels).

In rare cases, chloasma may occur, especially in women with a history of chloasma during pregnancy. Women with a tendency to chloasma should avoid exposure to sunlight or ultraviolet radiation during HRT.

Use during pregnancy or breastfeeding

The drug is contraindicated during pregnancy or breastfeeding. If the patient becomes pregnant while using Proginova, treatment should be discontinued immediately.

Most of the epidemiological studies available today, which contain data on accidental, unintentional exposure of the fetus to estrogens, have not revealed any teratogenic or toxic effects on the fetus of these drugs.

Ability to influence reaction speed when driving vehicles or other mechanisms

The effect of the drug on the reaction rate when driving or working with other mechanisms was not observed.

Method of administration and doses

For the initiation and continuation of treatment of postmenopausal symptoms, the minimum effective dosage should always be prescribed for the shortest possible period (see section "Special instructions").

After 3 weeks of treatment, a break of at least 1 week is necessary to avoid significant endometrial hyperplasia. The calendar blister of Proginova, containing 21 film-coated tablets of 2 mg, makes it easier for patients to follow the treatment regimen. Such a blister ensures regularity of administration and helps to avoid overdose.

Treatment of women after hysterectomy and postmenopausal women can be started on any day.

In patients who have not undergone hysterectomy, treatment with Proginova should be combined with the use of a monoprogestogen indicated for this clinical situation for at least 12-14 days per month or during a 28-day cycle. The dosage, nature and duration of treatment are determined depending on the method of administration of the progestogen (see section "Special instructions").

For women with a uterus removed, the addition of progestogen is not recommended, unless endometriosis has been diagnosed.

If a tablet is missed, it should not be taken in addition to the next tablet. Missing a tablet increases the likelihood of spotting or breakthrough bleeding.

Elderly patients

There are no data indicating the need for dose adjustment in elderly patients. For use in women aged 65 years and over, see section "Special warnings and precautions for use".

Patients with hepatic insufficiency

The use of Proginova in patients with impaired liver function has not been specifically studied. The use of Proginova is contraindicated in women with severe hepatic insufficiency (see section "Contraindications").

Patients with renal insufficiency

The use of Proginova in patients with renal impairment has not been specifically studied. Available data do not indicate the need for dose adjustment.

Method of administration and duration of administration

The tablets should be swallowed whole, without chewing, with sufficient liquid. It is advisable to take the drug at the same time every day.

The duration of treatment is determined by the doctor.

Children

The drug is not indicated for use in children and adolescents.

Overdose

Symptoms: nausea, vomiting, chest tightness, vaginal bleeding may be signs of overdose.

Treatment: symptomatic therapy.

Adverse reactions

Table 1 lists the adverse reactions by MedDRA system organ class reported with HRT. The MedDRA terms that most clearly describe the relevant adverse reactions are given. Synonyms and similar conditions are not listed, but should nevertheless be considered.

The following categories have been used to define the frequency of ADRs: very common (≥ 1/10), common (≥ 1/100 to < 1/10), uncommon (≥ 1/1,000 to < 1/100), rare (≥ 1/10,000 to < 1/1,000), and not known (frequency cannot be estimated from the available data).

For additional information, see section: “Application Features” and Table 1.

Table 1

The following adverse reactions associated with estrogen treatment have also been reported: changes in glucose tolerance, exacerbation of porphyria, mood changes, chorea, stroke, arterial hypertension, myocardial infarction, eczema, hemorrhagic rashes, chloasma (limited skin hyperpigmentation), the appearance or exacerbation of phlebitis, venous thromboembolism, muscle spasms, flatulence, diarrhea, impaired liver function, gallbladder disease (including cholestasis), cystitis-like symptom, vaginal candidiasis, excessive secretion of cervical mucus, ectropion, increase in the size of uterine leiomyomas, discharge from the mammary glands, breast cancer, endometrial cancer, nosebleeds.

Breast cancer

According to a number of epidemiological studies and the randomized placebo-controlled WHI trial in women who are taking or have recently taken HRT, the risk of breast cancer increases significantly with increasing duration of HRT.

For estrogen-only HRT, the relative risk (RR) estimates (taken from a new analysis of 51 epidemiological studies in which 80% of women used estrogen-only HRT) are similar to those in the MWS epidemiological study: 1.35 (95% CI 1.21–1.49) and 1.30 (95% CI 1.21–1.40).

Regarding combined estrogen/progestin HRT, numerous epidemiological studies have confirmed an increased overall risk of breast cancer compared with estrogen monotherapy.

The MWS study showed that in women who had never taken HRT, taking various combinations of estrogen/progestin as HRT increased the risk of developing breast cancer (HR = 2.00; 95% CI 1.88–2.12) compared with estrogen monotherapy (HR = 1.30; 95% CI 1.21–1.40) or tibolone (HR = 1.45; 95% CI 1.25–1.68).

The WHI study found an HR of 1.24 (95% CI 1.01–1.54) after 5–6 years of HRT with a combination of conjugated equine estrogens and MPA (compared to placebo for all women enrolled in the study).

The absolute risks calculated from the MWS study and the WHI study are given below.

The MWS study, based on known average breast cancer incidence rates in industrialized countries, estimated that about 32 per 1,000 women who were not taking HRT were diagnosed with breast cancer between the ages of 50 and 64. For every 1,000 women who were taking or had recently taken HRT, the following additional cases were found during the same period:

in case of estrogen monotherapy

0–3 (optimal value = 1.5) when taking estrogens for 5 years,

3–7 (optimal score = 5) when taking estrogens for 10 years;

in case of receiving HRT with a combination of estrogens/progestins

5–7 (optimal score = 6) when taking the combination for 5 years,

18–20 (optimal score = 19) when taking the combination for 10 years.

According to the WHI study, when monitoring women aged 50 to 79 years, 8 additional cases of invasive breast cancer per 10,000 women are detected for each year of HRT (conjugated equine estrogens/MPA) when calculating data after 5−6 years of therapy.

Calculations based on the study data showed that for every 1,000 women in the placebo group, about 16 cases of invasive breast cancer will be diagnosed over the next 5 years; for every 1,000 women taking HRT with a combination of estrogens/progestins (conjugated equine estrogens/MPA), the number of additional cases will range from 0 to 9 (optimal rate = 4) over the 5-year treatment period.

The number of additional cases of breast cancer in women who received HRT is similar for all women in the HRT group regardless of the age at which replacement therapy was started (the age range analyzed was 45–65 years) (see section “Special warnings and precautions for use”).

Liver cancer

After the use of steroid hormones similar to those contained in the drug Proginova, in isolated cases,