Femoston conti 1/5: Medicine to treat osteoporosis

2021-07-04 06:00 PM

Prevention of osteoporosis in postmenopausal women at high risk for fractures who are intolerant of, or contraindicated to, other drugs used to prevent osteoporosis.

Producer

Abbott.

Ingredient

Each tablet: Estradiol (as hemihydrate) 1mg, dydrogesteron 5mg.

Pharmacodynamic

Pharmacotherapeutic group: Genitourinary system and sex hormones, progestogen and oestrogen, fixed combination. ATC code: G03FA14.

Estradiol:

The active substance 17β-estradiol has been chemically and biologically identified as endogenous human estradiol.

It replaces estrogen that has been reduced in menopausal women, and relieves menopausal symptoms.

Estrogen helps prevent bone loss from menopause or ovarian surgery.

Dydrogesterone:

Dydrogesteron is an orally administered progestogen that is comparable in activity to an parenteral progestogen.

Because oestrogens stimulate endometrial growth, oestrogens increase the risk of endometrial hyperplasia and endometrial cancer. Addition of a progestogen significantly reduces the risk of oestrogen-induced endometrial hyperplasia in women without uterine surgery.

Clinical trial information:

Reduces symptoms and bleeding patterns due to lack of estrogen.

Relief of perimenopausal symptoms is achieved within the first weeks of treatment.

Frequent cessation of menstruation was seen in 88% of women during the 10-12 month of treatment. Abnormal bleeding and/or spotting occurred in 15% of women within the first 3 months of treatment and in 12% of women during October to 12 of treatment.

The effect of avoiding bone spongy:

Estrogen deficiency during menopause is often associated with increased turnover and decreased bone mass. The effect of oestrogens on bone mineral density is dose dependent. The anti-osteoporotic effect was maintained as long as treatment continued. After discontinuation of HRT, bone mass lost at the same rate as in untreated women. Evidence from the WHI trial and meta-analysis demonstrates that current use of HRT in healthy women, either alone or in combination with a progestogen, reduces the risk of osteoporosis-related fractures. bones in the hip, spine, and other bones. HRT may also prevent fractures in women with low bone density and/or who have already developed osteoporosis, but such evidence is limited.

After 1 year of treatment with Femoston, the bone mineral density of the lumbar spine increased by 4.0±3.4% (TB±SD). 90% of women have increased or constant bone mineral density during treatment. Femoston also has an effect on the mineral density of the hip bone. The increase after 1 year of treatment in the thigh was 1.5%±4.5% (TB±SD), 3.7%±6.0% (TB±SD) at the vertebra and in Ward's triangle increased by 2, 1%±7.2% (TB±SD). The percentages of women with the same or increased bone mineral density in the three hip regions after Femoston treatment were 71%, 66 and 81%, respectively.

Pharmacokinetics

Estradiol:

Absorption: The absorption of estradiol depends on the particle size, estradiol is absorbed from the gastrointestinal tract immediately.

The following table gives the mean pharmacokinetic parameters of estradiol (E2), estrone (E1) and estrone sulphate (E1S) for each dose of estradiol as a fraction. Data are shown as mean (SD).

Distribution: Oestrogens have been found in both free and conjugated forms. Approximately 98-99% of estradiol is bound to plasma proteins, of which about 30-52% are bound to albumin and 46-69% are weakly bound to sex hormone-binding globulin (SHBG).

Metabolism: Following oral administration, estradiol is extensively metabolised. The principal unbound and bound metabolites are estrone and estrone sulphate. These metabolites may contribute to oestrogenic activity, either directly or after conversion to estradiol. Estrone sulphate can participate in enterohepatic circulation.

Elimination: In the urine, the major compounds are the glucorunides of estrone and estradiol. The half-life is 10 -16 hours. Estrogen is secreted into breast milk.

Dose and time dependence: Following daily oral administration of Femoston, estradiol concentrations reach steady state after approximately 5 days. In general, steady-state concentrations are achieved within 8 to 11 days of dosing.

Dydrogesterone:

Absorption: Following oral administration, dydrogesterone is rapidly absorbed with a Tmax of 0.5 to 2.5 hours. The complete bioavailability of dydrogesterone (20 mg oral versus 7.8 mg intravenous infusion) is 28%.

The following table provides the mean single-dose pharmacodynamic parameters for dydrogesterone (D) and dihydrogesterone (DHD).

Distribution: Following intravenous administration of dydrogesterone, the volume of distribution of the drug is approximately 1400 liters. More than 90% of dydrogesterone and DHD are bound to plasma proteins.

Metabolism: After oral administration, dydrogesterone is rapidly converted to DHD. Concentrations of the major metabolite 20α-dihydrodydrogesterone (DHD) peak about 1.5 hours after oral administration. DHD plasma concentrations were significantly higher than that of the parent drug. The AUC and Cmax ratios of DHD and parent material are approximately 40 and 25, respectively. The mean half-lives of dydrogesterone and DHD vary between 5 to 7 and 14 to 17 hours, respectively. A common feature of all metabolites is the retention of the 4,6 dien-3-on configuration of the parent substance and the loss of 17β-hydroxy. This explains the lack of estrogenic and androgenic effects of dydrogesterone.

Elimination: Following oral administration of the above-mentioned dydrogesterone, approximately 63% of the dose is excreted in the urine. The total plasma clearance is 6.4 l/min. Within 72 hours the drug is completely eliminated. DHD is present in the urine mainly as conjugates with glucuronic acid.

Dose and time dependence: The pharmacokinetics of single (single dose) and multiple administration are linear over the oral dose range of 2.5 to 10 mg. A comparison of the pharmacokinetics between single and repeated administration shows that the pharmacokinetics of dydrogesterone and DHD are unchanged as a result of repeated doses. Stability was achieved after 3 days of treatment.

Indications and uses

Hormone replacement therapy (HRT) to treat symptoms of estrogen deficiency in women who have been past their last menstrual period for at least 12 months.

Prevention of osteoporosis in postmenopausal women at high risk for fractures who are intolerant of, or contraindicated to, other drugs used to prevent osteoporosis.

Elderly: There is limited experience in the treatment of women over 65 years of age.

Dosage and Administration

Drugs for oral use. This estrogen and progestogen is taken every day without interruption.

Dosage is one tablet per day for a 28-day cycle.

Take Femoston continuously with no interruptions between cartridges.

Regardless of whether it is for initiation or continuation of treatment of postmenopausal symptoms, the lowest effective dose should be used and for the shortest duration (see Precautions).

Continuous combination therapy that can be initiated with Femoston depends on the time since menopause and the severity of symptoms.

Based on clinical response, the dose may be adjusted thereafter.

Patients switching from sequential or cyclical formulations should complete a 28-day cycle and then switch to Femoston.

Patients switching from a continuously administered combination may begin treatment at any time.

If you forget to take a dose, take it as soon as possible. If more than 12 hours have passed, treatment should be continued with the next tablet without taking the missed tablet. The chance of abnormal bleeding or spotting may be increased.

Femoston may or may not be taken with food.

Children: Femoston is not indicated for use in children.

Warnings

For the treatment of postmenopausal symptoms, hormone replacement therapy (HRT) should only be initiated when symptoms adversely affect quality of life. In all cases, a careful assessment of the benefits and risks should be performed periodically, at least annually. Continue taking HRT only when the benefits outweigh the risks.

Evidence on the risks associated with HRT in the treatment of early menopause is rather limited. However, because of the low degree of absolute risk in younger women, the balance of benefits and risks in these women may be more favorable than in older women.

Examination/monitoring:

Before initiating or re-initiating HRT, a complete personal and family medical history should be obtained. Based on medical history and contraindications and warnings for dosing, a physical examination (including pelvic and breast areas) is required. During treatment, periodic examinations should be performed on the frequency and nature appropriate to the individual woman. The woman should be asked to inform her doctor or nurse of any breast changes (see “breast cancer” below). It should be checked, including by appropriate imaging methods such as mammography, that is consistent with existing screening guidelines and tailored to individual clinical needs.

Cases to monitor:

For any of the following, which have occurred previously, and/or worsened during pregnancy or prior to hormone therapy, the patient should be closely monitored. It should be taken into account that these conditions may recur or worsen during treatment with Femoston, in particular:

Smooth muscle tumors (fibroids) or endometriosis.

Risk factors for thromboembolic disorders (see below).

Estrogen-dependent tumor risk factors, eg first-degree heredity for breast cancer.

Hypertension.

Liver dysfunction (eg, liver adenoma).

Diabetes with or without vascular complications.

Gallstones.

Migraine or headache (severe).

Systemic lupus erythematosus.

History of endometrial hyperplasia (see below).

Epilepsy.

Hen.

Ear sclerosis.

Reasons to stop taking Femoston immediately:

Treatment should be stopped immediately in cases of contraindications and in the following cases:

Jaundice or impaired liver function.

Significant increase in blood pressure.

New onset of migraine headaches.

Pregnant.

Endometrial hyperplasia and carcinoma:

In women with an intact uterus, the risk of endometrial hyperplasia and carcinoma is increased with long-term use of oestrogens alone. Reports have shown that the risk of endometrial cancer in oestrogen-only users is 2 to 12 times higher than in nonusers, depending on the duration of treatment and the dose of oestrogen used (see section " Adverse Effects (ADR)”). This risk remains high for at least 10 years after stopping treatment.

Addition of a progestogen cyclically, at least 12 days per month/28 day cycle, or continuous use of an oestrogen-progestogen combination for women who have not had a hysterectomy may avoid the increased risk of cancer due to only estrogen alone.

Unusual bleeding or spotting may occur during the first month of treatment. If unusual bleeding or spotting occurs repeatedly during treatment or continues after treatment has been discontinued, notify your doctor immediately. Your doctor will investigate to determine the cause, such as a biopsy of the uterus to rule out uterine cancer.

Breast cancer:

The overall evidence suggests an increased risk of breast cancer progression in women taking the oestrogen-progestogen combination and possibly oestrogen-only, depending on the duration of treatment.

Combined oestrogen-progestogen therapy: Randomized placebo-controlled studies, WHI (Women's Health Research Organization) studies, and epidemiological studies have found an increased risk of breast cancer in In women taking HRT with an oestrogen-progestogen combination, it becomes apparent after about 3 years (see section "Adverse Reactions (ADR)").

Estrogen-only therapy: The WHI trial found no increased risk of breast cancer in women who had a hysterectomy using only estrogen for hormone replacement. Observational studies have shown a significantly lower increased risk of breast cancer in the oestrogen-only group than in the mixed oestrogen-progestogen group (see Adverse Reactions (ADRs)).

The increased risk began to be noticed a few years after treatment but returned to the same level several (usually 5) years after stopping the drug.

HRT, especially oestrogen-progestogen combination therapy, increases mammographic density, which may adversely affect radiological detection of breast cancer.

Ovarian Cancer:

Ovarian cancer is much rarer than breast cancer. Long-term use (at least 5-10 years) of oestrogen-only is associated with a slightly increased risk of ovarian cancer (see section "Adverse Reactions (ADRs)"). Several studies, including the WHI studies, suggest that long-term use of combination HRT may result in a similar or milder risk (see "Adverse Reactions (ADRs)").

Venous thrombosis:

HRT is associated with a 1.3-3-fold increased risk of developing venous thromboembolism (VTE), such as deep vein thrombosis or pulmonary embolism. This risk is higher in the first year of HRT use than in later years (see “Adverse Reactions (ADR)”).

Patients already in a hypercoagulable state are at increased risk for venous thrombosis, and HRT may aggravate this risk. Therefore, HRT is contraindicated in these patients (see “Contraindications”).

In general, risk factors for VTE include: estrogen use, old age, major surgery, long-term immobilization, obesity (BMI > 30kg/m2), pregnancy/postpartum, systemic lupus erythematosus (SLE), and cancer. The role of varicose veins is not relevant in VTE.

As with all postoperative patients, precautions should be taken to prevent VTE after surgery. If long-term immobilization is required after elective surgery, HRT should be temporarily discontinued 4 to 6 weeks in advance. Do not resume HRT until the patient is fully mobile.

If a woman has no history of VTE but has had a blood clot in her immediate family at a young age, screening may be needed after careful examination to limit this risk. (scan/scan only identify a certain percentage of thromboembolic defects).

If the thrombotic defect is determined to be unrelated to the thrombosis of other family members, or if the disability is severe (i.e., antithrombin, protein S or protein C deficiency, or a combination of defects) HRT is contraindicated in these cases.

Women already on chronic anticoagulant therapy need to carefully weigh the benefits and risks of taking HRT.

If VTE develops after initiation of HRT, the drug must be discontinued. Patients should seek immediate medical attention when they notice symptoms of a blood clot (such as painful swelling in one leg, or sudden angina, shortness of breath).

Coronary artery disease (CAD):

There is no evidence from randomized controlled trials of protection against myocardial infarction in women with or without coronary artery disease (CAD) receiving combined oestrogen-progestogen HRT or oestrogen alone.

Combination oestrogen-progestogen therapy: The relative risk of CAD is slightly increased with combined oestrogen-progestogen HRT. Because the baseline absolute risk of CAD is highly age-dependent, in healthy women nearing menopause, the number of additional CAD cases associated with oestrogen-progestogen use is small, but increases with increasing age. .

Estrogen-only therapy Randomized controlled data indicate no additional risk of CAD in women with oestrogen-only hysterectomies.

Brain stroke:

Combination oestrogen-progestogen therapy and oestrogen-only therapy increased the risk of ischemic stroke by 1.5-fold. This association was independent of age or time before menopause. However, because the overall risk of stroke is highly age-dependent, the overall stroke risk in women taking HRT also increases with age (see "Adverse Reactions (ADRs)").

Other cases:

Oestrogens can cause fluid retention, so patients with cardiac or renal dysfunction should be carefully monitored.

If there is an increase in blood lipid levels (hypertriglyceridemia), close monitoring is recommended during treatment with HRT (whether oestrogen-only or a combination product). In rare cases, blood lipids (triglycerides) are too high to lead to pancreatitis when treated with estrogen for these conditions.

Oestrogens increase thyroid-binding globulin (TBG), leading to an increase in the total amount of thyroid hormone in the circulation. Circulating thyroid hormone is determined by protein bound iodin (PBI), T4 content (measured by column or by immunofluorescence) or T3 (measured by immunofluorescence). The decrease in T3 particle absorption reflects high TBG. The concentrations of free T3 and T4 were constant. Other conjugate proteins may also be elevated in plasma, i.e. corticosteroid-binding globulin (CBG), sex hormone-binding globulin (SHBG) leading to increased levels of corticosteroids and sex steroids in the general circulation. The concentrations of free or biologically active hormones are unchanged. Concentrations of other plasma proteins may also be increased (precursor substrate angiotensin/renin, alpha-I antitrypsin, ceruloplasmin).

Using HRT did not clearly improve cognitive function. There is some evidence of an increased risk of neurologic crisis in women over 65 years of age who are starting HRT with either a continuous combination or an oestrogen-only product.

Do not take this medicine if you have a rare hereditary problem of: galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption.

This oestrogen and progestogen combination therapy is not a contraceptive.

Effects on ability to drive and use machines:

Femoston has no or negligible influence on the ability to drive and use machines.

Femoston contains lactose monohydrate. If you are intolerant to certain sugars, especially lactose, ask your doctor before taking this medicine.

Overdose

Both estradiol and dydrogesterone are active substances with low toxicity. However, symptoms of overdose may include: nausea, vomiting, breast tenderness, dizziness, abdominal pain, drowsiness/fatigue and cessation of menstruation. It is unlikely that symptomatic treatment of overdose is necessary. The information above also applies to cases of overdose in children.

Contraindications

Pre-existing or suspected breast cancer.

Known or suspected estrogen-dependent malignancies (eg, endometrial cancer).

Known or suspected progestogen-dependent tumors (eg, meningiomas).

Undiagnosed genital bleeding.

Untreated endometrial hyperplasia.

Previous or current spontaneous venous thromboembolism (deep vein thrombosis, pulmonary embolism).

Known bleeding disorder (eg, protein C, protein S, or anticoagulant deficiency (see "Warnings").

Acute or recent thromboembolic disease (eg, angina, myocardial infarction).

Acute liver disease or history of liver disease, as long as liver function tests have not returned to normal.

The rare pigmentary disorder "porphyria".

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

Use in pregnant and lactating women

Do not use Femoston during pregnancy. If you become pregnant while being treated with this Femoston, the drug should be stopped immediately. The results of most epidemiological studies to date involving accidental fetal exposure to a mixture of oestrogens and progestogens indicate no teratogenic or fetotoxic effects. There are no adequate data on the use of dydrogesterone/estradiol in pregnant women.

Breast-feeding: Do not take Femoston while breastfeeding.

Interactive

No studies have been done to investigate interactions between Femoston and other drugs.

The effectiveness of oestrogens and progestogens may be impaired:

Oestrogens and progestogens may be increased in metabolism when used concurrently with substances that increase enzyme metabolism, especially P450 enzymes 2B6, 3A4, 3A5, 3A7, as are antiepileptic drugs (eg, phenobarbital, carbamazepine). and phenytoin) and anti-infectives (eg, rifampicin, rifabutin, nevirapine, efavirenz).

Ritonavir and nelfinavir, although known to be potent inhibitors of CYP450 3A4, A5, A7, conversely potentiate their effects when co-administered with steroid hormones.

Herbal preparations containing St. John's Wort (Hypericum perfloratum) can induce metabolism of oestrogens and progestogens via the CYP450 3A4 pathway.

Clinically, increased metabolism of oestrogens and progestogens may lead to decreased efficacy and altered uterine bleeding characteristics.

Oestrogens may affect the metabolism of other drugs: Oestrogens may inhibit the drug-metabolizing enzyme CYP450 by competitive inhibition. This effect is particularly significant for substances with narrow therapeutic indications, such as:

Tacrolimus and cyclosporine A (CYP450 3A4, 3A3).

Fentanyl (CYP450 3A4).

Theophyllin (CYP450 1A2).

Clinically, this leads to increased plasma concentrations of the affected drug to toxic levels. Therefore, long-term close monitoring of drug levels may be indicated and dose reduction of tacrolimus, fentanyl, cyclosporine A and theophylline may be necessary.

Adverse Effects (ADRs)

The most commonly reported adverse drug reactions with estradiol/dydrogesterone treatment in clinical trials were headache, abdominal pain, breast tenderness, and back pain.

Adverse events reported in clinical trials were as follows (n=4929):

The study frequencies related to adverse events are ranked as follows: very common (more than 1 case in 10 treated patients); common (from 1 to 10 cases in 100 treated patients); uncommon (from 1 to 10 cases in 1000 treated patients); rare (from 1 to 10 cases in 10,000 treated patients).

Bacterial and parasitic infections: Common: Vaginal candidiasis.

Benign, malignant and unspecified tumors: Uncommon: Increased size of smooth muscle tumours.

Immune system disorders: Uncommon: Allergic reactions (hypersensitivity).

Psychosis:

Common: Depression, stress.

Uncommon: Affects libido.

Nervous system disorders:

Very common: Headache.

Common: Migraine, dizziness.

Heart disorders:

Rare: Myocardial infarction.

Vascular disorders:

Uncommon: Venous thromboembolism (see below for more information).

Digestive disorders:

Very common: Abdominal pain.

Common: Nausea, vomiting, flatulence.

Liver disorders:

Uncommon: Abnormal liver function, sometimes with jaundice or asthenia, and abdominal pain, gallbladder disorder.

Skin and subcutaneous tissue disorders:

Common: Allergic skin reactions (eg, rash, itching)

Rare: Angioedema, vascular purpura.

Musculoskeletal and connective tissue disorders:

Very common: Back pain.

Reproductive system and breast disorders:

Very common: Breast tenderness/tenderness.

Common: Menstrual disorders (postmenopausal bleeding, uterine bleeding, menorrhagia, amenorrhea, menstrual irregularities, dysmenorrhea), pelvic pain, cervical erosion.

Uncommon: Enlarged breasts, premenstrual syndrome.

General disorders and drug reactions:

Common: Asthenic states (asthenia, fatigue, malaise), peripheral edema.

Examination/test:

Common: Weight gain.

Uncommon: Weight loss.

Breast cancer risk:

It has been reported that the risk of breast cancer doubles in women taking a combination of oestrogens and progestogens for more than 5 years.

The increased risk of breast cancer in oestrogen-only users was significantly lower than in combined oestrogen-progestogen users.

The degree of risk depends on the duration of use (see “Warnings”).

The results of the largest, randomized, placebo-controlled study (WHI study) and the largest epidemiological study (MWS) are shown below.

Risk of endometrial cancer.

Postmenopausal women with a uterus: About 5/1000 women with a uterus who do not take HRT have an increased risk of endometrial cancer.

In women with a uterus, HRT should not be used with oestrogen alone because of the increased risk of endometrial cancer (see "Warnings").

Depending on the duration of individual estrogen therapy and the dose of estrogen used, for every 1000 women between the ages of 50 and 65, the risk of endometrial cancer increases by 5 to 55 cases.

This additional risk can be avoided by adding a progestogen for at least 12 days per cycle in monotherapy. In the MWS study, use of combination HRT for 5 years (continuous or intermittent) did not increase the risk of endometrial cancer (hazard ratio 1.0 (0.8-1.2) ).

Ovarian cancer: The risk of ovarian cancer is slightly increased with long-term use of HRT with oestrogen alone and a combination of oestrogen and progestogen. In the MWS study, out of 2500 people who used HRT for 5 years, 1 case increased.

Venous Thrombosis Risk: HRT increases the risk of developing venous thrombosis (VTE) by 1.3-3 times, i.e. deep vein thrombosis or pulmonary venous thrombosis. This phenomenon is more common during the first year of HRT use (see “Warnings”).

Risk of coronary artery disease:

The risk of coronary artery disease is slightly increased in older oestrogen-progestogen combination users (see "Warnings").

Stroke risk:

Estrogen alone and oestrogen-progestogen therapy were associated with a 1.5-fold increased relative risk of stroke. The risk of stroke was not increased during HRT use.

The relative risk did not depend on age or duration of drug use, but because the baseline risk was more age dependent, the overall risk of stroke in women taking HRT would not increase with age (see the newspaper").

Adverse reactions that have been reported in association with oestrogen-progestogen therapy (including estradiol/dydrogesterone):

Benign, malignant and unspecified tumors: Oestrogen-dependent tumors both benign and malignant, eg endometrial cancer, ovarian cancer. Progestogen-dependent tumor size increase (eg, meningioma).

Blood and lymphatic system disorders: Hemolytic anemia.

Immune system disorders: Systemic lupus erythematosus.

Metabolic and nutritional disorders: Hypertriglyceridemia.

Nervous system disorders: Increased likelihood of dementia, chorea, exacerbation of epileptic symptoms.

Eye disorders: infiltration of corneal curvature, intolerance to contact lenses.

Vascular disorders: blood clots in the arteries (arterial thrombosis).

Gastrointestinal disorders: Pancreatitis (in women with pre-existing hypertriglyceridemia).

Skin and Subcutaneous Tissue Disorders: Erythema multiforme, erythema nodosum, melasma/pimples, which may persist upon discontinuation of the drug.

Musculoskeletal and connective tissue disorders: Leg cramps.

Renal and urinary disorders: Loss of bladder control (incontinence).

Reproductive system and breast disorders: Benign breast disease, cervical erosion.

Congenital, genetic/familial disorders: Exacerbation of porphyria.

Examination/examination: Increased thyroid hormone.

Preservation

Do not store at temperatures above 30°C.

Store in original packaging and in a dry place.

Presentation and packaging

Film-coated tablets: box of 1 blister x 28 tablets.