Angeliq®

Brand Bayer Pharma AG

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Clinical Pharmacology

Anti-menopausal drug.

Angelic® contains estrogen - estradiol, which is identical to natural 17β-estradiol. Anzhelik® preparation also contains a spironolactone derivative - drospirenone, which has a gestagenic, antigonadotropic and antiandrogenic, as well as anti-mineralocorticoid action.

Angeliq® is a combination drug for hormone replacement therapy (HRT) for menopausal disorders in the postmenopausal period (natural menopause, hypogonadism, castration or premature ovarian depletion), including vasomotor symptoms (such as hot flashes, increased sweating), sleep disorders, decreased mood , irritability, atrophic changes of the urogenital tract in women with an unremoved uterus. Continuous hormone replacement therapy with Angeliq® allows you to avoid the regular withdrawal bleeding that occurs with cyclic or phase HRT.

Estradiol restores estrogen deficiency in the female body after menopause and provide effective treatment for psycho-emotional and vegetative menopausal symptoms (such as hot flushes, sweating, sleep disturbances, irritability, irritability, palpitations, false angina, dizziness, headache, decreased libido muscle and joint pain); involutions of the skin and mucous membranes, especially the urogenital system (urinary incontinence, dryness and irritation of the mucous membrane of the vagina, pain during sexual intercourse).

Estradiol prevents bone loss due to estrogen deficiency, which is mainly due to the suppression of osteoclast function and a shift in the bone remodeling process towards bone formation. It has been proven that prolonged use of HRT can reduce the risk of peripheral bone fractures in women after menopause. With the abolition of HRT, the rate of decrease in bone mass is comparable to the indicators characteristic of the period immediately after menopause. It is not proved that during the HRT can restore the bone mass to pre-menopausal level.

HRT also has a beneficial effect on the collagen content in the skin, as well as on its density, and can also slow down the formation of wrinkles. In addition, due to the antiandrogenic properties of drospirenone, Angeliq® has a therapeutic effect on androgen-dependent diseases such as acne, seborrhea, androgenic alopecia.

Drospirenone has anti-mineralocorticoid activity, increases the excretion of sodium and water, which can prevent an increase in blood pressure, weight gain, the appearance of edema, breast tenderness and other symptoms associated with fluid retention. After 12 weeks of using Angeliq®, there was a slight decrease in blood pressure (systolic - by an average of 2–4 mm Hg, diastolic - by 1-3 mm Hg). The effect on blood pressure was more pronounced in women with hypertension. After 12 months of using Angeliq®, the average body mass remained unchanged or decreased by 1.1-1.2 kg.

Drospirenone is deprived of any androgenic, estrogenic, glucocorticosteroid and antiglucocorticosteroid activity, does not affect glucose tolerance and insulin resistance. This, in combination with anti-mineralocorticoid and anti-androgenic effects, provides Drospirenone with a biochemical and pharmacological profile similar to natural progesterone.

Acceptance of Angeliq® leads to a decrease in total cholesterol and LDL cholesterol, as well as a slight increase in triglyceride levels. Drospirenone reduces the increase in triglyceride concentration caused by estradiol.

The addition of drospirenone prevents the development of endometrial hyperplasia and cancer.

Observational studies suggest that among postmenopausal women, the incidence of colon cancer is reduced when using HRT. The mechanism of action is still unclear.

Pharmacokinetics

Estradiol

Suction

After taking the drug inside estradiol is quickly and completely absorbed from the gastrointestinal tract. Exposed to the "first pass" effect to form estrone, estriol and estrone sulphate. Bioavailability when administered is about 5% and does not depend on food intake. C_max Serum estradiol is approximately 22 pg / ml and is reached after 6-8 hours. Eating does not affect the bioavailability of estradiol.

Distribution

It binds to albumin and globulin that binds sex steroids (GSM). The free fraction of estradiol in serum is about 1-12%, and the associated GSPS 40-45%. Seeming v_d after a single IV the introduction of about 1 l / kg. After repeated use, the concentration of estradiol is about 2 times higher than after a single dose, while C_ss ranges from 20 pg / ml to 43 pg / ml. After discontinuation, estradiol and estrone levels return to their original values for approximately 5 days.

Metabolism

Estradiol is metabolized mainly in the liver, partly in the intestine, kidneys, skeletal muscles and in target organs with the formation of estrone, estriol, catechol estrogen, as well as sulfate and glucuronide conjugates of these compounds, which have significantly less estrogenic activity compared to estradiol or inactive in general .

Removal

Serum estradiol clearance is about 30 ml / min / kg. Estradiol metabolites are excreted in the urine and bile. T_1/2 approximately 24 hours

Drospirenone

Suction

After oral administration, drospirenone is rapidly and completely absorbed from the gastrointestinal tract. Bioavailability is 76-85% and does not depend on food intake. Meal does not affect the bioavailability of drospirenone.

Distribution

After a single or multiple doses of 2 mg C_max in serum is reached after 1 h and is about 22 ng / ml. After that, a two-phase decrease in the concentration of drospirenone in serum with a final T is observed._1/2 about 35-39 hours. Drospirenone binds to albumin and does not bind to GSPS and the corticoid-binding globulin (CGC); about 3-5% is the free fraction. Due to the long T_1/2 C_ss It is achieved after 10 days of taking Anzhelik® daily and exceeds the concentration after a single dose by 2-3 times.

Metabolism

The main metabolites are the acidic form of drospirenone and 4,5-dihydro-drospirenone-3-sulfate, which are formed without the participation of isoenzymes of the cytochrome P450 system.

Removal

Serum drospirenone clearance is 1.2-1.5 ml / min / kg. Some of the dose received is displayed unchanged. Most of the dose is excreted by the kidneys and through the intestines in the form of metabolites in a ratio of 1.2: 1.4; T_1/2 - about 40 hours

Indications

Hormone replacement therapy for menopausal disorders in postmenopausal women.

Prevention of postmenopausal osteoporosis.

Composition

1 tablet contains:

Active substances: estradiol (in the form of hemihydrate) 1 mg; Drospirenone 2 mg.

Excipients: lactose monohydrate - 48.2 mg, corn starch - 14.4 mg, pregelatinized corn starch - 9.6 mg, Povidone C25 - 4 mg, magnesium stearate - 0.8 mg, hypromellose - 1,0112 mg, macrogol 6000 - 0 , 2024 mg, talc - 0.2024 mg, titanium dioxide - 0.5438 mg, iron dye red oxide - 0.0402 mg.

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Dosage and Administration

If a woman does not take estrogen or switches to Angeliq® from another combination drug for continuous use, she can start treatment at any time. Patients who switch to Angeliq® from the combined drug for cyclic HRT should begin taking after the end of withdrawal bleeding.

Each package is designed for a 28-day reception.

The drug should be taken daily for 1 tab. After the end of the intake of 28 pills from the current package, the next day, begin to start a new package of Angeliq®, taking the first tablet on the same day of the week as the first tablet from the previous package.

The pill is swallowed whole with a small amount of liquid.

The time of day when a woman takes the drug does not matter, but if she started taking pills at any particular time, she should stick to that time and beyond.

When you skip taking the missed pill must be taken as soon as possible. If more than 24 hours have elapsed after the usual reception time, an additional pill should not be taken. If you skip a few pills, vaginal bleeding may develop.

Adverse reactions

Most often, when using Angeliq®, such undesirable drug reactions as breast tenderness, genital tract bleeding, gastrointestinal pain and abdominal pain were observed. These reactions develop in ≥ 6% of women using the drug Angeliq®.

Irregular bleeding usually disappears with prolonged therapy. The frequency of bleeding decreases with increasing duration of treatment.

Serious adverse reactions include arterial and venous thromboembolic complications and breast cancer.

The undesirable drug reactions described in clinical trials using Anzhelik® are presented in order of decreasing severity. The incidence of adverse events was classified as follows:

very often (≥1 / 10);
often (≥1 / 10, <1/10);
infrequently (≥1 / 1000, <1/100);
rarely (<1/10 000).

Mental disorders: often - emotional lability.

From the side of the central nervous system: often - migraine.

Since the cardiovascular system: infrequently - venous and arterial thromboembolic complications (occlusion of peripheral deep veins, thrombosis and embolism / occlusion of the pulmonary vessels, thrombosis, embolism and myocardial infarction / cerebral infarction and stroke, except for hemorrhagic).

From the digestive system: often - gastrointestinal pain, abdominal pain.

From the reproductive system: very often - pain in the mammary glands (including discomfort in the mammary glands), bleeding from the genital tract; often - cervical polyp; infrequently - breast cancer *.

* - Data on the relationship with the use of the drug were obtained from the results of post-marketing observations; frequency data were obtained from clinical studies using Angelik®.

For more information on venous and arterial thromboembolic complications, breast cancer and migraine, see "Contraindications" and "Special Instructions".

Adverse reactions that occur in isolated cases, or the symptoms of which develop very long after the start of therapy and which are considered to be associated with the use of drugs from the group of combined means for continuous HRT: liver tumors (benign and malignant); hormone-dependent malignant tumors or hormone-dependent precancerous diseases (if it is known that the patient has similar conditions, this is a contraindication to the use of Anzhelik®); cholelithiasis; dementia; endometrial cancer; arterial hypertension; abnormal liver function; hypertriglyceridemia; changes in glucose tolerance or the effect on peripheral insulin resistance; increase in the size of uterine fibroids; endometriosis reactivation; prolactinoma; chloasma; jaundice and / or pruritus associated with cholestasis.

The occurrence or deterioration of conditions for which the relationship with the use of HRT is not exactly proven: epilepsy; benign breast diseases; bronchial asthma; porphyria; systemic lupus erythematosus; otosclerosis, small chorea.

In women with hereditary angioedema, exogenous estrogens may exacerbate the symptoms.

Hypersensitivity reactions (including symptoms such as rash and urticaria) have also been noted.

For more information on serious adverse events associated with hormone replacement therapy, see "Special Instructions".

Contraindications

It is not recommended to start taking Angeliq® in the presence of any of the following conditions; If any of these conditions occur while taking Angeliq®, you should immediately stop using the drug:

hypersensitivity to the components of Angeliq®;
vaginal bleeding of unknown etiology;
history of confirmed or suspected breast cancer or breast cancer;
confirmed or suspected diagnosis of a hormone-dependent precancerous disease or a hormone-dependent malignant tumor;
benign or malignant liver tumors (including history);
severe liver disease;
severe kidney disease now or in history or acute renal failure (until normalization of renal function);
acute arterial thrombosis or thromboembolism (including those leading to myocardial infarction, stroke);
deep vein thrombosis in the acute stage, venous thromboembolism at present or in history;
high risk of venous and arterial thrombosis;
pulmonary embolism;
severe hypertriglyceridemia;
pregnancy and lactation;
children and adolescents up to 18 years;
congenital lactase deficiency, lactose intolerance, glucose-galactose malabsorption.

Angelica® should be prescribed with caution in the following diseases: arterial hypertension, congenital hyperbilirubinemia (Gilbert, Dubin-Johnson and Rotor syndromes), cholestatic jaundice or cholestatic itch during a previous pregnancy, endometriosis, uterine myoma, diabetes mellitus. It is necessary to take into account that estrogens alone or in combination with gestagens should be used with caution in the following diseases and conditions: smoking, hypercholesterolemia, obesity, systemic lupus erythematosus, dementia, gallbladder disease, retinal thrombosis, moderate hypertriglyceridemia, edema in chronic heart disease insufficiency, severe hypocalcemia, endometriosis, bronchial asthma, epilepsy, migraine, porphyria, liver hemangiomas, hyperkalemia, conditions predisposing to the development of hypo erkalemia, taking drugs that cause hyperkalemia (potassium-saving diuretics, potassium drugs, ACE inhibitors, angiotensin II receptor antagonists and heparin).

Drug interactions

Long-term treatment with drugs that induce liver enzymes (for example, some anticonvulsant and antimicrobial drugs) can increase the clearance of sex hormones and reduce their clinical efficacy. A similar property - to induce liver enzymes - was found in hydantoins, barbiturates, primidone, carbamazepine and rifampicin, the presence of this feature is also expected in oxcarbazepine, topiramate, felbamate and griseofulvin. The maximum induction of enzymes is usually observed not earlier than in 2-3 weeks, but then it can persist for at least 4 weeks after stopping the drug.

In rare cases, a background of some antibiotics (for example, penicillins and tetracyclines) was observed, with a decrease in estradiol levels.

The major metabolites of drospirenone are formed in plasma without the participation of the cytochrome P450 system. Therefore, the effect of inhibitors of the cytochrome P450 system on the metabolism of drospirenone is unlikely. However, CYP3A4 inhibitors (for example, cimetidine, ketoconazole) can inhibit the metabolism of estradiol.

Based on in vitro interaction studies, as well as an in vivo study in female volunteers taking omeprazole, simvastatin and midazolam as markers, it can be concluded that the effect of drospirenone in a dose of 3 mg on the metabolism of other medicinal substances is unlikely.

The use of Angelica in women receiving antihypertensive therapy (for example, ACE inhibitors, angiotensin II receptor antagonists, hydrochlorothiazide), may slightly increase the antihypertensive effect.

An increase in the level of serum potassium in combination with Angelica and NSAIDs or antihypertensive drugs is unlikely. The combined use of the above three types of drugs can lead to a slight increase in serum potassium, more pronounced in women with type 1 and type 2 diabetes.

Excessive alcohol intake during HRT may lead to an increase in circulating estradiol levels.

Pregnancy and Lactation

HRT is contraindicated during pregnancy and lactation. If pregnancy is detected while taking Angeliq®, the drug should be immediately canceled. A small amount of sex hormones can be excreted in breast milk.

Special instructions

Angelic® is not used for contraception.

If contraception is necessary, non-hormonal methods should be used (except for calendar and temperature methods). If you suspect a pregnancy, pill should be suspended until pregnancy is excluded.

If any of the following conditions or risk factors are present or worsening, before you start or continue taking Angeliq®, the ratio of the individual risk and benefit of treatment should be evaluated.

When prescribing HRT to women with several risk factors for thrombosis or a high degree of severity of one of the risk factors, the possibility of mutual reinforcement of the action of risk factors and prescribed treatment for the development of thrombosis should be considered. In such cases, the total value of the existing risk factors increases. If there is a high risk, Angelik® is contraindicated.

Venous thromboembolism

In a number of controlled randomized, as well as epidemiological studies, an increased relative risk of developing venous thromboembolism (VTE) was revealed in the presence of HRT, i.e. deep vein thrombosis or pulmonary embolism. Therefore, when prescribing Angeliq® to women with VTE risk factors, the ratio of the risk and benefit of treatment should be carefully weighed and discussed with the patient.

Risk factors for VTE include an individual and family history (the presence of VTE in immediate relatives at a relatively young age may indicate a genetic predisposition) and severe obesity.

The risk of VTE also increases with age. The question of the possible role of varicose veins in the development of VTE remains controversial. The risk of VTE may temporarily increase with prolonged immobilization, "large" planned and traumatic operations or massive injury. Depending on the cause or duration of immobilization, the question of whether to temporarily stop taking Angeliq® should be resolved.

Treatment should be discontinued immediately if symptoms of thrombotic disorders appear or if they are suspected.

Arterial thromboembolism

In the course of randomized controlled trials with prolonged use of conjugated equine estrogens (CEE) and medroxyprogesterone acetate (MPA), no evidence of a positive effect on the cardiovascular system was obtained. In large-scale clinical trials of this compound, a possible increase in the risk of coronary artery disease in the first year of use was revealed, followed by the absence of a positive effect. In one large clinical study using only TLE, a potential reduction in the incidence of coronary artery disease among women aged 50–59 years was found, with no overall positive effect among the cumulative study population. As a secondary result in two large-scale clinical studies using CEA as monotherapy or in combination with MPA, a 30–40% increase in the risk of stroke was detected. Therefore, it is not known whether this increased risk extends to drugs for hormone therapy containing other types of estrogens and progestogens or to non-oral methods of administration.

Endometrial cancer

Long-term estrogen monotherapy increases the risk of endometrial hyperplasia or carcinoma. Studies have confirmed that adding progestogens reduces the risk of endometrial hyperplasia and cancer.

Mammary cancer

According to clinical trials and observational studies, an increase in the relative risk of developing breast cancer in women using HRT for several years has been found. This may be due to an earlier diagnosis, accelerated growth of an existing tumor on the background of HRT, or a combination of both factors.

The relative risk increases with increasing duration of therapy, but may be absent or be reduced when treated with estrogen alone. This increase is comparable to the increased risk of breast cancer in women with a later onset of natural menopause, as well as obesity and alcohol abuse. The increased risk gradually decreases to the usual level for several (but most of the five) years after the termination of HRT.

Assumptions regarding the increase in the risk of developing breast cancer are made on the basis of the results of more than 50 epidemiological studies (the risk varies from 1 to 2).

In two large-scale randomized studies with KLE, separately or with constant combination with MPA, risk estimates were obtained equal to 0.77 (95% confidence interval: 0.59-1.01) or 1.24 (95% confidence interval: 1.01-1, 54) after about 6 years of using HRT. It is not known whether this increased risk also applies to other products for HRT.

HRT increases the mammographic density of the mammary glands, which in some cases may have a negative effect on the x-ray detection of breast cancer.

Liver tumor

Against the background of the use of sex steroids, which include drugs for hormone replacement therapy, benign and, even more rarely, malignant tumors of the liver have been observed in rare cases. In some cases, these tumors led to life threatening intra-abdominal bleeding. For pain in the upper abdomen, an enlarged liver, or signs of intra-abdominal bleeding, a differential diagnosis should take into account the likelihood of a liver tumor.

Cholelithiasis

It is known that estrogen increases the lithogenicity of bile. Some women are predisposed to the development of cholelithiasis with estrogen therapy.

Dementia

There are limited data from clinical studies on the possible increase in the risk of dementia in women who are starting a medication containing CLE, 65 years of age or older.As observed in studies, the risk may be reduced if the administration of drugs for HRT containing CLE is begun in early menopause. It is not known whether it is spreading to other drugs for HRT.

Other states

Treatment should be discontinued immediately if migraine-like or frequent and unusually severe headaches appear for the first time, as well as when other symptoms appear — possible harbingers of a cerebral thrombotic stroke.

The relationship between HRT and the development of clinically severe arterial hypertension has not been established. In women taking HRT, a slight increase in blood pressure has been described, a clinically significant increase is rare. However, in some cases, with the development of persistent clinically significant arterial hypertension while receiving HRT, the withdrawal of HRT may be considered. In women with elevated blood pressure, there may be a slight decrease in blood pressure while taking the drug Angeliq®. In women with normal blood pressure, significant changes in blood pressure are not expected.

In renal failure, the ability of potassium excretion may decrease. Drospirenone intake does not affect serum potassium concentration in patients with mild or moderate renal failure. The risk of developing hyperkalemia is theoretically impossible to exclude only in the group of patients whose serum potassium concentration before treatment was determined on VGN, and who additionally take potassium-sparing drugs.

With mild abnormal liver function, including various forms of hyperbilirubinemia, such as Dubin-Johnson syndrome or Rotor syndrome, require physician supervision as well as periodic liver function tests. At deterioration of indicators of function of a liver drug Angelik® should be canceled.

When recurrent cholestatic jaundice or cholestatic pruritus, observed for the first time during pregnancy or prior steroid hormone treatment, taking Angeliq® should be immediately stopped.

Special care is needed for women with increasing triglyceride concentrations. In such cases, the use of HRT may cause a further increase in the concentration of triglycerides in the blood, which increases the risk of acute pancreatitis.

Although HRT may affect peripheral insulin resistance and glucose tolerance, it is usually not necessary to change the treatment regimen for diabetics when performing HRT. However, women with diabetes mellitus should be monitored during HRT.

In some patients, unwanted manifestations of estrogen stimulation, such as abnormal uterine bleeding, may develop under the influence of HRT. Frequent or persistent pathological uterine bleeding during treatment is an indication for the study of the endometrium in order to exclude diseases of an organic nature.

Under the influence of estrogen, uterine fibroids may increase in size. In this case, treatment should be discontinued.

It is recommended to stop treatment in case of endometriosis recurrence with HRT.

If you suspect the presence of prolactinomas before the start of treatment, this disease should be excluded. If prolactinomas are detected, the patient should be under close medical supervision (including periodic evaluation of the drug concentration).

In some cases, chloasma may be observed, especially in women with a history of chloasma in pregnant women. During Anzhelik® therapy, women with a tendency to chloasma should avoid prolonged exposure to the sun or ultraviolet radiation.

The following conditions may occur or worsen in the background of HRT, and women with these conditions during HRT should be under the supervision of a physician: epilepsy, benign breast tumor, bronchial asthma, migraine, porphyria, otosclerosis, systemic lupus erythematosus, minor trocha.

In women with hereditary forms of angioedema, exogenous estrogens can cause or worsen the symptoms of angioedema.

Additional Information

No data on the need for dose adjustment in women under 65 years of age.At use of the drug Anzhelik® for women over 65 years should take into account the information presented in the subsection "Dementia".

In women with mild or moderate liver failure, drospirenone is well tolerated.

In women with mild and moderate renal impairment, there was a slight slowdown in the elimination of drospirenone, which was not of a clinically significant nature.

Preclinical safety data Preclinical data obtained in the course of standard studies to identify toxicity with repeated doses of the drug, as well as genotoxicity, carcinogenic potential and toxicity to the reproductive system, do not indicate the presence of a particular risk to humans. However, it should be remembered that sex steroids can promote the growth of certain hormone-dependent tissues and tumors.

Medical examination

Before starting or resuming the taking of Anzhelik®, you should familiarize yourself with the patient's medical history and conduct a physical and gynecological examination. The frequency and nature of such examinations should be based on existing standards of medical practice, taking into account the individual characteristics of each patient (but not less than 1 time in 6 months) and should include measurement of blood pressure, assessment of the mammary glands, abdominal organs and pelvic organs, including cytological study of the epithelium of the cervix.

In the presence of prolactinoma, periodic determination of prolactin concentration is required.

Impact on laboratory results

Acceptance of sex steroids can affect the biochemical indicators of liver, thyroid, adrenal glands and kidney function, the plasma content of transport proteins such as globulin, sex hormone binding and lipid / lipoprotein fractions, carbohydrate metabolism, coagulation and fibrinolysis. Angeliq® does not adversely affect glucose tolerance.

Impact on the ability to drive vehicles and other mechanisms that require high concentration of attention

Not found.

Overdosage

Studies of acute toxicity did not reveal the risk of acute side effects if you accidentally take the drug in an amount many times higher than the daily therapeutic dose. In clinical studies, the use of drospirenone up to 100 mg or combined estrogen / progestin drugs with a content of 4 mg of estradiol was well tolerated.

Symptoms that may occur during overdose: nausea, vomiting, vaginal bleeding.

Treatment: There is no specific antidote, if necessary, symptomatic therapy is carried out.