Climara Fort 4 Flaster (Estradiol)

Climara

Pharmacological properties

Pharmacodynamic properties

Loss of ovarian function accompanied by decreased estrogen production leads to certain menopausal syndrome with vasomotor-vegetative and organic symptoms. Hormone replacement therapy aims to eliminate these complaints. Estradiol is the most potent in all physiological estrogens, showing the highest affinity to the estrogen receptor.

Like other steroid hormones, estrogen acts by regulating the transcription of a limited number of genes in estrogene-sensitive target organs, especially the uterus, hypothalamus, pituitary, vagina, urethra, breast, bones (osteoclasts). Following diffusion of the cell membrane, estradiol binds to the estrogen receptor with high affinity. Following activation of the estradiol ligand, the hormone receptor complex is translocated into the core. This complex binds to DNA sequences (hormone response elements) that accelerate transcription of neighboring genes. The number of proteins produced by Estrogen is not exactly known, but is estimated to be between 50-100.

Following menopause, the production of estradiol in women is reduced significantly. The remaining estradiol is mainly synthesized by the aromatization of androstenedione from precursors produced in the adrenal cortex and, less frequently, testosterone via the aromatase enzyme, respectively, as estrone and estradiol. Estron is converted to estradiol by means of 17-hydroxysteroid-dehydrogenase enzyme. Both enzymes are found in fat and muscle tissues and liver. The ratio of estradiol / estrone was greater than 1 in premenopausal women and about 0.2 in postmenopausal women.

Climacteric complaints can be improved by an estrogen replacement therapy with an average of 25-100 μg of estradiol per day via the transdermal route.

Estrogen doses required for the recovery of menopausal complaints show a dose-dependent stimulating effect on endometrium proliferation and mitosis regardless of the route of administration. Estrogen monotherapy increases the incidence of endometrial hyperplasia and thus increases the risk of endometrial cancer. For women who have not had hysterectomy, a 10-14 day cyclic progestagen treatment is recommended for the prevention of endometrial hyperplasia.

Pharmacokinetic properties

Following the dermal application of Climara, estradiol is well absorbed from the skin. An average absorption rate of 100 orpg per day was calculated for Climara.

During the weekly administration of Climara, regular estradiol and estrone serum level profiles are obtained in the desired range. As a result of repeated weekly applications, no accumulation of these substances was observed. After the application of 12.5 cm², approx. The mean serum levels of estradiol in the constant equilibrium, found at 35 pg / ml, indicate that the absolute height of the estradiol serum level profile is directly proportional to the patch area.

The metabolites of estradiol are mainly excreted in the form of sulphate and glucuronides.

Indications

Hormone replacement therapy (HRT) in the treatment of signs and symptoms of estrogen deficiency due to natural menopause or castration.

Prevention of postmenopausal osteoporosis.

Contraindications

Do not start HRT in the presence of the following conditions. If any of these conditions occur during HRT use, the treatment should be discontinued immediately:

• Pregnancy and lactation

• Unspecified abnormal genital bleeding

• Breast cancer or suspicion

• Pre-malignant conditions or suspicion of malignant disease or suspicion of sex hormones

• Liver tumor presence (benign or malignant)

• Acute arterial thromboembolism (eg. myocardial infarction, stroke)

• Active deep vein thrombosis, thromboembolic disorders, or a history documented for them.

• Hypersensitivity to any of the Climara patch components.

Warnings / precautions

An individual benefit / risk analysis should be performed before starting or continuing HRT if the following conditions / risk factors are present or deteriorating.

• Venous thromboembolism

Both randomized and epidemiological studies suggest that HRT may cause a relative risk increase for the development of venous thromboembolism (VTE; deep vein thrombosis or pulmonary embolism). While HRT treatment is recommended for women at risk for venous thromboembolism, the benefit / risk ratio should be carefully evaluated.

The risk factors generally defined for VTE are family history (VTE that occurs at a relatively early age, may indicate a genetic displacement) and obesity. The risk of VTE increases with age. There is no opinion about the possible role of varicose veins in VTE.

The risk of VTE may be increased temporarily by prolonged immobilization, major elective or posttraumatic surgical intervention or major trauma. Depending on the condition of the event and the duration of immobilization, HRT may be temporarily interrupted.

Treatment should be stopped immediately if there is any suspicion or suspicion of a thrombotic event.

• Arterial thromboembolism

A large clinical trial with conjugated mare estrogens (PPE) and medroxyprogesterone acetate (MPA) combination showed a possible risk increase for coronary heart disease in the first year of use and no benefit was identified during the subsequent use. In another clinical study using only PPE, there was a potential reduction in coronary heart disease rates among women 50-59 years of age, but all women participating in the study did not show additional benefit as arterial. Two major clinical trials of PPE alone or in combination with MPA showed a 30-40% increase in stroke risk as a secondary finding. It is unclear whether these findings are valid for other hormone replacement therapy products or non-oral routes of administration.

• Endometrial cancer

Prolonged untreated estrogen effect increases the risk of developing endometrial hyperplasia or carcinoma. Studies have shown that the addition of progestogens to treatment eliminates this increased risk.

• Breast cancer

Clinical and observational studies have reported an increased risk of breast cancer diagnosis for women using HRT for years. These findings may be due to earlier diagnosis, the growth-stimulating effect of HRT on previously existing tumors, or a combination of both. The relative risk of breast cancer diagnosis was estimated between 1 and 2 in the majority of more than 50 epidemiological studies.

Relative risk is directly proportional to increased treatment time. Only the use of estrogen-containing products reduces or does not affect this risk.

Two large randomized trials in which PPEs were used alone or in combination with MPA showed a risk estimation of 0.77 (95% confidence interval, 0.59 - 1.01) and 1.24 (95% confidence interval, 1.01 - 1.54) after 6 years of HRT use. The adaptability of this risk increase to other HRT products is not known.

Similar increases in the diagnosis of breast cancer, late menopause, alcohol use, obesity have been shown in the presence of factors such as. Increased risk disappears within a few years following the discontinuation of HRT.

In most studies, tumors diagnosed with women using or using HRT have been reported to tend to differentiate better than non-users. Findings about the spread of the tumor outside the breast is not certain.

In some cases, hormone replacement therapy may increase the density of mammographic images and adversely affect the radiological findings of breast cancer.

• Ovarian cancer In

an epidemiological study, women with long-term (longer than 10 years) estrogen replacement therapy (ERT) showed a slight increase in the risk of ovarian cancer. In addition, a meta-analysis of 15 studies examining ERT did not reveal an increased risk of ovarian cancer. Therefore, the effect of ERT on ovarian cancer is not clear.

• Liver tumor The

use of hormonal agents similar to those contained in HRT products has been observed in rare cases with benign and very rarely malignant liver tumors. In limited cases, these tumors cause life-threatening intra-abdominal bleedings. In case of severe upper abdominal pain, liver enlargement or signs of intraabdominal bleeding, a liver tumor should be considered in the differential diagnosis.

• Gallbladder

Estrogens are known to increase the lithogenesis of saffron. Some women are prone to gallbladder disease during estrogen treatment.

• Dementia

Findings from clinical trials provide evidence that the initiation of PPE-containing products in women aged 65 years or older may increase the risk of hormone treatment with possible dementia. This risk may decrease if the treatment is initiated in the early menopause period, as observed in other studies. The adaptability of these findings to other HRT products is not known.

• Other conditions The

treatment should be stopped immediately if symptoms similar to migraine or frequent and unusual severe headaches occur for the first time, or if there are possible symptoms of a cerebrovascular occlusion.

The decision to discontinue transdermal treatment should be taken into account if repetitive, permanent skin irritations are observed (eg, persistent erythema, or itching).

There is no general relationship between the use of HRT and the development of clinical hypertension. Small increases in blood pressure have been reported in women receiving HRT, with clinical-related increases being rare. However, HRT should be considered in patients with clinically significant prolonged hypertension during HRT use.

Sex steroids may be inadequately metabolized in patients with impaired liver function. While transdermally administered HRT is not affected by liver first-pass metabolism, HRT should be administered with caution in such patients.

Re-emergence of cholestatic jaundice or cholestatic pruritus, which occurred during pregnancy for the first time or during the use of sex steroids, requires immediate discontinuation of HRT.

During HRT use, some patients may develop undesirable symptoms such as abnormal uterine bleeding by estrogenic stimulation. Frequent recurrent or persistent abnormal uterine bleeding during treatment is an indication for endometrial evaluation.

Under the influence of estrogen uterine fibroids can grow. If this is observed, treatment should be discontinued.

If endometriosis is reactivated during treatment it is recommended to discontinue treatment.

In cases of suspected prolactinoma, this possibility should be ruled out before starting treatment.

Chloasma may sometimes develop in women with a history of chloasma gravidarum. Women with a tendency to chloasma should avoid sunlight or ultraviolet rays when using HRT.

The following cases have been reported to occur or deteriorate during HRT use. Although there is no evidence of its association with HRT use, women with these complaints and those receiving HRT should be carefully monitored:

Epilepsy

Benign breast disease

Asthma

Migraine

Porphyria

Otosclerosis

Systemic lupus erythematosus

Korea minor

Pregnancy and lactation

The use of HRT during pregnancy and lactation is contraindicated.

Extensive epidemiological studies with steroid hormones used for contraception and hormone replacement therapy have not shown any increase in the risk of congenital defect in children of women who have used such hormones before pregnancy, nor have they shown a teratogenic effect during their early pregnancy.

Low amounts of sex hormone can pass into milk.

Pregnancy category is X.

Effects

on the use of the machine and machinery

Side effects / adverse effectsYan

Serious adverse effects associated with the use of HRT are indicated in the section ciddi Warnings / precautions.

The following table indicates the adverse effects of Climara. The frequency of the effects indicated was taken from the clinical study results. In clinical studies, the most commonly reported adverse reaction with Climara is skin irritation at the site where the patch is adhered and sensitivity in the breasts (> 10%). Side effects at the site are typically mild and may include erythema, itching, stinging sensations or vesicle formation. The most common adverse reactions seen with Climara are summarized in the following tables: