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Neofolin Injection

SUMMARY OF PRODUCT CHARACTERISTICS 


1. NAME OF THE MEDICINAL PRODUCT
NEOFOLLIN
Solution for injection

2. QUALITATIVE AND QUANTITATIVE COMPOSITION 
Estradioli valeras 5 mg in 1 mL of oil solution

3. PHARMACEUTICAL FORM
Solution for injection
Clear, light yellowish or yellow-green oil solution 

4. CLINICAL PARTICULARS
4.1 Therapeutic indications
Hormone replacement therapy is used in case of estrogens deficiency (hypoestrogenism), for example, in primary or secondary amenorrhoea due to hormonal disorders in order to achieve the endometrial proliferation. The lack of ovarian estrogens has to be proven by their low plasma levels, negative progesterone test, endometrial atrophy and hypoestrogen image in the vaginal cytology. Therapy may be initiated after the exclusion of pregnancy, or in secondary amenorrhea at earliest 8 weeks after the last menstrual period. Replacement therapy is used at early ovarian function failure (premature menopause) before 40th year and after 40th year of age, e.g. at ovariectomy or radio-castration due to non-tumorous diseases. Replacement therapy in general and local development disorders caused by hypoestrogenism (eunuchoid growth, genital infantilism, uterine hypoplasia). Stop of dysfunctional uterine bleeding. Estrogen test.

4.2 Posology and method of administration
Irregularities of the menstrual cycle in the first years after menarche: on 4th, 11th and 18th day of cycle 2 mL of Neofollin (10 mg of estradiol valerate) i.m., on 18th day together with progesterone.
Replacement therapy of primary amenorrhea: 2 mL of Neofollin (10 mg of estradiol valerate) i.m. after 14 days add progesterone.
Replacement therapy in Turner syndrome: 2 mL of Neofollin (10 mg of estradiol valerate) i.m. On 1st, 8th and 15th day of cycle, combine with progesterone on 15th and 22nd day of cycle. After the initiation of bleeding 2 mL of Neofollin (10 mg of estradiol valerate) i.m. on day 4th, 11th and 18th day of cycle, on 18th and 25th day of cycle add progesterone.
Replacement therapy of a longterm secondary amenorrhea in fertile age, proven lack of endogenous estrogens and positive estrogen test: 2 mL of Neofollin (10 mg of estradiol valerate) i.m. on 1st, 8th and 15th day of cycle, on 15th and 22nd day of cycle add progesterone. After reaching the effects (uterine bleeding) the dose in subsequent cycles is reduced. Usually it is enough to administer 2 mL of Neofollin on 8th day of cycle and on 15th day again with progesterone. After the evocation of menstrual cycle it is enough to combine 1 – 2 mL of Neofollin together with progesterone on 18th day. After 3 - 6 cycles apply on 18th day progesterone alone. If no bleeding occurs, progesterone test is performed to verify the endogenous production of estrogens. 
Replacement therapy in secondary amenorrhea and negative estrogen test: 7-10 weeks 2-4 mL of Neofollin (10 - 20 mg of estradiol valerate) i.m. once a week. In the last week add progesterone.
Stop of dysfunctional bleeding: 2 mL of Neofollin (10 mg of estradiol valerate) i.m. together with proges-terone.
Estrogen test: 2 mL of Neofollin once weekly for 3-4 weeks. In a positive test, uterine bleeding occurs within 14 days after the last injection.
Injections of Neofollin are applied by deep intramuscular injection.
Estrogen without progesterone can be used for long-term treatment of women after hysterectomy only. In women with an intact uterus, estrogen therapy must always be combined with the application of progesterone to protect against endometrial over-stimulation. In view of the physiological production (estrogens 0.05 mg / day, progesterone 25 mg / day), the ratio of estrogen / progesterone during combination therapy should be 1:50. Cyclical, estrogen - progesterone therapy (e.g. 15 days estrogens, 7 to 10 days estrogens plus progesterone, 7 days nothing) maintains monthly bleeding, thus the risk of endometrial hyperplasia and carcinoma is reduced. Alternatively, estrogens can be applied continuously together with progesterone. In longer duration endometrium atrophies and menstruation should not occur. This route of administration of estrogen was introduced in order to induce amenorrhea in combined estrogen - progesterone therapy. However it seems to be less physiological and all its positive and adverse effects are not verified.
In ovarian insufficiency estrogens should be used in the lowest possible dose and in possible shortest time. Temporary administration of larger amount of estrogens (doubled maintenance dose) may be re-quired for the induction of fully developed secondary sexual characteristics in girls or to control menopausal symptoms.
Even higher doses are used parenterally (together with progesterone) in some types of uterine bleeding.
In women with premature menopause the replacement therapy has to be lasting at least till the age of natural menopause.
There are no indications for the use of estradiol in newborn babies. Estradiol was occasionally used to inhibit growth in high girls, but the benefits of this therapy are uncertain. As side effects in this therapy often occur nausea, increased body weight and menorrhagia.

4.3 Contraindications
Pregnancy. Active thromboembolic diseases. Liver diseases, liver tumours - existing or in anamnesis. Hepatopathy. Carcinomas and precancerosis of urogenital tract and mammary gland, particularly cystic mastopathy (also in family or personal anamnesis). Suspected TB of genitals. Undiagnosed vaginal bleeding. Uterine bleeding caused by high level of estrogens.

4.4 Special warnings and precautions for use
Administration of estradiol without concomitant administration of progesterone is in women with a functioning uterus associated with an increased risk of endometrial hyperplasia and endometrial cancer as a result of excessive growth stimulation of endometrium. Size of this risk depends on the dose and duration of treatment. During therapy by estradiol a serious abnormal uterine bleeding may occur. To exclude the presence of cancer, endometrial biopsy is needed. Women who received or receive estrogens for a long time, have to be examined annually on regular basis (breasts, genitals). All estrogen drugs especially at the beginning can cause slight side effects such as breast tension and hypertrophy, mastalgia, slight vaginal bleeding, fluid and sodium retention, weight gain, headache, paresthesia and nausea. These effects are dose dependent and often spontaneously disappear during long-term therapy.
Cardiovascular and cerebro-vascular diseases, thrombophlebitis. Estrogenic therapy may increase the risk of thrombosis. Natural estrogens do not seem themselves to be thrombogenic, even though in sus-ceptible individuals they may predispose creation of thromboembolic conditions. Estrogen therapy should be completed about 6 weeks before scheduled surgery.
Hypertension. Some estrogen medicinal products increase plasma renin activity, stimulate the synthesis of renin substrates, and their use is associated with an increased incidence of hypertension.
Liver diseases. Estrogens have multilateral metabolic effect on the liver and therefore their use is contra-indicated, if the liver functions are impaired. They can facilitate the formation of gallstones.
Endometrial hyperplasia. It is considered to be a potential precancerosis because sometimes it progrades in endometrial cancer. Since estradiol also stimulates the growth of hyperplastic endometrium, it is contraindicated in endometrial hyperplasia.
Herpes gestationis. Hemoglobinopathy. In diseases such as sickle cell disease the risk of occurrence of thromboembolic complications may be increased.
Porphyria. Estrogens stimulate the hepatic synthesis of porphyrins. Replacement therapy by estradiol may induce porphyria attacks.
Pruritus or pemphigoid gestationis may occur during pregnancy as a result of high level of estrogens.
Otosclerosis, migraine, diabetes, hypercalcemia can be exacerbated by estrogen.
Glucose tolerance may be slightly reduced, although the emergence of manifest diabetes is not prob-able.
Caution is needed in using of estrogen in patients with asthma, epilepsy, migraine, heart and kidney dis-eases due to water retention, which can be caused by estrogens. In children caution is necessary be-cause of possible closure of epiphyseal gaps of long bones.
Elderly. Some female patients can get estradiol because of postmenopausal osteoporosis also in the 6th to 7th decade of life. This therapy may be associated with an increased risk of endometrial hyperplasia and cancer. After discontinuation of estrogen therapy increases the breakdown of bone, which can lead to increased risk of fractures.
All absolute and relative contraindications were formulated particularly on the base of experiences with the use of estrogens as a contraceptive and in the treatment of prostate and mammary gland carcinomas. Due to the different dosage and different production of endogenous hormones the doctor is authorized to review individually the validity of these contraindications in estrogen replacement therapy, especially with regard to the incidence of adverse cardiovascular and hepatic effects.

4.5 Interaction with other medicinal products and other forms of interaction
Potentially dangerous interactions. Smoking increases the risk of thromboembolic complications in women undergoing estrogen therapy. However it does not reduce the effectiveness of estradiol therapy. Estrogens may increase the toxicity of chlorpromazine (amplification of cholestatic effect).
Other significant interactions. These are mostly the information about oral contraceptives. Very few data is available on the interaction of estradiol itself. Interaction with all medical products can be assumed that have the same metabolic routes in hepatic biotransformation and biliary excretion. Medical products such as rifampicin, barbiturates and phenytoin, which induce the synthesis of hepatic enzymes, increase the speed of metabolism of estrogens. On the contrary, estrogens may increase the activity of phenytoin and other drugs degraded by microsomal enzymes by inhibiting their metabolism. Long-term use of antibiotics may reduce the effectiveness of estrogen preparations by acceleration of their metabolism due to induction of microsomal enzymes. Destruction of intestinal flora the antibiotics can prevent enterohepatic circulation of estrogens. Estrogens may alter the therapeutic effect of antidiabetic agents, anticonvulsants and antihypertensives.
Interference with laboratory tests. Estradiol may affect thyroid function tests, plasma cortisol levels and the determination of 17-ketosteroids in urine by increasing the concentration of transport proteins. 
Neofollin causes false positivity or higher values of BSP determination, corticosteroids in plasma, protein-bound iodine and uptake of radioiodine by thyroid gland. On the other hand, it causes false negativity or lower values in determining the 17-hydroxy- and keto-steroids in urine.

4.6 Fertility, pregnancy and lactation 
Although the teratogenic effect of estradiol in humans is not directly proven, other estrogens, mainly diethylstilbestrol, have a teratogenic effect. In some animal species also estradiol has teratogenic effects. For these reasons, the estradiol should not be used during pregnancy. There are few indications for the use of estradiol in lactating mothers. Estradiol is excreted into breast milk, but its amount is very small, probably less than 0.02 % of the dose received by the mother. It means that estradiol can be administrated to mothers during lactation.

4.7 Effects on ability to drive and use machines
There is no presumption of affecting attention.

4.8 Undesirable effects
The incidence of undesirable effects depends on the age of female patient, in particular concerning symptoms of enhanced physiological effects of estrogen. Part of the undesirable effects arises as a result of hepatic metabolism of estradiol.
Potentially life-threatening undesirable effects. Administration of estradiol without concomitant administration of progesterone in women with a functioning uterus is associated with an increased risk of endometrial hyperplasia and endometrial cancer as a result of excessive growth stimulation of endometrium. Size of this risk depends on the dose and duration of treatment. It is smaller in the combined therapy of estrogen - progesterone. It is possible that the risk occurrence of endometrial cancer in long-time application of estrogen is exaggerated in retrospective clinical studies, regarding the problems with adequate control group. In addition, an increased incidence of endometrial cancer in women receiving long term estrogen treatment is not connected with increased mortality. This is obviously an increased incidence of forms of carcinoma with low malignancy that are difficult to be distinguished histologically from various forms of hyperplasia. According to some clinical studies, estrogen therapy may increase also the risk of mammary gland cancer. Other studies, however, did not confirm the association between application of estrogens and mammary gland carcinoma. Unconfirmed is also an increased risk of hepatic cancer. Experimentally proven is a correlation between the application of steroids and the development of benign and malignant liver tumors. Some clinical studies have also documented a possible association between oral estrogen therapy and an increased risk of liver tumors. However, other studies have not confirmed this dependence. Clearly documented is an increased risk of vaginal adenocarcinoma in girls who have come into contact with diethylstilboestrol in utero. This effect may be, however, a specific diethylstilbestrol effect. While taking oral contraceptives, benign and malignant liver tumors appear too. It is not clear whether this is a causal relationship or a random association. Estrogens significantly affect the cardiovascular system. Estrogen therapy increases risk for venous thromboembolic complications. The risk of arterial thrombosis, including ischemic heart disease is not proven clearly. Higher doses used to treat prostate cancer in men or to suppress lactation in women induced hypertension and a variety of thromboembolic complications (myocardial infarct, pulmonary embolism, ictus). According to some studies, these adverse effects were found even at the use of contraceptives. An increased incidence of thromboembolic complications oc-curred mainly in connection with the use of first-generation contraceptives with estrogens content of more than 80 µg. The introduction of new contraceptives with low doses of estrogen visibly reduced the incidence of thromboembolic complications. Although contraceptives cause significant changes of several haemostatic factors, mostly those are the changes in the range of normal values and their clinical significance is questionable. Increased risk of occurrence of cardiovascular diseases may be associated with the induction of insulin resistance syndrome, i.e. combination of hyperinsulinemia, reduced glucose tolerance, hypertriglyceridemia, decreased concentrations of high-density lipoproteins and increased concentrations of low-density lipoproteins, and hypertensions. Depending on the type of the used steroids and on the dose, oral contraceptives may induce the creation of all the features of insulin resistance syndrome. Reduction of estrogens content and progesterone component modification led to the removal of unwanted effect on high density lipoproteins and on blood pressure. The risk of occurrence of hypertriglyceridemia and insulin resistance, mainly caused by estrogens, however, remained. It can be seen, however, that the positive effects of estrogens on the vascular wall exceed some adverse metabolic effects. However, estrogen replacement therapy is probably not associated with an increased risk of hypertension and thromboembolic complications. Effect of estrogens on the cardiovascular system does not depend only on the dose and the duration of therapy, but also on sex of a patient, and in women, whether they are or are not post-menopausal. In men, administration of estrogens in the indication of prostate cancer has been associated with increased cardiovascular mortality. In women who received estrogens together with progesterone as oral contraceptives the incidence of cardiovascular disease increased. In contrary, more studies indicate the protective role of estrogens in post-menopausal women.
Severe or irreversible adverse reactions. During treatment with estradiol a severe abnormal uterine bleed-ing may occur. Endometrial biopsy is necessary to exclude the presence of carcinoma. When applied to men (prostate cancer therapy), it is necessary to count with feminization (gynecomastia, inhibition of spermatogenesis, loss of libido, impotence).
Symptomatic adverse reactions. All estrogen preparations can especially at the treatment beginning cause slight adverse effects such as breast tension and hypertrophy, mastalgia, slight vaginal bleeding, retention of sodium and fluids, weight gain, headache, paresthesia and nausea. These effects are dose-dependent and often spontaneously disappear during long-term therapy. Only rarely they are the reason for discontinuation of therapy. Intramuscular administration may remove these symptoms in some cases. High doses especially after per oral administration can moreover cause depression, nausea, anorexia, diarrhea, vomiting, edema and skin changes (chloasma, urticaria, various eruptions, erythema multiforme and nodosum, occasionally Stevens-Johnson syndrome). In children, there is a possibility of pre-mature close of epiphyseal gaps. After discontinuation of estrogen application the uterine bleeding often occurs.
Other reactions. Estradiol influences hepatic metabolism significantly (proteins synthesis, including binding proteins and coagulation factors, metabolism of saccharides, lipids and formation of bile). Mainly per oral preparations may increase the synthesis of high-density lipoproteins and other proteins synthesized in the liver, increase synthesis of heme and porphyrin and the risk of porphyria, increase level of angio-tensin and blood pressure, cause hypercoagulability by decreased activity of antithrombin III and induction of increased hepatic synthesis of blood coagulation factors, increase saturation biliary index and so increase the risk of developing gallstones. Parenteral administration (also transdermal) does not induce such effects. It can be seen, however, that at least during the first 4 months of treatment the parenteral admnistration has not so significant positive effect on lipoproteins than per oral preparations. Concomitant administration of progesterone antagonizes the positive effects of estrogens on blood lipids. Glucose tolerance may be slightly reduced, although the emergence of manifest diabetes is not probable. Hypercalcemia and various allergic reactions may appear.

4.9 Overdose
No information on the consequences of acute overdose by estradiol in humans is available. The treat-ment of potential overdose has to be symptomatic.


5. PHARMACOLOGICAL PROPERTIES

5.1 Pharmacodynamic properties
Pharmaceutical group: Natural and semisynthetic estrogens, alone
ATC classification: G03CA03

Molecular and cellular mechanisms of action.
Estradiol acts via estrogen receptors located in target tissues. Unoccupied estrogen receptors are local-ized in the cytoplasm, but have been found also in the cell membrane. After binding of estradiol to the estrogen receptor, this complex acts as a transcription factor that modulates the expression of target genes. Estrogens contain cyclopentanoperhydrophenanthrene structure. Phenolic ring is an essential chemical condition for binding to estrogen receptors. C17 oxygen is necessary for estrogen biological activity. Biological activity is affected by the type of radical bound to oxygen on C17. From the endogenous estrogens the most effective is 17-beta-estradiol. Efficiency of estradiol decreases ten-times following enzymatic or chemical oxidation of 17-hydroxyl group to a keto-group, such as in estrone.
Estrogens are steroid hormones, whose main task is to regulate the functions of the female genital organs and regulation of reproduction. Natural estrogens are 17-beta-estradiol, estrone and estriol. The most effective of these is a 17-beta-estradiol. Estradiol regulates the growth and activity of the female genitals, secondary genital characteristics and mammary glands, as well as some functions of uterus and supplementary organs, especially the proliferation of endometrium, decidual development and cyclic changes in cervical and vaginal epithelium. The level of estrogen in the blood must have a certain minimum critical value for the endometrium to proliferate. Estradiol in combination with progesterone also supports the secretory phase of the menstrual cycle. If the level of estrogens is too low, the endometrium is not maintained and uterine bleeding follows. Uterine bleeding can therefore be discontinued by large doses of estrogens, or induced by interruption of their application. Bleeding, however, may occur also despite of high level of estrogens (in prolonged use of high doses) as a result of heart attacks in excessively hypertrophied endometrium. Endometrial hyperplasia, when estrogens are administered, can be reduced by the concomitant application of progesterone. Also discontinuation of estrogen application in women after menopause, or after ovariectomy induces uterine bleeding. Chronic administration of estrogens without progesterone, anovulatory cycles (lack of progesterone secretion) or ovarian tumors secernating estrogens also induce uterine bleeding.
Estradiol by feedback regulates gonadotropins secretion at the level of hypophysis and hypothalamus. FSH secretion is progressively inhibited when level of estradiol increases (negative feedback). LH secre-tion is at low levels of estradiol suppressed to maximum. It increases as response to increasing levels of estradiol (positive feedback). FSH stimulates the secretion of estradiol from the ripening follicle. So estradiol during menstrual cycle participates in regulation of cyclic changes of gonadotropins and endometrium. Besides the effect on genitalia, secondary sexual characteristics, mammary gland, hypothalamus and hypophysis estradiol influences mainly the liver and skeleton, and has multiple metabolic effects. It affects significantly metabolism of lipids, reduces levels lipoproteins with low density, and in the contrary it increases levels of lipoproteins with high density and triglycerides. It stimulates the synthesis of transport globulins for hormones. It promotes the absorption of calcium from intestine and reduces its excretion in urine. Estradiol inhibits bone resorption. Severe consequences of long-lasting lack of circulating estrogens may be osteoporosis and cardiovascular complications.

5.2 Pharmacokinetic properties
Pharmacokinetics after single-dose administration. After intravenous administration estradiol has the initial half-life of about 20 minutes and the secondary one about 70 minutes. Metabolic clearance defined as the volume of blood from which the estradiol was irreversibly removed makes 600 to 800 liters per 24 hours. m-2 in pre-menopausal women and about 600 L per 24 hours.m-2  in post-menopausal women.
Resorption. After oral administration the natural estrogens resorb almost completely. However, efficiency of p.o. administration is limited with respect to intensive metabolism of estrogens during their first passage through liver (first pass effect). Estradiol valerate is already in the intestinal mucosa changed to estrone, so after p.o. administration of estradiol the plasma concentration of estrone is unphysiologically higher than concentration of estradiol. After p.o. administration, the significant part of estradiol valerate is inactivated even before entering the systemic circulation. Estradiol is well resorbed also through skin and mucosa. Alkyl and aryl esters of estradiol have lower polarity, so for them administered in an oil solution, their rate of absorption reduced depending on the size of the side chain.
Estradiol valerate, estradiol ester, is long-time acting ester suitable for i.m. application. Speed of its resorption is lower than estradiol benzoate (therapeutic doses are effective for several days) and greater than estradiol dipropionate (therapeutic doses are effective for several weeks). Estradiol valerate is in oil solution after i.m. application efficient for 1-3 weeks. Tissue esterases release active estradiol from estradiol valerate. Parenteral administration of estradiol valerate allows the reduction of its inactivation in intestinal mucosa and in liver. Onset and termination of action of estradiol valerate after i.m. application are slow, gradual and uncertain. Intensive conversion of estradiol to estrone in intestine and liver causes that per oral application of estradiol leads to a high concentration of circulating estrone and at the same time to a high ratio of estrone/estradiol. From this point of view, per orally administered estradiol does not restore the physiological situation in pre-menopausal women, when the ratio of estrone/estradiol is less than 1. Percutaneous, subcutaneous, vaginal and intramuscular application of estradiol allows the achievement of plasma concentrations similar to the estradiol levels in follicular phase, as well as low ratio of estrone/estradiol.
Distribution. Due to the high solubility in fats estradiol is distributed throughout the whole body. Extensive binding to plasma proteins, however, means that the distribution volume is only 9 to 15 L. Circulating estradiol is almost completely bound to plasma proteins. Approximately 60 % is bound to albumin, 38 % to sex hormone binding globulin, and 2 to 3 % remain free and mean biologically active fraction of hormone. Sex hormone binding globulin significantly influences the efficacy of estradiol. Testosterone is bound to the same glycoprotein with a higher affinity than estrogen, so these steroids may influence mutually their metabolism. Some conditions affect the level of sex hormone binding globulin and thus also the level of free estradiol.
Hyperthyroidism, cirrhosis, pregnancy and estrogen therapy increase the level of sex hormone binding globulin. In the contrary, hypothyroidism, hyperandrogenism, and obesity decrease its level. Estradiol is excreted in breast milk, its concentration however is not so high that the affection of child could be ex-pected. Estradiol passes through placenta.
Biotransformation. Estradiol is converted by 17-ß-hydroxysteroid dehydrogenase to estrone already in intestinal mucosa, then in liver. Estrone is rapidly converted to estrone-3-sulfate, which is the most im-portant circulating estrogen. However it is not physiologically active with regard to a poor binding to estrogen receptors. The main metabolic route is hydroxylation of the aromatic A ring at C-2 position. Hydroxylation can be carried out also in the C-16 position on D ring at the formation of 16-α-hydroxyestrone, which is reduced to estriol subsequently. Estriol has 1/10 activity of estradiol. Hydroxylation reaction to C-2 and C-16 is competitive. Hydroxylation may run also in the positions C-4, 6, 7, 11, 14, 15, 16 and 18. Estrogens produced by hydroxylation on the A ring may be methylated at the hydroxyl groups. In addition, they can form covalent bindings with sulfhydril groups of hepatic proteins. Estrone, estradiol and their metabolites are conjugated under formation of glucuronides and sulfates. The major circulating metabolite of estrogen is estrone-3-sulfate. It is easily deconjugated to free estrone, which can be changed by estradiol dehydrogenase in liver and endometrium to estradiol. Estrone-3-sulfate has therefore obviously a storage function and means an easily available source of free estradiol. Oxidation of estradiol to estrone is faster however, and is preferred to a reverse reaction.
All three estrogens (estradiol and its metabolites, estrone, estriol) are excreted in urine as glucuronide and sulfate conjugates, together with a small amount of unchanged estradiol. 40 to 100 % (average 80 %) of the administered dose of estradiol is excreted in urine within 96 - 120 hours. 20 % is excreted in stool. About 40 % of estradiol metabolites are excreted in bile and 80 % thereof are reabsorbed into enterohepatic circulation. Only a small part (about 7 %) of the administered dose of estradiol is excreted in stool. Hepatic metabolism of estradiol can be increased by microsomal enzymes induction. Liver dam-age can lead to hyperestrogenism. In addition, the hepatic metabolism causes that after per oral administration the majority of estrogens are changed in liver to pharmacologically less active substances. Estrogens are metabolized also in intestine by intestinal flora, allowing their enterohepatic circulation. Alterations of the normal intestinal flora may therefore affect the estrogen metabolism.
Dependence between plasma concentration and action. Daily production of estrogens from 90 to 350 nmol in women depends on the phase of cycle. After menopause, the production decreases to 17 to 35 nmol / 24 h. The plasma concentration of 300 to 800 pmol.l-1 is sufficient to eliminate menopausal symp-toms such as hot flushes, profuse sweating and to reduce increased levels of gonadotropins after menopause. Postmenopausal symptoms appear again, if plasmatic level of estradiol decreases to 100 – 120 pmol.l-1. Numerous documents indicate the existence of the relationship between plasma concentration of estradiol and effect of estradiol therapy.

5.3 Preclinical safety data
Reproductive toxicity. According to testing on animals, estradiol has a teratogenic effect on the urogenital tract, skeleton, heart and mammary glands. In some species of experimental animals, the in utero administration of estradiol reduces fertility in offspring, causes feminization in males.
Oncogenic potential. In some species of experimental animals estradiol promotes the development of various cancers, including tumors of mammary gland, uterus and cervix uteri. Testicular, lymphoid and osteogenic tumors were described, but only in certain types of mice. In most other species the induction of tumors by estrogens failed. Some experiments point out to a possible significant correlation between the action of estrogen and benign and malignant liver tumors. The role of estradiol in the etiology of mammary gland carcinoma is not clear by now.
Estradiol is in the list of known carcinogens. It is classified as "tumor promoter" and not as a genotoxic carcinogen. Some genotoxicity tests in bacteria indicate however that estradiol and its catechol metabo-lites are genotoxic carcinogens with probable ability to induce development of tumors. Estradiol and diethylstilbestrol have genotoxic effect also on mice epithelial cells.


6. PHARMACEUTICAL PARTICULARS

6.1 List of excipients
Helianthi oleum pro iniectione

6.2 Incompatibilities
Oxidizing agents, alkali and light cause decomposition.

6.3 Shelf life
4 years

6.4 Special precautions for storage 
Store at 15 - 25 °C, protect from light and frost. 

6.5 Nature and contents of container
1) 1 mL non-snap off ampoules with stuck label, file, plastic moulding, package leaflet: information for the user, box;
2) 1 mL snap off ampoules with stuck label, plastic moulding, package leaflet: information for the user, box.
Package size: 5 ampoules of 1 mL

6.6 Special precautions for disposal and other handling
The product is applied deep into the muscle.

7. MARKETING AUTHORISATION HOLDER
BB Pharma a.s., Pod Višňovkou 1662/21, Prague 4, Czech Republic
8. MARKETING AUTHORISATION NUMBER
56/0461/69-S, 56/461/69-S/C
9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION
1969 
10. DATE OF REVISION OF THE TEXT 
September 2013