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Folivirin Injection


1. NAME OF THE MEDICINAL PRODUCT
F O L I V I R I N 
Suspension for injection


2. QUALITATIVE AND QUANTITATIVE COMPOSITION
Estradioli benzoas 2.5 mg, testosteroni isobutyras 25 mg in 1 mL of micro-crystalline aqueous suspension.

3. PHARMACEUTICAL FORM
Suspension for injection. Micro-crystalline injection suspension after shaking of milky colour.

4. CLINICAL PARTICULARS
4.1. Therapeutic indications
Postmenopausal syndrome, particularly changes of sexual functions, if the only estrogen or combined estrogen and gestagen substitution therapy is not effective sufficiently (e.g. after surgically induced menopause).

4.2. Posology and method of administration
1 ampoule (2 mL) once in 4 – 6 weeks deep intramuscularly. Dosing has to be adjusted according to the individual response of female patient – subjective improvement and to treat with as low dose as possible, or to adjust on the base of levels of estrogens and testosterone so that levels of hormones reach a normal value. Uterine bleeding and virilization are signs of overdose.

4.3. Contraindications
Pregnancy, lactation. Tumors of liver. Carcinomas and precancerosis of urogenital tract and mammary gland, especially cystic mastopathy (in personal and family anamnesis). Suspected TBC of female genitals. Endometrial hyperplasia. Undiagnosed vaginal bleeding, uterine bleeding induced by high level of estrogens. Active thromboembolic disease. Nephrosis and nephrotoxic phase of nephritis, epilepsy, migraine, asthma, cardiac and renal diseases, prostate cancer. Administration to young patients with unfinished ossification. Hyperprolactemia.
Special care is necessary in cardiovascular, cerebro-vascular, hepatic and renal diseases, thrombophlebitis, hemoglobinopathy, porphyria, as well as in all diseases which can be worsen in consequence of sodium and water retention (e.g. epilepsy, migraine, diabetes mellitus, asthma). It should also not be given to the patients with hypercalcemia or with hypercalciuria or in the situation when there is a higher risk of occurrence of these disorders. Substitution therapy by esters of testosterone and estradiol may cause retention of sodium, particularly in sensitive patients and patients who are administered high doses. Manifest heart failure therefore may mean a contraindication to treatment by Folivirin.

4.4. Special warnings and special precautions for use
In women with intact uterus it is necessary to combine the treatment by Folivirin with progesterone in order to protect endometrium against overstimulation. In case of long-time treatment it is necessary to re-evaluate regu-larly the necessity of treatment and preventive examination of breast and sexual organs at least once a year because there exist certain risks of endometrial and breast carcinomas.
Estrogen preparations especially at the beginning of treatment may cause light undesirable effect such as ten-sion and enlargement of breast, mastalgia, light vaginal bleeding, retention of sodium and liquids, increased body weight, headache, paresthesia and nausea. These effects depend on a dose and they often disappear spontaneously in a long-time therapy.
Folivirin is not intended for application to children.

4.5. Interactions with other medicinal products and other forms of interaction
Potentially dangerous interactions. Smoking increases risk of thrombo-embolic complications in women who receive estrogen therapy. However it does not decrease the efficacy of treatment by estradiol. Estrogens may increase toxicity of chlorpromazine (enhancement of cholestatic effect). Undesirable interactions may be devel-oped in combination with antiepileptics. Anabolic and androgen steroids increase effect of anticoagulant sub-stances up to bleeding border.
Other significant interactions. Possible interactions with all medicinal products having the same metabolic paths in hepatic biotransformation and biliary excretion. The medicinal products such as rifampicin, barbiturates and phenytoin which induce synthesis of biotransformation enzymes, increase speed of metabolism of estrogens and androgens. In the contrary, estrogens may increase the activity of phenytoin and other medicinal products degradated by microsomal enzymes by inhibition of their metabolism. Long-time application of antibiotics may decrease efficacy of estrogen and androgen preparations by acceleration of their metabolism in consequence of induction of microsomal enzymes. By liquidation of intestinal flora antibiotics may inhibit enterohepatic circulation of estrogens. Therapeutic effect of antidiabetics, anticonvulsives and antihypertensives may be altered. 
Interference with laboratory tests. Estradiol and testosterone may affect functional tests of thyroid gland, glucose toleration test, plasmatic levels of cortisol and determination of 17-hydroxy- and ketosteroids in urine.

4.6. Pregnancy and lactation
Folivirin must not be applied in pregnancy and during lactation.

4.7. Effects on ability to drive and use machines
Effects on ability to drive and use machines are not expected.

4.8. Undesirable effects
Undesirable potential life-threatening effects
Hepatotoxicity. Hepatotoxicity is a common attribute of 17α-alkylated derivatives of testosterone.  
It is not described in parenterally applied esters of testosterone. 
Hepatic carcinoma. Known are the cases of occurrence of liver abscesses in patients who were applied 17α–alkylated derivatives of testosterone in high doses for a longer time (1 – 7 years), often in connection with treatment of Fanconi anemia. Occurrence of association of malign abscesses and substitution therapy by esters of testosterone is extremely rare. Not confirmed is also increased risk of development of hepatic carcinoma during use of estrogens. Experimentally is proven the correlation between application of steroids and development of benign and malign liver abscesses. Also some clinical studies documented a possible association between oral estrogen therapy and increased risk of liver abscesses occurrence. Other studies however have not confirmed this dependency. 
Endometrial hyperplasia and carcinoma. Application of estradiol without concomitant application of progesterone in women with functional uterus is connected with increased risk of occurrence of endometrial hyperplasia and endometrial carcinoma as a result of excessive growth stimulation of endometrium. Size of this risk depends on a dose and duration of treatment. Lower risk exists in combined estrogen-progesterone therapy. 
Breast carcinoma. Hormonal substitution therapy increases the risk of breast carcinoma during several years of application. The risk increases with the duration of therapy, but turns back to the original values during several years after ending of treatment. Risk of breast carcinoma in combined estrogen-testosterone therapy is not known. 
Heavy or other irreversible undesirable effects
Virilisation. All androgens, including anabolic steroids, may cause virilisation in women and boys before puberty, as well as virilisation of fetus. If the application of androgens is discontinued immediately after occurrence of virilization symptoms, they retreat slowly. Continuation of androgens application may lead to irreversible changes. The younger is the patient, the stronger are effects of androgens. However, a strong virilization may be developed also in adult women. Early symptoms of virilization in women are acne, hairy face (beard, hairs), deeper voice and irregular menstrual cycle caused by suppression of gonadotropins secretion. In long-time administration it comes to emphasizing of male figure, hirsutism and deepening of voice, bald spot, atrophy of breast and endometrium, hypertrophy of clitoris. Skin is fatty with acne. Libido increases and lactation is suppressed.
Cardiovascular diseases. Hormonal substitution therapy increases the risk of venous thrombo-embolitic complications, but risk of occurrence of arterial thromboses, including ischemic heart disease, is not proven definitely. The higher doses which were used at treatment of prostate carcinoma in men or in women to suppress lactation, induced hypertension and different thromboembolic complications (myocardial infarct, pulmonary embolism, iktus). Thromboembolic complications generally are not considered to be undesirable effects of androgenic therapy, although there exists experimental evidence that testosterone stimulates their creation.
During treatment by estradiol the stimulation of endometrium and serious abnormal uterine bleeding may ap-pear. Endometrial biopsy may be necessary to exclude presence of carcinoma.

Symptomatic undesirable effects
In consequence of testosterone application, at least at beginning of treatment, it comes to retention of sodium and subsequently of water and to increase of body weight. However the substitution testosterone therapy usually does not lead to such retention of sodium which would be shown clinically by evident edemas. It is a complication which usually occurs at treatment of mammary gland carcinoma, when the high doses of testosterone are used. By these complications may be rarely inflicted sensitive patients (e.g. by failure of heart of kidneys, cirrhosis, hypoproteinemia) or boys in puberty as well by substitution therapy. Edemas disappear after reduction of testosterone dose and are sensitive to natriuretics. 
All estrogen preparations especially at treatment beginning may cause light undesirable effects such as breast tension and hypertrophy, mastalgia, light vaginal bleeding, retention of sodium and liquids, increase of body weight, headache, paresthesia, nausea. These effects depend on a dose and disappear often spontaneously at a long-time therapy. Only rarely they are the reason for therapy discontinuation. Intramuscular administration may remove these symptoms in some cases. Moreover high doses particularly after per oral administration may induce depression, anorexia, nausea, vomiting, diarrhea, edemas and skin changes (chloasma, urticaria, various eruptions, erythema multiformae and nodosum, rarely Stevens-Johnson’s syndrome). 
Other effects
During long-time treatment by esters of testosterone no changes were found in level of cholesterol or triglycer-ides in serum. However, during treatment by methyl testosterone it came to increased total cholesterol, LDL cholesterol and decrease of HDL/LDL ratio. Mechanism of this androgen effect is not known, that is why it cannot be extrapolated expressly also on esters of testosterone. Hypercholesterolemia, however, may be relative contraindication of androgen therapy. Before start of treatment it is necessary to determine the level of lipids and to normalize potential undesirable deviations. Androgens may induce hypercalcemia, reduce glucose tolerance and increased growth of bones and skeleton weight.
Estradiol affects significantly the liver metabolism (synthesis of proteins, including binding proteins and coagulation factor, metabolism of saccharides, lipids and creation of bile). Glucose tolerance may be reduced slightly, although occurrence of manifesting diabetes is not probable. Hypercalcemia and various allergic reactions may appear. 

4.9. Overdose
No cases of overdose by testosterone and estradiol are known.

5. PHARMACOLOGICAL PROPERTIES

5.1. Pharmacodynamic properties
Pharmacotherapeutic group: hormone – androgen and estrogen. 
ATC code: G03EA02
Molecular and cellular mechanism of action
Testosterone is metabolized to further two hormonal active steroids. The final effect of testosterone is therefore summary of effects of testosterone itself, 5α-dihydrotestosterone and estrogen metabolites. Testosterone and dihydrotestosterone act by means of one androgen receptor localized in cores of androgen-sensitive cells.
Estradiol acts by means of estrogen receptors localized in target cells. After binding of androgens or estrogens to the particular receptor, this complex acts as transcription factor which modulates expression of target genes. 
Pharmacodynamic properties
Testosterone is natural androgen hormone partially responsible for development of male phenotype. It has various effects in various stages of ontogenetic development. Thus the common receptor intermediates as androgen so anabolic effects of testosterone. By modification of testosterone molecule it is not possible to separate these effects.
Estrogens are steroid hormones whose main task is the regulation of function of female sexual organs and the regulation of reproduction. Estradiol regulates growth and activity of female sexual organs, secondary sexual signs and mammary glands, as well as some functions of uterus and accessory organs, particularly proliferation of endometrium, development of decidua and cyclic changes of epithelium of cervix and vagina. It affects significantly the metabolism of lipids, reduces levels of lipoproteins with low density and in the contrary it increases the levels of lipoproteins with high density and of triglycerides. In women before menopause ovary excrete in average 150 µg. 24 h-1 of testosterone. Synergic effect of androgens and estrogens on metabolism of bones and on sexual functions is expected. Anabolic effect of parenteral testosterone connected with increased bone density in young, pre-menopausal and perimenopausal women was confirmed by several clinical studies. In older women exists correlation between decreased testosterone level and osteoporosis. Importance of testosterone for metabolism of bones is confirmed also by presence of functional androgen receptors on human osteoblasts.

5.2. Pharmacokinetic properties
Pharmacokinetics after single dose administration
Testosterone. Intensive presystem metabolism is expressed by plasmatic clearance 0.8 l . min-1 Plasmatic half-life of testosterone is from 10 to 100 minutes.
Estradiol. Metabolic clearance defined as volume of blood from which estradiol was removed irreversibly, is 600 up to 800 litres for 24 hours . m2 in women before menopause and about 600 litres for 24 hours . m2 in women after menopause.
Resorption
Testosterone. After i.m. application in oil vehicle testosterone is quickly absorbed, metabolized and excreted, so its androgen effect is minimal. For substitution therapy it was necessary to modify the molecule of testosterone, because also extremely high doses of testosterone in micronized form have only limited effects. Effect of testosterone prolongs alkylation in position 17α– and modification of ring structure or esterification with various carboxyl acids by means of 17ß–hydroxyl group. Esterification prolongs effect in proportion to length of aliphatic chain of ester. Deceleration of resorption from injection site can be reached also by application in form of microcrystalline aqueous suspension. Testosterone isobutyrate is hydrolyzed firstly and subsequently as free steroid it acts on cell. After hydrolysis of ester the circulating testosterone is bound to receptors in target tissues and acts in the same way as natural hormone. The testosterone released from esters is also metabolized in liver in the same way as natural hormone.
Estradiol. Estradiol is resorbed very well through mucosa and after intramuscular application. Alkyl- and aryl-esters of estradiol have lower polarity, therefore after i.m. application in suspension the speed of their resorption decreases in dependence on size of side chain. 
Distribution
Testosterone. After absorption testosterone circulates in blood bound to globulin binding sexual hormones and to albumin. Although albumin has thousand times lower affinity for testosterone than globulin binding sexual hormones, it has thousand times higher capacity. In women 30 % of testosterone is bound to albumin and 60 % to globulin binding sexual hormones. About 2 % circulate in free form and mean the efficient fraction of testosterone. Testosterone bound to albumin dissociates easily and passes through capillary membrane, so in fact for entry into cells is available about 50 % of the total testosterone. Also in the doses 100-times higher than physiological concentration the most of non-conjugated testosterone and dihydrotestosterone in blood specifically bound to globulin binding sexual hormones and unspecifically to albumin.
Estradiol. In regard to high solubility in fats estradiol is distributed in whole body. However, extensive binding to plasmatic proteins causes that the distribution volume is only 9 – 15 l. Circulating estradiol is almost totally bound to plasmatic proteins. About 60 % is bound to albumin, 38 % to globulin binding sexual hormones and 2 – 3 % remain free and mean biologically efficient fraction of hormone. Binding of steroids to plasmatic proteins may be important from the point of view of their distribution, protection against degradation, as well as deceleration of metabolic clearance. Changes of concentration of albumin and globulin binding sexual hormones run during various physiological and pathological conditions. Thus they change the efficient concentration of androgens and estrogens and their clearance. Both sexual hormones pass through placenta. 
Biotransformation
Testosterone. In tissues sensitive to androgens testosterone is converted irreversibly by 5-reductase to 5–dihydrotestosterone. Testosterone and androstenedione are metabolized in peripheral tissues to estrogens estradiol and estrone. Testosterone excreted by various organs, created from precursors in peripheral tissues or applied exogenously is metabolised intensively in liver to light androgen derivatives and inactive etiocholanolone. Inactivation includes oxidation of 17-hydroxyl group and reduction of A ring under formation of androstenedione. Androstenedione has only a weak androgen activity. Further reduction on 3-ketoposition leads to development of progesterone. Reduction of androstenedione in position 5- leads to development of etiocholanolone. From the applied dose of marked testosterone 90 % is excreted by urine and 6 % by stool in unchanged form by means of biliary system. Metabolites androsterone and etiocholanolone are excreted by urine mostly like glucuronides and sulfates. 
Estradiol. Estradiol is converted by 17-ß-hydroxy steroid dehydrogenase to estrone already in intestinal mucus, then in liver. Estrone is quickly changed to estrone-3-sulfate which is the most important circulating estrogen. But it is not physiologically active in regard to weak binding to estrogen receptors. Main metabolic route is hydroxylation of aromatic A ring in position C-2. Hydroxylation may be performed also in the position C-16 on D ring and 16--hydroxyestrone is created which is reduced further to estriol. Estriol has only 1/10 of activity of estradiol. Hydroxylation reactions on C-2 and C-16 are competitive. Hydroxylation may run also in the positions C-4, 6, 7, 11, 14, 15, 16 and 18. Estrogens created by hydroxylation on A-ring may be methylated on hydroxyl groups. Besides this they can create covalent bindings with sulfhydril groups of hepatic proteins. Estrone, estradiol and their metabolites are conjugated under creation of glucuronides and sulfates. Main circulating metabolite of estrogen is estrone-3-sulfate. It is easily deconjugated to free estrone which may be changed by estradiol dehydrogenase in liver and endometrium to estradiol. Estron-3-sulfate has therefore apparently the storage function and means easily available source of free estradiol. But oxidation of estradiol to estrone is quicker and more preferred than the opposite reaction.
All three estrogens (estradiol, estrone, estriol) are excreted by urine as glucuronide and sulfate conjugates to-gether with small amount of unchanged estradiol. 40 to 100 % (at average 80 %) of the applied dose of estradiol is excreted by urine during 96 – 120 hours. 20 % is excreted by stool. About 40 % of estradiol metabolites is excreted into bile and 80 % thereof is reabsorbed into enterohepatic circulation. Only a small part (about 7 %) of the applied dose of estradiol is excreted by stool. Estrogens are metabolized also in bowel by intestinal flora what enables their enterohepatic circulation. Alteration of normal intestinal flora may influence therefore the estrogen metabolism.

5.3. Preclinical safety data
Chronic toxicity
Supraphysiological levels of androgens and estrogens inhibit secretion of gonadotropins and the functions regulated by them. 
Reproductive toxicity
According to testing on animals estradiol has teratogenic effect on urogenital tract, skeleton, heart and mammary glands. In some species of experimental animals the contact with estradiol in utero decreases fertility in offspring, in males it causes feminisation.
Mutagenicity
Testosterone and its esters do not have mutagen activity. Some tests have detected mutagenicity of estradiol.  
Oncogenic potential
Testosterone and its esters do not have a proven oncogenic potential. 

Estradiol is on the list of known carcinogens. It is classified as “tumor promoter” and not as genotoxic carcino-gen. Some genotoxic tests on bacteria indicate however that estradiol and its catechol metabolites are genotoxic carcinogens with probable ability to induce development of tumors. In some species of experimental animals estradiol supports development of various tumors including tumors of mammary gland, uterus and cervix uteri. Testicular, lymphoid and osteogenic tumors were described only in some mice species. In most of other species the induction of tumors by estrogens was not successful. Some experiments point out the possible significant correlation between activity of estrogens and benign and malign tumors of liver. Task of estradiol in etiology of mammary gland carcinoma is not clear by now.  


6. PHARMACEUTICAL PARTICULARS 

6.1. List of excipients
Carmellosum natricum, sorbitolum, polysorbatum 80, phenolum, aqua ad iniectabilia. 
6.2. Incompatibilities
Oxidizing substances, alkali and light cause decomposition. 
6.3. Shelf life
36 months
6.4. Special precautions for storage
Store between 10 – 25 °C, protect from light and frost. Keep the ampoules in vertical position. 
6.5. Nature and contents of container
2 ml ampoules with stuck label, plastic moulding, package leaflet: information for the user, paperboard box.  
Package size: 5 ampoules of 2 mL
6.6. Special precautions for disposal and other handling
Injections are applied intramuscularly. 

7. MARKETING AUTHORISATION HOLDER
BB Pharma a.s., Pod Višňovkou 1662/21, Prague 4, Czech Republic
8. MARKETING AUTHORISATION NUMBER 
56/0487/69-S, 56/487/69-S/C
9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION
1969
10. DATE OF REVISION OF THE TEXT
September 2013