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Agofollin Depot Injection


SUMMARY OF PRODUCT CHARACTERISTICS

1. NAME OF THE MEDICINAL PRODUCT

                                                    AGOFOLLIN DEPOT

2. QUALITATIVE AND QUANTITATIVE COMPOSITION
Estradioli benzoas 5 mg in 1 mL of micro-crystalline aqueous suspension.

3. PHARMACEUTICAL FORM
Suspension for injection

4. CLINICAL PARTICULARS

4.1 Therapeutic indications
Substitution hormonal therapy in lack of ovarian estrogens proven by negative progesterone test. Substitution therapy in premature ovarian failure (premature menopause) in a woman younger than 40 years, e.g. after ovar-iectomy or radiocastration because of non-cancerous diseases. Substitution therapy in primary amenorrhea (total and local developmental disorders, eunuchoid growth, genital infantilism). Stop of dysfunctional uterine bleeding. Prostate carcinoma. Estrogen test.

4.2. Posology and method of administration
Irregularities of menstrual cycle in the first years after menarche: 4th, 11th and 18th day of cycle 2 mL of Agofollin Depot (10 mg of estradiol benzoate) i.m., on 18th day together with progesterone.
Substitution therapy in Turner syndrome: 2 mL of Agofollin Depot (10 mg of estradiol benzoate) i.m. on 1st, 8th and 15th day of cycle, combine with progesterone on 15th and 22nd day. When the bleeding starts, apply 2 mL of Agofollin Depot (10 mg of estradiol benzoate) i.m. on 4th, 11th and 18th day of cycle, add progesterone on 18th and 25th day of cycle.
Substitution therapy of long-lasting secondary amenorrhea in fertile age, in proven lack of endogenous estro-gens and positive estrogen test: 2 mL of Agofollin Depot (10 mg of estradiol benzoate) i.m. on 1st, 8th and 15th day of cycle, add progesterone on 15th and 22nd day. After achieving the effect (uterine bleeding) the dose is reduced in the next days. Mostly it is sufficient to apply on 8th day of cycle 2 mL of Agofollin Depot and on 15th day again together with progesterone. When the menstrual cycle is induced, the combined application of 1 – 2 mL of Agofollin Depot together with progesterone on 18th day is sufficient. After 3 – 6 cycles apply on 18th day the progesterone only. If the bleeding is not induced, perform the progesterone test to prove the endogenous production of estrogens. 
Substitution therapy in secondary amenorrhea and in negative estrogen test: during 7 – 10 weeks 2 – 4 mL of Agofollin Depot (10 – 20 mg of estradiol benzoate) i.m. once a week. In the last week add progesterone.
In secondary amenorrhea in fertile age of woman estrogens are applied only in proven lack of endogenous estrogens. In treatment of postmenopausal outage symptoms the application of estrogens without a concomitant application of androgens or gestagens is not effective.
Firstly apply on 7th day of cycle 10 mg, the second dose – 10 mg again – on 17th day together with Agolutin Depot. When the effect is achieved (pseudomenstruation) it is sufficient to apply the indicated combination only on 17th day of cycle. It is recommended to change the injection sites.
In treatment of outage postmenopausal effects, if the reaction of woman on androgenic component of Folivirin inj. is unsuitable, it is possible to combine 5 – 10 mg of Agofollin Depot inj. with 50 – 100 mg of Agolutin Depot inj. 
Estrogens without progesterone may be used for a long-term treatment only of women after hysterectomy. In women with intact uterus it is necessary to combine the estrogen treatment always with the application of pro-gesterone with the aim to protect endometrium against excessive stimulation. 
In women with premature menopause the substitution therapy should last at least up to the age of natural menopause. 

4.3. Contraindications 
A b s o l u t e :  Pregnancy, lactation. Active thromboembolic diseases also in anamnesis, liver diseases, liver tumors also in anamnesis, carcinomas and precancerosis of female genitals and breasts, mainly cystic mas-topathy (also in familiar or personal anamnesis), hepatitis, TBC of genitals (also suspected), undiagnosed bleeding induced by high level of estrogens, administration to young patients with ossification, porphyria, endometriosis. 
R e l a t i v e :  be careful in asthmatics, epileptics and cardiac patients. In renal dysfunction there is a risk of increased retention of liquids. 

4.4. Special warnings and precautions for use
All estrogen drugs can especially at the beginning of the treatment induce the light adverse reactions such as breast tension and hypertrophy, mastalgia, light vaginal bleeding, retention of sodium and liquids, increase of body weight, headache, paresthesia, nausea and different allergic reactions. These effects depend on the dose and they often fade spontaneously at a long-time treatment.
Otosclerosis, migraine, diabetes, hypercalcemia may be exacerbated by estrogens. 
Elderly. This treatment may be associated with an increased risk of endometrial hyperplasia and carcinoma. After discontinuation of estrogen treatment the degradation of bones increases what can lead to an increased risk of fractures. At treatment of menopausal problems by hormonal substitution therapy (HST) it is necessary to consider the risk and benefit of the treatment. It is necessary to use the minimal dose and for as short time as possible. The risk and profit ration of HST in long-term application is unfavorable.

4.5. Interaction with other medicinal products and other forms of interaction
Potentially dangerous interactions. Smoking increases the risk of thromboembolic complications in women who undergo estrogen therapy. However it does not decrease the efficiency of treatment by estradiol. Estrogens can increase toxicity of chlorpromazine (strengthening of cholestatic effect). 
Other significant interactions. There are a few data on interactions of the estradiol alone available. There can be assumed the interaction with all drugs which have the same metabolic ways. The drugs like rifampicin, barbitu-rates and phenytoin, which indicate synthesis of biotransformation enzymes, increase the metabolism speed of estrogens. Estrogens can increase the activity of phenytoin and other drugs degraded by microsomal enzymes by inhibition of their metabolism. At the concomitant application of hepatotoxic drugs the risk of liver impairment increases. Estradiol decreases the efficiency of dicumarol anticoagulants and antidiabetics, increases the efficiency of antagonists of folic acid and pethidine. Interactions can occur in a combination with antiepileptics. Interactions with corticoids, bromocriptine, cyclosporines, dantrolene. 
Long-time application of antibiotics can reduce the efficiency of estrogen preparations by acceleration of their metabolism in consequence of induction of microsomal enzymes. By liquidation of intestinal flora antibiotics can disable enterohepatic circulation of estrogens. 
Interference with laboratory tests. Estradiol can influence the functional tests of thyroid gland, plasmatic levels of cortisol and determination of 17-ketosteroids in urine.
Agofollin Depot induces false positivity or higher values of BSP determination, corticosteroids in plasma, iodine bound to albuminous and capture of radio-iodine by thyroid gland. In the contrary, it induces false negativity or lower values at the determination of 17-hydroxy- and ketosteroids in urine. 

4.6. Fertility, pregnancy and lactation
Although the teratogenic effect of estradiol in human is not proven directly, other estrogens, particularly diethylstilbestrol, have teratogenic effect. In some animal species estradiol has also teratogenic effects. From these reasons estradiol should not be administered in pregnancy. There are a few indications for application of estradiol in breastfeeding mother. Estradiol is excreted into breast milk, but its quantity is very low, probably less than 0.02 % of the dose received by mother. This means that estradiol can be applied to breast-feeding mothers only in exceptional cases. 

4.7. Effects on ability to drive and use machines
Effect on ability to drive and use machines is not supposed. 

4.8. Undesirable effects
Potentially life-threatening adverse reactions. Administration of estradiol without a concomitant administration of progesterone in women with functional uterus is connected with an increased risk of occurrence of endometrial hyperplasia and endometrial carcinoma as a result of excessive growth stimulation of endometrium. The size of this risk depends on the dose and treatment duration. It is lower at the combined estrogen-progesterone therapy. Epidemiological studies have shown the increased risk of breast abscesses in women who have used the hormonal substitution therapy. The increased risk appears after several years of application, it rises with a length of application and after the end of application its values return back to basic level during several years. The long-time treatment (minimum 5 – 10 years) by estrogen preparations in hysterectomy women was is some epidemiological studies connected with the higher risk of ovarian carcinoma.
Estrogen therapy increases the risk of venous thrombo-embolic complications. The risk of occurrence of arterial thrombosis is not proven definitely. Disorders of liver functions (jaundice, adenomas). Potential teratogenity. 

Serious or irreversible adverse reactions. During the treatment by estradiol a serious abnormal uterine bleeding may occur. Endometrial biopsy is necessary to exclude the presence of carcinoma. At the application to men (prostate carcinoma therapy) a feminization must be taken into account (gynecomastia, inhibition of spermato-genesis, loss of libido, impotence). 
Symptomatic adverse reactions. All estrogen preparations may, especially at the beginning of treatment, cause different adverse reactions such as tension and hypertrophy of breast, mastalgia, light vaginal bleeding, retention of sodium and liquids, increase of body weight, headache, paresthesia, anorexia, nausea, vomiting, diarrhea, tendency to depression and anxiety, chloasma, nettle rash and other skin eruptions, different allergic reactions. After discontinuation of estrogens application the uterine bleeding is induced often.
In children an early closure of epiphyseal plates can appear. 

4.9. Overdose
No information on consequences of acute overdose by estradiol in human is available. The treatment of potential overdose is to be symptomatic.

5. PHARMACOLOGICAL PROPERTIES

5.1. Pharmacological properties
Pharmacotherapeutic group: hormones – estrogens, G03CA03.

Molecular and cellular mechanism of action:
Estradiol acts through estrogen receptors localized in target tissues. Free estrogen receptors are localized in cytoplasm, however they were found also in cell membrane.
Estradiol regulates the growth and activity of female genitals, secondary sexual signs and mammary glands, as well as certain functions of uterus and accessory organs, particularly proliferation of endometrium, development of decidua and cyclic changes of cervical epithelium and vagina. Hyperplasia of endometrium during application of estrogens can be limited by concomitant application of progesterone. Besides effect on genitals, secondary sexual signs, lacteal gland, hypothalamus and hypophysis estradiol has effect particularly on liver and skeleton and has various metabolic effects. It effects 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 triglycerides. It stimulates the synthesis of transport globulins for hormones. It supports the absorption of calcium from intestines and reduces its excretion in urine. Estradiol inhibits resorption of bones. The serious consequences of long-lasting deficiency of circulating estrogens can be osteoporosis and cardiovascular complications.

5.2. Pharmacokinetic properties
Pharmacokinetics after a single application. Drug substance is absorbed slowly from oil vehicle and even slower from micro-crystalline aqueous suspension because estradiol benzoate is almost insoluble in water.
Parenteral application of estradiol benzoate allows the reduction of its inactivation in intestinal mucosa and in liver.
Distribution. In regard to a high solubility in fats estradiol is distributed in a whole body. Extensive binding to plasmatic proteins is the reason however that the distribution volume is only 9 – 15 l. Circulating estradiol is almost completely bound to plasmatic proteins. About 60 % is bound to albumin, 38 % to globulin binding sex hormones and 2 – 3 % remain free and represent the biologically active fraction of hormone. Hyperthyroidism, cirrhosis, pregnancy and therapy by estrogens increase the level of globulin binding sex hormones. In the contrary, hypothyroidism, hyperandrogenism and obesity decrease its level. Estradiol is excreted into breast milk. Estradiol crosses the placenta. 
Biotransformation. Estradiol is converted by 17-β-hydroxysteroid dehydrogenase to estrone already in intestinal mucosa, then in liver. All three estrogens (estradiol and its metabolites, estrone, estriol) are excreted by urine as glucuronide and sulfate conjugates together with small quantity of unchanged estradiol. 40 to 100 % (in the average 80 %) of the applied dose of estradiol is excreted by urine within 96 – 120 hours. 20 % is excreted by stool. About 40 % of estradiol metabolites are excreted by bile and 80 % thereof is reabsorbed into enterohepatic circulation. Only small part (about 7 %) of the applied dose of estradiol is excreted in stool. Hepatic metabolism of estradiol can be increased by induction of microsomal enzymes.

5.3. Preclinical safety data
Reproductive toxicity. According to the testing on animals estradiol has teratogenic effect on urogenital tract, skeleton, heart and mammary gland. In some species of experimental animals the application of estradiol in utero reduces fertility in offspring, it causes feminization in males.
Oncogenic potential. In some species of experimental animals estradiol supports the development of different tumors, including tumors of mammary gland, uterus and cervix uteri. Testicular, lymphoid and osteogenic tumors were described, but only in some species of mice. 
Estradiol is filed in the list of famous carcinogens. It is classified as “tumor promoter” and not as genotoxic carcinogen. However some genotoxic tests on bacteria indicate that estradiol and its catechol metabolites are genotoxic carcinogens with probable ability to induce the development of tumors. Estradiol and diethylstilbestrol have genotoxic effect also on mouse epithelial cells.

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 at 10 – 25 ºC, protect from light and frost. Keep the ampoules in vertical position.

6.5. Nature and contents of container, package size
1)  2 mL breaking ampoules with adhesive label, plastic moulding, package leaflet: information for the user, paperboard folding box.
2)  2 mL non-breaking ampoules with adhesive label, file, plastic moulding, package leaflet: information for the user, paperboard folding box.
Package size: 1 ampoule of 2 mL, 5 ampoules of 2 mL

6.6. Special precautions for use and other handling
Apply deep into the muscle. 

7. MARKETING AUTHORISATION HOLDER
BB Pharma a.s., Pod Višňovkou 1662/21, Prague 4, Czech Republic
8. MARKETING AUTHORISATION NUMBER
56/0452/69-S, 56/452/69-S/C
9. DATE OF FIRST AUTHORISATION / RENEWAL OF THE AUTHORISATION
1969
10. DATE OF REVISION OF THE TEXT
September 2013