Testosteroni isobutyras 25 mg in 1 mL of micro-crystalline aqueous suspension.

Complete list of excipients, see the Part 6.1

Suspension for injection. 

Micro-crystalline aqueous suspension after shaking of milky colour, which cannot contain any clumps of crystals. 

Absolute deficiency or reduced production of testicular androgens, heavy postmenopausal osteoporosis, aplastic anemia. 

At treatment of eunuchoidism, pseudoeunuchoidism, Klinefelter´s syndrome, delayed puberty, in so called male climacterium and some disorders of male fertility testosterone isobutyrate is applied at a dose of 25 – 50 mg once in 14 days, or also in longer intervals according to achieved effect. Therapy efficiency must be monitored by determination of testosterone levels and on the base of clinical changes. Dosing must be adapted to an individual reaction of patient. The first symptoms of hormonal effect appear in 1 – 2 weeks, full virilisation is achieved in 2 – 4 months. In boys in pubertal age with hypogonadotropic hypogonadism or primary testicular deficiency it is started usually with treatment by androgens between 12 and 14 year of age in dependence on subjective requirements. In constitutional delayed puberty (without positive diagnosis of hypogonadism) it is necessary to start with substitution therapy in the age of 15 – 17 years only in case that the psychic development is endangered. Treatment of delayed puberty is not indicated generally before 16 years of age. In patients of each age, in that hypogonadism was developed before puberty onset, it is necessary to increase the level of testosterone successively, similarly as level of testosterone is increased physiologically in puberty. Premature closure of epiphyseal plates and growth stoppage are prevented. In delayed puberty the treatment should last 4 – 6 months. This treatment has no effect on the final growth.

In treatment of aplastic anemia 1.5 – 2 mg of testosterone isobutyrate per kg of body weight is administered. Long-time treatment may be necessary.

In postmenopausal symptoms, in heavy osteoporosis it is necessary to combine a standard substitu-tion estradiol therapy with testosterone isobutyrate at a dose even 50 mg (Agovirin Depot 2 mL) once in 14 days. The dose must be adjusted according to the obtained effect and virilization signs. 

Agovirin Depot is injected deep into muscle; the injection sites must be changed.

Pregnancy and lactation (see the Part 4.6). Prostatic carcinoma and mammary gland carcinoma in men, benign prostatic hyperplasia, nephrosis and nephrotic phase of nephritis. The drug should not be administered either to patients with hypercalcemia or with hypercalciuria or in the situations when there is an increased risk that these disorders occur. Manifest heart failure means a contraindication of treatment with androgens. The drug is not suitable for treatment of potency disorders which are not of endocrine origin.

Aqueous micro-crystalline suspension of testosterone isobutyrate has a prolonged effect compared to oil solution. It crosses the placental barrier.

Special attention is required in cardio-vascular, liver and kidneys disorders, as well as in all disorders which may be worsen in consequence of sodium retention (e.g. epilepsy, migraine, diabetes mellitus).

Substitution therapy by esters of testosterone may cause retention of sodium in patients, especially in sensitive patients who are applied high doses.

Newborns. There are no indications for use of testosterone in newborns.

Children. Special care is required in use of androgens in children in regard to their masculinization effect and possible premature closure of epiphyseal plates. Before and during puberty it is necessary to choose the dose carefully in order to prevent a significant masculinization and a short stature in consequence of premature closure of epiphyseal plates.

Relative contraindication is application to adolescent girls.

Elderly patients. If it is necessary to use the substitution androgen therapy in patients in higher age, it is necessary to consider carefully the dose in regard to a possible risk of prostate enlargement and subsequent problems with urination, retention of liquids and increased sexual stimulation.

Agovirin Depot increases sensitivity to anticoagulation substances and efficiency of drug substances which are biotransformed by microsomal enzymes.

Testosterone increases a risk of kidneys impairment at a concomitant administration of hepatotoxic drugs. Increased cholesterolemia may occur. Agovirin Depot may influence the results of glucose tolerance test. 

Aqueous micro-crystalline suspension of testosterone isobutyrate crosses the placental barrier.

Testosterone is contraindicated in pregnancy in regard to possible risk of virilization of fetus. 

Testosterone is contraindicated during lactation because of possible virilization of child.

Agovirin Depot has no influence on the ability to drive and use machines.

They result from androgen and anabolic effect: increased retention of nitrogen, sodium, potassium, chlorides, hypercalcemia and increased skin vascularisation. Repeated high doses in childhood cause the closure of epiphyseal plates and discontinue the linear bone growth. Excessive doses in women induce hirsutism, deepening of voice, hypertrophy of clitoris, atrophy of mammary glands, acne, increased sexual appetite, inhibition of gonadotrophic function of hypophysis. They attenuate spermatogenesis in men, induce degenerative changes of testicles, stimulate formation of prostatic neoplasms. Relative common are disorders of liver functions and development of hepatic carcinomas. Teratogenity. Risk of occurrence of priapism. Manifestation of different psychic disorders. Risk of increased incidence of breast cancer in hormone replacement therapy (HRT) especially in combination with estrogens.

No cases of overdose have been reported.

Pharmacotherapeutic group:         hormone – androgen.

ATC code:                                  G03BA03

Mechanism of action

Testosterone is metabolized to another two hormonal active steroids. Final effect of testosterone is a summary of effects of testosterone itself and 5α-dihydrotestosterone and estrogen metabolites. Tes-tosterone and 5α-dihydrotestosterone act through one androgen receptor localized in liver in androgen-sensitive cells. Estrogen metabolites act through estrogen receptor. Cells containing androgen receptors are able to respond directly on change of androgens level. Cells without androgen receptors may be influenced by androgens indirectly through growth factors which are synthesized and secreted by other cells under effect of androgen stimulation. Testosterone enters the cell by passive diffusion and it has not a direct effect in many cells sensitive to androgens, but firstly it is converted to 5α-dihydrotestosterone. Only this androgen is bound then to androgen receptor. Steroid-5α-reductase 1 is localized mostly in skin out of genitals and in liver. Steroid-5α-reductase 2 is localized especially in male urogenital tract and in skin of external genitals of both sexes. Common localization of 5α-reductase and androgen receptor in liver of some cells may be an important mechanism of achievement of selective effect of androgens. In these cells which do not contain 5α-reductase, testosterone activates the androgen receptor directly.

Pharmacodynamic properties

Testosterone is natural androgen hormone. It has different effects at different stages of ontogenetic development. Common receptor intermediates as androgen, so anabolic effects of testosterone. Therefore through modification of testosterone molecule it is not possible to separate these effects. 

Resorption

Deceleration of resorption from injection site can be reached also by application in form of micro-crystalline aqueous suspension. Levels of testosterone after application of depot testosterone esters reach the maxima on 4th – 5th day after injection and decrease slowly in the following 3 weeks. Such application causes very significant fluctuation of testosterone level after each injection, and also after long-time application. Testosterone isobutyrate is hydrolyzed firstly and as a 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 a natural hormone. Testosterone released from esters is also metabolized in liver similarly as a natural hormone. 

Biotransformation

Testosterone secreted by different organs, created from precursors in peripheral tissues or applied exogenously, is intensively metabolized in liver to slightly androgen derivatives and inactive etiocholanolone. From the applied dose of marked testosterone, 90 % is excreted by urine and 6 % in unchanged form by stool through biliary system. Metabolites androsterone and etiocholanolone are excreted in urine mostly as glucuronides and sulfates. 

Dependency between plasmatic concentration and effect

The target of substitution therapy is to maintain a stable testosterone level in a normal range.

Elevated levels of testosterone increase progressively the weight of prostate and seminal vesicles. Effects of testosterone on CNS (libido and potency) have no exact connection with testosterone level in blood, if the level is normal or elevated. In principle testosterone is applied in minimal doses, which provide normal androgen function. So the problems which could be a result of application of high doses (e.g. prostatic hypertrophy) will not occur. 

Doses of testosterone or its esters, which increase the testosterone level high above the physiological values, suppress the secretion of gonadotropins, subsequently inhibit spermatogenesis and induce atrophy testis.

Carmellosum natricum, sorbitolum, polysorbatum 80, phenolum, aqua ad iniectabilia.

Testosterone is decomposited by substances with oxidation activity; alkaline substances cause hydrolysis of ester.

3 years

Store at 10 – 25 ºC in original package in order to protect from light. Do not freeze. 

Keep the ampoules in vertical position.

1)  2 mL breaking ampoules with self-adhesive label, plastic moulding, package leaflet: information for the user, paperboard folding box.

2)  2 mL non-breaking ampoules with self-adhesive label, file, plastic moulding, package leaflet: infor-mation for the user, paperboard folding box.

Package size: 5 ampoules of 2 mL

Agovirin Depot is applied intramuscularly.

Any unused medicinal product or waste material should be disposed of in accordance with local re-quirements.

BB Pharma a.s., Pod Višňovkou 1662/21, Prague 4, Czech Republic

56/0449/69-S, 56/449/69-S/C 

1969 

September 2013