NEBIDO Solution for injection Ref.[7121] Active ingredients: Testosterone

Absorption

Nebido is an intramuscularly administered depot preparation of testosterone undecanoate and thus circumvents the first-pass effect. Following intramuscular injection of testosterone undecanoate as an oily solution, the compound is gradually released from the depot and is almost completely cleaved by serum esterases into testosterone and undecanoic acid. An increase in serum levels of testosterone above basal values may be seen one day after administration.

Steady-state conditions

After the 1^st intramuscular injection of 1000 mg testosterone undecanoate to hypogonadal men, mean C_max values of 38 nmol/L (11 ng/mL) were obtained after 7 days. The second dose was administered 6 weeks after the 1^st injection and maximum testosterone concentrations of about 50 nmol/L (15 ng/mL) were reached. A constant dosing interval of 10 weeks was maintained during the following 3 administrations and steady-state conditions were achieved between the 3^rd and the 5^th administration. Mean C_max and C_min values of testosterone at steady-state were about 37 (11 ng/mL) and 16 nmol/L (5 ng/mL), respectively. The median intra- and inter-individual variability (coefficient of variation, ) of C_min values was 22 (range: 9-28%) and 34% (range: 25-48%), respectively.

Distribution

In serum of men, about 98% of the circulating testosterone is bound to sex hormone binding globulin (SHBG) and albumin. Only the free fraction of testosterone is considered as biologically active. Following intravenous infusion of testosterone to elderly men, the elimination half-life of testosterone was approximately one hour and an apparent volume of distribution of about 1.0 l/kg was determined.

Biotransformation

Testosterone which is generated by ester cleavage from testosterone undecanoate is metabolised and excreted the same way as endogenous testosterone. The undecanoic acid is metabolised by ß-oxidation in the same way as other aliphatic carboxylic acids. The major active metabolites of testosterone are oestradiol and dihydrotestosterone.

Elimination

Testosterone undergoes extensive hepatic and extrahepatic metabolism. After the administration of radio-labelled testosterone, about 90% of the radioactivity appears in the urine as glucuronic and sulphuric acid conjugates and 6% appears in the faeces after undergoing enterohepatic circulation. Urinary medicinal products include androsterone and etiocholanolone. Following intramuscular administration of this depot formulation the release rate is characterised by a half life of 90±40 days.

Toxicological studies have not revealed other effects than those which can be explained based on the hormone profile of Nebido.

Testosterone has been found to be non-mutagenic in vitro using the reverse mutation model (Ames test) or hamster ovary cells. A relationship between androgen treatment and certain cancers has been found in studies on laboratory animals. Experimental data in rats have shown increased incidences of prostate cancer after treatment with testosterone.

Sex hormones are known to facilitate the development of certain tumours induced by known carcinogenic agents. The clinical relevance of the latter observation is not known.

Fertility studies in rodents and primates have shown that treatment with testosterone can impair fertility by suppressing spermatogenesis in a dose dependent manner.