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Pharmacotherapeutic group: Androgens, 3-oxoandrosten (4) derivatives. ATC Code: G03BA03.
Pharmacology: Pharmacodynamics: Testosterone undecanoate is an ester of the naturally occurring androgen, testosterone. The active form, testosterone, is formed by cleavage of the side chain.
Testosterone is the most important androgen of the male, mainly synthesized in the testicles, and to a small extent in the adrenal cortex.
Testosterone is responsible for the expression of masculine characteristics during fetal, early childhood, and pubertal development and thereafter for maintaining the masculine phenotype and androgen-dependent functions (e.g. spermatogenesis, accessory sexual glands).
Insufficient secretion of testosterone results in male hypogonadism characterized by low serum testosterone concentrations. Signs and symptoms associated with male hypogonadism include but are not limited to, erectile dysfunction and decreased sexual desire, fatigue, depressive moods as well as a lacking of secondary sexual characteristics, their incomplete development, or their regression, an increased risk of osteoporosis, an increase of visceral fat and a decrease of lean body mass and muscle strength. Exogenous androgens are given to improve the deficient endogenous testosterone levels and related signs and symptoms.
Dependent on the target organ, the spectrum of activities of testosterone is mainly androgenic (e.g. prostate, seminal vesicles, epididymis) or protein-anabolic (muscle, bone, hematopoiesis, kidney, liver).
The effects of testosterone in some organs arise after peripheral conversion of testosterone to estradiol, which than binds to estrogen receptors in the target cell nucleus e.g. the pituitary, fat, brain, bone, and testicular Leydig cells.
In hypogonadal men androgens decrease the body fat mass, increase the body lean mass, muscle strength, and prevent bone loss. Androgens may improve sexual function and also may exert positive psychotropic effects by improving mood.
Pharmacokinetics: Absorption: Testosterone undecanoate (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.
Distribution: In two separate studies, mean maximum concentrations of testosterone of 24 and 45 nmol/L were measured about 14 and 7 days, respectively, after single i.m. administration of 1000 mg of testosterone undecanoate to hypogonadal men. Post-maximum testosterone levels declined with an estimated half-life of about 53 days.
Following intravenous infusion of testosterone to elderly men, an apparent volume of distribution of about 1.0 L/kg was determined.
Metabolism/Biotransformation: Testosterone which is generated by ester cleavage from testosterone undecanoate is metabolized and excreted the same way as endogenous testosterone. The undecanoic acid is metabolized by β-oxidation in the same way as other aliphatic carboxylic acids.
Elimination/Excretion: Testosterone undergoes extensive hepatic and extrahepatic metabolism. After the administration of radiolabeled testosterone, about 90% of the radioactivity appears in the urine as glucuronic and sulphuric acid conjugates and 6% appears in the feces after undergoing enterohepatic circulation. Urinary products include androsterone and etiocholanolone.
Steady state conditions: Following repeated i.m. injection of 1000 mg testosterone undecanoate to hypogonadal men using an interval of 10 weeks between two injections, steady state conditions were achieved between the 3rd and the 5th administration. Mean Cmax and Cmin values of testosterone at steady state were about 42 and 17 nmol/L, respectively. Post-maximum testosterone levels in the serum decreased with a half-life of about 90 days, which corresponds to the release rate from the depot.
Toxicology: Preclinical safety data: Systemic toxicity: Acute toxicity: As with steroid hormones in general, the acute toxicity of testosterone is very low.
Chronic toxicity: No effects which might indicate an unexpected risk to humans were observed during systemic toxicity studies in a rodent or non-rodent species after repeated administration of either the undecanoate or the enanthate ester of testosterone.
Mutagenic and tumorigenic potential: In vitro and in vivo investigations into a mutagenic effect of testosterone undecanoate itself as well as studies on testosterone itself gave no indications of a mutagenic potential.
Studies in rodents indicate a promoting effect of testosterone or of its esters on the development of hormone-dependent tumors. Generally, it should be born in mind that sex steroids can promote the growth of certain hormone-dependent tissues and tumors.
Reproduction toxicity: Fertility studies in rodents and primates have shown that treatment with testosterone can impair fertility by suppressing spermatogenesis in a dose-dependent manner. Furthermore, no embryolethal or teratogenic effects were observed in the offspring of testosterone-treated male rats. Administration of Testosterone undecanoate (Nebido) may cause virilization of female fetuses in certain development stages. However, investigations into the embryotoxic, in particular teratogenic, effects gave no indication that further impairment of organ development is to be expected.
Local tolerance and contact sensitizing potential: The local tolerance study on pigs following intramuscular administration showed that Testosterone undecanoate (Nebido) does not increase the irritative effects already caused by the solvent. The solvent of Testosterone undecanoate (Nebido) has been used for many years in numerous formulations for human use. In this time no local irritative effects have been observed which would object to its further use.
