Bayer HealthCare Pharma


Full Prescribing Info
Testosterone undecanoate.
Each mL solution for injection contains testosterone undecanoate 250 mg corresponding to testosterone 157.9 mg.
Each ampoule with 4 mL solution for injection contains testosterone undecanoate 1000 mg.
It also contains benzyl benzoate and refined castor oil as excipients.
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 (eg, spermatogenesis, accessory sexual glands). It also performs functions eg, in the skin, muscles, skeleton, kidney, liver, bone marrow and CNS.
Dependent on the target organ, the spectrum of activities of testosterone is mainly androgenic (eg, 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 then binds to estrogen receptors in the target cell nucleus eg, the pituitary, fat, brain, bone, and testicular Leydig cells.
Pharmacokinetics: Absorption: Nebido is an IM administered depot preparation of testosterone undecanoate and thus circumvents the first-pass effect. Following IM 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 1 day after administration.
Steady-State Conditions: After the 1st IM injection of testosterone undecanoate 1000 mg to hypogonadal men, mean Cmax values of 38 nmol/L (11 ng/mL) were obtained after 7 days. The 2nd dose was administered 6 weeks after the 1st 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 3rd and the 5th administration. Mean Cmax and Cmin 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 Cmin 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 IV infusion of testosterone to elderly men, the elimination half-life of testosterone was approximately 1 hr and an apparent volume of distribution of about 1 L/kg was determined.
Metabolism: 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. The major active metabolites of testosterone are estradiol and dihydrotestosterone.
Elimination: 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 sulfuric acid conjugates and 6% appears in the feces after undergoing enterohepatic circulation. Urinary medicinal products include androsterone and etiocholanolone. Following IM administration of this depot formulation the release rate is characterized by a half-life of 90±40 days.
Toxicology: Preclinical Safety Data: 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 nonmutagenic 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 tumors 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.
Testosterone replacement therapy for male hypogonadism when testosterone deficiency has been confirmed by clinical features and biochemical tests (see Precautions).
Dosage/Direction for Use
For IM use.
Adults and elderly men: 1 amp (corresponding to testosterone undecanoate 1000 mg) is injected every 10-14 weeks. Injections with this frequency are capable of maintaining sufficient testosterone levels and do not lead to accumulation. The injections must be administered very slowly. Care should be taken to inject Nebido deeply into the gluteal muscle following the usual precautions for IM administration. Special care must be given to avoid intravasal injection. The contents of an ampoule are to be injected IM immediately after opening the ampoule.
Start of Treatment: Serum testosterone levels should be measured before start and during initiation of treatment. Depending on serum testosterone levels and clinical symptoms, the 1st injection interval may be reduced to a minimum of 6 weeks as compared to the recommended range of 10-14 weeks for maintenance. With this loading dose, sufficient steady-state testosterone levels may be achieved more rapidly.
Maintenance and Individualization of Treatment: The injection interval should be within the recommended range of 10-14 weeks. Careful monitoring of serum testosterone levels is required during maintenance of treatment. It is advisable to measure testosterone serum levels regularly. Measurements should be performed at the end of an injection interval and clinical symptoms considered. These serum levels should be within the lower third of the normal range. Serum levels below normal range would indicate the need for a shorter injection interval. In case of high serum levels, an extension of the injection interval may be considered.
Application: Nebido must be injected IM. Experience shows that the short-lasting reactions (urge to cough, coughing fits, respiratory distress) which occur in rare cases during or immediately after the injection of oily solutions can be avoided by injecting the solution extremely slowly.
No special therapeutic measure apart from termination of therapy with the medicinal product or dose reduction is necessary after overdose.
Androgen-dependent carcinoma of the prostate or of the male mammary gland; past or present liver tumours; hypersensitivity to testosterone undecanoate or to any of the excipients.
Use in Pregnancy & Lactation: Nebido is not indicated for use in women and must not be used in pregnant or breastfeeding women.
Use in Children: Nebido is not indicated nor recommended for use in children and adolescents and it has not been evaluated clinically in males <18 years.
Special Precautions
Nebido should be used only if hypogonadism (hyper- and hypogonadotrophic) has been demonstrated and if other etiology, responsible for the symptoms, has been excluded before treatment is started. Testosterone insufficiency should be clearly demonstrated by clinical features (regression of secondary sexual characteristics, change in body composition, asthenia, reduced libido, erectile dysfunction, etc.) and confirmed by 2 separate blood testosterone measurements.
Medical Examination: Prior to testosterone initiation, all patients must undergo a detailed examination in order to exclude a risk of preexisting prostatic cancer. Careful and regular monitoring of the prostate gland and breast must be performed in accordance with recommended methods (digital rectal examination and estimation of serum PSA) in patients receiving testosterone therapy at least once yearly and twice yearly in elderly patients and at risk patients (those with clinical or familial factors).
Besides laboratory tests of the testosterone concentrations in patients on long-term androgen therapy, the following laboratory parameters should be checked periodically: Hemoglobin, hematocrit, and liver function tests.
Due to variability in laboratory values, all measures of testosterone should be carried out in the same laboratory.
Tumors: Androgens may accelerate the progression of subclinical prostatic cancer and benign prostatic hyperplasia.
Nebido should be used with caution in cancer patients at risk of hypocalcemia (and associated hypercalciuria), due to bone metastases. Regular monitoring of serum calcium concentrations is recommended in these patients.
Rarely, benign and malignant liver tumors have been reported in patients receiving testosterone replacement therapy.
Other Conditions: In patients suffering from severe cardiac, hepatic or renal insufficiency or ischemic heart disease, treatment with testosterone may cause severe complications characterized by edema with or without congestive cardiac failure. In such case, treatment must be stopped immediately. There are no studies undertaken to demonstrate the efficacy and safety of this medicinal product in patients with renal or hepatic impairment. Therefore, testosterone replacement therapy should be used with caution in these patients.
As a general rule, the limitations of using IM injections in patients with acquired or inherited blood clotting irregularities always have to be observed.
Nebido should be used with caution in patients with epilepsy and migraine, as the conditions may be aggravated.
Improved insulin sensitivity may occur in patients treated with androgens who achieve normal testosterone plasma concentrations following replacement therapy.
Certain clinical signs: Irritability, nervousness, weight gain, prolonged or frequent erections may indicate excessive androgen exposure requiring dosage adjustment.
Preexisting sleep apnea may be potentiated.
Athletes treated for testosterone replacement in primary and secondary male hypogonadism should be advised that the medicinal product contains an active substance which may produce a positive reaction in anti-doping tests.
Androgens are not suitable for enhancing muscular development in healthy individuals or for increasing physical ability.
Nebido should be permanently withdrawn if symptoms of excessive androgen exposure persist or reappear during treatment with the recommended dosage regimen.
Effects on the Ability to Drive or Operate Machinery: Nebido has no influence on the ability to drive and use machines.
Use in the Elderly: There is limited experience of the use of Nebido in elderly patients >65 years. Currently, there is no consensus about age-specific testosterone reference values. However, it should be taken into account that physiologically testosterone serum levels are lower with increasing age.
Use In Pregnancy & Lactation
Nebido is not indicated for use in women and must not be used in pregnant or breastfeeding women.
Adverse Reactions
The most frequently observed adverse reaction was injection site pain (10%).
The following adverse reactions were reported in clinical trials with a suspected relationship to Nebido (according to the HARTS Body System and Dictionary Term system):
Common* (>1/100, <1/10): Digestive: Diarrhea. Musculoskeletal System: Leg pain, arthralgia. Nervous System: Dizziness, increased sweating, headache. Respiratory System: Respiratory disorder. Skin and Appendages: Acne, breast pain, gynecomastia, pruritus, skin disorder. Urogenital: Testicular pain, prostate disorder. General Disorders and Administration Site Conditions: Subcutaneous hematoma at the injection site.
*Due to the small sample size of the studies, the frequency of each reported adverse event with a suggested causal relationship falls at least into the category common (>1/100).
In the literature, the following adverse reactions from testosterone-containing preparations have been reported:
Blood and the Lymphatic System Disorders: Rare cases of polycythemia (erythrocytosis).
Metabolism and Nutrition Disorders: Weight gain, electrolyte changes (retention of sodium, chloride, potassium, calcium, inorganic phosphate and water) during high dose and/or prolonged treatment.
Musculoskeletal System: Muscle cramps.
Nervous System: Nervousness, hostility, depression.
Respiratory System: Sleep apnea.
Hepatobiliary Disorders: In very rare cases, jaundice and liver function test abnormalities.
Skin and Appendages: Various skin reactions may occur including acne, seborrhea and balding (alopecia).
Reproductive System and Breast Disorders: Libido changes, increased frequency of erections; therapy with high doses of testosterone preparations commonly reversibly interrupts or reduces spermatogenesis, thereby reducing the size of the testicles; testosterone replacement therapy of hypogonadism can, in rare cases, cause persistent, painful erections (priapism), prostate abnormalities, prostate cancer**, urinary obstruction.
General Disorders and Administration Site Conditions: High-dose or long-term administration of testosterone occasionally increases the occurrences of water retention and edema; hypersensitivity reactions may occur.
**Data on prostate cancer risk in association with testosterone therapy are inconclusive.
Drug Interactions
Oral Anticoagulants: Testosterone and derivatives have been reported to increase the activity of oral anticoagulants. Patients receiving oral anticoagulants require close monitoring, especially at the beginning or end of androgen therapy. Increased monitoring of the prothrombin time, and INR determinations, are recommended.
Other Interactions: The concurrent administration of testosterone with ACTH or corticosteroids may enhance edema formation; thus, these active substances should be administered cautiously, particularly in patients with cardiac or hepatic disease or in patients predisposed to edema.
Laboratory Test Interactions: Androgens may decrease levels of thyroxine-binding globulin resulting in decreased total T4 serum levels and increased resin uptake of T3 and T4. Free thyroid hormone levels remain unchanged, however, and there is no clinical evidence of thyroid dysfunction.
Incompatibilities: In the absence of compatibility studies, this medicinal product must not be mixed with other medicinal products.
Caution For Usage
Instructions for Use and Handling: The solution for IM injection is to be visually inspected prior to use and only clear solutions free from particles should be used. The medicinal product is for single use only and any unused solution should be discarded.
Nebido does not require any special storage conditions.
Shelf-Life: 3 years. Nebido must be used immediately after first opening.
ATC Classification
G03BA03 - testosterone ; Belongs to the class of 3-oxoandrosten (4) derivative androgens used in androgenic hormone preparations.
Inj (vial) 1000 mg/4 mL (clear, yellowish oily soln) x 1's.
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