Nebido® produces testosterone concentrations in the physiological range and needs to be administered only about four times a year.
Nebido® is available in packages containing one vial. This product requires no particular precautions for storage. However, it should not be stored in the refrigerator. The contents of one vial should be administered slowly by intramuscular injection.
Nebido® is indicated for testosterone therapy for male hypogonadism when testosterone deficiency has been confirmed by clinical features and biochemical tests.
On clinical symptoms
Nebido® improves the symptoms associated with testosterone deficiency. Nebido® exerts a positive effect on sexual function and mood, increases muscle mass and muscle strength and decreases body fat.
Pulmonary oil microembolism has been observed after injection during routine clinical practice and in rare cases lead to signs and symptoms such as cough, dyspnea, malaise, hyperhidrosis, chest pain, dizziness, paraesthesia, or syncope. These reactions may occur during or immediately after the injection and are reversible. The patient should therefore be observed during and immediately after each injection in order to allow for early recognition of possible signs and symptoms of pulmonary oily microembolism. Treatment is usually supportive, e.g. by administration of supplemental oxygen.
Nebido® may not be used in patients with carcinoma of the prostate, mammary gland carcinoma, previous or existing liver tumours, and hypersensitivity to the constituents of Nebido®.
As with any testosterone treatment, before starting and during treatment with Nebido®regular monitoring of the prostate in accordance with recommended methods is necessary (digital rectal examination of the prostate, PSA measurement and transrectal ultrasound).
This monograph outlines the aetiology of hypogonadism, the physiology and pathophysiology of testosterone, the definition and rationale for testosterone therapy, and the diagnosis of male hypogonadism. The pharmaceutical and pharmacological data and the clinical profile of Nebido® (the first long-acting injection for the treatment of male hypogonadism) are described in detail.
Figure 2: Classification of hypogonadism.
Many systemic diseases (e.g. diabetes mellitus, generalized infections, metabolic syndrome) correlate with low testosterone levels.1 Therefore, hypogonadism as an early sign can contribute to an early diagnosis of the underlying condition. Another cause of male hypogonadism is the naturally occurring, age-related decrease of testosterone serum levels, which may lead to a state of androgen deficiency (Figure 3).
Figure 3: Prevalence of low levels of total and bioavailable testosterone as an index of male hypogonadism according to decade of life.6
Enzyme defects in testosterone biosynthesis and luteinizing hormone (LH) receptor defects may also be causative factors for hypogonadism.
Figure 4: Classification of hypogonadism.
|Target tissue||Biologic effect|
|Reproductive tissues||Stimulation of prenatal differentiation and pubertal development of the testes, penis, epididymis, seminal vesicles, and prostate. In adults, maintenance of these tissues, central and peripheral modulation of erectile function,15 initiation and maintenance of spermatogenesis.|
|Sexual function and behaviour||Key role in stimulating and maintaining sexual function in men. In hypogonadal men testosterone induces greater interest in sexual activity, while suppression of testosterone levels to the range of castrates in normal young men reduces sexual desire, sexual fantasies, and spontaneous erections. In non-human primates, aggression is directly correlated with serum testosterone levels, while in humans self-assessed aggression is less clearly correlated.|
|Muscle||Androgens increase nitrogen balance, lean body mass, and may increase body weight. Testosterone increases the size of the muscle cells with little effect on their number.|
|Skin and hair||Increase in sebum production, with acne as a possible consequence. Male hair pattern.|
|Liver||Increased synthesis of clotting factors, hepatic triglyceride lipase, sialic acid, α1-antitrypsin, and haptoglobin. Decreased production of SHBG, other hormone-binding proteins, transferrin, and fibrinogen.|
|Lipids||Androgens may decrease high-density lipoprotein (HDL)-cholesterol plasma concentrations in adolescent boys with delayed puberty and in hypogonadal men.|
|Bone||Hypogonadism is a risk factor for osteoporosis in men.16 Androgens stimulate the proliferation of bone cells in vitro and improve bone mineral density in hypogonadal men.17,18|
|Haematology and immunology||Stimulation of the erythropoietin production in the kidneys. Androgens exert suppressive effects on both humoral and cellular immune responses, and seem to represent natural anti-inflammatory hormones.19,20|
|Hypogonadism is a clinical condition characterised by low serum testosterone levels occurring in association with any of the signs and symptoms listed:|
*The definition is adapted from the 2002 position statement on diagnosis, treatment, and monitoring of hypogonadism by the Sexual Medicine Society of North America, a specialty society of the American Urological Association.
The recent recommendations on the investigation, treatment, and monitoring of late-onset hypogonadism in males suggest that total testosterone levels above 12 nmol/L (346 ng/dL) or free testosterone levels above 250 pmol/L (72 pg/mL) do not require therapy with testosterone. Total testosterone levels between 8 nmol/L and 12 nmol/L or free testosterone levels between 180 pmol/L and 250 pmol/L are regarded as borderline hypogonadal levels. A trial of testosterone treatment can be considered in those patients.4
The pharmaceutical and pharmacological data on Nebido® are reviewed in detail in the following chapter (7. Pharmaceutical and Pharmacological Data).
The medically active component in Nebido® is TU (3-oxoandrost-4-en-17b-yl-undecanoate). TU is produced through esterification of natural testosterone in the 17β position. Testosterone is a steroid with 19 carbon atoms (chemical formula: C19H28O2; Figure 5). Its chemical name is 17 beta-hydroxyandrost-4-en-3-one.
Figure 5: Chemical structure of testosterone undecanoate; TU.
The pharmacodynamic properties of TU are identical to the physiological action of testosterone described in chapter 3 of this monograph, Physiology and Pathophysiology.
Figure 6: The mechanism of action of testosterone.43
These different durations of action are due to the half-lives, which are dependent on the testosterone ester, the galenic formulation, and the route of administration. Thus, the half-life of injectable TE i.m. is 4.5 days, and of oral TU is 1.6 hours.1 Following i.m. administration of Nebido® the release rate is characterised by a half-life of approximately 90 days.41
Figure 7: Diagrammatic comparison of the kinetics of testosterone after 3 weeks of i.m. administration of testosterone enanthate, oral administration of testosterone undecanoate several times a day, and administration of Nebido® every 3 months.1
Following a single administration of Nebido® to 14 hypogonadal men, 2 days after the injection testosterone levels of 12.3 ± 1.7 nmol/L were reached and within 7 days, mean maximum testosterone concentrations were 22.0 ± 2.0 nmol/L and were reached within about 14 days post administration. Testosterone levels remained in the therapeutic range for 6–8 weeks (Figure 8).45
Figure 8: Mean serum testosterone levels (± standard deviation [SD]) in 14 hypogonadal men after a single i.m. administration of Nebido®.45
The oestradiol and DHT levels rose in parallel with the testosterone levels. Between day 7 and day 14 after the injection, DHT reached maximum values of 1.4 ± 0.3 nmol/L. The DHT level remained above the starting value for over 8 weeks (Figure 9). The serum oestradiol concentration rose significantly to a mean maximum value of 99.0 ± 9.0 pmol/L at day 14 after i.m. administration of Nebido® (Figure 10).45
Figure 9: Mean DHT serum concentrations (± SD) in 14 hypogonadal men after a single i.m. administration of Nebido®.45
Figure 10: Mean oestradiol serum concentrations (± SD) in 14 hypogonadal men after a single i.m. administration of Nebido®.45
In an open-label study 14 hypogonadal men first received four injections of Nebido®at intervals of 6 weeks. After the third injection, mean maximum testosterone values above the normal range were observed (Figure 11).46
Figure 11: Mean serum testosterone concentrations (± SD) in 14 hypogonadal men after repeated i.m. administration of Nebido® at intervals of 6 weeks.46
This study demonstrated that testosterone levels do not accumulate with an injection interval of 12 weeks.47
Figure 12: Mean serum testosterone concentrations (± SD) in 14 / 7 hypogonadal men after repeated i.m. administration of Nebido® at intervals of 4 x 6 weeks, 5 x 7–11 weeks and 5 x 12 weeks.47
Two cumulative registry studies examined the use of Nebido® in (mainly elderly) men with subnormal plasma total testosterone levels. The first study enrolled 255 patients (mean age 58 years; mean plasma total testosterone 9.93 ± 1.38 nmol/L),48 while the second enrolled 261 patients (mean age 59.5 years; mean plasma total testosterone 7.7 ± 2.1 nmol/L);49 all patients received Nebido® (1,000 mg) administered at baseline and 6 weeks and thereafter every 12 weeks for up to 60 months. Both studies demonstrated significant increases in total testosterone; within the first 12 months trough levels were 18 and 16.2 nmol/L, respectively and then stabilised to ~18 nmol/L for the remainder of the observation periods.
Figure 13: Mean serum testosterone concentrations (± SD) after the first and 13th injection of Nebido®.47
In a similar 60-month prospective study, treatment with Nebido® (n=20) was compared with no treatment (n=20) in men aged from 45 to 65 years with total serum testosterone levels below 11 nmol/L.50 At baseline, there was no significant difference between total serum testosterone levels in control patients (9.0 ± 1.7 nmol/L) and Nebido® recipients (8.3 ± 2.4 nmol/L). However, over 12, 24, 36, 48 and 60 months, levels of total serum testosterone in the Nebido® group increased and were significantly higher than the control group (Figure 14).
Figure 14: Mean trough total serum testosterone among hypogonadal men who received Nebido® or no treatment (matched controls) for up to 60 months.50
Figure 15: Recommended treatment regimen.
No effects which might indicate an unexpected risk to humans were observed during repeated-dose toxicity studies after repeated administration of the enanthate ester of testosterone. TU was not mutagenic in the standard battery of in vitro and in vivo mutagenicity tests. Studies in rodents indicate a promoting effect of testosterone or its esters on the development of hormone-dependent tumours. No clear correlation between these data and the existence of an actual risk for humans could be established. However, it is known that sex hormones in general can enhance the development of hormone-dependent tissues and tumours.
Figure 16: Effect of Nebido® treatment in patients with type 2 diabetes with and without depression.72
The efficacy of Nebido® in patients with T2DM was also evaluated in a prospective, non-randomized study.74 Of 212 men screened, 87 of whom had testosterone levels <300 ng/dL, 120 underwent follow-up. Nebido® was administered to 56 of the patients with hypogonadism, while 31 opted against treatment, and an additional 23 patients with eugonadal testosterone levels were observed for 3 months. Significant reductions in body weight and BMI were seen in hypogonadal men treated with Nebido®, but not in the untreated hypogonadal cohort. In addition, there was a significant positive correlation between the mean change in total testosterone and International Index of Erectile Function 5-item (IIEF-5) score in hypogonadal men. Increased serum testosterone correlated with reduced BMI, cholesterol, and triglyceride levels, and glycaemic control was also improved in patients treated with Nebido®.
Figure 17: Effect of Nebido® treatment in patients with mild or severe hypogonadism.73
Figure 18: Effect of Nebido® treatment in patients with mild or severe hypogonadism.73
Treatment with Nebido® for 2 years improved metabolic parameters and cardiovascular risk factors in a randomized, double-blind, double-dummy study in 50 patients with metabolic syndrome and LOH.81 Patients in this study were randomized 4:1 to receive Nebido® 12-weekly or daily doses of placebo gel. Nebido® significantly reduced waist circumference and fasting glucose levels from baseline, and significantly reduced the proportion of patients with metabolic syndrome after 1 year (p<0.0001 for all; Figure 19). At 1 year, Nebido® recipients had significant improvements in insulin resistance (HOMA-IR, p<0.001), carotid intima media thickness (p<0.0001) and hsCRP levels (p<0.001) compared with those receiving placebo. As a result, the placebo-group patients were switched to Nebido® for the remainder of the study; at 2 years these patients also had a significant improvement in HOMA-IR (p<0.001) and significantly fewer were classified as having metabolic syndrome compared with baseline (p<0.0001). There was no significant change in BMI, and the reduced numbers of patients with metabolic syndrome were therefore considered primarily due to reductions in waist circumference and visceral fat mass, increased fat-free mass, and improved HOMA-IR.
Figure 19: Changes in A) fasting glucose and waist circumference and B) proportion of patients with features of metabolic syndrome in patients metabolic sydrome and lateonset hypogonadism.81
Furthermore, a prospective registry study examined the effects of up to 6 years of treatment with Nebido® in men with osteoporosis and hypogonadism.17 Testosterone levels increased significantly from baseline, and were maintained in a eugonadal range. Significant and progressive improvements in T-scores were observed over 6 years, with osteoporosis improving to osteopenia (Figure 20).
Figure 20: T-scores during testosterone administration.17
Nebido® led to an improvement in the ability to concentrate, in self-confidence, in activity and in more positive moods. In contrast, feelings of fatigue and exhaustion were reduced (Figure 23).64
Figure 21: Development of muscle strength during long-term treatment with Nebido® and testosterone enanthate.62
Figure 22: Timetable of spontaneous morning erections in hypogonadal men receiving treatment with testosterone enanthate (TE) or Nebido® over 30 weeks.64
Figure 23: Decrease of fatigue during 30 weeks of treatment with Nebido® and testosterone enanthate.64
Confirming results previously published from an open-label study in 133 Korean men,58 in the BLAST study there was an improvement in all sexual function domains and overall satisfaction (all p<0.05) after 30 weeks of double-blind treatment with Nebido® , with benefit seen as early as 6 weeks and continued improvement through 18 months.71 The AMS score significantly improved in non-depressed men (p=0.02) but depression at baseline was associated with reduced benefit with respect to sexual function and psychological scores (Figure 24). In men taking phosphodiesterase (PDE)-5 inhibitors, there was no change in erectile function during the double-blind phase, but a 9-point improvement in erectile function occurred during openlabel treatment (Figure 25). After 30 weeks, 46% of patients felt that treatment had improved their health (vs. 17% for placebo), increasing to 70% after open-label treatment. Greater effects were seen in less obese and older patients.
Figure 24: Treatment effect in BLAST (baseline vs. 30 weeks) in men with and without depression.71
Figure 25: Treatment effect in BLAST, including the open-label phase 71
Additional results from the BLAST study, investigating treatment with Nebido® in men with T2DM and mild or severe hypogonadism, showed that men with severe hypogonadism (total testosterone ≤8.0 nmol/L or free testosterone ≤0.18 nmol/L) reported an improvement in erectile function from baseline and versus placebo after 30 weeks’ treatment, according to IIEF-15 scores. Intercourse satisfaction and sexual desire scores also improved at 6, 18 and 30 weeks versus baseline and placebo in these men after Nebido® treatment.105
Figure 26: Changes over time in mean scores of the amended version of the Beck Depression Inventory (BDI-IA; on a logarithmic scale), Aging Males’ Symptoms (AMS) scale, and International Index of Erectile Function (IIEF).101
Treatment with Nebido® is not associated with adverse events related to the prostate.62 No clinically significant pathological findings of the prostate were observed during treatment with Nebido®. Prostate volume increased slightly but remained within normal limits (Figure 27).
Figure 27: Changes in prostate specific antigen levels and prostate volume during long-term treatment with Nebido®.63
The event rate for haematocrit elevations above the normal physiological range was only 0.02% in a meta-analysis of 33 studies, including 11 placebo-controlled trials, in which 3,359 patients were treated with injectable TU.57
Figure 27: Changes in prostate specific antigen levels and prostate volume during long-term treatment with Nebido®.63
In a registry study of 255 men with subnormal plasma total testosterone levels who received Nebido® for up to 5 years, a number of significant improvements were observed in lipids and hepatic parameters. Levels of total serum cholesterol, LDL and triglycerides declined significantly (p<0.0001), while HDL levels increased.82 Additionally, AST and ALT levels significantly decreased (p<0.0001), suggesting that liver function is improved with Nebido®.84 In a 4-year study and an 18-week randomized, placebo-controlled trial, hepatic function remained stable during treatment although in the latter, a reduction in liver fat content was assessed by diagnostic imaging.63,132
Figure 29: Changes in total cholesterol, LDL and HDL cholesterol levels during longterm treatment with Nebido®.84
A study of 15 hypogonadal men with psoriasis treated with Nebido® showed similar improvements in disease-related symptoms over time.155 During the first 24 months of therapy, there were significant improvements in the scores for Psoriasis Area and Severity Index and Physician Global Assessment for Psoriasis, which were subsequently sustained. Treatment with Nebido® also reduced CRP levels, obesity, and lipid profiles in these men.
|AMS||Aging Male Symptoms|
|BMI||Body mass index|
|BMD||Bone mineral density|
|CDAI||Crohn’s disease activity index|
|CHF||Chronic heart failure|
|EAU||European Association of Urology|
|HOMA-IR||Homeostasis Model Assessment index of Insulin Resistance|
|HRQoL||Health-related quality of life|
|IIEF-5||International Index of Erectile Function 5-item|
|ISA||International Society of Andrology|
|ISSAM||International Society of the Study of the Aging Male|
|IPSS||International Prostate Symptom Scores|
|LUTS||Lower urinary tract symptoms|
|NCEP||National Cholesterol Education Program|
|SAQ||Sexual Activity Questionnaire|
|SHBG||Sex hormone binding globulin|
|T1DM||Type 1 diabetes mellitus|
|T2DM||Type 2 diabetes mellitus|
|TU||Testosterone undecanoate (3-oxoandrost-4-en-17β-yl-undecanoate)|
|System Organ Class||Common|
(≥ 1/100 to < 1/10)
(≥ 1/1000 to <1/100)
|Blood and lymphatic system disorders||Polycythemia||Haematocrit increased|
Red blood cell count increased
|Immune system disorders||Hypersensitivity|
|Metabolism and nutrition disorders||Weight increased||Increased appetite|
Glycosylated haemoglobin increased
Blood triglycerides increased
Blood cholesterol increased
|Nervous system disorders||Headache|
|Vascular disorders||Hot flush||Cardiovascular disorder|
|Respiratory, thoracic and mediastinal disorders||Bronchitis|
|Hepatobiliary disorders||Liver function test abnormal|
Aspartate aminotransferase increased
|Skin and subcutaneous tissue disorders||Acne||Alopecia|
|Musculoskeletal and connective tissue disorders||Arthralgia|
Pain in extremity
Blood creatine phosphokinase increased
|Renal and urinary disorders||Urine flow decreased|
Urinary tract disorder
|Reproductive system and breast disorders||Prostate specific antigen increased|
Prostate examination abnormal
Benign prostate hyperplasia
|Prostatic intraepithelial neoplasia|
|General disorders and administration site conditions||Various kinds of injection site reactions3||Fatigue|
[To be completed nationally]