Pharmacokinetic studies have shown that Nebido® maintains testosterone levels within the physiologic range. The recommended administration regime consists of one loading dose 6 weeks after the initial injection followed by intervals of 10 to 14 weeks (usually 3 months). The initial short interval (loading dose) is advisable to quickly achieve steady state conditions. In order to adjust the treatment regimen to individual needs, a blood sample prior to the 4th injection, i.e. at trough level, is suggested. If testosterone levels are below the normal range, a shortening of the interval to 10 weeks may be considered. If testosterone levels are in the lower third of the normal range the 3-monthly interval should be maintained. If testosterone levels are above the lower third of the normal range, an extension of injection intervals can be considered. In any case, the clinical symptomatology of the patient must be taken into consideration.3

      As a consequence of the restoration of testosterone levels, significant improvements of certain clinical signs associated with the androgen deficit can be shown:

       

      • Testosterone replacement therapy can have a favourable effect on body composition by increasing muscle mass and decreasing fat mass.
      • Muscle strength might improve with successful testosterone replacement therapy.
      • Sexual function parameters can be improved with TRT.
      • TRT can exert a positive effect on mood, thus improving self-confidence and activity, and reduces fatigue and the feeling of exhaustion.

      *Nebido is indicated for testosterone replacement therapy for male hypogonadism when testosterone deficiency has been confirmed by clinical features and biochemical tests. These are the secondary benefits expected from restoring the testosterone levels.

        There is no time limit for Nebido® treatment but regular monitoring should be performed in compliance with the guidelines.

        No, Nebido is not licensed for this indication. Bayer only recommends use according to the local labels.

        The injections must be administered very slowly (over 1 to 2 minutes). It is possible and advisable to use a 22 G injection needle. Care should be taken to inject Nebido® deeply into the gluteal muscle following the usual precautions for intramuscular administration. Special care must be given to avoid intravasal injection. The content of an ampoule has to be injected intramuscularly immediately after opening the ampoule.

         

        Pulmonary microembolism of oily solutions can in rare cases lead to signs and symptoms such as cough, dyspnea, malaise, hyperhidrosis, chest pain, dizziness, paresthesia, or syncope. These reactions may occur during or immediately after the injections and are reversible. This is not specific for Nebido® and has been described for injections of testosterone in oily solutions in general.3 This can usually be avoided by injecting the solution very slowly and by making sure that the injection is strictly intramuscular.

        It is advisable to reduce the interval between the first and second administration of Nebido® to 6 weeks. With this loading dose, sufficient steady state testosterone levels may be achieved more rapidly. After that “loading interval”, further injections should be given in intervals of about 12 weeks. Measurement of serum trough testosterone levels and clinical symptoms should be considered for individualisation of therapy with Nebido®. Serum trough testosterone levels should be in 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. The injection interval should remain within the recommended range of 10 to 14 weeks.

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        Since steady state serum testosterone levels can be assumed to be achieved after the first six months of treatment, it appears advisable to control serum testosterone before the fourth injection for individualisation of therapy (usual spacing between administrations provided).

        The first injection interval is shorter so that the sustained active drug levels are reached more rapidly and the shorter interval at the beginning of therapy will make sure that testosterone levels are normalised quickly which will ensure fast alleviation of symptoms and complaints.3

          No clinical studies have been performed applying such regimens. It would lead to insufficient testosterone substitution requiring a shorter interval until the next injections and therefore losing one of the products main features, the long intervals of about 3 months between administrations. Nebido is only licensed as a single 4ml injection.

          The following needles were used for the clinical trials with Nebido®: 1.10 x 50 mm (19 G x 2") (e.g. produced by Braun Melsungen). However, under practical clinical conditions, the use of a 22 G (0.9 mm) has been found to be most suitable for the injection of Nebido®. The small needles have two advantages:

           

          1. the injection pain is further reduced

          2. the injection must be performed very slowly.

            Like every androgen therapy, the use of Nebido® is contraindicated in diagnosed or suspected carcinoma of the prostate or of the male mammary gland; hypercalcemia accompanying malignant tumors, past or present liver tumors; hypersensitivity to the active substance or to any of the excipients.

             

            Nebido® is not indicated for use in children and adolescents and it has not been evaluated clinically in males under 18 years of age. Furthermore, the use of Nebido® in women is contra-indicated. Link: https://www.nebido.com/treatment/safety-profile-testosterone-therapy

            The most frequent side effects of Nebido® observed are acne and injection site pain. These reactions are generally mild and transient. Other common side effects observed are typical of testosterone (e.g. polycythemia, weigth increase, hot flushes, prostate specific antigen increased, prostate examination abnormal, benign prostate hyperplasia).

             

            Pulmonary microembolism of oily solutions can in rare cases lead to signs and symptoms such as cough, dyspnea, malaise, hyperhidrosis, chest pain, dizziness, paresthesia, or syncope. These reactions may occur during or immediately after the injections and are reversible. This is not specific for Nebido® and has been described for injections of testosterone in oily solutions in general. This can usually be avoided by injecting the solution very slowly and by making sure that the injection is strictly intramuscular. Like with any medication, allergic reactions to any of the ingredients of the preparation may occur. With Nebido®, this has only been observed in extremely rare cases.

             

              Intake of alcoholic drinks has no influence on the mode of action of Nebido®.

              As with every testosterone therapy, acne can occur at the beginning of Nebido® therapy. This is not permanent, however, but subsides at varying rates. This is comparable to the occurrence of acne in adolescent boys during puberty, which is also linked to the rise in testosterone levels, but which subsides again either during or at the end of puberty.

                The duration of one study is 4 years.5 Currently there is experience with Nebido® available of up to 9.5 years in individual patients.6

                  If the testosterone levels of a hypogonadal man (testosterone deficiency) are brought within the range of normal levels, this leads to a breakdown of fat and a build-up of muscle, the so-called anabolic effect. A very large testosterone overdose could be abused for doping purposes. However, all testosterone products are strictly prescription-only medicines. The indications for which they can be prescribed are listed in the package leaflet and have to be complied with very closely. Any exogenous AAS use is considered doping in most sports. Consult UKADA for more information for specific sports.

                  Nebido® is only available on medical prescription, which lessens the risk of abuse. Since Nebido® is usually administered at the doctor’s office, the potential for abuse is largely reduced.

                  A single injection of Nebido® cannot lead to overdosage, at least not to an elevation of mean testosterone serum levels above the normal range, provided that the testosterone serum levels have been in the low normal range or below. There have been studies with repeated injections in intervals of 6 weeks. Even then, most of the patients showed mean testosterone serum levels that remained within the normal range within 2-3 consecutive injections. One week after the injection, testosterone serum levels are at their maximum level. As with other depot-preparations, this peak may reach supraphysiological levels. However, peak levels have not been found to be of clinical relevance and sufficient for abuse as they are moderate and transient. In particular mood swings have not been reported under Nebido®, which could be explained by the slower velocity of level changes and the reduced absolute height.

                  Nebido® is packed in single units of one ampoule. Injections should be performed in the physician’s office in intervals of 10 to 14 weeks. Serum testosterone measurements should be performed for individualisation of the therapy. An inadvertent overdose can thus be practically excluded. There have been reports of extreme overdoses with injection products. Normally, abuse should not occur if both the prescription (strictly according to the indication) and use (strictly according to the doctor’s instructions) are carried out in accordance with the treatment recommendations.

                   

                  A single injection of Nebido® cannot lead to overdosage, at least not to an elevation of mean testosterone serum levels above the normal range, provided that the testosterone serum levels have been in the low normal range or below. There have been studies with repeated injections in intervals of 6 weeks. Even then, most of the patient showed mean testosterone serum levels that remained within the normal range within 2-3 consecutive injections. One week after the injection, testosterone serum levels are at their maximum level. As with other depot-preparation, this peak may reach supraphysiological levels. However, peak levels have not been found to be of clinical relevance and sufficient for abuse as they are moderate and transient. In particular mood swings similar to short acting injections have not been reported under Nebido®, which could be explained by the slower velocity of level changes and the reduced absolute height.

                    British guidelines7 today emphasise the need for screening for hypogonadism in patients with erectile dysfunction.8 Impaired erectile function is a classical symptom of hypogonadism.9 The prevalence for male hypogonadism amongst men with erectile dysfunction is estimated to be around 20%.10,12

                     

                    Testosterone therapy of hypogonadal men improves erectile function.12 Positive effects of testosterone are mediated by central stimulation of libido and sexual activity. Loss of libido has been shown to be one of the first symptoms of declining testosterone levels and may occur already at low-normal testosterone concentrations.13

                     

                    However, also has a direct effect on the penis.14 Recent studies have shown that more than 50% of hypogonadal ED patients reported restored erectile dysfunction sufficient for sexual intercourse after 12-24 weeks of testosterone therapy alone.16,17 indicating that men with erectile dysfunction and low serum testosterone may benefit from testosterone treatment alone. Testosterone given as adjunctive therapy with phosphodiesterase-inhibitors (PDE-5i) converts the majority of hypogonadal non-responders to monotherapy with PDE-5 inhibitors into responders within 10 to 12 weeks of added testosterone therapy18. The combination of phosphodiesterase 5-inhibitors and testosterone may be indicated in hypogonadal men who do not respond sufficiently to either treatment alone.2

                     

                    Although, from a scientific perspective, it would be best to start the evaluation of a patient with erectile dysfunction by measuring testosterone, psychological factors have to be considered. A patient presenting with ED has usually been waiting for years to come forward with an embarrassing condition. He expects a quick solution to his problem. Since the majority of men will respond favorably to treatment with a PDE5 inhibitor such as Levitra (vardenafil hydrochloride)®, he should receive a prescription for a PDE5 inhibitor. At the same time, the physician should keep in mind that “ED does not come alone”19 and take the opportunity to examine risk factors such as blood pressure and waist circumference (for assessing visceral obesity) and draw a blood sample to measure testosterone, lipids and blood sugar. In a very simplified phrase: “Treat ED and check for T.” This will also help to keep the patient who is at risk for cardiometabolic diseases under surveillance. If only a PDE-5 inhibitor is prescribed, many patients never return to the doctor’s office, and an opportunity is lost to assess the patient’s overall health.

                    Nebido® is not indicated to treat erectile dysfunction. Standard therapy for the treatment of erectile dysfunction are oral phosphodiesterase type 5-inhibitors (PDE5i; such as Viagra®, Cialis®, Levitra®). Nebido® restores sexual desire, i.e., it increases libido, and has a positive effect on erectile function in cases of testosterone deficiency. Lack of libido is only one symptom of hypogonadism. Further signs are: fatigue, concentration problems, changes in body composition (muscle breakdown/increase in fat).20 In order to determine the cause of sexual dysfunction, a thorough medical examination is required.

                     

                    Frequent causes for erectile disorder can be:

                     

                    • vascular diseases
                    • peripheral nerve diseases
                    • testosterone deficiency
                    • various medications
                    • excessive alcohol and nicotine consumption
                    • mental disorders

                     

                    Even when testosterone therapy alone fails to improve erectile function, and PDE-5I therapy is instituted, continuing with testosterone substitution in combination with the latter is often indicated as:

                     

                    • providing testosterone therapy may help in the restoration of sexual desire which is often low in ED patients. Low sexual desire is a frequent cause of discontinuation of therapy with PDE 5-inhibitors. Nebido is not licensed to restore sexual desire
                    • testosterone therapy may also improve other symptoms associated with hypogonadism, including lack of energy, mood disturbances and negative changes in body composition

                    References

                    • Zitzmann M, Jockenhövel F, Schubert M. Male Hypogonadism. 4th ed: Bremen: UNI-MED; 2014.Table 7 Return to content
                    • Wang C, Nieschlag E, Swerdloff R, Behre HM, Hellstrom WJ, Gooren LJ, Kaufman JM, Legros JJ, Lunenfeld B, Morales A, Morley JE, Schulman C, ,Thompson IM, Weidner W, Wu FCW: Investigation, Treatment and Monitoring of Late-Onset Hypogonadism in Males – ISA, ISSAM, EAU, EAA, and ASA Recommendations. Ageing Male 2008; in print (published online Sept. 2, 2008). Eur Urol 2008, in print Return to content
                    • Nebido (testosterone undecanoate) EMC Summary of Product Characteristics March 2020: https://www.medicines.org.uk/emc/product/3873 (Accessed September 2020) Return to content
                    • Mackey M-A et al.: Human Reprod 1995; 10: 862-865. Return to content
                    • Minnemann T et al. Ageing Male 2007; 10: 155-158 Return to content
                    • Zitzmann M and Nieschlag E. J Clin Endocrinol Metab 2007; 92: 3844-3853 Return to content
                    • British Society for Sexual Medicine Guidelines on the Management of Erectile Dysfunction in Men—2017 Geoff Hackett, MD, Mike Kirby, MD ET AL : Published: March 14, 2018•DOI:https://doi.org/10.1016/j.jsxm.2018.01.023 Return to content
                    • Hwang, T., Lin, YC. The relationship between hypogonadism and erectile dysfunction. Int J Impot Res 20, 231–235 (2008). https://doi.org/10.1038/sj.ijir.3901633 Return to content
                    • Morales A, Buvat J, Gooren L, Guay A, Kaufman JM, Tan H, Torres O: Endocrine Aspects of Sexual Dysfunction in Men. J Sex Med 2004; 1: 69-81 Return to content
                    • Behre: Testosterone and erections, in Nieschlag, Behre: Testosterone: Action, Deficiency, Substitution, 2004 Return to content
                    • Corona G, Mannucci E, Mansani R, Petrone L, Bartolini M, Giommi R, Forti G, Maggi M: Organic, relational and psychological factors in erectile dysfunction in men with diabetes mellitus. Europ Urol 2004; 46: 222-228 Return to content
                    • Hackett G, Cole N, Mulay A, Strange RC, Ramachandran S. Long-Term Testosterone Therapy in Type 2 Diabetes Is Associated with Decreasing Waist Circumference and Improving Erectile Function. The world journal of men's health. 2018;36:e33. Return to content
                    • Bodie J, Lewis, J, Schow D, Monga M: Laboratory evaluations of erectile dysfunction: an evidence based approach. J Urol 2003; 169: 2262-2264 Return to content
                    • Podlasek CA, Mulhall J, Davies K, et al. J Sex Med. 2016;13(8):1183-1198. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5333763 Return to content
                    • Zitzmann M, Faber S, Nieschlag E: Association of specific symptoms and metabolic risks with serum testosterone in older men. J Clin Endocrinol Metab 2006, 91(11): 4335-4343 Return to content
                    • Greenstein A, Mabjeesh N, Sofer M, Kaver I, Matzkin H, Chen J: Does sildenafil combined with testosterone gel improve erectile dysfunction in hypogonadal men in whom testosterone supplementation therapy alone failed? J Urol 2005; 173: 530-532 Return to content
                    • Yassin et al. J Sex Med 2007;4:497-501 Return to content
                    • Shabsigh R, Kaufman JM, Steidle C, Padma-Nathan H: Randomized study of testosterone gel as adjunctive therapy to sildenafil in hypogonadal men with erectile dysfunction who do not respond to sildenafil alone. j Urol 2004; 172: 658-663. Return to content
                    • Yassin AA et al. Andrologia 2008; 40: 259-264 Return to content
                    • Jockenhövel F: Male Hypogonadism. UNI-MED Verlag Bremen 2004., p.32 Return to content

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