Summary of Product Characteristics
1 NAME OF THE MEDICINAL PRODUCT
Nebido 1000 mg/4 ml, solution for injection
2 QUALITATIVE AND QUANTITATIVE COMPOSITION
Each ml of solution for injection contains 250 mg testosterone undecanoate corresponding to 157.9 mg testosterone.
Each ampoule with 4 ml of solution for injection contains 1000 mg testosterone undecanoate.
For a full list of excipients, see section 6.1.
3 PHARMACEUTICAL FORM
Solution for Injection
Clear, yellowish oily solution.
4 CLINICAL PARTICULARS
4.1 Therapeutic Indications
Testosterone replacement therapy for male hypogonadism when testosterone deficiency has been confirmed by clinical
features and biochemical tests (see section 4.4).
4.2 Posology and method of administration
One ampoule of Nebido (corresponding to 1000 mg testosterone undecanoate) is injected every 10 to 14 weeks.
Injections with this frequency are capable of maintaining sufficient testosterone levels and do not lead to accumulation.
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 first injection interval may be reduced to a minimum of 6 weeks as
compared to the recommended range of 10 to 14 weeks for maintenance. With this loading dose, sufficient steady state
testosterone levels may be achieved more rapidly.
Maintenance and individualisation of treatment
The injection interval should be within the recommended range of 10 to 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
Nebido is not indicated for use in children and adolescents and it has not been evaluated clinically in males under 18
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Limited data do not suggest the need for a dosage adjustment in elderly patients (see section 4.4).
Patients with hepatic impairment
No formal studies have been performed in patients with hepatic impairment. The use of Nebido is contraindicated in
men with past or present liver tumours (see section 4.3).
Patients with renal impairment
No formal studies have been performed in patients with renal impairment.
Method of administration
For intramuscular use.
The injections must be administered very slowly. Nebido is strictly for intramuscular injection. Care should be taken to
inject Nebido deeply into the gluteal muscle following the usual precautions for intramuscular administration. Special
care must be taken to avoid intravasal injection (see section 4.4 under “Application”). The contents of an ampoule are
to be injected intramuscularly immediately after opening the ampoule (see section 6.6 for instructions on opening the
The use of Nebido is contraindicated in men with:
· androgen-dependent carcinoma of the prostate or of the male mammary gland
· past or present liver tumours
· hypersensitivity to the active substance or to any of the excipients
The use of Nebido in women is contraindicated.
4.4 Special warnings and precautions for use
Nebido is not recommended for use in children and adolescents.
Nebido should be used only if hypogonadism (hyper- and hypogonadotrophic) has been demonstrated and if other aetiology,
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 two separate blood testosterone measurements.
There is limited experience of the use of Nebido in elderly patients over 65 years of age. 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.
Prior to testosterone initiation, all patients must undergo a detailed examination in order to exclude a risk of pre-existing 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: haemoglobin, haematocrit, and liver function tests (see section 4.8).
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Androgens may accelerate the progression of sub-clinical prostatic cancer and benign prostatic hyperplasia.
Nebido should be used with caution in cancer patients at risk of hypercalcaemia (and associated hypercalciuria), due to bone
metastases. Regular monitoring of serum calcium concentrations is recommended in these patients.
Cases of benign and malignant liver tumours have been reported in users of hormonal substances such as androgen compounds. If
severe upper abdominal complaints, liver enlargement or signs of intra-abdominal haemorrhage occur in men using Nebido, a
liver tumour should be included in the differential-diagnostic considerations.
In patients suffering from severe cardiac, hepatic or renal insufficiency or ischemic heart disease, treatment with testosterone may
cause severe complications characterised by oedema 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.
Caution should be exercised in patients predisposed to oedema, as treatment with androgens may result in increased sodium
retention (see section 4.8).
As a general rule, the limitations of using intramuscular 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.
Pre-existing sleep apnoea 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.
As with all oily solutions, Nebido must be injected strictly intramuscularly and very slowly. Pulmonary microembolism of oily
solutions can in rare cases lead to signs and symptoms such as cough, dyspnoea, malaise, hyperhidrosis, chest pain, dizziness,
paraesthesia, or syncope. These reactions may occur during or immediately after the injection and are reversible. Treatment is
usually supportive, e.g. by administration of supplemental oxygen.
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4.5 Interaction with other medicinal products and other forms of interaction
Testosterone and derivatives have been reported to increase the activity of oral anti-coagulants. Patients receiving oral
anti-coagulants require close monitoring, especially at the beginning or end of androgen therapy. Increased monitoring
of the prothrombin time, and INR determinations, are recommended.
The concurrent administration of testosterone with ACTH or corticosteroids may enhance oedema formation; thus these
active substances should be administered cautiously, particularly in patients with cardiac or hepatic disease or in
patients predisposed to oedema.
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.
4.6 Fertility, pregnancy and lactation
Testosterone replacement therapy may reversibly reduce spermatogenesis (see sections 4.8 and 5.3).
Pregnancy and lactation
Nebido is not indicated for use in women and must not be used in pregnant or breast-feeding women, see section 4.3.
4.7 Effects on ability to drive and use machines
Nebido has no influence on the ability to drive and use machines.
4.8 Undesirable effects
Regarding undesirable effects associated with the use of androgens, please also refer to section 4.4.
The most frequently reported undesirable effects during treatment with Nebido are acne and injection site pain:
Table 1 below reports adverse drug reactions (ADRs) by MedDRA system organ classes (MedDRA SOCs) reported with Nebido.
The frequencies are based on clinical trial data and defined as common ( 1/100 to < 1/10) and uncommon ( 1/1000 to < 1/100).
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Table 1: Categorised relative frequency of men with ADRs, by MedDRA SOC – based on pooled data of six, clinical trials, N=422
(100.0%), i.e. N=302 hypogonadal men treated with i.m. injections of 4 ml and N=120 with 3 ml of TU 250 mg/ml
System Organ Class Common
( 1/100 to < 1/10) Uncommon
( 1/1000 to < 1/100)
Blood and lymphatic
system disorders Polycythaemia Haematocrit increased
Red blood cell count increased
nutrition disorders Weight increased Increased appetite
Blood triglycerides increased
Blood cholesterol increased
Psychiatric disorders Depression
Vascular disorders Hot flush Cardiovascular disorder
disorders Liver function test abnormal
Skin and subcutaneous
tissue disorders Acne Alopecia
Pain in extremity
Muscle disorders 2
Blood creatine phosphokinase
Renal and urinary
disorders Urine flow decreased
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The most appropriate MedDRA term to describe a certain adverse reaction is listed. Synonyms or related conditions are
not listed, but should be taken into account as well.
1 Rash including Rash papular
Muscle disorders: Muscle spasm, Muscle strain and Myalgia
Various kinds of injection site reaction: Injection site pain, Injection site discomfort, Injection site pruritus, Injection site erythema,
Injection site haematoma, Injection site irritation, Injection site reaction
Hyperhidrosis: Hyperhidrosis and Night sweats
Pulmonary microembolism of oily solutions can in rare cases lead to signs and symptoms such as cough, dyspnea, malaise,
hyperhydrosis, chest pain, dizziness, paresthesia, or syncope. These reactions may occur during or immediately after the injections
and are reversible. Cases suspected by the company or the reporter to represent oily pulmonary microembolism have been
reported rarely in clinical trials (in 1/10,000 and < 1/1,000 injections) as well as from postmarketing experience (see 4.4 Special
warnings and precautions for use).
Suspected anaphylactic reactions after Nebido injection have been reported.
In addition to the above mentioned adverse reactions, nervousness, hostility, sleep apnoea, various skin reactions
including seborrhoea, increased frequency of erections and in very rare cases jaundice have been reported under
treatment with testosterone containing preparations.
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). High-dosed or long-term administration of testosterone occasionally increases
the occurrences of water retention and oedema.
No special therapeutic measure apart from termination of therapy with the medicinal product or dose reduction is
and breast disorders Prostate specific antigen
Benign prostate hyperplasia Prostatic intraepithelial neoplasia
General disorders and
conditions Various kinds of injection site
reactions 3 Fatigue
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5 PHARMACOLOGICAL PROPERTIES
5.1 Pharmacodynamic properties
Pharmacotherapeutic group: Androgens, 3-oxoandrosten (4) derivatives
ATC code: G03B A03
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
Testosterone is responsible for the expression of masculine characteristics during foetal, early childhood, and pubertal
development and thereafter for maintaining the masculine phenotype and androgen-dependent functions (e.g.
spermatogenesis, accessory sexual glands). It also performs functions, e.g. 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 (e.g. prostate, seminal
vesicles, epididymis) or protein-anabolic (muscle, bone, haematopoiesis, kidney, liver).
The effects of testosterone in some organs arise after peripheral conversion of testosterone to oestradiol, which then
binds to estrogen receptors in the target cell nucleus e.g. the pituitary, fat, brain, bone, and testicular Leydig cells.
5.2 Pharmacokinetic properties
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
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
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, %)
min values was 22% (range: 9 -28%) and 34% (range: 25-48%), respectively.
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
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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 ß-oxidation in the same way as other aliphatic
carboxylic acids. The major active metabolites of testosterone are oestradiol and dihydrotestosterone.
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.
5.3 Preclinical safety data
Toxicological studies have not revealed other effects than those which can be explained based on the hormone profile
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.
6 PHARMACEUTICAL PARTICULARS
6.1 List of excipients
Castor Oil, Refined
In the absence of compatibility studies, this medicinal product must not be mixed with other medicinal products.
6.3 Shelf life
The medicinal product must be used immediately after first opening.
6.4 Special precautions for storage
This medicinal product does not require any special storage conditions.
6.5 Nature and contents of container
5 ml amber glass (type I) ampoules, containing a fill volume of 4 ml.
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6.6 Special precautions for disposal and other handling
The solution for intramuscular injection is to be visually inspected prior to use and only clear solutions free from particles should
The medicinal product is for single use only and any unused solution should be discarded in accordance with local requirements.
Notes on handling the OPC (One-Point-Cut) ampoule:
There is a pre-scored mark beneath the coloured point on the ampoule eliminating the need to file the neck. Prior to opening,
ensure that any solution in the upper part of the ampoule flows down to the lower part. Use both hands to open; while holding the
lower part of the ampoule in one hand, use the other hand to break off the upper part of the ampoule in the direction away from the
7 MARKETING AUTHORISATION HOLDER
8 MARKETING AUTHORISATION NUMBER
9 DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION
Date of first authorization: 12 November 2004
Date of last renewal: 25 November 2008
10 DATE OF REVISION OF THE TEXT
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