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NEBIDO

Main information

  • Trade name:
  • NEBIDO Solution for Injection 250 Milligram
  • Available from:
  • Bayer Limited
  • Dosage:
  • 250 Milligram
  • Pharmaceutical form:
  • Solution for Injection
  • Medicine domain:
  • Humans
  • Medicine type:
  • Allopathic drug
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Documents

Localization

  • Available in:
  • NEBIDO Solution for Injection 250 Milligram
    Ireland
  • Language:
  • English

Other information

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Status

  • Source:
  • IMB
  • Authorization date:
  • 30-11-2007
  • Last update:
  • 09-08-2016

Summary of Product characteristics

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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

Posology

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

be considered.

Special populations

Paediatric population

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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Geriatric patients

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

ampoule safely).

4.3 Contraindications

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.

Medical examination

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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Tumours

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.

Other conditions

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.

Application

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

Oral anti-coagulants:

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.

Other interactions:

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

Fertility

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

Haemoglobin increased

Immune system

disorders Hypersensitivity

Metabolism and

nutrition disorders Weight increased Increased appetite

Glycosylated haemoglobin

increased

Hypercholesterolaemia

Blood triglycerides increased

Blood cholesterol increased

Psychiatric disorders Depression

Emotional disorder

Insomnia

Restlessness

Aggression

Irritability

Nervous system

disorders Headache

Migraine

Tremor

Vascular disorders Hot flush Cardiovascular disorder

Hypertension

Dizziness

Respiratory, thoracic

and mediastinal

disorders Bronchitis

Sinusitis

Cough

Dyspnoea

Snoring

Dysphonia

Gastrointestinal

disorders Diarrhoea

Nausea

Hepatobiliary

disorders Liver function test abnormal

Aspartate aminotransferase

increased

Skin and subcutaneous

tissue disorders Acne Alopecia

Erythema

Rash 1

Pruritus

Dry skin

Musculoskeletal and

connective tissue

disorders Arthralgia

Pain in extremity

Muscle disorders 2

Musculoskeletal stiffness

Blood creatine phosphokinase

increased

Renal and urinary

disorders Urine flow decreased

Urinary retention

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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

2

Muscle disorders: Muscle spasm, Muscle strain and Myalgia

3

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

4

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.

4.9 Overdose

No special therapeutic measure apart from termination of therapy with the medicinal product or dose reduction is

Nocturia

Dysuria

Reproductive system

and breast disorders Prostate specific antigen

increased

Prostate examination

abnormal

Benign prostate hyperplasia Prostatic intraepithelial neoplasia

Prostate induration

Prostatitis

Prostatic disorder

Libido changes

Testicular pain

Breast induration

Breast pain

Gynaecomastia

Oestradiol increased

Testosterone increased

General disorders and

administration site

conditions Various kinds of injection site

reactions 3 Fatigue

Asthenia

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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

adrenal cortex.

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

Absorption

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

administration.

Steady-state conditions

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

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 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, %)

of C

min 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 intravenous infusion of

testosterone to elderly men, the elimination half-life of testosterone was approximately one hour and an apparent

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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 ß-oxidation in the same way as other aliphatic

carboxylic acids. The major active metabolites of testosterone are oestradiol and dihydrotestosterone.

Elimination

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

of Nebido.

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

Benzyl Benzoate

Castor Oil, Refined

6.2 Incompatibilities

In the absence of compatibility studies, this medicinal product must not be mixed with other medicinal products.

6.3 Shelf life

5 years.

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

be used.

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

colored point.

7 MARKETING AUTHORISATION HOLDER

Bayer Limited

The Atrium

Blackthorn Road

Dublin 18

8 MARKETING AUTHORISATION NUMBER

PA 1410/20/1

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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Date Printed 29/08/2011 CRN 2101653 page number: 9

There are no safety alerts related to this product.

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testosterone undecanoate (Aveed)

Title: testosterone undecanoate (Aveed)Category: MedicationsCreated: 3/2/2005 12:00:00 AMLast Editorial Review: 10/13/2015 12:00:00 AM

US - MedicineNet

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