Superceded

Newly approved

4.2         Posology and method of administration

4.3         Posology and method of administration

For intramuscular use.

Adult and Elderly men

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.

The injections must be administered very slowly. 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 contents of an ampoule are to be injected intramuscularly 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 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.

Children and Adolescents

Nebido is not indicated for use in children and adolescents and it has not been evaluated clinically in males under 18 years of age.

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 years of age (see section 4.4)

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

4.3     Contraindications

The use of Nebido is contraindicated in 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 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

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: hemoglobin, hematocrit and liver function tests.

Due to variability in laboratory values, all measures of testosterone should be carried out in the same laboratory.

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.

Rarely, benign and malignant liver tumours 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 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.

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, dyspnea, malaise, hyperhydrosis, 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. 

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).

Due to variability in laboratory values, all measures of testosterone should be carried out in the same laboratory.

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.

4.6 Pregnancy and lactation

4.6 Fertility, pregnancy and lactation

Nebido is not indicated for use in women and must not be used in pregnant or breastfeeding women.

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.

4.8 Undesirable effects

4.8 Undesirable effects

Regarding undesirable effects associated with the use of androgens, please also refer to section 4.4.

The most frequent undesirable effects under treatment with Nebido are acne and    injection site pain.

Table 1 below reports adverse reactions (ADRs) by MedDRA system organ classes (MedDRA SOCs). The frequencies are based on clinical trial data. The adverse reactions were recorded in 6 clinical studies (N=422) and considered at least possibly causally related to Nebido.

Table 1, adverse reactions, clinical trials, N=422 (100.0%) i.e. N=302 hypogonadal men treated with i.m. injections of 4 ml and N=120 with 3ml of TU 250 mg/ml.

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 (³ 1/100 to < 1/10) and uncommon (³ 1/1000 to < 1/100). The ADRs were recorded in 6 clinical studies (N=422) and considered at least possibly causally related to Nebido.

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

Although these adverse reactions were not reported during the clinical studies performed with Nebido, the possibility that they also occur under treatment cannot be ruled out.

6.6 Special precautions for disposal of a used medicinal product or waste materials derived from such medicinal product and other handling of the product

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 solution free from particles should be used.

The medicinal product is for single use only and any unused solution should be discarded.

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.

10. Date of Revision of the Text

10. Date of Revision of the Text

April 2009

February 2011

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