Nebido® Prescribing Information

Nebido® essential prescribing information

Essential information

Nebido^® 1000 mg/ 4ml, solution for injection.
Refer to SmPC (date of revision: 25. Nov 2008) before prescribing.

Composition

4 ml solution containing 1000 mg testosterone undecanoate as active ingredient and benzyl benzoate and castor oil as excipients.

Indications

Testosterone therapy of confirmed male hypogonadism.

Contraindications

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.

Special warnings and precautions

Nebido^® is not recommended for use in children and adolescents. Nebido^® is not indicated for use in women. 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. The following laboratory parameters should be checked periodically: testosterone, hemoglobin, hematocrit, and liver function tests. 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. 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. 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. 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. Athletes should be advised that Nebido^® 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. 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.

Undesirable effects

Most frequent undesirable effects: acne and injection site pain. Other known adverse drug reactions of Nebido^® are: polycythemia, haematocrit increased, weight increased, hot flush, 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. Other known adverse drug reactions of testosterone containing preparations are: nervousness, hostility, sleep apnoea, various skin reactions including seborrhoea, increased frequency of erections, rare cases of persistent, painful erections (priapism) and in very rare cases jaundice. Therapy with high doses of testosterone preparations commonly reversibly interrupts or reduces spermatogenesis, thereby reducing the size of the testicles. High-dosed or long-term administration of testosterone occasionally increases the occurrences of water retention and oedema.

Posology and method of administration

Nebido^® is injected every 10 to 14 weeks and 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 first injection interval may be reduced to a minimum of 6 weeks.

Legal category

Medicinal product subject to medical prescription.

Contact

Bayer Pharma AG, 13353 Berlin, Germany. For further details contact your local Bayer organisation. 27 Aug 2009

Nebido® - full summary of product characteristics (SPC)

Name of the medicinal product

Nebido 1000 mg/ 4ml, solution for injection.

Qualitative and quantitative composition

Each ml solution for injection contains 250 mg testosterone undecanoate corresponding to 157.9 mg testosterone.

Each ampoule with 4 ml solution for injection contains 1000 mg testosterone undecanoate.

For a full list of excipients, see section (Pharmaceutical Particulars / List of excipients).

Pharmaceutical form

Solution for injection.

Clear, yellowish oily solution.

Clinical particulars

Therapeutic indications

Testosterone replacement therapy for male hypogonadism when testosterone deficiency has been confirmed by clinical features and biochemical tests (see section Therapeutic indications / Special warnings and precautions for use).

Posology and method of administration

For intramuscular use.

Adults 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.

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.

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.

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 anticoagulants. 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.

Pregnancy and lactation

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

Effects on ability to drive and use machines

Nebido has no influence on the ability to drive and use machines.

Undesirable effects

Regarding undesirable effects associated with the use of androgens, please also refer to section Clinical Particulars / Special warnings and precautions for use.

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

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 Rash¹ Pruritus Dry skin
Musculoskeletal and connective tissue disorders		Arthralgia Pain in extremity Muscle disorders² Musculoskeletal stiffness Blood creatine phosphokinase increased
Renal and urinary disorders		Urine flow decreased Urinary retention Urinary tract disorder 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 reactions³	Fatigue Asthenia Hyperhidrosis⁴

The most appropriate MedDRA term (version 11.0) to describe a certain adverse reaction is listed. Synonyms or related conditions are not listed, but should be taken into account as well.

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, hyperhidrosis, 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 in clinical trials (2 cases in more than 4000 injections) as well as from postmarketing experience (see section Clinical Particulars / Special warnings and precautions for use.).

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.

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.

Overdose

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

Pharmacological properties

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 synthesised 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 estradiol, which then binds to estrogen receptors in the target cell nucleus e.g. the pituitary, fat, brain, bone, and testicular Leydig cells.

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 Cmax 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 Cmax and Cmin 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 Cmin 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 volume of distribution of about 1.0 l/kg was determined.

- Metabolism

Testosterone which is generated by ester cleavage from testosterone undecanoate is metabolised and excreted the same way as endogenous testosterone. The undecanoic acid is metabolised 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 radiolabelled 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.

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.