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Drug Details

NEBIDO 1000 mg/4ml

• Drug Class Description
  Androgens, 3-oxoandrosten (4) derivatives
• Generic Name
  Testosterone Undecanoate
• Presentation
  Solution for injection. Clear, yellowish oily solution.
• Description
  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.
• Indications
  

  Testosterone replacement therapy for male hypogonadism when testosterone deficiency has been confirmed by clinical features and biochemical tests

• Adult Dosage
  

   

  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.

  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.

  Patients with renal impairment

  No formal studies have been performed in patients with renal impairment.

  Method of administration

  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. The contents of an ampoule are to be injected intramuscularly immediately after opening the ampoule.

   

• Child Dosage
  

  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.

• Elderly Dosage
  

  Geriatric patients

  Limited data do not suggest the need for a dosage adjustment in elderly patients.

• Contra Indications
  

  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.

• Special Precautions
  

  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.

  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.

  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.

  Suspected anaphylactic reactions after Nebido injection have been reported.

• Interactions
  

  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.

• Adverse Drug Reactions
  

  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). The frequencies are based on clinical trial data and defined as Common (1/100 to < 1/10) and Uncommon (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 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.

  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.