Nebido 1000 mg / 4 ml Solution for injection

Testosterone replacement in primary and secondary male hypogonadism.

Posology
NEBIDO (1 ampoule/vial 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 the start of treatment. The first injection interval may be reduced to a minimum of 6 weeks. With this loading dose, steady-state levels will be reached quickly.
Individualisation of treatment
It is advisable to occasionally measure testosterone serum levels at the end of an injection interval. Serum levels below normal range would indicate the need for a shorter injection interval. In the case of high serum levels, an extension of the injection interval may be considered. The injection interval should remain within the recommended range of 10 to 14 weeks.
Special populations
Paediatric population
NEBIDO is not indicated for use in children and adolescents, and it has not been clinically evaluated 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 (IM) use. The injections must be administered very slowly (over 2 minutes). NEBIDO is strictly for intramuscular injection. Special care must be given to avoid intravasal injection. See section 6.6 to avoid injury when opening. The contents of an ampoule / vial are to be injected intramuscularly immediately after opening.

NEBIDO must not be used in androgen-dependent carcinoma of the prostate or of the male mammary gland; hypercalcaemia accompanying malignant tumours; past or present liver tumours; hypersensitivity to the active substance or to any of the excipients. The use of NEBIDO in women is contraindicated.

Older patients treated with NEBIDO may be at an increased risk for the development of prostatic hyperplasia. Although there are no clear indications that NEBIDO actually generates prostatic carcinoma, it can enhance the growth of any existing prostatic carcinoma. Therefore, carcinoma of the prostate has to be excluded before starting therapy with NEBIDO. As a precaution, regular examinations of the prostate are recommended in men. Haemoglobin and haematocrit should be checked periodically in patients on long-term NEBIDO therapy to detect cases of polycythaemia (see section 4.8). As a general rule, the risk of bleeding from using intramuscular injections in patients with acquired or inherited bleeding disorders always has to be taken into account. Testosterone and derivatives have been reported to increase the activity of coumarin derived oral anticoagulants (see also section 4.5). Testosterone as contained in NEBIDO should be used with caution in patients with thrombophilia, or risk factors for venous thromboembolism (VTE), as there have been post-marketing studies and reports of thrombotic events (e.g. deep-vein thrombosis, pulmonary embolism, ocular thrombosis) in these patients during testosterone therapy. In thrombophilic patients, VTE cases have been reported even under anticoagulation treatment, therefore continuing testosterone treatment after first thrombotic event should be carefully evaluated. In case of treatment continuation, further measures should be taken to minimise the individual VTE risk. Cases of benign and malignant liver tumours have been reported in users of androgen hormonal substances, such as NEBIDO. 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. Caution should be exercised in patients predisposed to oedema, e.g., in case of severe cardiac, hepatic, or renal insufficiency or ischaemic heart disease, as treatment with NEBIDO may result in increased retention of sodium and water. In case of severe complications characterised by oedema with or without congestive heart failure, treatment must be stopped immediately (see section 4.8). Testosterone may cause a rise in blood pressure and NEBIDO should be used with caution in men with hypertension. Clinical trials with NEBIDO in children or adolescents under the age of 18 have not been conducted so far. In children, besides masculinisation, NEBIDO can cause accelerated growth, bone maturation and premature epiphyseal closure, thereby reducing final height. Pre-existing sleep apnoea may be potentiated. Testosterone has been subject to abuse, typically at doses higher than recommended for the approved indication(s) and in combination with other anabolic androgenic steroids. Testosterone abuse may result in dependence and withdrawal symptoms upon significant dose reduction or abrupt discontinuation of use. Abuse of testosterone along with other anabolic androgenic steroids can lead to serious adverse reactions including cardiovascular (with fatal outcomes in some cases), hepatic and/or psychiatric events. NEBIDO must be injected strictly intramuscularly. Pulmonary microembolism of oily solutions can 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.

Medicines that affect testosterone
Barbiturates and other enzyme inducers
Interactions can occur with medicines that induce microsomal enzymes, which can result in increased clearance of NEBIDO.
Effects of NEBIDO on other medicinal products
Oxyphenbutazone
Increased oxyphenbutazone serum levels have been reported.
Oral anticoagulants
Testosterone and its derivates, such as NEBIDO have been reported to increase the activity of coumarin derived oral anticoagulants, possibly requiring dose adjustment. Independent of this finding, the risk of bleeding from using intramuscular injections in patients with acquired or inherited bleeding disorders always has to be taken into account as a general rule.
Hypoglycaemics
NEBIDO may enhance the blood-sugar reducing effects of insulin. Therefore, the dosage of the hypoglycaemic agent may need to be lowered.

Pregnancy and lactation
Not applicable.
Fertility
NEBIDO may reversibly reduce spermatogenesis (see section 4.8).

Dizziness has been reported as uncommon side effect (see section 4.8). Patients experiencing dizziness should avoid driving and use of machines.

Regarding side effects associated with the use of NEBIDO, please also refer to section 4.4. The most frequent side effects under treatment with NEBIDO are acne and injection site pain. Table 1 below reports adverse drug reactions (ADRs) [by MedDRA system organ classes*] reported with NEBIDO. The frequencies are based on clinical trial data and defined as Common (u22651/100 to <1/10) and Uncommon (u22651/1000 to <1/100). The ADRs were recorded in 6 clinical studies (N=422) and considered at least possibly causally related to NEBIDO.
System Organ Class
Common
Uncommon
Blood and lymphatic system disorders
Polycythaemia
Increased haematocrit
Increased red blood cell count
Increased haemoglobin
Immune system disorders
Hypersensitivity
Metabolism and nutrition disorders
Increased weight
Increased appetite
Increased glycosylated haemoglobin
Hypercholesterolaemia
Increased blood triglycerides
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
Abnormal liver function test
Increased aspartate aminotransferase
Skin and subcutaneous tissue disorders
Acne
Alopecia
Erythema
Rash
Papular rash
Pruritus
Dry skin
Musculoskeletal and connective tissue disorders
Arthralgia
Pain in extremity
Muscle spasm
Muscle strain
Myalgia
Musculoskeletal stiffness
Increased blood creatinine phosphokinase
Renal and urinary disorders
Decreased urine flow
Urinary retention
Urinary tract disorder
Nocturia
Dysuria
Reproductive system and breast disorders
Increased Prostate specific antigen
Prostatic intraepithelial neoplasia
Prostate induration
Abnormal Prostate examination
Benign prostate hyperplasia
Prostatitis
Prostatic disorder
Increased libido
Decreased libido
Testicular pain
Breast induration
Breast pain
Gynaecomastia
Increased estradiol
Increased testosterone
General disorders and administration site conditions
Various kinds of injection site reactions***
Fatigue
Asthenia
Hyperhidrosis
Night sweats
*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.
**n=302 hypogonadal men treated with i.m. injections of 4 ml and N=120 of 3ml of TU 250 mg/ml
***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
Pulmonary microembolism of oily solutions such as NEBIDO can 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 injections and are reversible. Cases suspected to represent oily pulmonary microembolism associated with NEBIDO injection have been reported in clinical trials (in u2265 1/10 000 and < 1/1000) as well as from postmarketing experience (see section 4.4). 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 hair growth, increased frequency of erections and in very rare cases jaundice have been reported under treatment with testosterone containing preparations. Therapy with high doses of NEBIDO 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 NEBIDO occasionally increases the occurrences of water retention and oedema. Reporting of suspected adverse reactions
Reporting suspected adverse reactions after authorisation of the medicine is important. It allows continued monitoring of the benefit/risk balance of the medicine. Healthcare professionals are asked to report any suspected adverse reactions to SAHPRA via the u201c6.04 Adverse Drug Reaction Reporting Formu201d, found online under SAHPRAu2019s publications: http://www.sahpra.org.za/Publications/index/8

No special therapeutic measure apart from termination of therapy with the drug or dose reduction is necessary after overdosage.