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

Testosterone undecanoate is intended for use under the guidance of a healthcare professional.

Posology

One vial of Testosterone undecanoate (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.

Paediatric population

Testosterone undecanoate 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).

Elderly

Limited data do not suggest the need for a dosage adjustment in elderly patients (see section 4.4).

Hepatic impairment

No formal studies have been performed in patients with hepatic impairment. The use of Testosterone undecanoate is contraindicated in men with past or present liver tumours (see section 4.3).

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 (over two minutes). Testosterone undecanoate is strictly for intramuscular injection. Care should be taken to inject Testosterone undecanoate 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 a vial are to be injected intramuscularly immediately after opening.

4.3. Contraindications

The use of Testosterone undecanoate 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 (listed in section 6.1)

The use of Testosterone undecanoate in women is contraindicated.

4.4. Special warnings and precautions for use

Testosterone undecanoate is not recommended for use in children and adolescents.

Testosterone undecanoate 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.

Elderly population

There is limited experience on the safety and efficacy of the use of Testosterone undecanoate in 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 and laboratory tests

Medical examinations

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). Local guidelines for safety monitoring under testosterone replacement therapy should be taken into consideration.

Laboratory tests

Testosterone level should be monitored at baseline and at regular intervals during treatment. Clinicians should adjust the dosage individually to ensure maintenance of eugonadal testosterone levels.

In patients receiving long-term androgen therapy, the following laboratory parameters should also be monitored regularly: haemoglobin and haematocrit, liver function tests and lipid profile (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.

Testosterone undecanoate 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 Testosterone undecanoate, a liver tumour should be included in the differential-diagnostic considerations.

Cardiac, hepatic or renal insufficiency

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.

Hepatic or renal insufficiency

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.

Cardiac insufficiency

Caution should be exercised in patients predisposed to oedema, e.g. in case of severe cardiac, hepatic, or renal insufficiency or ischemic heart disease, as treatment with androgens may result in increased retention of sodium and water. In case of severe complications characterized 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 Testosterone undecanoate should be used with caution in men with hypertension.

Clotting disorders

As a general rule, the limitations of using intramuscular injections in patients with acquired or inherited bleeding disorders always have to be observed.

Testosterone and derivatives have been reported to increase the activity of coumarin derived oral anticoagulants (see also section 4.5)

Testosterone 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.

Other conditions

Testosterone undecanoate 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. Therefore, the dosage of hypoglycaemic agents may need to be lowered.

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.

Testosterone undecanoate should be permanently withdrawn if symptoms of excessive androgen exposure persist or reappear during treatment with the recommended dosage regimen.

Drug abuse and dependence

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. Abuse of testosterone and other anabolic androgenic steroids can lead to serious adverse reactions including: cardiovascular (with fatal outcomes in some cases), hepatic and/or psychiatric events.

Testosterone abuse may result in dependence and withdrawal symptoms upon significant dose reduction or abrupt discontinuation of use. The abuse of testosterone and other anabolic androgenic steroids carries serious health risks and is to be discouraged.

Application

As with all oily solutions, Testosterone undecanoate must be injected strictly intramuscularly and very slowly (over two minutes). Pulmonary micro embolism 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. The patient should therefore be observed during and immediately after each injection in order to allow for early recognition of possible signs and symptoms of pulmonary oily micro embolism. Treatment is usually supportive, e.g. by administration of supplemental oxygen.

Suspected anaphylactic reactions after Testosterone undecanoate injection have been reported.

Information about excipients

This medicine contains 2000 mg Benzyl benzoate in each 4 ml vial which is equivalent to 500 mg/ml.

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 coumarin derived 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 thyroxin-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 breastfeeding

Testosterone undecanoate 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

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

4.8. Undesirable effects

Summary of the safety profile

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 Testosterone undecanoate are acne and injection site pain.

Pulmonary micro embolism 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. Cases suspected by the company or the reporter to represent oily pulmonary micro embolism have been reported rarely in clinical trials (in ≥ 1/10,000 and < 1/1,000 injections) as well as from postmarketing experience (see section 4.4).

Suspected anaphylactic reactions after Testosterone undecanoate injection have been reported.

Androgens may accelerate the progression of sub-clinical prostatic cancer and benign prostatic hyperplasia.

Table 1 below reports adverse drug reactions (ADRs) by MedDRA system organ classes (MedDRA SOCs) reported with Testosterone undecanoate.

The frequencies are based on clinical trial data and defined as common (≥ 1/100 to < 1/10), uncommon (≥ 1/1000 to < 1/100) and rare (≥1/10,000 to <1/1,000). The ADRs were recorded in 6 clinical studies for marketing authorisation (N=422) and considered at least possibly causally related to Testosterone undecanoate.

Tabulated list of adverse reactions

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)

Rare

(≥1/10,000 to <1/1,000)

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

Prostatic specific antigen increased

Prostate examination abnormal

Benign prostatic hyperplasia

Prostatic dysplasia

Prostate induration

Prostatitis

Prostatic disorder

Libido disorder

Testicular pain

Breast induration

Breast pain

Gynaecomastia

Oestradiol increased

Blood testosterone increased

General disorders and administration site conditions

Various kinds of injection site reactions3

Fatigue

Asthenia

Hyperhidrosis4

Injury, poisoning and procedural complications

Pulmonary oil microembolism

**

* Respective frequency has been observed in relation to the use in testosterone containing products.

** Frequency is based on the number of injections.

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 spasms, 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

Description of selected adverse reactions

Pulmonary micro embolism of oily solutions can in rare cases lead to signs and symptoms such as cough, dyspnea, malaise, hyperhidrosis, chest pain, dizziness, paraesthesia, 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 micro embolism have been reported rarely in clinical trials (in ≥1/10,000 and <1/1,000 injections) as well as from postmarketing experience (see section 4.4).

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 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.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the Yellow Card Scheme at: www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store.

4.9. Overdose

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