Testosterone Pd 1000 mg/ 4 mL Solution for injection.

Testosterone replacement in primary and secondary male hypogonadism.

TESTOSTERONE PD (1 ampoule/vial corresponding to testosterone undecanoate 1000 mg) 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 depending on serum testosterone levels and clinical symptoms. 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
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 PD 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.
Paediatric population
TESTOSTERONE PD 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).

Method of administration
For intramuscular use. The injections must be administered very slowly (over two minutes). TESTOSTERONE PD is strictly for intramuscular injection. Special care must be given to avoid intravasal injection. See section 6.6 to avoid injury when opening. The content of an ampoule/vial are to be injected intramuscularly immediately after opening.

• hypersensitivity to testosterone undecanoate or to any of the ingredients of TESTOSTERONE PD (see section 6.1)
• androgen-dependent carcinoma of the prostate or of the male mammary gland
• past or present liver tumours
• hypercalcaemia accompanying malignant tumours.

The use of TESTOSTERONE PD in women is contraindicated.

There may be an increased risk for the development of prostatic hyperplasia in older patients treated with TESTOSTERONE PD. Although there are no clear indications that TESTOSTERONE PD actually, generates prostatic carcinoma, it can enhance the growth of any existing prostatic carcinoma. Therefore before starting therapy with TESTOSTERONE PD, carcinoma of the prostate has to be excluded.

TESTOSTERONE PD should be used only if hypogonadism (hyper- and hypogonadotropic) 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.

Medical examinations
Prior to TESTOSTERONE PD 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 breasts 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).

Laboratory tests
Testosterone level should be monitored at baseline and at regular intervals during TESTOSTERONE PD treatment. Healthcare practitioners 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 (to detect cases of polycythaemia), 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 PD 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.

Benign liver tumours and malignant liver tumours have been reported in users of hormonal substances, for example, testosterone compounds. A hepatic tumour should be considered in the differential diagnosis when severe upper abdominal pain, liver enlargement or signs of intra-abdominal haemorrhage occur in men using TESTOSTERONE PD.

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 with TESTOSTERONE PD must be stopped immediately.

Hepatic or renal insufficiency
There are no studies undertaken to demonstrate the efficacy and safety of TESTOSTERONE PD 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 TESTOSTERONE PD 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 PD 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, as in TESTOSTERONE PD, 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 PD 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 PD 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 TESTOSTERONE PD who achieve normal testosterone plasma concentrations following replacement therapy. Certain clinical signs: irritability, nervousness, weight gain, prolonged or frequent erections may indicate excessive TESTOSTERONE PD 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 TESTOSTERONE PD contains an active substance which may produce a positive reaction in anti-doping tests. TESTOSTERONE PD is not suitable for enhancing muscular development in healthy individuals or for increasing physical ability. TESTOSTERONE PD should be permanently withdrawn if symptoms of excessive androgen exposure persist or reappear during treatment with the recommended dosage regimen.

Suspected anaphylactic reactions after TESTOSTERONE PD injection have been reported. Pulmonary micro embolism of oily solutions can in 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.

Drug abuse and dependence
Testosterone, as contained in TESTOSTERONE PD, 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.

Paediatric population
Clinical trials with TESTOSTERONE PD in children or adolescents under the age of 18 have not been conducted so far. In children, besides masculinisation, TESTOSTERONE PD can cause accelerated growth and bone maturation and premature epiphyseal closure, thereby reducing final height.

Hypoglycaemics
TESTOSTERONE PD may enhance the blood-sugar reducing effects of insulin. The dosage of the hypoglycaemic medicine may need to be lowered.

Barbiturates and other enzyme inducers
Interactions can occur with medicines that induce microsomal enzymes, which can result in increased clearance of TESTOSTERONE PD (e.g. barbiturates).

Oral anticoagulants
Testosterone and derivatives, such as TESTOSTERONE PD have been reported to increase the activity of coumarin derived oral anticoagulants, possibly requiring dose adjustment. Independently of this finding, as a general rule, the limitations of using intramuscular injections in patients with acquired or inherited blood clotting irregularities always have to be observed, especially at the beginning or end of TESTOSTERONE PD therapy. Increased monitoring of the prothrombin time, and INR determinations, are recommended.

Oxyphenbutazone
Increased oxyphenbutazone serum levels have been reported.

Other interactions
The concurrent administration of TESTOSTERONE PD with ACTH or corticosteroids may enhance oedema formation; thus these medicines should be administered cautiously, particularly in patients with cardiac or hepatic disease or in patients predisposed to oedema.

Laboratory test interactions:
TESTOSTERONE PD 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.

Pregnancy and lactation
Not applicable. TESTOSTERONE PD is not indicated for use in women.

Fertility
Testosterone replacement therapy as in TESTOSTERONE PD may reversibly reduce spermatogenesis (see section 4.8).

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

a). Summary of the safety profile
The most frequently reported undesirable effects during treatment with TESTOSTERONE PD are acne and injection site pain. Pulmonary micro embolism can occur after TESTOSTERONE PD injection (see section 4.4). Suspected anaphylactic reactions after TESTOSTERONE PD injection have been reported.

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

b). Tabulated summary of adverse reactions
System Organ Class
Frequency
Side effects
Blood and lymphatic system disorders
Frequent
Less frequent
Polycythaemia
Haematocrit increased*, red blood cell count increased*, haemoglobin increased*
Immune system disorders
Less frequent
Hypersensitivity
Metabolism and nutrition disorders
Frequent
Less frequent
Weight gain
Increased appetite, glycosylated haemoglobin increased, hypercholesterolaemia, blood triglycerides increased
Psychiatric disorders
Less frequent
Frequency unknown
Depression, emotional disorder, insomnia, restlessness, aggression, irritability
Nervousness, hostility
Nervous system disorders
Less frequent
Headache, migraine, tremor
Vascular disorders
Frequent
Less frequent
Hot flush
Cardiovascular disorder, hypertension, dizziness
Respiratory, thoracic and mediastinal disorders
Frequent
Less frequent
Frequency unknown
Respiratory disorder
Bronchitis, sinusitis, cough, dyspnoea, snoring, dysphonia
Sleep apnoea
Gastrointestinal disorders
Less frequent
Nausea, diarrhoea
Hepatobiliary disorders
Less frequent
Jaundice, liver function test abnormalities, aspartate aminotransferase increased
Skin and subcutaneous tissue disorders
Frequent
Less frequent
Frequency unknown
Acne, Alopecia, erythema, rash, dry skin, pruritus, papular rash
Seborrhoea
Musculoskeletal, connective tissue and bone disorders
Less frequent
Frequency unknown
Arthralgia, pain in extremity, muscle disorders (including muscle spasm, muscle strain and myalgia), musculoskeletal stiffness, blood creatine phosphokinase increased
Muscle cramps
Renal and urinary disorders
Less frequent
Urine flow decreased, urinary retention, urinary tract disorder, nocturia, dysuria
Reproductive system and breast disorders
Frequent
Less frequent
Frequency unknown
Prostate specific antigen increased, prostate examination abnormal, benign prostate hyperplasia
Prostatic intraepithelial neoplasia, prostate induration, prostatitis, prostatic disorder, testicular pain, breast induration, breast pain, gynaecomastia, estradiol increased, testosterone increased, increased libido, decreased libido
Increased frequency of erections, reversible interrupted or reduced spermatogenesis, thereby reducing the size of the testicles, persistent painful erections (priapism)
General disorders and administrative site conditions
Frequent
Less frequent
Frequency unknown
Injection site pain, subcutaneous haematoma at the injection site
Fatigue, asthenia, hyperhidrosis, night sweats
Water retention, oedema
Injury and poisoning
Less frequent
Pulmonary oil micro-embolism
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 Med Safety APP (Medsafety X SAHPRA) and e Reporting platform (who-umc.org) found on the SAHPRA website. An email can be sent directly to the company, [email protected] to ensure safety of the product.

No special therapeutic measure apart from termination of therapy with TESTOSTERONE PD or dose reduction is necessary after overdose.