This information is intended for use by health professionals

1. Name of the medicinal product

Sustanon 250, 250mg/ml solution for injection

2. Qualitative and quantitative composition

Sustanon 250 is a solution in oil. Each ampoule contains 1 ml arachis oil containing the following active substances:

- 30 mg Testosterone propionate

- 60 mg Testosterone phenylpropionate

- 60 mg Testosterone isocaproate

- 100 mg Testosterone decanoate

All four components are esters of the natural hormone testosterone. The total amount of testosterone per ml is 176 mg.

For the full list of excipients, see section 6.1.

3. Pharmaceutical form

Solution for injection

A clear, pale yellow solution

4. Clinical particulars
4.1 Therapeutic indications

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

Testosterone administration may also be used as supportive therapy for female-to-male transsexuals.

4.2 Posology and method of administration

Posology

In general, the dose should be adjusted to the response of the individual patient.

Adults (incl. elderly):

Usually, one injection of 1ml per 3 weeks is adequate.

Paediatric population:

Safety and efficacy have not been adequately determined in children and adolescents. Pre-pubertal children treated with Sustanon 250 should be treated with caution (see section 4.4).

Female-to-male transsexuals:

Different specialist centres have used doses varying from one injection of 1ml every two weeks to one injection of 1ml every four weeks.

Method of administration

Sustanon 250 should be administered by deep intramuscular injection.

4.3 Contraindications

• Pregnancy (see section 4.6).

• Known or suspected carcinoma of the prostate or breast (see section 4.4.).

• Breast-feeding.

• Hypersensitivity to the active substance or to any of the excipients listed in section 6.1, including arachis oil. Sustanon 250 is therefore contraindicated in patients allergic to peanuts or soya (see section 4.4).

4.4 Special warnings and precautions for use

Medical examination:

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.

Physicians should consider monitoring patients receiving Sustanon 250 before the start of treatment, at quarterly intervals for the first 12 months and yearly thereafter for the following parameters:

• Digital rectal examination (DRE) of the prostate and PSA to exclude benign prostate hyperplasia or a sub-clinical prostate cancer (see section 4.3),

• Haematocrit and haemoglobin to exclude polycythaemia.

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.

Conditions that need supervision:

Patients, especially the elderly, with the following conditions should be monitored for:

Tumours - Mammary carcinoma, hypernephroma, bronchial carcinoma and skeletal metastases. In these patients hypercalcaemia or hypercalciuria may develop spontaneously, also during androgen therapy. The latter can be indicative of a positive tumour response to the hormonal treatment. Nevertheless, the hypercalcaemia or hypercalciuria should first be treated appropriately and after restoration of normal calcium levels, hormone therapy can be resumed.

Pre-existing conditions - In patients suffering from severe cardiac, hepatic or renal insufficiency or ischaemic heart disease, treatment with testosterone may cause severe complications characterised by oedema with or without congestive cardiac failure. In such cases treatment must be stopped immediately. Patients who experienced myocardial infarction, cardiac-, hepatic- or renal insufficiency, hypertension, epilepsy, or migraine should be monitored due to the risk of deterioration of or reoccurrence of disease. In such cases treatment must be stopped immediately.

Testosterone may cause a rise in blood pressure and Sustanon 250 should be used with caution in men with hypertension.

Epilepsy or Migraine - (or a history of these conditions), since androgens may occasionally induce fluid and sodium retention.

Diabetes mellitus – Androgens in general and Sustanon 250 can improve glucose tolerance in diabetic patients (see section 4.5).

Anti-coagulant therapy – Androgens in general and Sustanon 250 can enhance the anti-coagulant action of coumarin-type agents (see also section 4.5).

Sleep apnoea- Caution should be applied when treating men with sleep apnoea. There have been reports that testosterone can cause or exacerbate pre-existing sleep apnoea. However, there is a lack of evidence regarding the safety of testosterone in men with the condition. Good clinical judgment and caution should be employed in patients with risk factors such as adiposity or chronic lung diseases.

Adverse events:

If androgen-associated adverse reactions occur (see section 4.8), treatment with Sustanon 250 should be discontinued and, upon resolution of complaints, resumed with a lower dose.

Virilisation:

Patients should be informed about the potential occurrence of signs of virilisation. In particular, singers and women with speech professions should be informed about the risk of deepening of the voice. The voice changes may be irreversible.

If signs of virilisation develop, the risk/benefit ratio has to be newly assessed with the individual patient.

(Mis)use in sports:

Patients who participate in competitions governed by the World Anti-Doping Agency (WADA) should consult the WADA-code before using this product as Sustanon 250 can interfere with anti-doping testing. The misuse of androgens to enhance ability in sports carries serious health risks and is to be discouraged.

Excipients:

Sustanon 250 contains Arachis oil (peanut oil) and should not be taken / applied by patients known to be allergic to peanut. As there is a possible relationship between allergy to peanut and allergy to soya, patients with soya allergy should also avoid Sustanon 250 (see section 4.3).

Sustanon 250 contains 100 mg benzyl alcohol per ml solution and must not be given to premature babies or neonates. Benzyl alcohol may cause toxic reactions and anaphylactoid reactions in infants and children up to 3 years old.

Female-to-male transsexual supportive therapy:

Before initiating Sustanon 250 for female-to-male transsexuals, specialist assessment should be undertaken, including psychiatric assessment. A complete personal and medical history should be taken. During treatment, periodic check-ups are recommended of a frequency and nature adapted to the individual. The following should be monitored:

▪ signs of osteoporosis,

▪ changes in lipid profile.

In patients with a personal or family history of breast cancer and with a personal history of endometrial cancer, careful monitoring should be undertaken.

Subject to specialist advice, hysterectomy and bilateral oophorectomy should be considered after 18-24 months of testosterone treatment, to reduce the possible increased risk of endometrial and ovarian cancer.

Continued surveillance is required to detect osteoporosis in patients who have undergone oophorectomy, as testosterone may not fully reverse the decline in bone density in these patients.

Continued surveillance is required to detect endometrial and ovarian cancer in patients on long term treatment who have not proceeded to hysterectomy and bilateral oophorectomy.

Paediatric population:

In pre-pubertal children statural growth and sexual development should be monitored since androgens in general and Sustanon 250 in high dosages may accelerate epiphyseal closure and sexual maturation.

Older People:

There is limited experience on the safety and efficacy of the use of Sustanon 250 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.

Clotting disorders:

Testosterone should be used with caution in patients with thrombophilia, as there have been post-marketing studies and reports of thrombotic events in these patients during testosterone therapy.

4.5 Interaction with other medicinal products and other forms of interaction

Enzyme-inducing agents may decrease and enzyme-inhibiting drugs may increase testosterone levels. Therefore, adjustment of the dose of Sustanon 250 may be required.

Insulin and other anti-diabetic medicines:

Androgens may improve glucose tolerance and decrease the need for insulin or other anti-diabetic medicines in diabetic patients (see section 4.4).

Patients with diabetes mellitus should therefore be monitored especially at the beginning or end of treatment and at periodic intervals during Sustanon 250 treatment.

Anti-coagulant therapy:

High doses of androgens may enhance the anticoagulant action of coumarin type agents (see section 4.4). Therefore, close monitoring of prothrombin time and if necessary a dose reduction of the anti-coagulant is required during therapy.

ACTH or Corticosteroids:

The concurrent administration of testosterone with ACTH or corticosteroids may enhance oedema formation therefore these active substances should be administered cautiously, particularly in patients with cardiac or hepatic disease or in patients predisposed to oedema (see section 4.4).

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, and there is no clinical evidence of thyroid dysfunction.

4.6 Fertility, pregnancy and lactation

Sustanon 250 is contra-indicated in women who are pregnant (see section 4.3).

Pregnancy:

There are no adequate data for the use of Sustanon 250 in pregnant women. In view of the risk of virilisation of the foetus, Sustanon 250 should not be used during pregnancy (see section 4.3). Treatment with Sustanon should be discontinued when pregnancy occurs.

Lactation:

There are no adequate data for the use of Sustanon 250 during lactation. Therefore, Sustanon 250 should not be used during lactation.

Fertility:

In men treatment with androgens can lead to fertility disorders by repressing sperm-formation (see section 4.8).

In women treatment with androgens can lead to an infrequent or repressed menstrual cycle (see section 4.8).

4.7 Effects on ability to drive and use machines

Sustanon 250 has no influence on the ability to drive and use machines.

4.8 Undesirable effects

Due to the nature of Sustanon 250 side effects cannot be quickly reversed by discontinuing medication. Injectables in general, may cause a local reaction at the injection site.

The following adverse reactions have been associated with androgen therapy in general.

All adverse reactions are listed by system organ class and frequency; common (1/100 to < 1/10) and not known (cannot be estimated from the available data).

System Organ Class

MedDRA term*

Frequency

Neoplasms benign, malignant and unspecified (incl. cysts and polyps)

Prostatic cancer1

Not known

Blood and lymphatic system disorders

Polycythaemia

Not known

Metabolism and nutrition disorders

Fluid retention

Not known

Psychiatric disorders

Depression,

Nervousness

Mood altered

Libido increased,

Libido decreased

Not known

Vascular disorders

Hypertension

Not known

Gastrointestinal disorders

Nausea

Not known

Hepatobiliary disorders

Hepatic function abnormal

Not known

Skin and subcutaneous tissue disorders

Pruritus

Acne

Not known

Musculoskeletal and connective tissue disorders

Myalgia

Not known

Reproductive system and breast disorders

Ejaculation disorder

Gynaecomastia

Oligospermia

Priapism

Benign prostatic hyperplasia2

Not known

Investigations

Lipids abnormal3

PSA increased

Haematocrit increased

Red blood cell count increased

Haemoglobin increased

Not known

Common

* MedDRA version 17.0

1 Progression of a sub-clinical prostatic cancer

2 Prostatic growth (to eugonadal state)

3 Decrease in serum LDL-C, HDL-C and triglycerides

The terms used to describe the undesirable effects above are also meant to include synonyms and related terms.

Treatment in women:

Treatment with Sustanon 250 my induce signs of virilisation in women (see section 4.4). Symptoms of virilisation may include hoarseness, acne, hirsutism, menstrual irregularity and alopecia.

Paediatric population:

The following undesirable effects have been reported in prepubertal children using androgens (see section 4.4): precocious sexual development, an increased frequency of erections, phallic enlargement and premature epiphyseal closure.

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.

4.9 Overdose

The acute toxicity of testosterone is low.

If symptoms of chronic overdose occur (e.g. polycythaemia, priapism) treatment should be discontinued and after disappearance of the symptoms, be resumed at lower dosage.

5. Pharmacological properties
5.1 Pharmacodynamic properties

Pharmacotherapeutic group: Androgens. ATC code G03B A03

Treatment of hypogonadal men with Sustanon 250 results in a clinically significant rise of plasma concentrations of testosterone, dihydrotestosterone, estradiol and androstenedione, as well as decrease of SHBG (Sex hormone binding globulin). Luteinizing hormone (LH) and follicle-stimulating hormone (FSH) are restored to the normal range. In hypogonadal men, treatment with Sustanon 250 results in an improvement of testosterone deficiency symptoms. Moreover, treatment increases bone mineral density and lean body mass, and decreases body fat mass. Treatment also improves sexual function, including libido and erectile function. Treatment decreases serum LDL-C, HDL-C and triglycerides and increases haemoglobin and haematocrit, which may lead to polycythaemia. No clinically relevant changes in liver enzymes and PSA have been reported. Testosterone also produces systemic effects, such as increasing the retention of sodium, potassium and chloride leading to an increase in water retention. Treatment may result in an increase in prostate size, and worsening of lower urinary tract symptoms, but no adverse effects on prostate symptoms have been observed. In hypogonadal diabeteic patients, improvement of insulinsensitivity and/or reduction in blood glucose have been reported with the use of androgens. In boys with constitutional delay of growth and puberty, treatment with Sustanon 250 accelerates growth and induces development of secondary sex characteristics. In female-to-male transsexuals, treatment with Sustanon 250 induces masculinisation.

5.2 Pharmacokinetic properties

Sustanon 250 contains four esters of testosterone with different durations of action. The esters are hydrolysed into the natural hormone testosterone as soon as they enter the general circulation.

Absorption:

A single dose of Sustanon 250 leads to an increase of total plasma testosterone with peak levels of approximately 70nmol/l (Cmax), which are reached approximately 24-48 h (tmax) after administration. Plasma testosterone levels return to the lower limit of the normal range in males in approximately 21 days.

In female-to-male transsexuals, a single dose of Sustanon 250 repeated every two weeks resulted in mean trough testosterone levels towards the upper end of the normal male range at 2, 4 and 12 months.

Distribution:

Testosterone displays a high (over 97%) non-specific binding to plasma proteins and sex hormone binding globulin in in vitro tests.

Biotransformation:

Testosterone is metabolised to dihydrotestosterone and estradiol, which are further metabolised via the normal pathways.

Elimination:

Excretion mainly takes place via the urine as conjugates of etiocholanolone and androsterone.

5.3 Preclinical safety data

Preclinical data with androgens in general reveal no hazard for humans. The use of androgens in different species has been demonstrated to result in virilisation of the external genitals of female foetuses.

6. Pharmaceutical particulars
6.1 List of excipients

Arachis Oil

Benzyl Alcohol

6.2 Incompatibilities

Not applicable

6.3 Shelf life

3 years

6.4 Special precautions for storage

Store below 30°C

Do not refrigerate or freeze

Store in the original package in order to protect from light

6.5 Nature and contents of container

Each colourless glass ampoule is filled with 1 ml of Sustanon 250.

A box of Sustanon 250 contains 1 ampoule. Not all pack sizes may be marketed. In correspondence please quote batch number.

6.6 Special precautions for disposal and other handling

Any unused product or waste material should be disposed of in accordance with local requirements.

7. Marketing authorisation holder

ASPEN PHARMA TRADING LIMITED

3016 LAKE DRIVE

CITYWEST BUSINESS CAMPUS

DUBLIN 24

IRELAND

8. Marketing authorisation number(s)

PL 39699/0059

9. Date of first authorisation/renewal of the authorisation

28/02/1973 / 29/11/2002

10. Date of revision of the text

06/12/2016