Core Safety Profile

Active substance: Androstanolone Pharmaceutical form(s)/strength: Gel for local application P-RMS: FR/H/PSUR/0018/001 Date of FAR: 16.07.2010 4.3 Contraindications

In men : As with all androgens, /.../ is contra-indicated in suspected or known prostate or breast cancer.

In women : The use of /.../ is contraindicated as systemic androgen therapy due to the virilising effects of the product.

4.4 Special Warnings and Precautions for Use

Attentive and regular monitoring of the prostate and breast is to be conducted, using the recommended methods (rectal touch and determination of Prostate Antigen Specific (PSA) at least once a year. In hypogonadal subjects aged over 40 and in patients at risk, regular monitoring is recommended every 3 months for the first year, then twice yearly subsequently..

In patients with cardiac disorders : The use of androgens in patients with a history of cardio-vascular disorders or with risk factors should be carried out with caution and under medical surveillance. In patients presenting with severe heart, liver or kidney failure or ischaemic heart disease:androgen therapy may induce complications characterized by edema with or without congestive heart failure, requiring immediate discontinuation of treatment.

Transfer events:If no precaution is taken, dihydrotestosterone gel can be transferred to other persons by close skin-to-skin contact with the gel application area, resulting in increased dihydrotestosterone serum levels and, in case of repeated contacts (inadvertent androgenization), possible adverse effects (e.g. growth of facial and/or body hair, deepening of the voice, irregularities of the menstrual cycle) may appear.

The physician should inform the patient about the risk of dihydrotestosterone transfer and about safety instructions (see below). /.../ should not be prescribed in patients with a major risk of non-compliance with safety instructions (e.g. severe alcoholism, drug abuse, severe psychiatric disorders).

Transfer is avoided by wearing clothes covering the application area or showering with soap prior to contact.

As a result, the following precautions are recommended:

For the patient:

- Wash hands with soap and water after applying the gel - Cover the application area with clothing once the gel has dried, - Shower with soap before any situation in which a close contact is foreseen.

For people not treated with /.../:

2 / 5 - In the event of contact with an application area which has not been washed or is not covered with clothing, wash the area of skin onto which dihydrodihydrotestosterone may have been transferred as soon as possible, using soap and water,

- Report the development of signs of excessive androgen exposure such as acne or hair modification.

To guarantee partner safety, the patient should be advised for example to:

- Observe a long interval between /.../ application and sexual intercourse, - To wear a cloth (T-shirt…) covering the application site during contact period - Or to shower before sexual intercourse.

Furthermore, it is recommended to wear a cloth, covering the application site, during contact period with children, in order to avoid a contamination risk of children skin.

Pregnant women should avoid any contact with /.../ application sites. In case of pregnancy of the partner, the patient must reinforce his attention to the precautions for use (see section 4.6).

In patients receiving long-term androgen therapy, the following laboratory parameters should be monitored regularly: haemoglobin, hematocrit (to detect polyglobulia) and liver function parameters.

In men : certain clinical signs (irritability, agitation, weight increase) reflecting a hyper-androgenisation: a reduction in dose rapidly brings clinical and biological levels of androgen back to normal. The appearance of seborrhea or acne in certain areas (face, shoulders, chest) is a sign of excessive local receptivity to androgens. This can be avoided by reducing the dose and by applying on areas such as the thighs and abdomen.

In women: pelvic hypertrichosis can be observed during local treatment. Hypertrophy of the clitoris is a sign of exaggerated local effect and warrants a dose reduction. All signs of general androgenisation (seborrhea, acne, hirsutism, deep voice) are caused by overdose.

In athletes : The attention of athletes is drawn to the fact that this proprietary medicinal product contains an active substance which may produce a positive reaction in anti- doping tests.

4.5 Interactions With Other Medicines and Other Forms of Interaction

Drug interactions Oral anticoagulants Changes in anticoagulant activity (the increased effect of the oral anticoagulant by modification of coagulation factor hepatic synthesis and competitive inhibition of plasma protein binding): Increased monitoring of the prothrombin time and INR determinations, are recommended. Patients receiving oral anticoagulants require close monitoring especially when androgens are started or stopped.

3 / 5 Concomitant administration ofdihydrotestosterone and ACTH or corticosteroids may increase the risk of developing oedema. As a result, these medicinal products should be administered cautiously, particularly in patients suffering from cardiac, renal or hepatic disease.

Interaction with laboratory tests Androgens may decrease levels of thyroxin binding globulin, resulting in decreased T4 serum concentrations and in increased resin uptake of T3 and T4. Free thyroid hormone levels, however, remain unchanged and there is no clinical evidence of thyroid insufficiency.

4.6 Pregnancy and Lactation

/.../ should not be used in pregnant or lactating women, or in women who suspect they are pregnant.

Pregnant women should avoid all contact with the application sites of /.../. The product can cause undesirable virilising effects on the fetus.

In case of accidental exposure during pregnancy, the use of /.../ should be stopped and the contact zone should be washed with water and soap as soon as possible.(see section 4.4)

4.7 Ability to Drive and Use Machines

The effects of /.../ on driving and using machinery have not been assessed.

4.8 Undesirable Effects 1) 2)

The following adverse events were reported during post-marketing (spontaneous reports, literature) and are presented by system organ class with an unknown frequency.

Muscusckeletal and connective tissue disorders Myalgia, bone development disorders

Reproductive system and breast disorders Breast pain, breast enlargement

Respiratory, thoracic and mediastinal disorders: Dysphonia

Skin and subcutaneous tissue disorders: Seborrhoea

Gastrointestinal disorders: Abdominal pain

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Other adverse events have been reported in literature with androgens by oral or parenteral route and are as follows:

Metabolism and nutition disorders: Weight gain, electrolyte changes (sodium retention, potassium, calcium, inorganic phosphate) during high dose and prolonged treatment.

Musculoskeletal and connective tissue disorders: Muscular cramps

Nervous system disorders: nervosity, depression, aggressiveness

Respiratory, thoracic and mediastinal disorders: Sleep apnoea

Hepatobiliaty disorders: Jaudnice and hepatic tests abnormalities

Skin and subcutaneous tissue disorders: Acnea, seborrhea and alopecia

Reproductive system and breast disorders: Libido changes, erection frequency changes, high dose of androgens may induce decrease or reversible disruption of spermatogenesis leading to a testis volume reduction, priapism, prostate disorders, prostate cancer and urinary retention.

General disorders and administration site conditions: High dose or prolonged therapy may enhance hydric retention and oedema, hypersensitivity reactions.

4.9 Overdose No cases of overdose have been reported.

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