1. NAME OF THE MEDICINAL PRODUCT

Restandol® Testocaps™ 40 mg capsule.

2. QUALITATIVE AND QUANTITATIVE COMPOSITION

Each capsule contains Testosterone Undecanoate 40.0 mg which is equivalent to 25.3 mg testosterone.

For the full list of excipients, see section 6.1.

3. PHARMACEUTICAL FORM

Capsule

Soft oval, glossy capsules, transparent, orange in colour, with a yellow oily fill.

4.1    Therapeutic indications

Clinical Indications

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

Examples of hypogonadal disorder are:

after castration; eunuchoidism; hypopituitarism; endocrine impotence;

male climacteric symptoms like decreased libido and decreased mental and physical activity; certain types of infertility due to disorders of spermatogenesis

Testosterone therapy may also be indicated in osteoporosis due to androgenic deficiency.

4.2    Posology and method of administration

Posology

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

Adults

The initial dosage required will usually be 120-160 mg daily for 2-3 weeks. Subsequent dosage (40-120 mg daily) should be based on the clinical effect obtained during the first weeks of therapy.

Elderly Patients

It should be noted that smaller and less frequent doses may achieve the same response.

Paediatric population

Safety and efficacy has not been determined in children and adolescents. Pre-pubertal children treated with Restandol Testocaps should be treated with caution (see section 4.4).

Method ofAdministration

Oral.

To ensure absorption, Restandol Testocaps must be taken with a normal meal, if necessary with a little fluid, and be swallowed whole without chewing. It is preferable that half of the daily dose be taken in the morning and the other half in the evening. If an uneven number of capsules is taken daily, the greater part should be taken in the morning.

4.3    Contraindications

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

History of liver tumours

Hypersensitivity to the active substance or to any of the excipients (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 Restandol Testocaps 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 in men over the age of 45 years, to exclude benign prostate hyperplasia or a subclinical prostate cancer (see section 4.3),

•    hematocrit and haemoglobin to exclude polycythemia. In case of severe polycythemia, treatment with Restandol Testocaps should be stopped or the dosage should be lowered.

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 should first be treated appropriately and after restoration of normal calcium levels, hormone therapy can be resumed.

Tumours and other histological abnormalities and disturbances of liver function have been reported in patients subjected to prolonged treatment with some testosterone derivatives. Most of these compounds were 17-alpha alkyl derivatives but a smaller number of cases have occurred with certain 17-beta esters of testosterone. The possibility that such changes result from the use of Restandol Testocaps has not been excluded.

•    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 case, 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 or reoccurrence of disease. In such cases, treatment must be stopped immediately. In addition to discontinuation of the drug, diuretic therapy may be required.

Testosterone may cause a rise in blood pressure and Restandol Testocaps should be used with caution in men with hypertension

•    Diabetes mellitus - Androgens in general and Restandol Testocaps can improve glucose tolerance in diabetic patients (see section 4.5).

•    Anti-coagulant therapy - Androgens in general and Restandol Testocaps can enhance the anti-coagulant action of coumarin-type agents (see section 4.5).

•    Sleep Apnea - There is insufficient evidence for a recommendation regarding the safety of treatment with testosterone esters in men with sleep apnea. Good clinical judgment and caution should be employed in subjects with risk factors such as adiposity or chronic lung diseases.

Androgen therapy should only be used in male hypogonadism in which testosterone levels have been demonstrated to be low.

In treating males, stimulation to the point of increasing nervous, mental and physical activities beyond the patient’s cardiovascular capacity should be avoided.

Adverse events:

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

(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 Restandol Testocaps 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:

Restandol Testocaps contains Sunset Yellow (E110, FD&C Yellow no. 6) which may cause allergic reactions.

Paediatric Population:

In pre-pubertal children statural growth and sexual development should be monitored since androgens in general and Restandol Testocaps 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 Restandol Testocaps 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 physiological testosterone serum levels are lower with increasing age.

4.5 Interaction with other medicinal products and other forms of interaction

Concurrent administration of liver enzyme inducing drugs such as rifampicin, barbiturates, carbamazepine, dichloralphenazone, phenylbutazone, phenytoin or primidone may decrease the effect of Restandol Testocaps.

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 Restandol Testocaps treatment.

Anti-coagulant therapy:

High doses of androgens may enhance the anti-coagulant action of coumarin-type agents (see section 4.4). Therefore close monitoring of the 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: thus 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, however, and there is no clinical evidence of thyroid dysfunction.

Restandol Testocaps must be taken with a normal meal to ensure absorption (see section 4.2).

4.6    Fertility, pregnancy and lactation

Pregnancy and lactation:

Restandol Testocaps are not indicated for treatment in women and therefore must not be used by pregnant or breast-feeding women. If used during pregnancy Restandol Testocaps pose a risk of virilisation of the fetus.

Fertility:

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

4.7    Effects on ability to drive and use machines

Restandol Testocaps has no influence on the ability to drive or use machines.

4.8 Undesirable effects

The following adverse reactions have been associated with androgen therapy in general. The most appropriate MedDRA term to describe a certain adverse event is listed.

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

Prostatic growth (to normogonadal size)

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.

With high doses and prolonged treatment electrolyte changes (sodium, potassium, calcium, inorganic phosphate and water retention), hypertension, oligozoospermia, or azospermia, priaprism, changes in lipid metabolism, polycythaemia.

In a few patients diarrhoea and abdominal pain or discomfort have been reported during use of Restandol Testocaps.

Paediatric population:

The following undesirable effects have been reported in pre-pubertal 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.

High doses of Restandol Testocaps may cause gastrointestinal complaints due to the castor oil present in the capsule. Treatment consists of supportive measures.

5    PHARMACOLOGICAL PROPERTIES

5.1    Pharmacodynamic properties

Pharmacotherapeutic group: Androgens. ATC code G03B A03

Restandol Testocaps, after oral administration, delivers physiological amount of testosterone in the circulation. Treatment of hypogonadal men also results in a clinically significant rise of plasma concentrations of dihydrotestosterone and oestradiol, as well as a decrease of SHBG (sex hormone binding globulin). Treatment of males with primary (hypergonadotropic) hypogonadism results in a normalization of gonadotropin levels.

Endogenous androgens, principally testosterone, secreted by the testes and its major metabolite DHT, are responsible for the development of the external and internal genital organs and for maintaining the secondary sexual characteristics (stimulating hair growth, deepening of the voice, development of the libido); for a general effect on protein anabolism; for development of skeletal muscle and body fat distribution; for a reduction in urinary nitrogen, sodium, potassium, chloride, phosphate and water excretion.

Androgens are also responsible for the growth spurt of adolescence and for the eventual termination of linear growth and stimulate the production of red blood cells by enhancing erythropoietin production.

The effects of testosterone in some target organs arise after peripheral conversion of testosterone to oestradiol, which then binds to oestrogen receptors in the target cell nucleus e.g. the pituitary, fat, brain, bone and testicular Leydig cells.

Exogenous administration of androgens inhibits endogenous testosterone release. With large doses of exogenous androgens, spermatogenesis may be suppressed.

5.2 Pharmacokinetic properties

Absorption

Restandol Testocaps must be taken with a normal meal or breakfast to ensure absorption. Food enhances the absorption of Restandol Testocaps: In healthy volunteers the AUC of testosterone was increased more than 12 -fold compared with fasted conditions when Restandol Testocaps was taken with a normal meal. No differences were found in the AUC of testosterone when Restandol Testocaps was taken with a normal meal (containing 18.8 grams of fat) as compared to a high fat meal (containing 44.1 grams of fat). The absorption is about 7%. Following oral administration of Restandol Testocaps, an important part of the active substance testosterone undecanoate is coabsorbed with the lipophilic solvent from the intestine into the lymphatic system, thus circumventing the first pass inactivation by the liver.

Distribution

From the lymphatic system testosterone undecanoate is released into the plasma. Single administration of 20-80 mg Restandol Testocaps to postmenopausal women leads to peak-levels of total plasma testosterone of approximately 1.5-2.0, 2.5-5.5 and 5.2-10.3ng/ml after a dose of 20, 40 and 80 mg Restandol Testocaps, respectively. These levels are reached approximately 5-6 h (t_max) after administration. Plasma testosterone levels remain elevated for at least 8 hours. In Japanese women the testosterone levels are about two fold higher.

During steady state after 28 days of administration plasma levels of total testosterone in hypogonadal men were increased after administration of 40 mg t.i.d, 40 b.i.d+80 mg, 80 mg b.i.d and 80 mg t.i.d. The dose of 80 mg b.i.d or 80 mg t.i.d. resulted in levels in the male physiological range for a considerable proportion of the time during the day. Testosterone and testosterone undecanoate display a high (over 97%) non-specific binding to plasma proteins and sex hormone binding globulin in in vitro tests.

Biotransformation

In plasma and tissues testosterone undecanoate is hydrolyzed to yield the natural male androgen testosterone. Testosterone is further metabolized to dihydrotestosterone and oestradiol, which are further metabolized via the normal pathways.

Elimination

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

Linearity

Dose-linearity has been demonstrated for 20-240 mg/day.

5.3 Preclinical safety data

Preclinical data with androgens in general reveal no special hazards for humans. Experimental data in rodents have shown testosterone can promote the development of certain tumours in hormone responsive tissues. In reproductive studies the use of androgens in different species has been demonstrated to result in virilisation of the external genitals of female fetuses.

6.1 List of excipients

Capsule contents

Each capsule contains Castor oil

Propylene glycol laurate (E477)

Capsule shell

Glycerin

Sunset Yellow (E110) Gelatin

Printing ink Opacode WB® white

Auxiliary substances Medium-chain triglycerides Lecithin

6.2    Incompatibilities

None.

6.3    Shelf life

3 years.

6.4    Special precautions for storage

Do not store above 30 °C Do not refrigerate or freeze.

Store in the original package and keep the blister in the outer carton.

6.5    Nature and contents of container

A box of Restandol Testocaps contains either 3 or 6 sachets, each containing a blister with 10 capsules

6.6 Special precautions for disposal

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

See also “Special precautions for storage” (section 6.4) and “Posology and method of administration” (section 4.2)

7    MARKETING AUTHORISATION HOLDER

Merck Sharp & Dohme Limited Hertford Road

Hoddesdon Hertfordshire EN11 9BU