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

Posology:

In general, the dosage should be established on the basis of the response of the individual patient.

Adults (including elderly):

Normally, the initial dosage is 120-160 mg daily for 2-3 weeks. The following maintenance dosage of 40-120 mg daily should be based on the clinical effect that has been achieved during the first weeks of treatment.

Pediatric population:

The safety and efficacy of Andriol Testocaps in children and adolescents has not been established. Caution should be exercised when treating prepubertal children with Andriol Testocaps (see section 4.4).

Method of administration:

In order to ensure good absorption, the capsules must be taken with a meal and, if needed, with some fluid, and be swallowed without chewing. Preferably, half of the daily dose should be taken in the morning and the other half in the evening. If an uneven number of capsules are taken, the larger number should be taken in the morning.

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 subjects before the start of testosterone 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 and subclinical 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 which require additional monitoring:

Patients with the following conditions, the elderly in particular, require a medical examination:

·               Specific types of tumours: - Patients with breast carcinoma, hypernephroma, lung carcinoma, bone metastases can develop hypercalcaemia, either spontaneously (hypercalcaemia of malignancy) or during therapy with androgens/anabolic steroids. It is recommended that serum calcium levels be monitored regularly in these patients. In the case of hypercalcaemia, treatment should be stopped. Hypercalcaemia should first be treated appropriately and treatment with androgens may only be resumed after restoration of normal calcium levels.

·               Heart, kidney or liver conditions - In patients suffering from severe cardiac, hepatic or renal insufficiency or ischaemic heart disease, treatment with testosterone may cause severe complications characterized by edema with or without congestive cardiac failure. In such cases treatment must be stopped immediately. Due to the risk of deterioration or reoccurrence, patients should be monitored after myocardial infarction, cardiac, hepatic or renal insufficiency, hypertension, epilepsy or migraine. In case of worsening or reoccurrence of the condition, treatment should be stopped immediately. Testosterone may cause a rise in blood pressure and Andriol Testocaps should be used with caution in men with hypertension. During long-term treatment, examination of the liver function is recommended.

·               Prostate hypertrophy - In case of benign prostatic hypertrophy, complaints related to prostatism may increase.

·               Diabetes mellitus - Androgens in general, and Andriol Testocaps can increase glucose tolerance in diabetic patients (see section 4.5).

·               Anticoagulant therapy - Androgens in general, and Andriol Testocaps can increase the effect of coumarin-type anticoagulants (see section 4.5).

·               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.

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

Taking Andriol Testocaps may affect your blood cholesterol level. Tell your doctor if you have or ever had heart problems or have experienced a heart attack.

1.       There have been post marketing reports of venous thromboembolic events, including deep vein thrombosis (DVT) and  pulmonary embolism (PE), in patients using testosterone products. Evaluate patients who report symptoms of pain, edema, warmth and  erythema in the lower extremity for DVT and  those who present with acute shortness of breath for PE. If a venous thromboembolic event is suspected, discontinue treatment with testosterone and  initiate appropriate workup management.

2.       Because androgens may alter serum cholesterol concentration, caution should be used when administering these drugs to patients with a history of myocardial infarction or coronary artery disease. Serial determinations of serum cholesterol should be made and  therapy adjusted accordingly. A causal relationship between myocardial infarction and  hypercholesterolemia has not been established.

3.       If cholestatic hepatitis with jaundice appears  or liver function tests become abnormal, the androgen should be discontinued and  the etiology should be determined. Drug induced jaundice is reversible when the medication is discontinued.

Adverse events:

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

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.

Excipients:

Andriol Testocaps contains Sunset Yellow FCF (E110), which may cause allergic reactions.

Pediatric population:

In pre-pubertal boys, treatment should take place under careful supervision, since androgens in general and Andriol Testocaps at high dosages may accelerate epiphyseal closure and sexual maturation.

Older People:

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

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

Insulin and other antidiabetic drugs

Androgens may increase glucose tolerance and decrease the need for insulin or other antidiabetic drugs in patients with diabetes (see section 4.4). Diabetic patients should therefore be monitored

especially at the beginning or end of the treatment with Andriol Testocaps, and periodically during treatment.

Anticoagulant therapy:

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

ACTH or corticosteroids

Concurrent administration of testosterone with ACTH or corticosteroids may enhance oedema formation. Caution should therefore be exercised when administering these medicinal products, particularly in patients with cardiac or hepatic disease or in patients predisposed to oedema (see section 4.4).

Laboratory test interactions

Androgens may decrease the levels of thyroxin-binding globulin, resulting in decreased total T4 serum levels and an increased resin uptake of T3 and T4. Free thyroid hormone levels remain unchanged, however, and there is no clinical evidence of thyroid dysfunction.

A decrease of the protein-bound iodine (PBI) may occur; however, this has no clinical relevance. Andriol Testocaps must be taken with a meal to ensure adequate absorption (see section 4.2).

Pregnancy and lactation

Andriol Testocaps is not indicated for the treatment of women and must therefore not be used by pregnant or breast-feeding women. The use of Andriol Testocaps during pregnancy poses a risk of virilisation of the foetus.

Fertility

In men, treatment with androgens can lead to fertility disorders, due to the suppression of sperm formation (see section 4.8).

Andriol Testocaps has no or negligible influence on the ability to drive and use machines.

The following undesirable effects are associated with androgen therapy in general. The most suitable MedDRA term to describe the adverse event was used. All adverse events were reported according to system/organ class and frequency; common (≥ 1/100 tot < 1/10) and not known (cannot be estimated from the available data).

1 Progression of sub-clinical prostate cancer

2 Reported by a number of patients during the use of Andriol Testocaps

3 In very rare cases

4 Prostatic growth (to normogonadal size)

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

The terminology to describe the side-effects listed above also includes synonyms and related terms.

Pediatric population

The following side-effects have been reported in prepubertal children who have used androgens (see also section 4.4): precocious sexual development, an increased frequency of erections, enlargement of the penis and premature epiphyseal closure.

Post marketing Experience:

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:

·         Saudi Arabia:

The National Pharmacovigilance and Drug Safety Centre (NPC). SFDA

o Fax: +966-11-205-7662

o Call NPC at +966-11-20382222, Exts: 2317-2356-2353-2354-2334-2340.

o Toll free phone: 8002490000

o E-mail: npc.drug@sfda.gov.sa

o Website: www.sfda.gov.sa/npc

·         Other GCC States:

Please contact the relevant competent authority.

The acute oral toxicity of testosterone undecanoate is very low. High dosages of Andriol Testocaps may cause gastrointestinal complaints (such as nausea and diarrhoea) due to the oily solvent in the capsules.

Pharmacotherapeutic group: Androgens. ATC-Code: G03BA03

Testosterone, the principal androgenic hormone, is responsible for the normal growth and development of the male sex organs and for the maintenance of the secondary sex characteristics (stimulation of hair growth, change in voice, and development of sexual desire). Andriol Testocaps delivers a physiological amount of testosterone into the circulation after oral administration to hypogonadal men. In addition, it leads to a clinically significant increase of plasma concentrations of dihydrotestosterone and estradiol as well as a decrease of SHBG (sex hormone binding globulin). Treatment of males with primary (hypergonadotropic) hypogonadism results in normalisation of gonadotropin levels.

Hypogonadism in the male is characterised by low serum testosterone concentrations. Symptoms associated with male hypogonadism are amongst others: impotence, decreased sex drive, fatigue and lack of energy, depression and regression of the secondary sex characteristics.

Androgen therapy has a general effect on protein synthesis, development of skeletal muscle and body fat distribution. In addition, retention of fluids and salts can occur. Androgens are generally also responsible for the growth spurt of adolescence and for the eventual termination of linear growth. They stimulate the production of red blood cells by increasing the production of erythropoietin. The effects of testosterone in some target organs arise after peripheral conversion of testosterone to estradiol, which subsequently binds to the estradiol receptors in the target cell nucleus. This process occurs in the pituitary gland, adipose tissue, brain, bone and in Leydig cells present in the testes, amongst others.

Exogenous administration of androgens inhibits endogenous

Absorption, distribution and biotransformation

Testosterone undecanoate is, in contrast to testosterone, orally active because it is partly taken up in the chylomicrons after absorption and released with the lymph in the systemic circulation.

During this process a small proportion of the ester is metabolized into the also active 5a-dihydrotestosterone undecanoate. After absorption, the remaining part of the dose is

metabolized in the intestinal wall and liver into inactive biotransformation products. In the peripheral circulation hydrolysis of the lymphatically absorbed esters and conversion to estradiol takes place, after which the free steroids exert their androgen activity on the target organs. Under “steady state” conditions, the plasma testosterone level reaches a maximum of approximately 40 nmol/l, 4-5 hours after administration of a dose of 80-160 mg Andriol Testocaps; the plasma level remains elevated 8-12 hours after administration.

Elimination

As with the natural androgens, elimination occurs via glucuronisation. The end-products are mainly excreted via the kidneys; a small part is recovered in the faeces.

Toxicological studies with testosterone only showed effects that can be explained on the basis of the hormone profile. Testosterone was shown not to be genotoxic. Non-clinical studies on the relation between testosterone treatment and cancer show that high doses of testosterone in laboratory animals may enhance tumour growth in genital organs, mammary glands and liver. The clinical relevance of this observation is unknown. In view of the oral administration of Andriol Testocaps and the probability of the development of diarrhoea due to the castor oil when administrating a large amount of capsules, it is unlikely that such prolonged high concentrations of testosterone will be reached. Fertility research in rodents and primates has shown that treatment with testosterone can reduce fertility by dose-dependent suppression of spermatogenesis.

Testosterone has a virilising effect on female foetuses when administered to pregnant animals during organogenesis.

Capsule content:

Each capsule contains 175.8 mg castor oil. In addition, this medicine contains 117.2 mg propylene glycol monolaurate (E477) in each capsule. This quantity corresponds to 34.5 mg propylene glycol which is equivalent to 0.5 mg/kg.

Capsule shell*:

Glycerin, Sunset Yellow FCF (E110) and gelatin.

* the capsules may contain traces of the excipients medium-chain triglycerides and lecithin. Printing ink:

Opacode WB^®.

Not applicable.

Store below 30 °C. Do not refrigerate or freeze.

Store in the original package in order to protect from light.

A carton of Andriol Testocaps contains either 3, 6 or 12 aluminium-laminated pouches (sachets), each containing a PVC/aluminium blister with 10 capsules.

Not all pack sizes will be marketed.

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