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

Posology

Adult men

The recommended starting dose of Testavan is 23 mg testosterone (one pump actuation) applied once daily. To ensure proper dosing, serum testosterone levels should be periodically measured and dose titrated to maintain eugonadal serum testosterone levels (see section 4.4.).

The serum testosterone level should be measured 2-4 hours after dosing approximately 14 days and 35 days after starting treatment or after a dose adjustment. If the serum testosterone concentration is below 17.3 nmol/L (500 ng/dL), the daily Testavan dose may be increased by 1 pump actuation. If the serum testosterone concentration exceeds 36.4 nmol/L (1050 ng/dL), the daily Testavan dose may be decreased by 1 pump actuation.

Dose titration should be based on both serum testosterone levels and the existence of clinical signs and symptoms related to testosterone deficiency.

Elderly

Same dose as for adults. However, it should be taken into account that physiologically testosterone levels are lower with increasing age (see section ‎ 4.4).

Maximum recommended dose

The maximum recommended dose is 69 mg testosterone per day, which is equivalent to 3 pump actuations.

Renal and hepatic impairment

There are no dedicated studies undertaken to demonstrate the efficacy and safety of this medicinal product in patients with renal or hepatic impairment. Therefore, testosterone replacement therapy should be used with caution in these patients (see section 4.4). After treatment with Testavan, testosterone levels are similar in subjects with mild or moderate renal impairment compared to subjects with normal renal function (see section 5.2).

Female population

Testavan is not indicated for use in women.

Paediatric population

Testavan is not indicated in children and has not been clinically evaluated in males under 18 years of age.

Method of administration

Transdermal use.

Testavan is a gel, which should be applied to the upper arm and shoulder, using the applicator. Patients should be instructed not to apply Testavan with fingers or hands.

Priming of new pump

To ensure correct dosing, patients should be instructed to prime each new pump before using it for the first time by pressing the pump head all the way down over a tissue paper until gel appears. Discard the initial gel and 2 additional pump actuations and safely throw away the used tissue paper.

Administration

Testavan should be applied once daily at about the same time, preferably in the morning to clean, dry, intact skin of the upper arm and shoulder using the applicator. A lower amount of testosterone will be delivered if Testavan is applied to the abdomen or thigh and changing application site is therefore not recommended (see section 5.2).

To apply the gel after removal of the applicator lid, the pump head should be pressed all the way down once over the applicator head. Patients should be instructed to only make one pump actuation onto the applicator at a time. The applicator should be used to spread the gel evenly across the maximum surface area of one upper arm and shoulder, making sure not to get any gel on the hands. When more than one pump actuation is required to achieve daily dose, the procedure is repeated to the other upper arm and shoulder.

Cleaning of the applicator

After use, the applicator should be cleaned with a tissue and the protective lid restored on top of the applicator. The used tissue paper should be safely thrown away and the product stored safely out of reach of children.

Following administration

If the gel was touched with the hands during the application procedure, patients should be instructed to wash their hands with water and soap immediately after applying Testavan.

Patients should be advised to let the application site dry completely before getting dressed.

Patients should be advised to wait at least 2 hours before showering, swimming or bathing to prevent reduced testosterone absorption (see section 4.4).

Wear clothing that covers the application side at all times to prevent accidental transfer to others.

• Hypersensitivity to the active substance, propylene glycol or to any of the excipients listed in section 6.1.

• Known or suspected carcinoma of the breast or the prostate

Testavan should be used only if male hypogonadism has been demonstrated and if other etiology, responsible for the symptoms, has been excluded before treatment is started. Testosterone deficiency 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 before initiating therapy with any testosterone replacement, including Testavan treatment.

Prior to initiation of testosterone replacement therapy, 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 breast must be performed in accordance with recommended methods (digital rectal examination and estimation of serum prostate specific antigen (PSA)) in patients receiving testosterone therapy at least annually and twice yearly in elderly patients and at risk patients (those with clinical or familial factors).

Testosterone levels should be monitored at baseline and at regular intervals during treatment. Clinicians should adjust the dosage individually to ensure maintenance of eugonadal testosterone levels. Certain clinical signs: irritability, nervousness, weight gain, prolonged or frequent erections may indicate excessive androgen exposure requiring dosage adjustment.

Androgens may accelerate the progression of sub-clinical prostate cancer and benign prostatic hyperplasia.

Testavan 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.

Testavan is not a treatment for male sterility or impotence.

There is limited experience on the safety and efficacy of the use of Testavan in patients over 65 years of age. Currently, there is no consensus concerning age specific reference values for testosterone. However, it should be taken into consideration that the physiologically testosterone serum levels are lower with increasing age.

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

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 this case, treatment must be stopped immediately.

Clotting disorders:

Testosterone 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 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.

Testosterone should be used with caution in patients with ischemic heart disease, epilepsy and migraine as these conditions may be aggravated.

There are published reports of increased risk of sleep apnoea in hypogonadal men treated with testosterone esters, especially in those with risk factors such as obesity or chronic respiratory disease.

If the patient develops a severe application site reaction, treatment should be reviewed and discontinued if necessary.

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.

Testavan should not be used in women due to possible virialising effects.

As washing after Testavan administration reduces testosterone levels, patients are advised not to wash or shower for at least 2 hours after applying Testavan. When washing occurs up to 2 hours after the gel application, the absorption of testosterone may be reduced.

Testavan contains propylene glycol, which may cause skin irritation.

Alcohol based products including Testavan are flammable; therefore avoid fire, flame or smoking until the gel has dried.

Potential for Transfer

If no precaution is taken, testosterone gel can be transferred to other persons by close skin to skin contact, resulting in increased testosterone serum levels and possibly adverse effects (e.g. growth of facial and/or body hair, acne, deepening of the voice, irregularities of the menstrual cycle) in case of repeat contact (inadvertent androgenisation).

The physician should inform the patient carefully about the risk of testosterone transfer and about safety instructions (see below). Testavan 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).

This transfer is avoided by wearing clothes covering the application area or showering prior to contact.

As a result, the following precautions are recommended:

For the patient:

• use the cap applicator for hands-free administration to reduce the risk of secondary exposure to testosterone.

• if the gel was touched with the hands during the application procedure, wash hands thoroughly with soap and water after applying the gel.

• cover the application area with clothing once the gel has dried.

• shower before any situation in which skin to skin contact with another person is foreseen.

For people not being treated with Testavan:

• 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 testosterone 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 improve partner safety, the patient should be advised for example to wear a T-shirt covering the application site during contact period, or to shower before sexual intercourse.

Furthermore, it is recommended to wear a T-shirt covering the application site during contact periods with children in order to avoid a contamination risk of children's skin.

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

Patients must be cautioned to minimise use of body lotion and sunscreen products at the area of application, at and just after application of Testavan gel.

Laboratory test interactions: Androgens may decrease concentrations of thyroxin-binding globulins, resulting in decreased total thyroxine (T4) serum concentration and increased resin uptake of triiodothyronine (T3) and T4. Free thyroid hormone concentration remains unchanged and there is no clinical evidence of thyroid dysfunction.

When androgens are given simultaneously with anticoagulants, the anticoagulant effects can increase. Patients receiving oral anticoagulants require close monitoring of their international normalized ratio (INR) especially when androgen treatment is started or stopped.

The concurrent administration of testosterone with adrenocorticotropic hormone (ACTH) or corticosteroids may increase likelihood of oedema; thus these drugs should be administered with caution, particularly in patients with cardiac, renal or hepatic disease.

Improved insulin sensitivity may occur in patients treated with androgens who achieve normal testosterone plasma concentrations following replacement therapy.

Interaction studies with body lotion and sunscreen products have not been performed.

Testavan is intended for use by men only.

No clinical trials have been conducted with Testavan for assessment of male fertility. Spermatogenesis may be reversibly suppressed with Testavan (see section 5.3).

Pregnant women should avoid skin contact with Testavan application sites (see section 4.4).

In the event that unwashed or unclothed skin to which Testavan has been applied does come into direct contact with the skin of a pregnant woman, the general area of contact on the woman should be washed with soap and water immediately.

Testosterone may induce virilising effects on the foetus.

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

a. Summary of the safety profile

The most commonly reported adverse reactions in phase 2 and phase 3 clinical trials lasting up to 9 months were application site reactions (4%) including: rash, erythema, pruritus, dermatitis, dryness, and skin irritation. The majority of these reactions were mild to moderate in severity.

b. Tabulated summary of adverse events

Adverse drug reactions reported in phase 2 and phase 3 clinical trials with Testavan are listed in the following table. All adverse reactions reported with a suspected relationship are listed by class and are listed according to the following frequency: common (≥ 1/100 to < 1/10); uncommon (≥ 1/1.000 to < 1/100);

Testavan drug-related adverse reactions reported during clinical trials with more than one case (N=379)

According to literature and spontaneous reporting from testosterone gels, other known undesirable effects are listed in the below table:

* Data on prostate cancer risk in association with testosterone therapy are inconclusive.

Because of the alcohol contained in the product, frequent applications to the skin may cause irritation and dry skin.

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, website: www.mhra.gov.uk/yellowcard.

No case of overdose with Testavan has been reported in clinical trials.

Symptoms

Clinical signs such as irritability, nervousness, weight gain, prolonged or frequent erection can indicate overexposure to androgen and serum testosterone levels should therefore be measured.

Treatment

Treatment of overdosage consists of discontinuation of Testavan together with appropriate symptomatic and supportive care.

Pharmacotherapeutic group: Androgens, ATC code: G03B A03

Testosterone and dihydrotestosterone (DHT), endogenous androgens, are responsible for the normal growth and development of the male sex organs and for the maintenance of secondary sex characteristics. These effects include the growth and maturation of the prostate, seminal vesicles, penis and scrotum; the development of male hair distribution on the face, chest, axillae and pubis; laryngeal enlargement, vocal chord thickening, alterations in body musculature and fat distribution.

Insufficient secretion of testosterone due to testicular failure, pituitary pathology or gonadotropin or luteinising hormone-releasing hormone deficiency results in male hypogonadism and low serum testosterone concentration. Symptoms associated with low testosterone include decreased sexual desire with or without impotence, fatigue, loss of muscle mass, mood depression and regression of secondary sexual characteristics.

Restoring testosterone levels to within the normal range can result in improvements over time in muscle mass, mood, sexual desire, libido and sexual function including sexual performance and number of spontaneous erections.

During exogenous administration of testosterone to normal males, endogenous testosterone release may be decreased through feedback inhibition of pituitary luteinising hormone (LH). With large doses of exogenous androgens, spermatogenesis may also be suppressed through inhibition of pituitary follicle stimulating hormone (FSH).

Androgen administration causes retention of sodium, nitrogen, potassium, phosphorus and decreased urinary excretion of calcium. Androgens have been reported to increase protein anabolism and decrease protein catabolism. The nitrogen balance is improved only with sufficient intake of calories and protein. Androgens have been reported to stimulate production of red blood cells by enhancing the production of erythropoietin.

Testavan delivers physiologic amounts of testosterone, which provide a level of circulating testosterone similar to the normal level in healthy men (i.e., 300-1050 ng/dL). Testavan was evaluated in a multi-center, open-label, 120 day Phase 3 clinical study (study 000127) in 159 hypogonadal men ages 18 to 75 years (mean age 54.1 years). Subjects were white (77%), black (20%), Asian (2%), and multiracial (1%). In the phase 3 study, at the end of a 90 day treatment period during which the dose of Testavan could be titrated based on total testosterone concentrations, 76.1% of men had average testosterone concentrations over a 24 hour period (Cave) within the eugonadal range (300 – 1050 ng/dL).

The mean testosterone concentration profile on Day 90 is shown in Figure 1, while the pharmacokinetic parameters for total testosterone on Day 90 are summarised for each Testavan dose in Table 11.

Figure 1 Mean ± SD serum concentrations of testosterone on day 90 after dose titration of Testavan

Table 1 Pharmacokinetic parameters for total testosterone on day 90 after titration, study 000127 full analysis set

C_min: minimum concentration; C_ave: average concentration over a 24 hour period; C_max: maximum concentration; T_max: time of maximum concentration; SD: standard deviation

Absorption

Testavan provides transdermal delivery of testosterone, with a median Tmax of approximately 2-4 hours after dosing. Total testosterone concentrations return to pre-dose values approximately 12 hours after application and no accumulation occurs after daily application for 10 days. Application on the upper arm and shoulder results in higher serum testosterone concentrations compared to application on the abdomen or the inner side of the thigh. The mean Cmax was 926, 451 and 519 ng/dL, respectively, and the mean Cave 557, 372 and 395 ng/dL, respectively.

Phase 2 study results show that total testosterone concentrations increased with increasing dose after daily application of 23, 46 and 69 mg Testavan.

Distribution

Circulating testosterone is chiefly bound in the serum to sex hormone-binding globulin (SHBG) and albumin. The albumin-bound fraction of testosterone easily dissociates from albumin and is presumed to be biologically active. The portion of testosterone bound to SHBG is not considered biologically active. Approximately 40% of testosterone in plasma is bound to SHBG, 2% remains unbound (free) and the rest is bound to albumin and other proteins.

Biotransformation

There is considerable variation in the half-life of testosterone, as reported in the literature, ranging from ten to 100 minutes.

Testosterone is metabolised to various 17-keto steroids through two different pathways. The major active metabolites of testosterone are oestradiol and dihydrotestosterone (DHT).

Elimination

About 90% of testosterone given intramuscularly is excreted in the urine as glucuronic and sulphuric acid conjugates of testosterone and its metabolites; about 6% of a dose is excreted in the faeces, mostly in the unconjugated form.

Effect of Showering

Showering 1 hour and 2 hours following Testavan administration decreased Cave by 19.2% and 14.3%, respectively, compared with subjects who did not shower after Testavan administration. Showering 6 hours following Testavan administration did not result in a decrease in Cave.

Renal function

Testosterone Cave and Cmax was similar in subjects with normal renal function and subjects with mild and moderate renal impairment. No data is available in subjects with severe renal impairment.

Toxicological studies have not revealed other effects than those which can be explained on the base of the hormone profile of Testavan.

Fertility studies in rodents and primates have shown that treatment with testosterone can impair male fertility by suppressing spermatogenesis in a dose dependent manner.

Testosterone has been found to be non-mutagenic in vitro using the reverse mutation model (Ames test) or Chinese hamster ovary cell line. A relationship between androgen treatment and certain cancer forms has been found in laboratory animals. Data in rats have shown increased incidences of prostate cancer after treatment with testosterone.

Sex hormones are known to facilitate the development of certain types of tumour induced by known carcinogenic agents. No correlation between these findings and the actual risk in human beings has been established.

Environmental risk assessment (ERA)

Environmental risk assessment studies have shown that Testavan may pose a risk to the aquatic environment, (See section 6.6).

Ethanol (96%)

Water, purified

Propylene glycol (E 1520)

Diethylene glycol monoethyl ether

Carbomer 980

Trolamine

Disodium edetate

Not applicable.

3 years.

This medicinal product does not require any special storage conditions.

Testavan is supplied in a multidose container consisting of a metering pump with a laminate foil pouch in a bottle, and is provided with a cap applicator with a hygienic lid. The pump is composed of polypropylene, ethylene propylene diene monomer and stainless steel and the pouch is a polyethylene/polyethylene terephthalate/aluminium/polyethylene laminate encased in a rigid polypropylene bottle.

The product is available in packs of one multidose container. Each pump contains 85.5 g Testavan gel and is capable of dispensing 56 metered doses.

This medicinal product may pose a risk to the environment, (See section 5.3).

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