4.1. Therapeutic indications

Testosterone replacement therapy for male hypogonadism when testosterone deficiency has been confirmed by clinical features and biochemical tests. (see Section 4.4).

4.2. Posology and method of administration

Posology

Male Adults and Elderly Men

The recommended starting dose of Tostran is 3 g gel (60 mg of testosterone) applied once daily at approximately the same time each morning. Dose titration should be based on both serum testosterone levels and the existence of clinical signs and symptoms related to androgen deficiency. It should be taken into account that physiological testosterone levels decline with increasing age.

The daily dose should not exceed 4 g of gel (80 mg testosterone).

Paediatric Population

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

Method of administration

For transdermal use.

The dose can be applied to the abdomen (entire dose over an area of at least 10 by 30 cm), or to both inner thighs (one half of the dose over an area of at least 10 by 15 cm for each inner thigh). Daily rotation between the abdomen and inner thighs is recommended to minimise application site reactions.

The gel should be applied to clean, dry, intact skin. It should be rubbed in gently with one finger until dry. Hands should then be washed carefully with soap and water.

Once the gel has dried, Patients should be advised to wear clothing that covers the application site at all times to prevent accidental transfer to other persons as well as pets. Before close physical contact with another person (adult or child) or pets, wash the application site with soap and water once the recommended time period (at least 2 hours) has passed and cover again with clean clothing.

Each full depression of the canister piston delivers one half gram of gel (10 mg testosterone). To obtain a full first dose, it is necessary to prime the canister pump. To do so, with the canister in the upright position, slowly and fully depress the actuator repeatedly until gel appears. Depress the actuator a further six times. Discard the gel from the six depressions. It is only necessary to prime the pump before the first dose. The canister should be stored in an upright position between use.

In Table 1 below the amount of gel dispensed once the pump is primed, and the amount of testosterone which would be applied to the skin from a number of piston depressions are shown.

Table 1: Dose of Tostran dispensed after pump priming

No of Depressions

Amount of Gel (g)

Amount of Testosterone Applied to the Skin (mg)

1

0.5

10

2

1

20

4

2

40

6

3

60

8

4

80

Patients who wash in the morning should apply Tostran after washing, bathing or showering.

Tostran must not be applied to the genitals.

Treatment Control

Serum testosterone concentration should be measured approximately 14 days after initiation of therapy and at regular intervals to ensure proper dosing. The blood sample for measurement of serum testosterone level should be obtained 2 hours after application of Tostran. If the serum testosterone concentration is between 5.0 and 15.0 µg/l, the dose should not be changed from 3 g/day. If the serum testosterone concentration is below 5.0 µg/l, the dose should be increased to 4 g/day (80 mg testosterone). If the testosterone concentration is above 15.0 µg/l, the dose should be reduced to 2 g/day (40 mg testosterone). Smaller 0.5 g gel (10 mg testosterone) dosage adjustment may be made if necessary.

Because of the variability in analytical values amongst diagnostic laboratories, all testosterone measurements should be performed in the same laboratory.

There is limited experience of treating men older than 65 years of age with Tostran.

No formal studies have been conducted with the product in patients with renal or hepatic impairment (see also Section 4.4).

4.3. Contraindications

Tostran 20mg/g transdermal gel is contraindicated in patients with:

- hypersensitivity to the active substance(s) or to any of the excipients listed in section 6.1.

- known or suspected carcinoma of the breast or the prostate

4.4. Special warnings and precautions for use

Tostran should not be used to treat non-specific symptoms suggestive of hypogonadism if testosterone deficiency has not been demonstrated and if other aetiologies responsible for the symptoms have not been excluded. Testosterone deficiency should be clearly demonstrated by clinical features and confirmed by two separate blood testosterone measurements before initiating therapy with any testosterone replacement, including Tostran treatment.

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.

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

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.

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.

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

Tostran is not indicated for treatment of male sterility or sexual impotence.

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).

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

There are no 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.

The treatment of hypogonadal men with testosterone may potentiate sleep apnoea in some patients, especially those with risk factors such as obesity or chronic lung disease.

Care should be taken in patients with skeletal metastases due to the risk of hypercalcaemia/hypercalciuria developing from androgen therapy. Regular monitoring of the serum levels of calcium in these patients is recommended.

Tostran should be used with caution in patients with epilepsy and migraine as these conditions may be aggravated.

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

General: Certain clinical signs may indicate excessive androgen exposure requiring dosage adjustment. The physician should instruct patients to report any of the following:

- Irritability, nervousness, weight gain.

- Too frequent or persistent erections of the penis.

- Any nausea, vomiting, changes in skin colour or ankle swelling.

- Breathing disturbances, including those associated with sleep.

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

Athletes should be informed that Tostran contains an active substance (testosterone), which may give positive results in a doping test. Androgens are not suitable for enhancing muscular development in healthy individuals or for increasing physical ability.

Tostran should not be used in women due to possible virilising effects.

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.

Potential for transfer

If no precautions are taken, testosterone gel can be transferred to other persons by close physical contact at any time after dosing, resulting in increased testosterone serum levels and possibly adverse effects (e.g., growth of facial and/or body hair, deepening of the voice, irregularities of the menstrual cycle in women or premature puberty and genital enlargement in children) 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). Tostran 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 can be avoided by wearing clothes covering the application area or bathing or showering 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,

- bathe or shower before any situation in which this type of contact is foreseen.

For the health care professional or carer:

- disposable gloves should be used if a health care professional or carer needs to apply the testosterone gel to the patient,

- the disposable gloves should be resistant to alcohols as the gel contains both ethanol and isopropyl alcohol, which facilitate the penetration of testosterone.

For people not being treated with Tostran:

- 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 reduce risk to a partner the patient should be advised for example to observe a minimum of four hours between Tostran application and sexual intercourse, to wear clothing covering the application site during contact period or to bathe or shower before sexual intercourse.

Additional caution should be taken when using this product and in close physical contact with children as secondary transmission of testosterone through clothing cannot be excluded. It is essential to adhere to the application technique (see section 4.2) when in physical contact with children, including covering the application site with clean clothing once the gel has dried. Furthermore please wash the application site with soap once the recommended time period (at least 2 hours) has passed and cover again with clean clothing before any physical contact with children.

Pregnant women must avoid contact with Tostran application sites. In case of pregnancy of a partner, the patient must take extra care with the precautions for use described above (see also Section 4.6).

Absorption studies of testosterone conducted in patients treated with Tostran indicate that patients should wait at least two hours between gel application and bathing or showering.

This Medicine contains butylhydroxytoluene (E321) which may cause local skin reactions (e.g., contact dermatitis) or irritation of the eyes and mucous membranes.

This medicinal product contains 175 mg propylene glycol in each pump depression.

This medicinal product contains 75 mg ethanol in each pump depression.

It may cause burning sensation on damaged skin.

This product is flammable until dry.

4.5. Interaction with other medicinal products and other forms of interaction

When androgens are given simultaneously with anticoagulants, the anticoagulant effect can increase. Patients receiving oral anticoagulants require close monitoring of their INR especially when the androgen treatment is started, stopped or the dose of Tostran changed.

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

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 Tostran treatment.

Concomitant use of testosterone replacement therapy and sodium-glucose co-transporter 2 (SGLT-2) inhibitors has been associated with an increased risk of erythrocytosis. Since both substances may independently elevate haematocrit levels, a cumulative effect is possible (see also section 4.4). Monitoring of haematocrit and haemoglobin levels is recommended in patients receiving both treatments.

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

4.6. Fertility, pregnancy and lactation

Tostran is only intended to be used by men.

Tostran is not indicated for pregnant or breastfeeding women. No studies on women have been carried out. Pregnant women should avoid all contact with skin treated with Tostran (see Section 4.4). Tostran can give rise to adverse, virilising effects on the foetus. In the event of contact with treated skin, the area should be washed with soap and water as soon as possible.

4.7. Effects on ability to drive and use machines

No studies on the effects on the ability to drive and use machines have been performed.

4.8. Undesirable effects

The most commonly reported adverse reactions in a controlled clinical study (up to 4 g Tostran) were application site reactions (ASR; 26%) including; paresthesia, xerosis, pruritus and rash or erythema. The majority of these reactions were mild to moderate in severity and diminished or cleared, despite continued application.

All adverse reactions reported with a suspected relationship to Tostran use are listed in the table below.

Organ System

Very Common

(≥ 1/10)

Common

(≥ 1/100 to < 1/10)

Uncommon

(≥ 1/1,000 to < 1/100)

Rare

(≥ 1/10,000 to < 1/1,000)

Very rare

(< 1/10,000)

Not known (cannot be estimated from the available data)

Blood and lymphatic system disorders

Haematocrit increased

Red blood cell count increased, Haemoglobin increased

Endocrine disorders

Increase in male pattern hair distribution

Vascular disorders

Hypertension

Reproductive system and breast disorders

Gynaecomastia

General disorders and administration site conditions

Application site reactions

Peripheral oedema

Investigations

Increased PSA

Hyperglycaemia was reported as an adverse event in two patients with a history of diabetes mellitus.

Gynaecomastia developed in 1.5% of patients being treated with testosterone for hypogonadism and occasionally persists.

According to literature, other adverse events have been reported following use of other testosterone treatments (per MedDRA SOC and PT Terms): and are listed in the following table:

Organ System

Adverse reactions

Immune system disorders

Hypersensitivity

Metabolism and nutrition disorders

Abnormal weight gain, sodium retention andfluid retention

Psychiatric disorders

Nervousness, hostility, depression, libido decreased andlibido increased

Respiratory, thoracic and mediastinal disorders

Sleep apnoea syndrome (see section 4.4)

Gastrointestinal disorders

Nausea

Hepatobiliary disorders

Jaundice and liver function test abnormal (see section 4.4)

Skin and subcutaneous tissue disorders

Skin reaction including acne, seborrhoea and alopecia

Musculoskeletal and connective tissue disorders

Muscle spasms and myalgia

Renal and urinary disorders

Urinary tract obstruction

Reproductive system and breast disorders

Erection increased, azoospermia, painful erection and prostate cancer*

General disorders and administration site conditions

Oedema (see section 4.4)

Investigations

Blood electrolytes abnormal (blood chloride abnormal, blood potassium abnormal, blood calcium abnormal, blood phosphorus abnormal) and prostate examination abnormal

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

Other rare known undesirable effects associated with excessive dosages of testosterone treatments include hepatic neoplasms.

Because of the excipients (butylhydroxytoluene and propylene glycol) contained in the product, applications to the skin may cause irritation and dry skin which usually reduce over time.

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 yellow card scheme. Website: www.mhra.gov.uk/yellowcard or alternatively, you can search for MHRA Yellow Card in the Google Play or Apple App Store.

4.9. Overdose

There is a single case of acute overdosage after parenteral administration of testosterone enanthate reported in the literature. This resulted in testosterone concentrations of up to 114.0 µg/l, which was implicated in a cerebrovascular accident. Oral ingestion of Tostran will not result in clinically significant testosterone concentrations due to extensive first-pass metabolism. It is unlikely that such serum testosterone levels could be achieved using the transdermal route of administration.

Treatment of transdermal overdosage is by washing the site of application with soap and water as soon as possible, discontinuing application of Tostran and treatment of any symptoms.