- 1. Name of the medicinal product
- 2. Qualitative and quantitative composition
- 3. Pharmaceutical form
- 4. Clinical particulars
- 4.1 Therapeutic indications
- 4.2 Posology and method of administration
- 4.3 Contraindications
- 4.4 Special warnings and precautions for use
- 4.5 Interaction with other medicinal products and other forms of interaction
- 4.6 Fertitilty, pregnancy and lactation
- 4.7 Effects on ability to drive and use machines
- 4.8 Undesirable effects
- 4.9 Overdose
- 5. Pharmacological properties
- 5.1 Pharmacodynamic properties
- 5.2 Pharmacokinetic properties
- 5.3 Preclinical safety data
- 6. Pharmaceutical particulars
- 6.1 List of excipients
- 6.2 Incompatibilities
- 6.3 Shelf life
- 6.4 Special precautions for storage
- 6.5 Nature and contents of container
- 6.6 Special precautions for disposal and other handling
- 7. Marketing authorisation holder
- 8. Marketing authorisation number(s)
- 9. Date of first authorisation/renewal of the authorisation
- 10. Date of revision of the text
Adults and Elderly MenThe 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 PopulationTostran is not indicated for use in children and has not been clinically evaluated in males under 18 years of age.
Method of administrationFor cutaneous useThe 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, then the application site should be covered, preferably with loose clothing. Hands should then be washed with soap and water.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 8 times to ensure that the pump is fully primed. The first few depressions may result in no discharge of gel. Discard the gel dispensed during priming (i.e., from the first eight 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)|
Treatment ControlSerum testosterone concentration should be measured approximately 14 days after initiation of therapy 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).
Potential for transferIf no precautions are 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, 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). 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 is 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 guarantee partner safety 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.Furthermore, it is recommended to wear clothing covering the application site during contact periods with children, in order to avoid a risk of contamination to children's skin.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.Tostran contains butylhydroxytoluene (E321) which may cause local skin reactions (eg contact dermatitis) or irritation of the eyes and mucous membranes. Tostran contains propylene glycol which may cause skin irritation.
|Organ System||Very Common(≥ 1/10)||Common(≥ 1/100 to < 1/10)|
|Blood and lymphatic system disorders||Haematocrit increased Red blood cell count increased, Haemoglobin increased|
|Endocrine disorders||Increase in male pattern hair distribution|
|Reproductive system and breast disorders||Gynaecomastia|
|General disorders and administration site conditions||Administration site reactions||Peripheral oedema|
|Organ System||Adverse reactions|
|Metabolism and nutrition disorders||Weight gain, electrolyte changes (retention of sodium, chloride, potassium, calcium, inorganic phosphate and water) during high dose and/or prolonged treatment.|
|Nervous system disorders||Nervousness, hostility, depression.|
|Respiratory, thoracic and mediastinal disorders||Sleep apnoea|
|Hepatobiliary disorders||In very rare cases jaundice and liver function test abnormalities.|
|Skin and subcutaneous tissue disorders||Various skin reactions may occur including acne, seborrhoea and balding (alopecia).|
|Musculoskeletal and connective tissue disorders||Muscle cramps, muscle pain|
|Reproductive system and breast disorders||Libido changes, increased frequency of erections; therapy with high doses of testosterone preparations commonly reversibly interrupts or reduces spermatogenesis, thereby reducing the size of the testicles; testosterone replacement therapy of hypogonadism can in rare cases cause persistent, painful erections (priapism), prostate abnormalities, prostate cancer*, urinary obstruction.|
|General disorders and administration site conditions||High dose or long-term administration of testosterone occasionally increases the occurrences of water retention and oedema; hypersensitivity reactions may occur.|
Reporting of suspected adverse reactionsReporting 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
AbsorptionTostran is a hydroalcoholic formulation that dries quickly when rubbed into the skin. The skin acts as a reservoir for the sustained release of testosterone into the systemic circulation. Testosterone absorption into the blood continues throughout the entire 24 hour dosing interval, with concentrations significantly above the base level the whole time. Varying application areas between 200 and 800 cm2 in size has not been shown to have any clinically relevant effect on serum testosterone concentrations.Application on the inside of the thighs and the abdomen results in comparable serum testosterone concentrations. The bioavailability of Tostran is estimated to be 12%. Administration of 3 g gel daily over 6 months results in time-averaged serum testosterone concentrations of 5.0 ± 2.0 µg/l and individual minimal concentrations of 3.0 ± 1.0 µg/l and maximum concentrations of 12.0 ± 7.0 µg/l.
DistributionAbout 40% of the testosterone in plasma is bound to sex hormone binding globulin (SHBG), 2% remains unbound (free) and the rest is loosely bound to albumin and other proteins. Albumin bound testosterone easily dissociates and is considered to be biologically active. However the binding to SHBG is strong. Thus, the concentration of serum bioactive testosterone is the unbound fraction plus that bound to albumin.
MetabolismThe major active metabolites of testosterone are oestradiol and DHT. DHT binds with greater affinity to SHBG than does testosterone. DHT is further metabolised to 3-α and 2-β androstanediol.
ExcretionAbout 90% of a dose of testosterone given intramuscularly is excreted in the urine as glucuronic acid and sulphate conjugates of testosterone and its metabolites; about 6% of a dose is excreted in the faeces, mostly in the unconjugated form.
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