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TOSTRAN 2% GEL

Active substance: TESTOSTERONE

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SUMMARY OF PRODUCT CHARACTERISTICS

1

NAME OF THE MEDICINAL PRODUCT
Tostran 2% Gel.

2

QUALITATIVE AND QUANTITATIVE COMPOSITION
One gram of gel contains 20 mg testosterone. One press of the canister piston
delivers 0.5 g of gel containing 10 mg testosterone.
One gram of gel contains 1 mg butylhydroxytoluene.
One gram of gel contains 350 mg propylene glycol.
For a full list of excipients, see Section 6.1.

3

PHARMACEUTICAL FORM
Gel.
Clear, colourless gel.

4

CLINICAL PARTICULARS

4.1

Therapeutic indications
Replacement therapy with testosterone for male hypogonadism when testosterone
deficiency has been confirmed by clinical symptoms and laboratory analyses (see
Section 4.4).

4.2

Posology and method of administration
For cutaneous use
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).
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, 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)

1
2
4
6
8

0.5
1
2
3
4

Amount of Testosterone
Applied to the Skin (mg)
10
20
40
60
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 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).
Children
Tostran is not indicated for use in children and has not been clinically evaluated in
males under 18 years of age.

4.3

Contraindications
Tostran 2% Gel is contraindicated in patients with:



4.4

known or suspected carcinoma of the breast or the prostate
known hypersensitivity to testosterone or any of the excipients

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.
For the time being there is no consensus concerning age specific reference values for
testosterone. However it should be taken into consideration that the physiological
serum levels of testosterone decrease with age.
To ensure proper dosing, serum testosterone concentrations should be measured (see
Section 4.2).
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.

Oedema with or without congestive heart failure may be a serious complication in
patients with pre-existing cardiac, renal or hepatic disease. The treatment must be
discontinued immediately if such complications occur. In addition, diuretic therapy
may be required.
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.
The following checks should be carried out periodically: full blood count (including
haemoglobin and haematocrit to detect polycythaemia), lipid profile and liver
function tests.
Care should be taken in patients with skeletal metastases due to the risk of
hypercalcaemia/hypercalcuria developing from androgen therapy. Regular
monitoring of the serum levels of calcium in these patients is recommended.
Testosterone may cause a rise in blood pressure and Tostran should be used with
caution in men with hypertension.
Tostran should be used with caution in patients with ischemic heart disease, 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.
Potential for transfer

If 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

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.
Laboratory test interactions: Androgens may decrease concentrations of thyroxinbinding 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

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

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 are listed by class and
frequency (very common ( 1/10), common ( 1/100 to < 1/10), uncommon (
1/1,000 to < 1/100) and rare ( 1/10,000 to < 1/1,000)).





Very Common
( 1/10)



Blood and lymphatic
system disorders
Endocrine disorders
Vascular disorders
Reproductive system and
breast disorders
General disorders and
administration site
conditions
Investigations

Administration site
reactions

Common
( 1/100 to < 1/10)
Increase in haemoglobin
and haematocrit
Increase in male pattern
hair distribution
Hypertension
Gynaecomastia





Organ System



4.8

Peripheral oedema

Increased PSA

Hyperglycaemia was reported as an adverse event in two patients with a history of
diabetes mellitus.
Gynaecomastia develops in 1.5% of patients being treated with testosterone for
hypogonadism and occasionally persists.
According to the literature, other known undesirable effects have been reported
following testosterone treatment and are listed in the following table:
Organ System
Metabolism and
nutrition disorders
Nervous system
disorders
Respiratory, thoracic
and mediastinal
disorders
Gastrointestinal
disorders
Hepatobiliary
disorders
Skin and subcutaneous
tissue disorders
Musculoskeletal and
connective tissue
disorders

Adverse reactions
Weight gain, electrolyte changes (retention of sodium,
chloride, potassium, calcium, inorganic phosphate and
water) during high dose and/or prolonged treatment.
Nervousness, hostility, depression.
Sleep apnoea

Nausea
In very rare cases jaundice and liver function test
abnormalities.
Various skin reactions may occur including acne,
seborrhoea and balding (alopecia).
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
High dose or long-term administration of testosterone
administration site
occasionally increases the occurrences of water retention
conditions
and oedema; hypersensitivity reactions may occur.
* 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.

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.

5

PHARMACOLOGICAL PROPERTIES

5.1

Pharmacodynamic properties
Pharmacotherapeutic group: Androgens; ATC-code G03BA03
Endogenous androgens, which are excreted by the testicles, mainly testosterone and
its main metabolite dihydrotestosterone (DHT) are responsible for the development of
the external and internal male sex organs and for maintaining secondary sex
characteristics (stimulation of the hair growth, voice breaking and development of

libido). They have a general effect on the protein anabolism, affect the development
of the skeletal muscles and the distribution of body fat, reduce the excretion in the
urine of nitrogen, sodium, potassium, chloride, phosphates and water.
Testosterone does not affect the development of the testicles but reduces the excretion
of gonadotrophin from the pituitary gland.
The effect of testosterone on certain target organs occurs after a peripheral
transformation of testosterone to oestradiol which then binds to the oestradiol
receptors in the nuclei of the target cell, e.g., in the pituitary gland, fat tissue, brain,
bone tissue and the Leydig cells in the testicle.

Pharmacokinetic properties
Absorption
Tostran 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.
Distribution
About 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.
Metabolism
The 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- and 2- androstanediol.

β

α

5.2

Excretion
About 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.

5.3

Preclinical safety data
Toxicological studies have not revealed other effects than those which can be
explained based on the hormone profile of Tostran.
Testosterone has been found to be non-mutagenic in vitro using the reverse mutation
model (Ames test) or hamster ovary cells. A relationship between androgen
treatment and certain cancers has been found in laboratory animals. Experimental
data in rats have shown increased incidences of prostate cancer after treatment with
testosterone. Sex hormones are known to facilitate the development of certain
tumours induced by known carcinogenic agents. The clinical relevance of this
observation is not known.
Fertility studies in rodents and primates have shown that treatment with testosterone
can impair fertility by suppressing spermatogenesis in a dose dependent manner.

6

PHARMACEUTICAL PARTICULARS

6.1

List of excipients
Propylene glycol
Ethanol, anhydrous
Isopropyl alcohol
Oleic acid
Carbomer 1382
Trolamine
Butylhydroxytoluene (E321)
Water, purified
Hydrochloric acid (for pH adjustment)

6.2

Incompatibilities
Not applicable

6.3

Shelf life
2 years.

6.4

Special precautions for storage
Do not store above 25ºC.
Do not refrigerate or freeze.
Store canister upright.

6.5

Nature and contents of container
60 g multi-dose container (comprised of an epoxy phenolic lined aluminium canister)
with a fixed volume metering pump.
Pack sizes: 60 g, 2 x 60 g or 3 x 60 g
Not all pack sizes may be marketed.

6.6

Special precautions for disposal
No special requirements.

7

MARKETING AUTHORISATION HOLDER
ProStrakan Ltd
Galabank Business Park
Galashiels
TD1 1QH
United Kingdom

8

MARKETING AUTHORISATION NUMBER(S)
PL 16508/0025

9

DATE OF FIRST AUTHORISATION/RENEWAL OF THE
AUTHORISATION
12/12/2009

10

DATE OF REVISION OF THE TEXT
12/12/2009

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Source: Medicines and Healthcare Products Regulatory Agency

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