Tostran 2 % Gel

Sverige - svenska - Läkemedelsverket (Medical Products Agency)

Bipacksedel Bipacksedel (PIL)

23-11-2018

Produktens egenskaper Produktens egenskaper (SPC)

31-03-2020

Aktiva substanser:
testosteron
Tillgänglig från:
2care4 ApS
ATC-kod:
G03BA03
INN (International namn):
testosterone
Dos:
2 %
Läkemedelsform:
Gel
Sammansättning:
etanol, vattenfri Hjälpämne; butylhydroxitoluen Hjälpämne; testosteron 20 mg Aktiv substans; propylenglykol Hjälpämne
Receptbelagda typ:
Receptbelagt
Bemyndigande status:
Avregistrerad
Godkännandenummer:
56329
Tillstånd datum:
2017-12-20

Dokument på andra språk

Bipacksedel Bipacksedel - engelska

31-03-2020

Produktens egenskaper Produktens egenskaper - engelska

31-03-2020

Offentlig bedömningsrapport Offentlig bedömningsrapport - engelska

18-02-2013

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PACKAGE LEAFLET:

INFORMATION FOR THE USER

Tostrex 2% Gel

Testosterone

Read all of this leaflet carefully before you start using this medicine because it contains

important information for you.

Keep this leaflet. You may need to read it again.

If you have any further questions, ask your doctor or pharmacist.

This medicine has been prescribed for you only. Do not pass it on to others. It may harm them,

even if their signs of illness are the same as yours.

If you get any side effects, talk to your doctor or pharmacist. This includes any possible side

effects not listed in this leaflet. See section 4.

What is in this leaflet:

What Tostrex is and what it is used for

What you need to know before you use Tostrex

How to use Tostrex

Possible side effects

How to store Tostrex

Contents of the pack and other information

1.

WHAT TOSTREX IS AND WHAT IT IS USED FOR

The active substance, testosterone, is a male hormone, which is a type of androgen.

Tostrex is used in adult men for testosterone replacement to treat various health problems caused by a

lack of testosterone (male hypogonadism). This should be confirmed by two separate blood

testosterone measurements and also include clinical symptoms such as:

impotence

infertility

low sex drive

tiredness

depressive moods

bone loss caused by low hormone levels

2.

WHAT YOU NEED TO KNOW BEFORE YOU USE TOSTREX

Tostrex must only be used if hypogonadism has been confirmed by your doctor, based on your

symptoms and laboratory tests. Other reasons for your symptoms must have been excluded by your

doctor prior to the start of treatment.

Only men can use Tostrex. Tostrex has not been tested in males less than 18 years of age, and there is

limited experience of treating men older than 65 years of age.

Do not use Tostrex:

If you:

are allergic to testosterone or to any of the other ingredients of this medicine (listed in section

have or are suspected of having cancer of the breast or prostate

If any of these applies to you, tell your doctor or pharmacist.

Warnings and precautions:

A check-up is necessary before you begin treatment, and periodically during treatment (usually once

or twice a year).

If you are suffering from severe heart, liver or kidney disease, treatment with Tostrex may cause

severe complications in the form of water retention in your body sometimes accompanied by

(congestive) heart failure.

The following blood checks should be carried out by your doctor before and during the treatment:

testosterone blood level, full blood count.

Tell your doctor if you have high blood pressure or if you are treated for high blood pressure, as

testosterone may cause a rise in blood pressure.

Testosterone treatment may increase the risk of development of an enlarged prostate gland (benign

prostatic hyperplasia) or prostate cancer. Testosterone treatment may also affect the number of red

blood cells you have, your blood fat profile and your liver function.

Tell your doctor before treatment if you:

have swollen hands and feet

are overweight or suffer from a chronic lung disease, as testosterone treatment may worsen

sleep apnoea (temporary cessation of breathing during sleep)

have diabetes and use insulin to control your blood sugar levels, as testosterone treatment may

affect your response to insulin

have or develop epilepsy or migraines, as these conditions may get worse during treatment

suffer from skeletal cancer, as your doctor will have to monitor your blood calcium levels

during treatment

have or have ever had blood clotting problems

thrombophilia (an abnormality of blood coagulation that increases the risk of thrombosis -

blood clots in blood vessels)

have factors that increase your risk of blood clots in a vein: previous blood clots in a vein;

smoking; obesity; cancer; immobility; if one of your immediate family has had a blood

clot in the leg, lung or organ at a young age (e.g. below the age of about 50); or as you get

older.

How to recognise a blood clot: painful swelling in one leg or sudden change in colour of

the skin e.g. turning pale, red or blue, sudden breathlessness, sudden unexplained cough

which may bring up blood; or sudden chest pain, severe lightheadedness or dizziness,

severe pain in your stomach, sudden loss of vision. Seek urgent medical attention if you

experience one of these symptoms.

Contact your doctor if you:

have frequently-occurring or persistent erections

feel irritable, nervous, or notice weight gain

feel nauseous, vomit, notice changes in your skin colour or your ankle joints become swollen

notice any changes in breathing patterns including during sleep

These symptoms may mean that your dose of Tostrex is too high, and your doctor may need to adjust

your dose.

Contact your doctor if you notice any skin reactions at the site of application such as burning or

prickling sensation, dryness, rash, redness or itchiness. If the reaction is severe, treatment should be

reviewed by your doctor and stopped if necessary.

If you are an athlete please note that Tostrex contains testosterone, which may give positive results in

a doping test.

Tostrex should not be used to treat male sterility or sexual impotence.

Tostrex should not be used by women due to possible virilising effects (such as growth of facial or

body hair, deepening of the voice or changes in the menstrual cycle).

How to prevent transfer of Tostrex to someone else:

It is important not to transfer the product to others, especially women and children. Transfer occurs

through close skin to skin contact, resulting in increased testosterone levels in the other person. If the

contact is repeated or prolonged, it may cause side-effects such as growth of facial or body hair,

deepening of the voice or changes in the menstrual cycle of women.

This transfer can be avoided by covering the application site with loose clothing, or by showering or

bathing prior to contact.

The following precautions are therefore recommended:

wash your hands thoroughly with soap and water after applying the gel;

cover the application site with loose clothing once the gel has dried;

shower or bathe before any situation involving close skin to skin contact with someone else.

In order to guarantee the safety of your partner you should wait for at least four hours after application

of Tostrex before having sexual intercourse and wear clothing which covers the application site at the

time of contact or wash the site of application with soap and water before sexual intercourse.

You should wear clothing which covers the application site when in contact with children, in order to

avoid the risk of transferring the gel to the child’s skin.

If you transfer some of the testosterone gel to another person by skin-to-skin contact, or someone else

is exposed by direct contact with the gel itself, wash the contact area of the other person with soap and

water as soon as possible.

If Tostrex is applied to a patient by a health care professional or carer, they should wear suitable

disposable gloves. The gloves should be resistant to alcohol as the gel contains ethanol and isopropyl

alcohol.

Contact your doctor if you notice changes in body hair, significantly increased acne or other signs of

development of male characteristics in

people not being treated with Tostrex (i.e., female partner

or children).

Other medicines and Tostrex:

Tell your doctor or pharmacist if you are taking, have recently taken, or might take any other

medicines, especially the following:

anticoagulants

corticosteroids

Also tell your doctor or pharmacist about any medicines that you may have bought for yourself

without prescription.

Tostrex with food and drink:

Tostrex is not affected by your intake of food or drink.

Pregnancy and breast-feeding

Tostrex is only intended to be used by men.

Tostrex must not be used by pregnant or breastfeeding women.

Pregnant women should avoid all contact with skin treated with Tostrex. Tostrex may cause

harm or abnormalities in the unborn baby. If your partner becomes pregnant, you

must

follow

the advice regarding avoiding transfer of the testosterone gel given in this section. In the event

of contact with treated skin, the area should be washed immediately with soap and water.

Driving and using machines:

Tostrex is unlikely to have an effect on your ability to drive and use machines.

Tostrex contains butylhydroxytoluene and propylene glycol

Butylhydroxytoluene may cause local skin reactions (e.g. contact dermatitis) or irritation of the eyes

and mucous membranes. This medicine contains up to 1400 mg propylene glycol in each dosage unit

which is equivalent to 350 mg/g.

3.

HOW TO USE TOSTREX

Always use this medicine exactly as your doctor has told you. You should check with your doctor or

pharmacist if you are unsure about how and when to apply the gel.

The usual starting dose is 3 g of gel (containing 60mg of testosterone) per day. The dose may be

adjusted by your doctor, and the maximum dose is 4 g of gel (80 mg of testosterone) per day.

Tostrex is supplied in a canister with a pumping mechanism which delivers one half gram of gel (10

mg of testosterone) each time the piston is depressed (when the pump mechanism is pushed right

down).

Using the canister for the first time:

Before you use the dosing pump for the first time it must be primed. To do so, with the canister in the

upright position, slowly and fully depress the actuator eight times. The first few depressions may

result in no discharge of gel. Discard the gel from the eight depressions. It is only necessary to prime

the pump before the first dose.

Administration of Tostrex:

Your doctor will tell you how many depressions of the piston to make to get the correct dose of gel for

you once the pump has been primed. The table below gives you more information on this.

Number of Depressions

Amount of Gel (g)

Quantity of Testosterone

Applied to the Skin (mg)

Apply the gel onto clean, dry intact skin, once a day at the same time each day, for example in the

morning after showering.

The gel should either be rubbed onto the abdomen (over an area of at least 10 by 30 cm) or divided in

half and one half rubbed onto the inside of

each

thigh (over an area of at least 10 by 15 cm). It is

recommended that you rub Tostrex onto your abdomen and

both

your inner thighs on alternate days.

Application to other sites should be avoided. In particular do not apply Tostrex to the genitals.

Rub the gel in gently with one finger until dry, and then cover the area with loose clothing (e.g. T-

shirt, shorts, pants). When finished, wash your hands thoroughly with soap and water.

If you are thinking of taking a shower or bath, do so either before application of Tostrex or wait for at

least two hours after the application.

Two weeks after beginning to use your medicine your doctor will take blood samples to see if your

dose needs to be changed. Whilst you are taking Tostrex, you should expect to have regular medical

follow-up.

If you are arranging for testing of blood samples while using Tostrex you must ensure that all

testosterone measurements are performed in the same laboratory, because of the variability in

analytical values among diagnostic laboratories.

If you use more Tostrex than you should:

If you have applied too much Tostrex, contact a doctor, hospital or pharmacist.

If you forget to use Tostrex:

Do not take a double dose to make up for forgotten individual doses. Apply the next dose at the usual

time.

If you stop using Tostrex:

Always talk to your doctor or pharmacist before stopping using Tostrex.

If you have any further questions on the use of this medicine, ask your doctor or pharmacist.

4.

POSSIBLE SIDE EFFECTS

Like all medicines, this medicine can cause side effects, although not everybody gets them.

Very common side effects

(affects more than 1 user in 10)

are skin reactions at the site of application

such as burning or prickling sensation, dryness, rash, redness or itchiness. These are usually mild

transient side effects of Tostrex but if they are troublesome or last for more than a few days, talk to

your doctor or pharmacist as soon as possible.

Common side effects

(affects 1 to 10 users in 100)

are: swelling of hands or feet, high blood pressure,

prostate changes (including: increased blood levels of a protein called prostate specific antigen that is

produced by the prostate), increased body hair growth, increase in breast size, increased number of red

blood cells (measured in blood samples). Increase in red blood cell count, haematocrit (percentage of

red blood cells in blood) and haemoglobin (the component of red blood cells that carries oxygen),

identified by periodic blood tests.

Other known undesirable effects associated with testosterone treatments include: baldness, seborrhoea,

acne, jaundice (liver problems which sometimes may be associated with yellowing of the skin and the

whites of the eyes), abnormal liver function tests, nausea, changes in libido, increased frequency of

erections, difficulty in passing urine, depression, nervousness, hostility, weight gain, muscle cramps or

pain, fluid retention, swelling of ankles, sleep apnoea, and rare cases of painful and persistent

erections. A reduction in sperm production and the size of the testicles may occur at high doses.

Prolonged testosterone administration may cause changes in the levels of salts (electrolytes) in the

body.

There is no convincing evidence that testosterone replacement in hypogonadal men induces prostate

cancer. However, testosterone therapy is to be avoided in men already known or thought to have

prostate cancer.

Hyperglycaemia (too much sugar in the bloodstream) has been reported in the case of 2 people with a

history of diabetes mellitus.

Reporting of side effects

If you get any side effects, talk to your doctor or pharmacist. This includes any possible side effects

not listed in this leaflet. You can also report side effects directly via the national reporting system

listed in Appendix V*. By reporting side effects you can help provide more information on the safety

of this medicine.

5.

HOW TO STORE TOSTREX

Keep this medicine out of the sight and reach of children.

Do not use this medicine after the expiry date which is stated on the canister after EXP. The expiry

date refers to the last day of that month.

Do not store above 25

Do not refrigerate or freeze.

Once opened store canister upright.

Do not throw away any medicines via wastewater or household waste. Ask your pharmacist how to throw

away medicines you no longer use. These measures will help protect the environment.

6.

CONTENTS OF THE PACK AND OTHER INFORMATION

What Tostrex contains

The active substance is testosterone. One gram of gel contains 20 mg of testosterone.

The other ingredients are propylene glycol; ethanol, anhydrous; isopropyl alcohol; oleic acid;

carbomer 1382; trolamine; butylhydroxytoluene (E321); water, purified and hydrochloric acid

(for pH adjustment).

What Tostrex looks like and contents of the pack

Tostrex is a clear gel, which varies from colourless to slightly yellow in appearance.

Tostrex comes in canisters each containing 60 grams of gel. The canisters have a pumping mechanism,

which delivers a fixed amount of gel.

A carton may contain one, two or three canisters of gel. Not all pack sizes may be available.

Marketing Authorisation Holder

Kyowa Kirin Ltd

Galabank Business Park

Galashiels

TD1 1QH

United Kingdom

Manufacturer

PHARBIL Waltrop GmbH

Im Wirrigen 25

45731 Waltrop

Germany

This medicinal product is authorised in the Member States of the EEA under the following

names:

Austria, Denmark, Finland, Germany, Greece, Hungary, Ireland, Netherlands, Norway, Poland,

Portugal, United Kingdom: Tostran

Italy, Sweden: Tostrex

Belgium, Spain, Luxembourg: Itnogen

France: Fortigel

This leaflet was last revised in 2020-03-23

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SUMMARY OF PRODUCT CHARACTERISTICS

1.

NAME OF THE MEDICINAL PRODUCT

Tostrex 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.

Excipient(s) with known effect:

One gram of gel contains 1 mg butylhydroxytoluene.

One gram of gel contains 350 mg propylene glycol.

For the full list of excipients, see Section 6.1.

3.

PHARMACEUTICAL FORM

Gel.

Clear, colourless to slightly yellow gel.

4.

CLINICAL PARTICULARS

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

Adults and Elderly Men

The recommended starting dose of Tostrex 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

Tostrex is not indicated for use in children and has not been clinically evaluated in males under 18

years of age.

Method of administration

For cutaneous 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, 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 tostrex dispensed after pump priming

No of Depressions

Amount of Gel (g)

Amount of Testosterone

Applied to the Skin (mg)

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

Tostrex 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 Tostrex. 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 Tostrex.

No formal studies have been conducted with the product in patients with renal or hepatic impairment

(see also Section 4.4).

4.3

Contraindications

Tostrex 2% 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

Tostrex 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 Tostrex 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 Tostrex 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 Tostrex 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.

Tostrex 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.

Tostrex 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 Tostrex 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.

Tostrex 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 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). Tostrex 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 Tostrex:

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 Tostrex 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 Tostrex 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 Tostrex indicate that patients

should wait at least two hours between gel application and bathing or showering.

Tostrex contains butylhydroxytoluene (E321) which may cause local skin reactions (e.g., contact

dermatitis) or irritation of the eyes and mucous membranes.

This medicine contains up to 1400 mg propylene glycol in each dosage unit which is equivalent to

350 mg/g.

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 Tostrex 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 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

Tostrex is only intended to be used by men.

Tostrex 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 Tostrex (see Section 4.4). Tostrex

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 Tostrex) 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 (≥ 10,000 to

<1/1,000).

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

Vascular disorders

Hypertension

Reproductive system and breast

disorders

Gynaecomastia

General disorders and

administration site conditions

Administration site reactions

Peripheral oedema

Investigations

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

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

Gastrointestinal disorders

Nausea

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.

* 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 the national reporting system

listed in Appendix V*.

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 Tostrex 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 Tostrex 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.

5.2

Pharmacokinetic properties

Absorption

Tostrex 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 cm

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 Tostrex 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-α and 2-β androstanediol.

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 Tostrex.

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.

Once opened 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

Kyowa Kirin Ltd

Galabank Business Park

Galashiels

TD1 1QH

United Kingdom

8.

MARKETING AUTHORISATION NUMBER(S)

19526

9.

DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

Date of first authorisation:

22 December 2004

Date of latest renewal:

22 December 2009

10.

DATE OF REVISION OF THE TEXT

2020-03-23

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