- Approval Id
- e49b4635966e48af
- Drug Approval Emc Name
- Testogel 16.2mg/g gel
- Drug Name
- Testogel 16.2mg/g gel
- Company Name
- Besins Healthcare (UK) Ltd
- Company Address
- Lion Court, 25 Procter Street, Holborn, London, WC1V 6NY, UK
- Company Website
- http://www.besinshealthcare.co.uk
- Company Telephone
- +44 (0) 203 862 0920
- Company Medical Info Direct Line
- +44 (0)1748 828 789
- Company Medical Info Email
- besins@eu.propharmagroup.com
- Atc Code
- G03BA03
- Legal Category
- Prescription only medicine
- Authorisation Holder
- Besins Healthcare
Rue Washington 80
1050 Ixelles
Belgium
- Authorisation Number
- PL 28397/0007
- Authorisation Date
- First Authorisation: 09/12/2015
Renewal: 01/05/2024
- Instruction Authorisation Holder
- Besins Healthcare
Rue Washington 80
1050 Ixelles
Belgium
- Instruction Authorisation Number
- PL 28397/0007
- Instruction Authorisation Date
- First Authorisation: 09/12/2015
Renewal: 01/05/2024
- Instruction Composition
- One gram of gel contains 16.2 mg testosterone. One pump actuation delivers 1.25 g of gel containing 20.25 mg of testosterone.
Excipients with known effect: This medicine contains 0.9 g alcohol (Ethanol) in each dose of 1.25 g gel.
For the full list of excipients, see section 6.1.
- Instruction Dosage Form
- Transdermal Gel
Transparent or slightly opalescent, colourless gel.
- Instruction Clinical Particulars
- 4.1 Therapeutic indications
This medicine is indicated in adults for testosterone replacement therapy for male hypogonadism when testosterone deficiency has been confirmed by clinical features and biochemical tests (see 4.4 Special warnings and precautions for use).4.2 Posology and method of administration
Posology
\*Adult and elderly men\*
The recommended dose is two pump actuations of gel (\*i.e.\* 40.5 mg of testosterone) applied once daily at about the same time, preferably in the morning. The daily dose should be adjusted by the physician depending on the clinical or laboratory response in individual patients, not exceeding four pump actuations or 81 mg testosterone per day. The adjustment of posology should be achieved by increments of one pump actuation of gel.
The dose should be titrated based on the pre-dose morning testosterone blood levels. Steady state blood testosterone levels are reached usually by the second day of treatment with this medicine. In order to evaluate the need to adjust the testosterone dosage, blood testosterone levels should be measured in the morning before application of the product, after the steady state is reached. Testosterone blood levels should be assessed periodically to ensure that the patient is on the correct dose. The dose may be reduced if the testosterone blood levels are raised above the desired level. If the levels are low, the dosage may be increased stepwise, to a daily administration of 81 mg of testosterone (four actuations of gel) per day.
Therapy should be discontinued if the blood testosterone levels consistently exceeds the normal range at the lowest daily dose of 20.25 mg (1.25 g gel, equivalent to one pump actuation) or if blood testosterone levels in the normal range cannot be achieved with the highest dose of 81 mg (5 g gel, equivalent to four pump actuations).
\*Patient suffering from severe renal or hepatic insufficiency\*
Please see section 4.4 Special warnings and precautions for use.
\*Paediatric population\*
The safety and efficacy of this medicine in males under 18 years have not been established.
No data are available.
\*Use in women\*
This medicine is not indicated for use in women.
Method of administration
Transdermal use
Patients should be informed that other persons (including children and adults) should not come in contact with the area of the body where testosterone gel has been applied (see Section 4.4).The gel should be administered by the patient himself, onto clean, dry, healthy skin over both shoulders, or both arms.
The gel should be simply spread on the skin gently as a thin layer. It is not necessary to rub it on the skin. Allow to dry for at least 3-5 minutes before dressing.
- Wash hands thoroughly with soap and water after applying the gel
- Once the gel has dried, cover the application site(s) with clean clothing (such as a T-shirt).
After applying this medicine patients should wait at least 1 hour before showering or bathing.
Do not apply to the genital areas as the high alcohol content may cause local irritation.
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 three times. Safely discard the gel from the first three actuations. It is only necessary to prime the pump before the first dose.
After the priming procedure, fully depress the actuator once for delivering 1.25 g of this medicine into the palm of the hand and then apply to the upper arms and shoulders.
Skin to skin contact
Before close physical contact with another person (adult or child), wash the application site with soap and water once the recommended time period (at least 1 hour) has passed and cover again with clean clothing.
For more information regarding post dose washing see section 4.4 (subsection Skin to skin transfer).4.3 Contraindications
This medicine contraindicated:
- Hypersensitivity to the active substance or any of the excipients listed in Section 6.1
- Known or suspected prostate cancer or breast carcinoma.4.4 Special warnings and precautions for use
This medicine should be used only if hypogonadism (hyper- and hypogonadotrophic) has been demonstrated and if other aetiology, 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, fatigue, reduced libido, erectile dysfunction etc.) and confirmed by two separate blood testosterone measurements. Currently, there is no consensus about age-specific testosterone reference levels. However, it should be taken into account that physiologically testosterone serum levels are lower with increasing age.
Due to variability in laboratory values, all measures of testosterone for any given individual should be carried out by the same laboratory.
Prior to testosterone initiation, all patients should undergo a detailed examination in order to exclude a risk of pre-existing prostate 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 once yearly and twice yearly in elderly patients and at risk patients (those with clinical or familial risk factors).
Androgens may accelerate the progression of sub-clinical prostate cancer and benign prostate hyperplasia.
This medicine should be used with caution in cancer patients at risk of hypercalcaemia (and associated hypercalciuria), due to bone metastases. Regular monitoring of blood calcium levels is recommended in these patients.
In patients suffering from severe cardiac, hepatic or renal insufficiency, or ischaemic 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. In addition, diuretic therapy may be required.
Testosterone may cause a rise in blood pressure and this medicine should be used with caution in men with hypertension.
Testosterone should be used with caution in patients with thrombophilia or risk factors for venous thromboembolism (VTE), as there have been post-marketing 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 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.
In patients receiving long-term androgen therapy, the following laboratory parameters should also be monitored regularly: haemoglobin, and haematocrit (to detect polycythaemia), liver function tests and lipid profile.
Currently, there is no consensus about age specific testosterone reference values. It should be taken into account that physiologically testosterone serum levels are lower with increasing age.
This medicine should be used with caution in patients with epilepsy and migraine as these conditions may be aggravated.
There are published reports of increased risk of sleep apnoea in hypogonadal subjects treated with testosterone esters, especially in those with risk factors such as obesity and chronic respiratory disease.
Improved insulin sensitivity may be observed in patients treated with androgens and may require a decrease in the dose of antidiabetic medications (see section 4.5). Monitoring of the glucose level and HbA1c is advised for patients treated with androgens.
Certain clinical signs: irritability, nervousness, weight gain, prolonged or frequent erections may indicate excessive androgen exposure requiring dosage adjustment.
If the patient develops a severe application site reaction, treatment should be reevaluated and discontinued if necessary.
The attention of athletes should be drawn to the fact that this proprietary medicinal product contains an active substance (testosterone) that may produce a positive result in doping control tests.
With large doses of exogenous androgens, spermatogenesis may be reversibly suppressed through feedback inhibition of pituitary follicle-stimulating hormone (FSH) which could possibly lead to adverse effects on semen parameters including sperm count.
Gynecomastia occasionally develops and occasionally persists in patients being treated with androgens for hypogonadism.
This medicine should not be used by women due to possibly virilising effects.
\*\*Skin to skin 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 and premature puberty and genital enlargement in children) in the event of repeated contact (inadvertent androgenisation).
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. Consult a physician in case of signs and symptoms in another person that may have been exposed accidentally to testosterone gel. The physician should inform the patient carefully about the risk of testosterone transfer, for instance during contact with another person including children and about safety instructions. The treating physician should give extra attention to patients with a major risk of not being able to follow these instructions in Method of Administration (see Section 4.2). It is essential to adhere to the application technique when in physical contact with another person. Before close physical contact with another person (adult or child), wash the application site with soap and water once the recommended time period (at least 1 hour) has passed and cover the site again with clean clothing. In the event of a person coming into contact with this medicine, the person affected should immediately wash the affected area with soap and water.
This product contains ethanol: in neonates (pre-term and term newborn infants), high concentrations of ethanol may cause severe local reactions and systemic toxicity due to significant absorption through immature skin (especially under occlusion).
Pregnant women must avoid any contact with this medicine's application sites. In case of pregnancy of a partner, the patient must pay extra attention to the precautions for use described above (also see section 4.6).
This medicine contains 0.9 g alcohol (ethanol) in each dose of 1.25 g gel.
It may cause a burning sensation on damaged skin.
This medicine contains ethanol to aid transdermal delivery and is flammable.
Care should be taken to avoid sources of heat / naked flames when administering the product, until the gel has dried on the skin.4.5 Interaction with other medicinal products and other forms of interaction
\*Oral anticoagulants\*
Changes in anticoagulant activity (increased effect of the oral anticoagulant by modification of hepatic synthesis of coagulation factor and competitive inhibition of plasma protein binding) increased monitoring of the prothrombin time and international normalized ratio (INR) determinations are recommended. Patients receiving oral anticoagulants require close monitoring especially when androgens are started or stopped.
\*Corticosteroids\*
Concomitant administration of testosterone and ACTH or corticosteroids may increase the risk of developing oedema. As a result, these medicinal products should be administered cautiously, particularly in patients suffering from cardiac, renal or hepatic disease.
\*Laboratory tests\*
Interactions with laboratory tests: androgens may decrease levels of thyroxin binding globulin, resulting in decreased T4 serum concentrations and in increased resin uptake of T3 and T4. Free thyroid hormone levels, however, remain unchanged and there is no clinical evidence of thyroid insufficiency.
\*Diabetic Medication\*
Changes in insulin sensitivity, glucose tolerance, glycaemic control, blood glucose and glycosylated haemoglobin levels have been reported with androgens. In diabetic patients, antidiabetic's medication might need dose reduction (see section 4.4).
\*Sunscreens\*
Application of sunscreen or lotion does not reduce efficacy.
Washing 2 hours after application doesn't have significant effect on blood testosterone levels.4.6 Fertility, pregnancy and lactation
\*Fertility\*
Spermatogenesis may be reversibly suppressed with this medicine.
\*Pregnancy\*
This medicine is intended for use by men only.
This medicine is not indicated in pregnant or breast-feeding women.
Pregnant women must avoid any contact with this medicine(see section 4.4) because this product may have adverse virilising effects on the foetus. In the event of inadvertent skin-to-skin contact, thoroughly wash with soap and water as soon as possible.
\*Breast-feeding\*
This medicine is not indicated in women who are breast-feeding.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 adverse reactions listed in the table are based on post-marketing data, clinical trials and class-effects.
a. \*Summary of the safety profile\*
The most frequently observed clinical adverse drug reactions at the recommended dosage per day were skin reactions at the application site, (erythema, acne, dry skin), anxiety and asthenia.
\*b. Tabulated list of adverse reactions\*
\*\*Adverse reactions reported in clinical trials and derived from post-marketing experience via spontaneous reports or literature cases are listed below.\*\*
Adverse effects have been ranked under headings of frequency using the following
convention: very common (≥ 1/10); common (≥ 1/100; <1/10); uncommon (≥ 1/1,000;<1/100); rare (≥ 1/10,000;<1/1,000); very rare (<1/10,000); frequency not known (cannot be estimated from the available data). Within each frequency category, adverse reactions are presented in order of decreasing seriousness.
| | | | | | |
| --- | --- | --- | --- | --- | --- |
| | \*\*Adverse Reaction Tabulation for Transdermal Testosterone.\*\* | | | | |
| \*\*MedDRA\*\* \*\*System Organ Class\*\* | \*\*Adverse reactions – preferred term\*\* | | | | |
| \*\*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)\*\* | \*\*Frequency not known\*\* (cannot be estimated from the available data) | |
| Neoplasms benign, malignant and unspecified (incl. cysts and polyps) | | | Hepatic Neoplasm | | Prostate Cancer | |
| 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 | |
| Psychiatric disorders | Mood Disorders, Emotional symptoms (mood swings, affective disorder, anger, aggression, impatience, insomnia, abnormal dreams, increased libido) | | | | Nervousness, Depression, Hostility | |
| Nervous system disorders | Dizziness, Paraesthesia, Amnesia, Hyperaesthesia Headache | | | | | |
| Vascular disorders | Hypertension | Malignant hypertension, Hot flushes/flushing, Phlebitis | | | | |
| Respiratory, thoracic and mediastinal disorders | | | | | Sleep apnoea | |
| Gastrointestinal disorders | Diarrhoea | Oral pain, Abdominal distension | | | | |
| Hepatobiliary disorders | | | | Jaundice, Liver function test abnormalities | | |
| Skin and subcutaneous tissue disorders | Alopecia Urticaria, | Acne, , Hirsutism, Rash, Dry Skin, Seborrhoea, Skin lesions, Contact dermatitis, Hair colour changes, application site hypersensitivity, application site pruritus | | | skin reactions2 | |
| Renal and urinary disorders | | | | | Urinary tract obstruction | |
| Musculoskeletal and connective tissue disorders | | | | | Muscle Cramps | |
| Reproductive system and breast disorders | Gynaecomastia1 | Nipple disorder, Prostate-abnormalities, Testicular pain, Increased frequency of erections | Priapism | | Libido changes, therapy with high dose of testosterone preparations commonly reversibly interrupts or reduces spermatogenesis, thereby reducing the size of the testicles | |
| General disorders and administration site conditions | Application site reaction | Pitting oedema, | | | Asthenia, Malaise, oedema, hypersensitivity reactions, increases the occurrences of water retention and oedema3 | |
| Investigations | Changes in laboratory tests (polycythaemia, lipids), Haematocrit increased, Haemoglobin increased, Red blood cell count increased | PSA increased | | | Weight gain | |
| 1. May develop and persist in patients treated for hypogonadism with testosterone 2. skin reactions, because of the alcohol contained in the product, frequent applications to the skin may cause irritation and dry skin 3. High dose or long-term administration of testosterone occasionally increases the occurrences of water retention and oedema | | | | | | |
\*\*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
Yellow Card Scheme
Website: www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store4.9 Overdose
\*Symptoms\*
Serum testosterone levels should be measured if clinical signs and symptoms indicative of overexposure to androgen are observed. Application site rash has also been reported in case reports of overdose with this medicine.
\*Treatment\*
Treatment of overdosage consists of washing the application site immediately and discontinuing treatment if advised by the treating physician.
- Instruction Pharmacology
- 5.1 Pharmacodynamic properties
Pharmacotherapeutic group: Androgens. ATC code: G03B A03.
Endogenous androgens, testosterone, secreted by the testes and its major metabolite DHT, are responsible for the development of the external and internal genital organs and for maintaining the secondary sexual characteristics (stimulating hair growth, deepening of the voice, development of the libido). Androgens have also an effect on protein anabolism, on development of skeletal muscle and body fat distribution and also reduce urinary nitrogen, sodium, potassium, chloride, phosphate and water excretion.
Testosterone reduces the pituitary secretion of gonadotropins.
The effects of testosterone in some target organs arise after peripheral conversion of testosterone to estradiol, which than binds to oestrogen receptors in the target cell nucleus \*e.g.\* the pituitary, fat, brain, bone and testicular Leydig cells.5.2 Pharmacokinetic properties
\*Absorption\*
The percutaneous absorption of testosterone after administration of this medicine lies between 1% and 8.5%.
\*Distribution\*
Following percutaneous absorption, testosterone diffuses into the systemic circulation and provides relatively constant concentrations during the 24 hour cycle.
Serum testosterone concentrations increase from the first hour after an application, reaching steady state from day two. Daily changes in testosterone levels are then of similar amplitude to those observed during the circadian rhythm of endogenous testosterone. The percutaneous route therefore avoids the blood distribution peaks produced by injections. It does not produce supra-physiological hepatic concentrations of the steroid in contrast to oral androgen therapy.
\*Biotransformation\*
Administration of 2.5 g of this medicine produces an average testosterone level increase of approximately 2.2 ng/ml (7.7 nmol/l) in plasma.
When treatment is stopped, testosterone levels start decreasing approximately 24 hours after the last administration. Testosterone levels return to baseline approximately 72 to 96 hours after the final administration.
The major active metabolites of testosterone are dihydrotestosterone and oestradiol.
\*Elimination\*
Testosterone is excreted mostly in urine as conjugated testosterone metabolites and a small amount is excreted unchanged in the faeces.
In the phase III double blind study at the end of a 112 day treatment period, during which the dose of this medicine could be titrated based on total testosterone concentrations, 81.6% (CI 75.1-87.0%) of men had total testosterone levels within the normal range for eugonadal young men (300 -1000 ng/dl). In patients on a daily dose of this medicine the average (± SD) daily testosterone concentration on day 112 (Cav) was 561 (± 259) ng/dl, mean Cmax was 845 (± 480) ng/dl and mean Cmin was 334 (± 155) ng/dl. The corresponding concentrations on Day 182 (double blind period) were Cav 536 (± 236) ng/dl, mean Cmax 810 (± 497) ng/dl and mean Cmin 330 (± 147) ng/dl.
In the phase III open label study at the end of a 264 day treatment period, during which the dose of this medicine could be titrated based on total testosterone concentrations, 77 % (CI 69.8-83.2%) of men had total testosterone levels within the normal range for eugonadal young men (300 -1000 ng/dl).
In patients on a daily dose of this medicine the average (± SD) daily testosterone concentration on day 266 (Cav) was 459 (± 218) ng/dl, mean Cmax was 689 (± 414) ng/dl and mean Cmin was 305 (± 121) ng/dl. The corresponding concentrations on Day 364 (extended open-label period) were Cav 454 (± 193) ng/dl, mean Cmax 698 (± 382) ng/dl and mean Cmin 302 (± 126) ng/dl.5.3 Preclinical safety data
Testosterone has been found to be non-mutagenic \*in vitro\* using the reverse mutation model (Ames test) or Chinese hamster ovary cells. A relationship between androgen treatment and certain cancers has been found in studies on 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 importance of these findings and the actual risk in human beings is unknown.
The administration of exogenous testosterone has been reported to suppress spermatogenesis in the rat, dog and non-human primates, which was reversible on cessation of the treatment.
- Instruction Pharmaceutical Particulars
- 6.1 List of excipients
Carbomer 980
Isopropyl myristate
Ethanol 96%
Sodium hydroxide
Purified water6.2 Incompatibilities
Not applicable.6.3 Shelf life
3 years.6.4 Special precautions for storage
This medicinal product does not require any special storage conditions.6.5 Nature and contents of container
Multi-dose container (comprised of a polypropylene canister with an LDPE lined pouch) with metering pump that contains 88 g gel and delivers a minimum of 60 doses.
| | |
| --- | --- |
| Pack sizes: | |
| | 1 container per carton Supplied in packs of 1, 2, 3 or 6 containers |
Not all pack sizes may be marketed.6.6 Special precautions for disposal and other handling
No special requirements.
- Instruction Content
- ## Composition
One gram of gel contains 16.2 mg testosterone. One pump actuation delivers 1.25 g of gel containing 20.25 mg of testosterone.
Excipients with known effect: This medicine contains 0.9 g alcohol (Ethanol) in each dose of 1.25 g gel.
For the full list of excipients, see section 6.1.
## Pharmaceutical Form
Transdermal Gel
Transparent or slightly opalescent, colourless gel.
## Clinical Particulars
4.1 Therapeutic indications
This medicine is indicated in adults for testosterone replacement therapy for male hypogonadism when testosterone deficiency has been confirmed by clinical features and biochemical tests (see 4.4 Special warnings and precautions for use).4.2 Posology and method of administration
Posology
\*Adult and elderly men\*
The recommended dose is two pump actuations of gel (\*i.e.\* 40.5 mg of testosterone) applied once daily at about the same time, preferably in the morning. The daily dose should be adjusted by the physician depending on the clinical or laboratory response in individual patients, not exceeding four pump actuations or 81 mg testosterone per day. The adjustment of posology should be achieved by increments of one pump actuation of gel.
The dose should be titrated based on the pre-dose morning testosterone blood levels. Steady state blood testosterone levels are reached usually by the second day of treatment with this medicine. In order to evaluate the need to adjust the testosterone dosage, blood testosterone levels should be measured in the morning before application of the product, after the steady state is reached. Testosterone blood levels should be assessed periodically to ensure that the patient is on the correct dose. The dose may be reduced if the testosterone blood levels are raised above the desired level. If the levels are low, the dosage may be increased stepwise, to a daily administration of 81 mg of testosterone (four actuations of gel) per day.
Therapy should be discontinued if the blood testosterone levels consistently exceeds the normal range at the lowest daily dose of 20.25 mg (1.25 g gel, equivalent to one pump actuation) or if blood testosterone levels in the normal range cannot be achieved with the highest dose of 81 mg (5 g gel, equivalent to four pump actuations).
\*Patient suffering from severe renal or hepatic insufficiency\*
Please see section 4.4 Special warnings and precautions for use.
\*Paediatric population\*
The safety and efficacy of this medicine in males under 18 years have not been established.
No data are available.
\*Use in women\*
This medicine is not indicated for use in women.
Method of administration
Transdermal use
Patients should be informed that other persons (including children and adults) should not come in contact with the area of the body where testosterone gel has been applied (see Section 4.4).The gel should be administered by the patient himself, onto clean, dry, healthy skin over both shoulders, or both arms.
The gel should be simply spread on the skin gently as a thin layer. It is not necessary to rub it on the skin. Allow to dry for at least 3-5 minutes before dressing.
- Wash hands thoroughly with soap and water after applying the gel
- Once the gel has dried, cover the application site(s) with clean clothing (such as a T-shirt).
After applying this medicine patients should wait at least 1 hour before showering or bathing.
Do not apply to the genital areas as the high alcohol content may cause local irritation.
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 three times. Safely discard the gel from the first three actuations. It is only necessary to prime the pump before the first dose.
After the priming procedure, fully depress the actuator once for delivering 1.25 g of this medicine into the palm of the hand and then apply to the upper arms and shoulders.
Skin to skin contact
Before close physical contact with another person (adult or child), wash the application site with soap and water once the recommended time period (at least 1 hour) has passed and cover again with clean clothing.
For more information regarding post dose washing see section 4.4 (subsection Skin to skin transfer).4.3 Contraindications
This medicine contraindicated:
- Hypersensitivity to the active substance or any of the excipients listed in Section 6.1
- Known or suspected prostate cancer or breast carcinoma.4.4 Special warnings and precautions for use
This medicine should be used only if hypogonadism (hyper- and hypogonadotrophic) has been demonstrated and if other aetiology, 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, fatigue, reduced libido, erectile dysfunction etc.) and confirmed by two separate blood testosterone measurements. Currently, there is no consensus about age-specific testosterone reference levels. However, it should be taken into account that physiologically testosterone serum levels are lower with increasing age.
Due to variability in laboratory values, all measures of testosterone for any given individual should be carried out by the same laboratory.
Prior to testosterone initiation, all patients should undergo a detailed examination in order to exclude a risk of pre-existing prostate 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 once yearly and twice yearly in elderly patients and at risk patients (those with clinical or familial risk factors).
Androgens may accelerate the progression of sub-clinical prostate cancer and benign prostate hyperplasia.
This medicine should be used with caution in cancer patients at risk of hypercalcaemia (and associated hypercalciuria), due to bone metastases. Regular monitoring of blood calcium levels is recommended in these patients.
In patients suffering from severe cardiac, hepatic or renal insufficiency, or ischaemic 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. In addition, diuretic therapy may be required.
Testosterone may cause a rise in blood pressure and this medicine should be used with caution in men with hypertension.
Testosterone should be used with caution in patients with thrombophilia or risk factors for venous thromboembolism (VTE), as there have been post-marketing 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 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.
In patients receiving long-term androgen therapy, the following laboratory parameters should also be monitored regularly: haemoglobin, and haematocrit (to detect polycythaemia), liver function tests and lipid profile.
Currently, there is no consensus about age specific testosterone reference values. It should be taken into account that physiologically testosterone serum levels are lower with increasing age.
This medicine should be used with caution in patients with epilepsy and migraine as these conditions may be aggravated.
There are published reports of increased risk of sleep apnoea in hypogonadal subjects treated with testosterone esters, especially in those with risk factors such as obesity and chronic respiratory disease.
Improved insulin sensitivity may be observed in patients treated with androgens and may require a decrease in the dose of antidiabetic medications (see section 4.5). Monitoring of the glucose level and HbA1c is advised for patients treated with androgens.
Certain clinical signs: irritability, nervousness, weight gain, prolonged or frequent erections may indicate excessive androgen exposure requiring dosage adjustment.
If the patient develops a severe application site reaction, treatment should be reevaluated and discontinued if necessary.
The attention of athletes should be drawn to the fact that this proprietary medicinal product contains an active substance (testosterone) that may produce a positive result in doping control tests.
With large doses of exogenous androgens, spermatogenesis may be reversibly suppressed through feedback inhibition of pituitary follicle-stimulating hormone (FSH) which could possibly lead to adverse effects on semen parameters including sperm count.
Gynecomastia occasionally develops and occasionally persists in patients being treated with androgens for hypogonadism.
This medicine should not be used by women due to possibly virilising effects.
\*\*Skin to skin 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 and premature puberty and genital enlargement in children) in the event of repeated contact (inadvertent androgenisation).
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. Consult a physician in case of signs and symptoms in another person that may have been exposed accidentally to testosterone gel. The physician should inform the patient carefully about the risk of testosterone transfer, for instance during contact with another person including children and about safety instructions. The treating physician should give extra attention to patients with a major risk of not being able to follow these instructions in Method of Administration (see Section 4.2). It is essential to adhere to the application technique when in physical contact with another person. Before close physical contact with another person (adult or child), wash the application site with soap and water once the recommended time period (at least 1 hour) has passed and cover the site again with clean clothing. In the event of a person coming into contact with this medicine, the person affected should immediately wash the affected area with soap and water.
This product contains ethanol: in neonates (pre-term and term newborn infants), high concentrations of ethanol may cause severe local reactions and systemic toxicity due to significant absorption through immature skin (especially under occlusion).
Pregnant women must avoid any contact with this medicine's application sites. In case of pregnancy of a partner, the patient must pay extra attention to the precautions for use described above (also see section 4.6).
This medicine contains 0.9 g alcohol (ethanol) in each dose of 1.25 g gel.
It may cause a burning sensation on damaged skin.
This medicine contains ethanol to aid transdermal delivery and is flammable.
Care should be taken to avoid sources of heat / naked flames when administering the product, until the gel has dried on the skin.4.5 Interaction with other medicinal products and other forms of interaction
\*Oral anticoagulants\*
Changes in anticoagulant activity (increased effect of the oral anticoagulant by modification of hepatic synthesis of coagulation factor and competitive inhibition of plasma protein binding) increased monitoring of the prothrombin time and international normalized ratio (INR) determinations are recommended. Patients receiving oral anticoagulants require close monitoring especially when androgens are started or stopped.
\*Corticosteroids\*
Concomitant administration of testosterone and ACTH or corticosteroids may increase the risk of developing oedema. As a result, these medicinal products should be administered cautiously, particularly in patients suffering from cardiac, renal or hepatic disease.
\*Laboratory tests\*
Interactions with laboratory tests: androgens may decrease levels of thyroxin binding globulin, resulting in decreased T4 serum concentrations and in increased resin uptake of T3 and T4. Free thyroid hormone levels, however, remain unchanged and there is no clinical evidence of thyroid insufficiency.
\*Diabetic Medication\*
Changes in insulin sensitivity, glucose tolerance, glycaemic control, blood glucose and glycosylated haemoglobin levels have been reported with androgens. In diabetic patients, antidiabetic's medication might need dose reduction (see section 4.4).
\*Sunscreens\*
Application of sunscreen or lotion does not reduce efficacy.
Washing 2 hours after application doesn't have significant effect on blood testosterone levels.4.6 Fertility, pregnancy and lactation
\*Fertility\*
Spermatogenesis may be reversibly suppressed with this medicine.
\*Pregnancy\*
This medicine is intended for use by men only.
This medicine is not indicated in pregnant or breast-feeding women.
Pregnant women must avoid any contact with this medicine(see section 4.4) because this product may have adverse virilising effects on the foetus. In the event of inadvertent skin-to-skin contact, thoroughly wash with soap and water as soon as possible.
\*Breast-feeding\*
This medicine is not indicated in women who are breast-feeding.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 adverse reactions listed in the table are based on post-marketing data, clinical trials and class-effects.
a. \*Summary of the safety profile\*
The most frequently observed clinical adverse drug reactions at the recommended dosage per day were skin reactions at the application site, (erythema, acne, dry skin), anxiety and asthenia.
\*b. Tabulated list of adverse reactions\*
\*\*Adverse reactions reported in clinical trials and derived from post-marketing experience via spontaneous reports or literature cases are listed below.\*\*
Adverse effects have been ranked under headings of frequency using the following
convention: very common (≥ 1/10); common (≥ 1/100; <1/10); uncommon (≥ 1/1,000;<1/100); rare (≥ 1/10,000;<1/1,000); very rare (<1/10,000); frequency not known (cannot be estimated from the available data). Within each frequency category, adverse reactions are presented in order of decreasing seriousness.
| | | | | | |
| --- | --- | --- | --- | --- | --- |
| | \*\*Adverse Reaction Tabulation for Transdermal Testosterone.\*\* | | | | |
| \*\*MedDRA\*\* \*\*System Organ Class\*\* | \*\*Adverse reactions – preferred term\*\* | | | | |
| \*\*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)\*\* | \*\*Frequency not known\*\* (cannot be estimated from the available data) | |
| Neoplasms benign, malignant and unspecified (incl. cysts and polyps) | | | Hepatic Neoplasm | | Prostate Cancer | |
| 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 | |
| Psychiatric disorders | Mood Disorders, Emotional symptoms (mood swings, affective disorder, anger, aggression, impatience, insomnia, abnormal dreams, increased libido) | | | | Nervousness, Depression, Hostility | |
| Nervous system disorders | Dizziness, Paraesthesia, Amnesia, Hyperaesthesia Headache | | | | | |
| Vascular disorders | Hypertension | Malignant hypertension, Hot flushes/flushing, Phlebitis | | | | |
| Respiratory, thoracic and mediastinal disorders | | | | | Sleep apnoea | |
| Gastrointestinal disorders | Diarrhoea | Oral pain, Abdominal distension | | | | |
| Hepatobiliary disorders | | | | Jaundice, Liver function test abnormalities | | |
| Skin and subcutaneous tissue disorders | Alopecia Urticaria, | Acne, , Hirsutism, Rash, Dry Skin, Seborrhoea, Skin lesions, Contact dermatitis, Hair colour changes, application site hypersensitivity, application site pruritus | | | skin reactions2 | |
| Renal and urinary disorders | | | | | Urinary tract obstruction | |
| Musculoskeletal and connective tissue disorders | | | | | Muscle Cramps | |
| Reproductive system and breast disorders | Gynaecomastia1 | Nipple disorder, Prostate-abnormalities, Testicular pain, Increased frequency of erections | Priapism | | Libido changes, therapy with high dose of testosterone preparations commonly reversibly interrupts or reduces spermatogenesis, thereby reducing the size of the testicles | |
| General disorders and administration site conditions | Application site reaction | Pitting oedema, | | | Asthenia, Malaise, oedema, hypersensitivity reactions, increases the occurrences of water retention and oedema3 | |
| Investigations | Changes in laboratory tests (polycythaemia, lipids), Haematocrit increased, Haemoglobin increased, Red blood cell count increased | PSA increased | | | Weight gain | |
| 1. May develop and persist in patients treated for hypogonadism with testosterone 2. skin reactions, because of the alcohol contained in the product, frequent applications to the skin may cause irritation and dry skin 3. High dose or long-term administration of testosterone occasionally increases the occurrences of water retention and oedema | | | | | | |
\*\*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
Yellow Card Scheme
Website: www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store4.9 Overdose
\*Symptoms\*
Serum testosterone levels should be measured if clinical signs and symptoms indicative of overexposure to androgen are observed. Application site rash has also been reported in case reports of overdose with this medicine.
\*Treatment\*
Treatment of overdosage consists of washing the application site immediately and discontinuing treatment if advised by the treating physician.
## Pharmacological Properties
5.1 Pharmacodynamic properties
Pharmacotherapeutic group: Androgens. ATC code: G03B A03.
Endogenous androgens, testosterone, secreted by the testes and its major metabolite DHT, are responsible for the development of the external and internal genital organs and for maintaining the secondary sexual characteristics (stimulating hair growth, deepening of the voice, development of the libido). Androgens have also an effect on protein anabolism, on development of skeletal muscle and body fat distribution and also reduce urinary nitrogen, sodium, potassium, chloride, phosphate and water excretion.
Testosterone reduces the pituitary secretion of gonadotropins.
The effects of testosterone in some target organs arise after peripheral conversion of testosterone to estradiol, which than binds to oestrogen receptors in the target cell nucleus \*e.g.\* the pituitary, fat, brain, bone and testicular Leydig cells.5.2 Pharmacokinetic properties
\*Absorption\*
The percutaneous absorption of testosterone after administration of this medicine lies between 1% and 8.5%.
\*Distribution\*
Following percutaneous absorption, testosterone diffuses into the systemic circulation and provides relatively constant concentrations during the 24 hour cycle.
Serum testosterone concentrations increase from the first hour after an application, reaching steady state from day two. Daily changes in testosterone levels are then of similar amplitude to those observed during the circadian rhythm of endogenous testosterone. The percutaneous route therefore avoids the blood distribution peaks produced by injections. It does not produce supra-physiological hepatic concentrations of the steroid in contrast to oral androgen therapy.
\*Biotransformation\*
Administration of 2.5 g of this medicine produces an average testosterone level increase of approximately 2.2 ng/ml (7.7 nmol/l) in plasma.
When treatment is stopped, testosterone levels start decreasing approximately 24 hours after the last administration. Testosterone levels return to baseline approximately 72 to 96 hours after the final administration.
The major active metabolites of testosterone are dihydrotestosterone and oestradiol.
\*Elimination\*
Testosterone is excreted mostly in urine as conjugated testosterone metabolites and a small amount is excreted unchanged in the faeces.
In the phase III double blind study at the end of a 112 day treatment period, during which the dose of this medicine could be titrated based on total testosterone concentrations, 81.6% (CI 75.1-87.0%) of men had total testosterone levels within the normal range for eugonadal young men (300 -1000 ng/dl). In patients on a daily dose of this medicine the average (± SD) daily testosterone concentration on day 112 (Cav) was 561 (± 259) ng/dl, mean Cmax was 845 (± 480) ng/dl and mean Cmin was 334 (± 155) ng/dl. The corresponding concentrations on Day 182 (double blind period) were Cav 536 (± 236) ng/dl, mean Cmax 810 (± 497) ng/dl and mean Cmin 330 (± 147) ng/dl.
In the phase III open label study at the end of a 264 day treatment period, during which the dose of this medicine could be titrated based on total testosterone concentrations, 77 % (CI 69.8-83.2%) of men had total testosterone levels within the normal range for eugonadal young men (300 -1000 ng/dl).
In patients on a daily dose of this medicine the average (± SD) daily testosterone concentration on day 266 (Cav) was 459 (± 218) ng/dl, mean Cmax was 689 (± 414) ng/dl and mean Cmin was 305 (± 121) ng/dl. The corresponding concentrations on Day 364 (extended open-label period) were Cav 454 (± 193) ng/dl, mean Cmax 698 (± 382) ng/dl and mean Cmin 302 (± 126) ng/dl.5.3 Preclinical safety data
Testosterone has been found to be non-mutagenic \*in vitro\* using the reverse mutation model (Ames test) or Chinese hamster ovary cells. A relationship between androgen treatment and certain cancers has been found in studies on 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 importance of these findings and the actual risk in human beings is unknown.
The administration of exogenous testosterone has been reported to suppress spermatogenesis in the rat, dog and non-human primates, which was reversible on cessation of the treatment.
## Pharmaceutical Particulars
6.1 List of excipients
Carbomer 980
Isopropyl myristate
Ethanol 96%
Sodium hydroxide
Purified water6.2 Incompatibilities
Not applicable.6.3 Shelf life
3 years.6.4 Special precautions for storage
This medicinal product does not require any special storage conditions.6.5 Nature and contents of container
Multi-dose container (comprised of a polypropylene canister with an LDPE lined pouch) with metering pump that contains 88 g gel and delivers a minimum of 60 doses.
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| --- | --- |
| Pack sizes: | |
| | 1 container per carton Supplied in packs of 1, 2, 3 or 6 containers |
Not all pack sizes may be marketed.6.6 Special precautions for disposal and other handling
No special requirements.
