Consumer medicine information

Testavan

Testosterone

BRAND INFORMATION

Brand name

Testavan

Active ingredient

Testosterone

Schedule

SUMMARY CMI

TESTAVAN^®

Consumer Medicine Information (CMI) summary

The full CMI on the next page has more details. If you are worried about using this medicine, speak to your doctor or pharmacist.

1. Why am I using TESTAVAN?

TESTAVAN contains the active ingredient testosterone. TESTAVAN is used only in adult men, to replace the body's natural hormone, testosterone, when not enough is made by the body.

For more information, see Section 1. Why am I using TESTAVAN? in the full CMI.

2. What should I know before I use TESTAVAN?

Do not use if you have ever had an allergic reaction to testosterone, propylene glycol or any of the ingredients listed at the end of the CMI.

Talk to your doctor if you have any other medical conditions, take any other medicines, or are pregnant or plan to become pregnant or are breastfeeding.

For more information, see Section 2. What should I know before I use TESTAVAN? in the full CMI.

3. What if I am taking other medicines?

Some medicines may interfere with TESTAVAN and affect how it works.

A list of these medicines is in Section 3. What if I am taking other medicines? in the full CMI.

4. How do I use TESTAVAN?

The usual starting dose is 23 mg testosterone (one pump actuation) per day.
Read the package leaflet before use.

More instructions can be found in Section 4. How do I use TESTAVAN? in the full CMI.

5. What should I know while using TESTAVAN?

Things you should do	Remind any doctor, dentist or pharmacist you visit that you are using TESTAVAN. Keep all of your doctor's appointments.
Things you should not do	Do not stop using TESTAVAN or lower the dosage without first checking with your doctor.
Driving or using machines	This medicine is not expected to affect your ability to drive a car or operate machinery.
Looking after your medicine	Keep TESTAVAN in a cool dry place where the temperature stays below 25°C. Store TESTAVAN in the original container. Store TESTAVAN away from moisture, heat or sunlight

For more information, see Section 5. What should I know while using TESTAVAN? in the full CMI.

6. Are there any side effects?

Common side effects are headaches, skin reactions, easy bruising, and high blood pressure.

For more information, including what to do if you have any side effects, see Section 6. Are there any side effects? in the full CMI.

FULL CMI

TESTAVAN^®

Active ingredient: testosterone

Consumer Medicine Information (CMI)

This leaflet provides important information about using TESTAVAN. You should also speak to your doctor or pharmacist if you would like further information or if you have any concerns or questions about using TESTAVAN.

For detailed instructions on how to apply TESTAVAN, please read the package insert before use.

Where to find information in this leaflet:

1. Why am I using TESTAVAN?
2. What should I know before I use TESTAVAN?
3. What if I am taking other medicines?
4. How do I use TESTAVAN?
5. What should I know while using TESTAVAN?
6. Are there any side effects?
7. Product details

1. Why am I using TESTAVAN?

TESTAVAN contains the active ingredient testosterone.

TESTAVAN is used only in adult men, to replace the body's natural hormone, testosterone, when not enough is made by the body.

Testosterone is a natural male hormone, known as an androgen, which controls normal sexual development and function in men.

2. What should I know before I use TESTAVAN?

Warnings

Do not use TESTAVAN if:

you are allergic to testosterone, propylene glycol, or any of the ingredients listed at the end of this leaflet.
Always check the ingredients to make sure you can use this medicine.
you are a woman or a child.
you have or are suspected to have prostate cancer.
you have or are suspected to have breast cancer in males.

Check with your doctor if you:

have or have had any other medical conditions including the following:
- high blood calcium levels associated with tumours (hypercalcaemia)
- high levels of calcium in the urine (hypercalciuria)
- high blood pressure or problems with your heart
- a tendency to retain fluid (signs may include swollen feet or ankles)
- problems with your liver
- problems with your kidneys
- epilepsy
- migraines
- sleep apnoea (problems with breathing during sleep)
- a blood disorder where your body produces too many red blood cells
- thrombophilia (a condition where you have an increased risk of blood clots in your blood vessels)
- thrombosis (blood clots) in the deeper veins of the body such as in your legs (deep-vein thrombosis), in the lungs (pulmonary embolism) or in the veins of the eye (ocular thrombosis).

Before treatment with TESTAVAN your doctor will organise tests for prostate or breast cancer.

TESTAVAN may increase the risk of benign prostatic hyperplasia (enlargement of the prostate gland) and/or prostate cancer. It may also increase the risk of breast cancer in males.

If you use TESTAVAN over long periods of time, you may develop an abnormal increase in the number of red blood cells in the blood (polycythaemia). Your doctor may organise regular blood counts to monitor this.

Athletes should note that the active ingredient, testosterone, may produce a positive reaction in anti-doping tests.

Tell your doctor if you take any medicines for any other condition.

During treatment, you may be at risk of developing certain side effects. It is important you understand these risks and how to monitor for them. See additional information under Section 6. Are there any side effects?

Women

TESTAVAN must not be used by women, particularly if they are, or anticipate becoming, pregnant or are breastfeeding.

Pregnant women must avoid any contact with TESTAVAN treated skin.

Men capable of fathering children

TESTAVAN should not be used by men desiring fertility.

Children

TESTAVAN must not be used by children under the age of 18 years.

3. What if I am taking other medicines?

Tell your doctor or pharmacist if you are taking any other medicines, including any medicines, vitamins or supplements that you buy without a prescription from your pharmacy, supermarket or health food shop.

Some medicines may interfere with TESTAVAN and affect how it works. These include:

oral anticoagulants, such as warfarin, medicines used to thin blood and to treat or prevent blood clots
corticosteroids such as prednisone or hydrocortisone, or adrenocorticotropic hormone (ACTH), hormones used to control inflammation
insulin, a medicine used to control blood sugar levels.

These medicines may be affected by TESTAVAN, or may affect how well it works. You may need to take different amounts of your medicine, or you may need to take different medicines. Your doctor will advise you.

Check with your doctor or pharmacist if you are not sure about what medicines, vitamins or supplements you are taking and if these affect TESTAVAN.

4. How do I use TESTAVAN?

How much to use

The usual starting dose is 23 mg testosterone (one pump actuation) per day. You should not use more than 69 mg testosterone per day (which is equivalent to three pump actuations). Your doctor will tell you the dose of TESTAVAN that is right for you.

When to use TESTAVAN

Apply TESTAVAN once daily at approximately the same time each day, preferably in the morning.
TESTAVAN helps control the symptoms of your condition but does not cure it. Continue taking your medicine for as long as your doctor tells you.

How to use TESTAVAN

Before beginning therapy and each time you get a new pack, you should read the package insert, which contains detailed instructions for use.

Prior to using TESTAVAN you should read the package insert, which contains detailed instructions for use.

If you do not understand the instructions printed on the pharmacist label or in the package insert, ask your doctor or pharmacist for help.

Use TESTAVAN exactly as your doctor tells you to use it.

TESTAVAN is to be applied to the skin of the upper arm and shoulder only.

Before applying TESTAVAN, make sure the skin is clean, dry and that there is no broken skin.

Apply TESTAVAN to the skin using the applicator. Do not apply TESTAVAN with fingers or hands.

Hands should be washed well with soap and water after TESTAVAN has been applied.

Avoid swimming or showering for at least two (2) hours after applying TESTAVAN.

TESTAVAN is flammable until dry. Avoid fire, flame or smoking until the gel has dried.

Follow these steps when using TESTAVAN multi-dose pump:

Before using the pump for the first time, prime the pump by pressing the pump head all the way down over a tissue paper until gel appears.
Repeat (4) four more times by pressing the pump head all the way down into a tissue. Do not use the gel that appears.
Throw the used tissue into a rubbish bin to avoid accidental exposure to others.
Your TESTAVAN pump is ready to use.
The content of only one pump actuation should be applied to the applicator at a time.
The applicator should be used to spread the gel evenly across the skin of one upper arm and shoulder. Do not get any gel on your hands.
Allow the gel to dry completely before getting dressed.
When more than one pump actuation is needed, the procedure is repeated to the other arm and shoulder (as described in Table 1).

Table 1: Dosing Information for TESTAVAN 2% w/w Gel

Testosterone Dose	Application Method
23 mg (1 pump actuation)	Apply one pump actuation to an upper arm and shoulder.
46 mg (2 pump actuations)	Apply one pump actuation to an upper arm and shoulder. Repeat to apply one pump actuation to the opposite upper arm and shoulder.
69 mg (3 pump actuations)	Apply one pump actuation to an upper arm and shoulder. Repeat to apply one pump actuation to the opposite upper arm and shoulder. Repeat again to apply the third pump actuation to the initial upper arm and shoulder.

If you forget to use TESTAVAN

TESTAVAN should be used regularly at the same time each day.

If you forget to apply a dose, apply it as soon as you remember.

If you do not remember to apply the dose until the next dose is due, then just apply one dose.

Do not apply a double dose to make up for the dose that you missed.

If you use too much TESTAVAN

If you think that you have used too much TESTAVAN, you may need urgent medical attention.

Wash the skin with soap and water and immediately:
phone the Poisons Information Centre
(by calling 13 11 26), or
contact your doctor, or
go to the Emergency Department at your nearest hospital.

You should do this even if there are no signs of discomfort or poisoning.

5. What should I know while using TESTAVAN?

Things you should do

If you are about to be started on any new medicine, remind your doctor and pharmacist that you are taking TESTAVAN.

Remind any other doctors, dentists, and pharmacists who treat you that you are using this medicine.

Keep all of your doctor's appointments. Your doctor may monitor your blood pressure, examine your prostate, and conduct other tests (including blood tests) from time to time, particularly if you are elderly. This is to make sure the medicine is working and to check for unwanted side effects.

The use of TESTAVAN may affect the results of certain laboratory tests. If you are about to have any tests, tell your doctor that you are using this medicine.

Athletes should note that the active ingredient, testosterone, may produce a positive reaction in anti-doping tests.

Things you should not do

Do not use TESTAVAN to treat any other complaints unless your doctor tells you to.
Do not give your TESTAVAN to anyone else, even if they have the same condition as you.
Do not stop using TESTAVAN or lower the dosage without first checking with your doctor.

Unwanted transfer of TESTAVAN to others

TESTAVAN can transfer from your body to others. This can happen if other people come into contact with the area where TESTAVAN was applied.
If you expect another person to have direct skin-to-skin contact with the application area, wash the contact area well with soap and water.
Unwanted transfer of testosterone to another person can be substantially reduced by wearing a shirt or similar.
You should have a shower or bath before having intimate physical contact.
Women and children should avoid contact with the unwashed or unclothed area where TESTAVAN has been applied. If your partner is pregnant, it is particularly important that you take care to protect her from testosterone. If a woman or child contacts the application area, the contact area on the woman or child should be washed well with soap and water immediately.

Signs of increased testosterone in children include enlarged penis or clitoris, early development of pubic hair, increased erections or sex drive, and aggressive behaviour. In women, this may include changes in body hair and the development or worsening of acne.

Driving or using machines

This medicine is not expected to affect your ability to drive a car or operate machinery.

Drinking alcohol

Tell your doctor if you drink alcohol.

Alcohol may [insert effect relevant to use of the medicine].

Looking after your medicine

Keep TESTAVAN in a cool dry place where the temperature stays below 25°C.
Store TESTAVAN in the original container.

Store TESTAVAN away from moisture, heat or sunlight; for example, do not store it:

in the bathroom or near a sink, or
in the car or on window sills.

Follow the instructions in the carton on how to take care of your medicine properly.

Keep it where young children cannot reach it.

When to discard your medicine (as relevant)

Discard the medicine, if your doctor tells you to stop using this medicine, the expiry date has passed, or more than 60 days have passed since you first opened the dispenser bottle.

Getting rid of any unwanted medicine

Take it to any pharmacy for safe disposal.

6. Are there any side effects?

All medicines can have side effects. If you do experience any side effects, most of them are minor and temporary. However, some side effects may need medical attention.

See the information below and, if you need to, ask your doctor or pharmacist if you have any further questions about side effects.

Less serious side effects

Less serious and common effects	What to do
headaches Skin-related: skin reactions such as rash, redness, itching, dryness, and/or irritation Blood or heart-related: high levels of haemoglobin, the substance that carries oxygen in the blood high triglyceride (fat) levels in the blood increased levels of an enzyme, prostate-specific antigen (PSA), in the blood easy bruising and/or the formation of blood clots high blood pressure	Speak to your doctor if you have any of these less serious side effects and they worry you.
Side effects due to high doses or long-term treatment	What to do
increased tendency to retain fluid (signs may include swollen feet or ankles) decreased sperm count, which may affect fertility unwanted, frequent or prolonged and painful erections severe stomach pain or tenderness, which do not disappear within a short time increased risk of weight gain	Speak to your doctor if you have any of these less serious side effects and they worry you.

Serious side effects

Serious side effects	What to do
Allergic reaction Some of the symptoms of an allergic reaction may include: shortness of breath wheezing or difficulty breathing swelling of the face, lips, tongue, or other parts of the body. rash, itching or hives on the skin	Call your doctor straight away, or go straight to the Emergency Department at your nearest hospital if you notice any of these serious side effects.

Tell your doctor or pharmacist if you notice anything else that may be making you feel unwell.

Other side effects not listed here may occur in some people.

Reporting side effects

After you have received medical advice for any side effects you experience, you can report side effects to the Therapeutic Goods Administration online at www.tga.gov.au/reporting-problems. By reporting side effects, you can help provide more information on the safety of this medicine.

Always make sure you speak to your doctor or pharmacist before you decide to stop taking any of your medicines.

7. Product details

This medicine is only available with a doctor's prescription.

What TESTAVAN contains

Active ingredient (main ingredient)	23 mg of testosterone per 1.15 g of gel.
Other ingredients (inactive ingredients)	ethanol purified water propylene glycol diethylene glycol monoethyl ether carbomer 980 trolamine disodium edetate

Do not take this medicine if you are allergic to any of these ingredients.

Each metered-dose pump contains 85.5 g of gel. Each pump can dispense 56 metered individual doses of 1.15 g of gel (1.25 mL). Each dose contains 23 mg of testosterone.

What TESTAVAN looks like

TESTAVAN is a clear to slightly rainbow-like gel in a non-aerosol metered-dose pump dispenser with a cap applicator. (Aust R 277958).

Who distributes TESTAVAN

Clinect Pty Ltd
120-132 Atlantic Drive
Keysborough VIC 3173
Telephone: 1800 899 005

This leaflet was prepared in August 2022

Published by MIMS October 2022

BRAND INFORMATION

Brand name

Testavan

Active ingredient

Testosterone

Schedule

1 Name of Medicine

Testosterone.

2 Qualitative and Quantitative Composition

Testavan contains 20 mg (2% w/w) testosterone in one gram of gel. It is presented in a metered-dose pump. One pump actuation delivers 1.15 g (in 1.25 mL) of gel, equivalent to 23 mg of testosterone. Each pump contains 85.5 g of gel capable of dispensing 56 metered individual doses.

Excipient with known effect.

Propylene glycol.
For the full list of excipients, see Section 6.1 List of Excipients.

3 Pharmaceutical Form

Gel.
Testavan is a translucent to slightly opalescent, hydroalcoholic transdermal gel.

4 Clinical Particulars

4.1 Therapeutic Indications

Testavan is indicated for use as testosterone replacement therapy for adult male hypogonadism when testosterone deficiency has been confirmed by clinical features and biochemical tests.

4.2 Dose and Method of Administration

Dosage.

Adult men.

The recommended starting dose is 23 mg testosterone (one pump actuation) applied once daily, preferably in the morning. To ensure proper dosing, serum testosterone levels should be periodically measured and dose titrated to maintain serum testosterone levels.
The serum testosterone level should be measured 2 to 4 hours after dosing approximately 14 days and 35 days after starting treatment or after a dose adjustment. If the serum testosterone concentration is below 17.3 nanomol/L (500 nanogram/dL), the daily Testavan dose may be increased by 1 pump actuation. If the serum testosterone concentration exceeds 36.4 nanomol/L (1050 nanogram/dL), the daily dose may be decreased by 1 pump actuation.
Dose titration should be based on both serum testosterone levels and the existence of clinical signs and symptoms related to testosterone deficiency.
Patients switching from another testosterone product to Testavan should have their dosage titrated according to serum testosterone levels and clinical signs and symptoms following the instructions in the dosage and administration section.

Maximum recommended dose.

The maximum recommended dose is 69 mg testosterone per day, which is equivalent to 3 pump actuations of Testavan.

Dosage adjustment in special populations.

Elderly.

Use the same dosage in the elderly as recommended under Adult men. However, it should be taken into account that physiological testosterone levels are lower with increasing age (see Section 4.4 Special Warnings and Precautions for Use).

Renal impairment.

There are no studies undertaken to demonstrate the efficacy and safety of this medicinal product in patients with renal impairment. Therefore, testosterone replacement therapy should be used with caution in these patients (see Section 4.4 Special Warnings and Precautions for Use).

Hepatic impairment.

There are no studies undertaken to demonstrate the efficacy and safety of this medicinal product in patients with hepatic impairment. Therefore, testosterone replacement therapy should be used with caution in these patients (see Section 4.4 Special Warnings and Precautions for Use).

Female population.

Testavan is not indicated for use in women.

Paediatric use.

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

Method of administration.

For transdermal use.
Testavan should be administered by the patient using the applicator, onto clean, dry, healthy skin over the upper arm and shoulder. Patients should be instructed not to apply Testavan with fingers or hands.

Priming of new pump.

To ensure correct dosing, patients should be instructed to prime each new pump before using it for the first time by pressing the pump head all the way down over a tissue paper until gel appears. Discard the initial gel that appears and the gel from 4 subsequent pump actuations and safely discard the used tissue paper.
To apply the gel to the applicator head first remove the applicator lid and place the applicator head under the pump head. The pump head should be pressed all the way down once over the applicator head.
Patients should be instructed that the content of only one pump actuation should be applied onto the applicator at a time. The applicator should be used to spread the gel evenly across the maximum surface area of one upper arm and shoulder, making sure not to get any gel on the hands. When more than one pump actuation is needed to achieve the required daily dose, the procedure is repeated to the other upper arm and shoulder. See Table 1.

Cleaning of the applicator.

After use the applicator should be cleaned with a tissue and the protective lid restored on top of the applicator. The used tissue paper should be safely thrown away and the product stored safely out of reach of children.

Following administration.

If the gel was touched with the hands during the application procedure, patients should be instructed to wash their hands with water and soap immediately after applying Testavan.
Patients should be advised to let the application site dry completely before getting dressed. Patients should be advised to wait 1-2 hours before showering, swimming or bathing to prevent reduced testosterone absorption (see Section 4.4 Special Warnings and Precautions for Use).
Patients should be advised to wear clothing that covers the application site at all times to prevent accidental transfer to others.

4.3 Contraindications

Testavan is contraindicated in cases of known hypersensitivity to the active substance, propylene glycol or to any of the excipients.
Testavan is contraindicated in men with known or suspected carcinoma of the breast or the prostate (see Section 4.4 Special Warnings and Precautions for Use).
Testavan is contraindicated in all women, including women who are or may become pregnant or who are breastfeeding (see Section 4.4 Special Warnings and Precautions for Use).

4.4 Special Warnings and Precautions for Use

Testavan should only be used if hypogonadism 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 and confirmed by 2 separate blood testosterone measurements before initiating therapy with any testosterone replacement, including Testavan treatment.
Androgens may accelerate the progression of sub-clinical prostate cancer and benign prostatic hyperplasia.
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).
Testavan should be used with caution in cancer patients at risk of hypercalcaemia (and associated hypercalciuria), due to bone metastases. Regular monitoring of serum calcium concentrations is recommended in these patients.
Testavan is not a treatment for male sterility or impotence. Testavan should not be used in men desiring fertility.
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. Certain clinical signs: irritability, nervousness, weight gain, prolonged or frequent erections may indicate excessive androgen exposure requiring dosage adjustment.
There is limited experience on the safety and efficacy of the use of Testavan in patients over 65 years of age. Currently, there is no consensus concerning age specific reference values for testosterone. However it should be taken into consideration that physiological testosterone serum levels are lower with increasing age.
Testosterone may cause a rise in blood pressure and Testavan should be used with caution in men with hypertension.
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 this case, treatment must be stopped immediately.
Testosterone should be used with caution in patients with ischemic heart disease, epilepsy and migraine, as these conditions may be aggravated.
There are published reports of an increased risk of sleep apnoea in hypogonadal men treated with testosterone esters, especially in those with risk factors, such as obesity or chronic respiratory disease.
If the patient develops a severe application site reaction, treatment should be reviewed and discontinued if necessary.
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.
Athletes treated for testosterone replacement in primary and secondary male hypogonadism should be advised that the product contains an active substance which may produce a positive reaction in anti-doping tests. Androgens are not suitable for enhancing muscular development in healthy individuals or for increasing physical ability.
Testavan should not be used in women due to possible virilising effects.
As washing after Testavan administration reduces testosterone levels, patients are advised not to wash or shower for at least 1 to 2 hours after applying Testavan. When washing occurs up to 1 to 2 hours after the gel application, the absorption of testosterone may be reduced.
Testavan contains propylene glycol, which may cause skin irritation.
Alcohol-based products including Testavan are flammable; therefore avoid fire, flame or smoking until the gel has dried.

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 precaution is taken, testosterone gel can be transferred to other persons by close skin to skin contact, resulting in increased testosterone serum levels in the recipient 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 doctor should inform the patient carefully about the risk of testosterone transfer and about the safety instructions below. Testavan should not be prescribed for patients who are unlikely to comply with the safety instructions (e.g. severe alcoholism, drug abuse, severe psychiatric disorders).
Testosterone transfer can be prevented by wearing clothes covering the application area or showering prior to contact.
As a result, the following Safety Instructions are recommended.

For the patient.

Use the cap applicator for hands-free administration to reduce the risk of secondary exposure to testosterone.
If the gel was touched with the hands during the application procedure, wash hands thoroughly with soap and water after applying the gel.
Cover the application area with clothing once the gel has dried.
Shower before any situation in which skin to skin contact with another person is foreseen.

For people not being treated with Testavan.

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 to 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 long interval between Testavan application and sexual intercourse, to wear a T-shirt covering the application site during contact period, or to shower before sexual intercourse.
Furthermore, it is recommended to wear a T-shirt covering the application site during contact periods with children in order to avoid a contamination risk of children's skin.
Pregnant women must avoid any contact with Testavan application sites. In case of pregnancy of the partner, the precautions for use must be reinforced to the patient (see Section 4.6 Fertility, Pregnancy and Lactation, Use in pregnancy).

Use in hepatic impairment.

Use in renal impairment.

Use in the elderly.

There is limited experience on the safety and efficacy of the use of Testavan in patients over 65 years of age.

Paediatric use.

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

Effects on laboratory tests.

Androgens may decrease concentrations of thyroxin-binding globulins, resulting in decreased total serum thyroxine (T4) concentration and increased resin uptake of triiodothyronine (T3) and T4. Free thyroid hormone concentration remains unchanged and there is no clinical evidence of thyroid dysfunction.

4.5 Interactions with Other Medicines and Other Forms of Interactions

When androgens are given simultaneously with anticoagulants, the anticoagulant effects can increase. Patients receiving oral anticoagulants require close monitoring of their international normalized ratio (INR), especially when androgen treatment is started or stopped.
The concurrent administration of testosterone with adrenocorticotropic hormone (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.
Improved insulin sensitivity may occur in patients treated with androgens who achieve normal testosterone plasma concentrations following replacement therapy.

4.6 Fertility, Pregnancy and Lactation

Effects on fertility.

Fertility studies in rodents and primates have shown that treatment with testosterone can impair fertility by suppressing spermatogenesis in a dose dependent manner.
Testavan should not be used in men desiring fertility (see Section 4.4 Special Warnings and Precautions for Use).
(Category D)
Testavan must not be used in women who are or may become pregnant (see Section 4.3 Contraindications).
Pregnant women should avoid skin contact with Testavan application sites (see Section 4.4 Special Warnings and Precautions for Use, Potential for transfer).
In the event that unwashed or unclothed skin to which Testavan has been applied does come into direct contact with the skin of a pregnant woman, the general area of contact on the woman should be washed with soap and water immediately.
Testosterone may induce virilising effects on the fetus.
Testavan is contraindicated during breastfeeding. In the event of accidental contact, women are advised to immediately wash with soap and water.

4.7 Effects on Ability to Drive and Use Machines

Testavan has no or negligible influence on the ability to drive and use machines.

4.8 Adverse Effects (Undesirable Effects)

The most commonly reported adverse reactions in phase 2 and phase 3 clinical trials lasting up to 9 months were application site reactions (4%), including rash, erythema, pruritus, dermatitis, dryness, and skin irritation. The majority of these reactions were mild to moderate in severity.
Adverse drug reactions reported in 1 to < 10% of patients treated with Testavan in the phase 2 and phase 3 clinical trials are listed in Table 2. This safety data is based on 395 hypogonadal patients studied in clinical trials. All adverse reactions reported with a suspected relationship are listed by class and frequency in Table 2:
Because of the alcohol contained in the product, frequent applications to the skin may cause irritation and dry skin.
A meta-analysis of clinical trials of testosterone replacement therapy have identified the following additional adverse effect: slight reduction in serum high-density lipoprotein (HDL) cholesterol.

Post marketing experience.

There have been reports of venous thromboembolism in patients using products containing testosterone.
Increased risk of weight gain.

Reporting suspected adverse effects.

Reporting suspected adverse reactions after registration 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 at www.tga.gov.au/reporting-problems.

4.9 Overdose

No case of overdose with Testavan has been reported in clinical trials.

Symptoms.

Clinical signs such as irritability, nervousness, weight gain, prolonged or frequent erection can indicate overexposure to androgen and serum testosterone levels should therefore be measured.

Treatment.

Treatment of overdosage consists of discontinuation of Testavan together with appropriate symptomatic and supportive care.
For information on the management of overdose, contact the Poison Information Centre on 13 11 26 (Australia). Do this even if there are no signs of discomfort or poisoning. Wash the skin with soap and water.

5 Pharmacological Properties

5.1 Pharmacodynamic Properties

Pharmacotherapeutic group: Androgens.
ATC code: G03B A03.

Mechanism of action.

Testavan is an androgen replacement therapy containing the male hormone testosterone.
Testosterone and its major metabolite dihydrotestosterone (DHT), endogenous androgens, are responsible for the normal growth and development of the male sex organs and for the maintenance of secondary sex characteristics. These effects include the growth and maturation of the prostate, seminal vesicles, penis and scrotum; the development of male hair distribution on the face, chest, axillae and pubis; and laryngeal enlargement, vocal cord thickening, alterations in body musculature and fat distribution.
Insufficient secretion of testosterone, due to testicular failure, pituitary pathology or gonadotropin or luteinising hormone-releasing hormone deficiency, results in male hypogonadism and low serum testosterone concentration. Symptoms associated with low testosterone include decreased sexual desire with or without impotence, fatigue, loss of muscle mass, mood depression and regression of secondary sexual characteristics.
Restoring testosterone levels to within the normal range can result in improvements over time in muscle mass, mood, sexual desire, libido and sexual function, including sexual performance and number of spontaneous erections.
During exogenous administration of testosterone to normal males, endogenous testosterone release may be decreased through feedback inhibition of pituitary luteinising hormone (LH). With large doses of exogenous androgens, spermatogenesis may also be suppressed through inhibition of pituitary follicle stimulating hormone (FSH).
Androgen administration causes retention of sodium, nitrogen, potassium and phosphorus and decreased urinary excretion of calcium. Androgens have been reported to increase protein anabolism and decrease protein catabolism. The nitrogen balance is improved only with sufficient intake of calories and protein. Androgens have been reported to stimulate the production of red blood cells by enhancing the production of erythropoietin.

Clinical trials.

Testavan was evaluated in a multi-centre, open-label, 120-day phase 3 clinical study (Study 000127) in 159 hypogonadal men aged 18 to 75 years (mean age 54.1 years). Subjects were white (77%), African American (20%), Asian (2%) or multiracial (1%).
Subjects applied 23, 46 or 69 mg of testosterone (i.e. one, two or three pump actuations of Testavan) each morning to the skin of the shoulders and upper arms. The starting dose of testosterone was 23 mg, and the dose was titrated based on the testosterone levels at 4 hours after gel application on Days 14, 35 and 56. For the rest of the 120-day study, subjects continued to administer the dose based on the Day 56 testosterone level.
The primary efficacy analysis was the percent of responders, defined as subjects with an average serum total testosterone concentration over 24 hours (C_avg(0-24)) between 10.4 and 36.4 nanomol/L, on Day 90. The primary analysis included 155 subjects who had sufficient testosterone profile data to determine a C_avg(0-24) at any time point or had discontinued study treatment early for safety reasons. Subjects who discontinued the study early for safety reasons were considered non-responders. If the Day 90 C_avg(0-24) value was not available, the last available value was used.
Of the 153 subjects included in the analysis (Full Analysis Dataset (FAS) population), 77.8% had a C_avg(0-24) between 10.4 and 36.4 nanomol/L at Day 90; the study therefore met the pre-determined efficacy criteria (responder rate ≥ 75%) (Table 3, Figure 1). A total of 143 subjects had a full pharmacokinetic assessment at Day 90; the response rate for this group was 80.4% (Table 3, Figure 1).

The mean serum concentration of testosterone on Day 90 after titration by dose in Study 000127 is shown in Figure 1.

In the 139 subjects who completed the Day 90 assessment, total testosterone and DHT mean concentrations were in the normal range for all Testavan doses. On Day 90, the median T_max for testosterone occurred approximately 2 hours after the 46 mg and 69 mg doses and 4 hours after the 23 mg dose.
Table 4 summarises the pharmacokinetic parameters for total testosterone at Day 90 by Testavan Day 90 dose.

The long-term efficacy of Testavan was evaluated over 9 months in the 90-day Study 000023 and the 6-month extension Study 000077. In Study 000023, 180 hypogonadal men with a mean age of 18 to 75 years (mean age 56.8 years) were treated. Subjects were white (87.7%), African American (10.6%), Asian (1.1%), or American Indian or Alaskan Native (0.6%). Subjects applied 23, 46 or 69 mg of testosterone each morning to the skin of the shoulders and upper arms.
In Study 000023, the starting dose of testosterone was 46 mg; the dose was titrated up or down on Days 21 and 56. Subjects continued to administer the Day 56 dose for the rest of the 90-day study.
In the 6-month extension Study 000077, doses of 23, 46 or 69 mg testosterone were administered based on the final titrated dose and the pharmacokinetic assessment on Day 90 in Study 000023.
In the 110 subjects who completed 9 months of treatment with Testavan, the responder rate was 83%.

Effect of showering.

In a randomised, open-label, four-way crossover study, the effects of showering on the pharmacokinetics of total testosterone following application of Testavan 69 mg were assessed in 16 hypogonadal men. Subjects showered 1, 2 or 6 hours following application of Testavan, or did not shower. Each subject was randomly assigned to one of four showering condition sequences.
Showering 1 hour and 2 hours following Testavan administration decreased C_{avg (0-24)} by 19.2% and 14.3% respectively compared with subjects who did not shower after Testavan administration. Showering 6 hours following Testavan administration did not result in a decrease in C_avg(0-24).
In this study, residual testosterone on the skin at the application site was also determined. The concentration of residual testosterone ranged between 21.3 and 211 micrograms/mL in subjects who did not shower, and was between 0.885 (below the limit of detection) and 14.7 micrograms/mL in subjects who showered one hour after Testavan application.

5.2 Pharmacokinetic Properties

Absorption.

Testavan provides transdermal delivery of testosterone, mimicking the natural circadian rhythm in terms of temporal changes in testosterone levels, with a median T_max of approximately 2-4 hours after dosing.
Testavan delivers physiological amounts of testosterone, by providing a level of circulating testosterone similar to the normal level in healthy men (i.e. 10.4-36.4 nanomol/L).
In a phase 1 randomised open-label crossover bioavailability trial in 11 men in whom endogenous testosterone had been down-regulated, the bioavailability of Testavan when administered as a 50 mg dose on Days 1 and 7 of the study was 1.6-fold (p < 0.001) and 1.4-fold (p = 0.050) higher, respectively, than observed with the same dose of another proprietary testosterone gel (Testogel 1%; Figure 2).

In a phase 2 open-label, sequential, dose-escalation trial in 20 hypogonadal men, greater absorption of testosterone occurred following application to the shoulder and upper arm than following application to the thigh or abdomen, based on difference in C_avg (p < 0.05). In this study, serum testosterone concentration, with repeat dosing, generally decreased to their lowest levels approximately 8-9 hours after each dose. No accumulation in serum testosterone was observed after 10 days of daily applications.
In another phase 2 open-label, sequential, dose-escalation study in 20 hypogonadal men, the administration of 23, 46 and 69 mg Testavan with the applicator resulted in total serum testosterone and DHT concentrations that increased with increasing dose. Average serum total testosterone concentration profiles after 7 days of treatment are shown in Figure 3.
The dose effects of testosterone gel on C_max, C_min and C_avg were statistically significant (p < 0.05).

Distribution.

Circulating testosterone is chiefly bound in the serum to sex hormone-binding globulin (SHBG) and albumin. The albumin-bound fraction of testosterone easily dissociates from albumin and is presumed to be biologically active. The portion of testosterone bound to SHBG is not considered biologically active. Approximately 45% of testosterone in plasma is bound to SHBG, 2% remains unbound (free) and the rest is bound to albumin and other proteins.

Metabolism.

As reported in the literature, there is considerable variation in the half-life of testosterone, ranging from ten to 100 minutes. Testosterone is metabolised to various 17-keto steroids through two different pathways. The major active metabolites of testosterone are oestradiol and DHT.

Excretion.

About 90% of testosterone given intramuscularly is excreted in the urine as glucuronic and sulphuric acid 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

Genotoxicity.

Testosterone has been found to be non-mutagenic in vitro in bacteria using the reverse mutation model (Ames test), and non-clastogenic in vitro in assays with hamster lung fibroblasts and mouse hamster embryo fibroblasts, and negative in vivo in the mouse bone marrow micronucleus test. Testosterone was also negative in assays for unscheduled DNA synthesis in rat and human hepatocytes.

Carcinogenicity.

Sex hormones are known to promote the growth of certain hormone-dependent tissues and tumours. Subcutaneous implantation of testosterone produced cervical-uterine tumours in female mice, which metastasised in some cases. Metastasising prostatic adenocarcinomas occurred in male rats after chemical induction and subcutaneous implantation of testosterone. Testosterone promotes hepatocarcinogenesis in mice and rats. Hepatocellular carcinoma has been reported in patients receiving long-term therapy with androgens.
Chronic androgen deficiency is a protective factor for prostatic disease, and hypogonadal men receiving androgen replacement therapy require surveillance for prostatic disease similar to that recommended for eugonadal men of comparable age.

6 Pharmaceutical Particulars

6.1 List of Excipients

The excipients are ethanol, purified water, propylene glycol, diethylene glycol monoethyl ether, carbomer 980, trolamine and disodium edetate.
See Section 2 Qualitative and Quantitative Composition.

6.2 Incompatibilities

Incompatibilities were not assessed as part of the registration of this medicine.

6.3 Shelf Life

In Australia, information on shelf life can be found on the public summary of the Australian Register of Therapeutic Goods (ARTG). The expiry date can be found on the packaging.

6.4 Special Precautions for Storage

Store below 25°C. Store in the original package.
Once opened, do not use this product for longer than 60 days.

6.5 Nature and Contents of Container

Testavan is available for use in a metered-dose dispenser consisting of a pump with a laminate foil pouch in a bottle, and is provided with a cap applicator with a hygienic lid.
The pump is composed of polypropylene, ethylene propylene diene monomer and stainless steel and the pouch is a polyethylene/polyethylene terephthalate/aluminium/polyethylene laminate encased in rigid polypropylene bottle.
The product is available in packs of one metered-dose dispenser and a cap applicator with a hygienic lid.

6.6 Special Precautions for Disposal

In Australia, any unused medicine or waste material should be disposed of in accordance with local requirements.

6.7 Physicochemical Properties

Chemical structure.

Structure of the active substance.

Testosterone is an androgen.

Chemical name.

17β-hydroxyandrost-4-en-3-one and has the following structural formula:
Chemical Formula: C₁₉H₂₈O₂.
Molecular Weight: 288.4.
Physicochemical characteristics: Testosterone is an odourless or almost odourless, white, crystalline powder, produced semi-synthetically from plant origin. It is practically insoluble in water, freely soluble in ethanol (96%) and slightly soluble in ethyl oleate.

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