Consumer medicine information

ANDROFORTE 2

Testosterone

BRAND INFORMATION

Brand name

AndroForte 2

Active ingredient

Testosterone

Schedule

What is in this leaflet

This leaflet answers some of the common questions about ANDROFORTE® 2. It does not contain all the available information. It does not take the place of talking to your doctor or pharmacist. All medicines have risks and benefits. Your doctor has weighed the possible risks of you using ANDROFORTE® 2 against the benefits it can have for you.

If you have any concerns about using ANDROFORTE® 2 talk to your doctor or pharmacist. Keep this leaflet with the medicine. You may need to read it again.

What ANDROFORTE® 2 is used for?

ANDROFORTE® 2 contains the active ingredient testosterone. This form of testosterone is identical to the testosterone produced by the testes of men and the ovaries of women. Testosterone plays an important role in physical and sexual development, sexual arousal, sexual response, libido, maintenance of bone, energy levels and wellbeing in men and women. When men suffer from a deficiency of testosterone one or more of these areas may be affected and ANDROFORTE® 2 provides testosterone to address this deficiency. The skin reasily absorbs testosterone and ANDROFORTE® 2 is a simple and effective means of getting testosterone into the bloodstream.

Prior to using ANDROFORTE® 2

ANDROFORTE® 2 cream is only for use in men. ANDROFEME® 1% testosterone cream is recommended for use in women. ANDROFORTE® 2 cream should not be used if you are allergic to testosterone or any of the ingredients contained within ANDROFORTE® 2. These are listed at the end of the leaflet. This product contains almond oil.

If you have used ANDROFORTE® 2 or any other testosterone preparation before and became unwell, tell your doctor or pharmacist before using the cream. Other testosterone containing preparations include Testogel®, (AndroGel® and Testim® USA only), Reandron®, Sustanon®, Andriol®, Primodian® depot and Primoteston® depot. Do not use ANDROFORTE® 2 if you have cancer especially prostatic cancer, breast cancer, kidney cancer or have high calcium levels in the blood. If you have heart disease, high blood pressure or liver disease make sure your doctor is aware of these conditions before using ANDROFORTE® 2 because it may not be appropriate for you. Check with your doctor or pharmacist if you are unsure about whether you have any of these conditions before starting ANDROFORTE® 2. If you are taking other medications check with your doctor or pharmacist before starting ANDROFORTE® 2. High level athletes need to be aware of the rules governing androgen use if prescribed ANDROFORTE® 2 cream. Do not use ANDROFORTE® 2 after the expiry date which is printed on the base (crimp) of the tube. If you use this medicine after the expiry date has passed, it may not work as well. Do not use ANDROFORTE® 2 if the foil seal at the top of the tube is damaged or broken.

ANDROFORTE® 2 is not indicated for use in children or women

How to use ANDROFORTE® 2

Your doctor or pharmacist will explain how to apply ANDROFORTE® 2. Follow all directions exactly as they are explained. If you are unclear talk to your doctor. The dose of ANDROFORTE® 2 will be determined for you by your doctor. This dose is specific to your condition and should not be varied unless directed to do so by your doctor. You will need to return to your doctor at regular intervals so that the dose can be checked via a blood test.

Opening the tube

To open the tube remove the cap and peel off the foil seal. Dispose of the foil seal and replace the camp firmly after using the cream.

Measuring the correct dose of ANDROFORTE® 2 cream

A measuring applicator (syringe style) in a sealed sleeve is enclosed in the ANDROFORTE® 2 box. The dose of ANDROFORTE® 2 is measured in milllilitres. The applicator is marked with 0.5 mL graduations for dosing accuracy. Your doctor will have determined with dose is appropriate for you. To measure the correct dose of cream insert the tip of the applicator into the open nozzle of ANDROFORTE® 2 cream so that the nozzle and the shoulder of the applicator are in contact. GENTLY squeeze the base of the ANDROFORTE® 2 tube until the cream reaches the open nozzle of the tube. At the same time slowly withdraw the plunger of the applicator. The cream will flow into the barrel of the applicator. Fill to the required dose. For example: a 1 mL dose of ANDROFORTE® 2 (20 mg testosterone) needs the flat part of the plunger level with the 1 mL mark. If there are any air bubbles in the measured does fill slightly past the required dose mark then depress the plunger so that the excess cream flows back into the tube. Depress the plunger of the applicator containing the dose of ANDROFORTE® 2 directly onto the scrotal area. Massage the cream into the scrotal area until absorbed. Rinse the applicator in warm water after use and replace in box with ANDROFORTE® 2 testosterone cream ready for the next day's application. Each 1 mL of ANDROFORTE® 2 contains 20 mg of testosterone.

Where to apply ANDROFORTE® 2 cream

Always apply ANDROFORTE® 2 cream to clean dry skin. The best area to use ANDROFORTE® 2 is the scrotum (the skin sack that holds the testicles). This is the recommended site of application because absorption is greatest from this part of the body. If a dose greater than 1.5 mL (30 mg testosterone) once daily is required it is recommended that ANDROFORTE® 5 testosterone cream be used. Many men experience a warming sensation of the scrotal skin for a few minutes after applying ANDROFORTE® 2 - this is normal and quickly subsides. No perfume, deodorant, or moisturizing creams or gels should be used on the area because this may interfere with ANDROFORTE® 2 from being absorbed.

Never apply the cream to broken or damaged skin. ANDROFORTE® 2 cream should be applied at approximately the same time every day. It is recommended that patients do not swim or shower until at least 1 hr after application of ANDROFORTE® 2 cream. Close skin contact with the area of application within an hour of application by a partner should be avoided. This may result in the partner absorbing some testosterone via skin contact.

If you miss a dose

If you forget to apply your cream, you should apply it as soon as you remember provided this is within 9 hours of your usual time of application. Otherwise do not apply the cream until the next application time. Missing a dose will not create an undue disruption to your treatment.

If you use too much (overdose)

Because of the way ANDROFORTE® 2 is used, an unintentional overdose is unlikely. If you think that you or anyone else may have used too much ANDROFORTE® 2, immediately telephone your doctor or your local Poisons Information Centre for advice or go to the Accident and Emergency Department at your nearest hospital. Do this even if there are no signs of discomfort or poisoning. If ANDROFORTE® 2 is accidently swallowed or eaten contact a doctor.

During ANDROFORTE® 2 use

Do's

Inform your doctor or pharmacist that you are using ANDROFORTE® 2 before starting any other prescribed medicine. Some medicines interact with other medications. Tell all doctors, dentists and pharmacists who are treating you that you are using ANDROFORTE® 2. Have your testosterone blood levels measured regularly by your doctor. This is especially important in the first few weeks of starting ANDROFORTE® 2 to ensure that testosterone levels are within the normal levels for men.

Do Not's

Do not give ANDROFORTE® 2 to anyone else, even if they have the same symptoms or condition as you. Observe care when driving or operating machinery at the start of treatment using ANDROFORTE® 2 until you know how ANDROFORTE® 2 affects you. There is no evidence that ANDROFORTE® 2 will affect your ability to drive or operate heavy machinery.

Side effects

Tell your doctor as soon as possible if you do not feel well while you are using ANDROFORTE® 2. All medicines can have side effects in some people. Sometimes they are serious, most of the time they are not. Some side effects may need medical treatment. Tell your doctor if you notice any of the following that troublesome or ongoing:

skin irritation, for example rash or slight redness and itching of the skin where the cream has been applied. Any irritation will usually disappear within a few days. If it persists contact your doctor or pharmacist. Many men experience a warm sensation of the scrotal skin for a few minutes after applying ANDROFORTE® 2 - this is normal.
Acne
Loss of head hair (male pattern baldness)
Headache
Nausea, sickness
Swelling of the ankles
Yellowing of the skin
Increased body hair
Weight gain
Deepening of the voice
Frequent or persistent erections

Rarely reported events associated with testosterone supplementation include:

Electrolyte imbalances in the blood
A reduction in the number of sperm produced

Tell your doctor if you observe any other effects not listed about. Do not be alarmed by this list of possible side effect. You most likely will not experience any of them. ANDROFORTE® 2 has not been associated with these effects but because it contains testosterone there is a potential for side effects.

After using ANDROFORTE® 2

Storage

Keep the tube sealed until time for use.

Replace cap firmly on the tube once opened.

Do not transfer the cream out of the original tube into another container. Keep the tube in a cool dry place where the temperature stays below 25°C.

DO NOT FREEZE. Once opened, the contents of the tube should be used with 12 weeks. Keep medicines out of reach of children.

Disposal

If your doctor tells you to stop using ANDROFORTE® 2 ask your pharmacist how to dispose of any cream that is left over.

Product description

ANDROFORTE® 2 cream is a white opaque odorless cream in a laminated tube. The crimp at the base of the tube has the batch number and expiry date imprinted on it.

The tube is boxed together with a consumer information sheet and graduated measuring applicator.

Ingredients

Each 50 mL tube contains 1000 milligram (1000 mg) of testosterone. Each 1 mL dose delivers 20 mg of testosterone. Other ingredients in the cream include cetomacrogol 1000, cetostearyl alcohol, almond oil, dl-a-tocopherol (vitamin E acetate), butylated hydroxtoluene, anhydrous citric acid, triethanolamine, Carbomer 940, B&J Phenonip® and purified water.

ANDROFORTE® 2 is available in a 50 mL sealed laminated tube

Name and Address of Supplier

Lawley Pharmaceuticals Pty Ltd for Lawley Pharmaceuticals
Unit 2/15A Harrogate St,
West Leederville, 6007
Western Australia, AUSTRALIA

Postal Address
P.O. Box 1146,
West Leederville, 6901
Western Australia, AUSTRALIA

International Telephone: +61 8 9388 0096
Fax: +61 8 9388 0098

website: www.lawleypharm.com.au
Email: [email protected]

Date of preparation: Sept 2011.

ANDROFORTE® 2 is a registered trademark.

Published by MIMS March 2013

BRAND INFORMATION

Brand name

AndroForte 2

Active ingredient

Testosterone

Schedule

1 Name of Medicine

Testosterone.

2 Qualitative and Quantitative Composition

AndroForte 2 contains 2% w/v testosterone (20 mg in 1 mL).
Contains tree nut products (almond oil) and hydroxybenzoates.
For the full list of excipients, see Section 6.1 List of Excipients.

3 Pharmaceutical Form

Cream.
AndroForte 2 is a white, opaque, oil-in-water cream.

4 Clinical Particulars

4.1 Therapeutic Indications

In men, AndroForte 2 is indicated for use as testosterone replacement therapy for male hypogonadism when testosterone deficiency has been confirmed by clinical features and biochemical tests.
In women, AndroForte 2 is indicated for the treatment of hypoactive sexual desire dysfunction (HSDD) in postmenopausal women.
Therapeutic intervention with AndroForte 2 should only be initiated in women following failure of appropriate education and correction of modifiable biopsychosocial factors (which may include neuroendocrine imbalance, physical ill health or disease, interpersonal difficulties, psychological distress or specific cultural or religious beliefs), according to the International Society for the Study of Women's Sexual Health (ISSWSH) process of care (see Figure 1).

4.2 Dose and Method of Administration

Adult men (18 years old and above).

Application to the scrotum.

The recommended starting dose of AndroForte 2 when applied to the entire scrotum is 1.25 mL of cream (i.e. 25 mg of testosterone) applied once daily at about the same time, preferably in the morning. The daily dose should be adjusted by the doctor depending on the clinical and/or laboratory response in individual patients, not exceeding 2.5 mL of cream per day. The adjustment of dosage should be achieved by 0.6 mL increments.
The application should be administered by the patient himself, onto clean, dry, healthy skin on the scrotum. The scrotum is not required to be shaved prior to application.

Adult women (18 years old and above).

Application to the upper outer thigh or buttock.

The recommended starting dose is 5 mg testosterone (0.25 mL) applied once daily, at approximately the same time each day, to either the upper outer thigh or buttock.
If no improvement in symptoms is seen within 3 months and if the testosterone concentration is within the premenopausal reference range a dose increase up to 10 mg testosterone (0.5 mL) daily can be used with follow up clinical and biochemical monitoring. This dose should only rarely be exceeded. (See Monitoring).
Clinical trials have shown that there is a four to eight-week time lag between starting testosterone treatment and an improvement in sexual motivation. If there is no improvement in symptoms after 6 months of continuous therapy, treatment should be discontinued and alternative options be considered.

Method of administration.

The patient should be directed to measure the appropriate dose using the supplied graduated applicator and immediately apply to clean dry skin at the appropriate site of application. The cream should be spread on the skin gently and massaged in until vanished. Typically, this takes 30 seconds or so. Wash hands with soap and water after applications. To clean the applicator after use, rinse in hot water.
Absorption may be more variable if applied to other areas of the body. The dose can be varied according to severity of symptoms and clinical response.
Do not apply to the female genitalia or perineum.

Prior to prescribing in women.

Female sexual dysfunction, including HSDD, has many etiologies including biopsychosocial factors such as neuroendocrine imbalance, physical ill health or disease, interpersonal difficulties, psychological distress and specific cultural or religious beliefs.
The diagnosis of HSDD in clinical practice should be based on thorough clinical assessment guided by diagnostic criteria such as ISSWSH or the International Classification of Diseases 11th Edition (ICD-11).
Therapeutic intervention with AndroForte 2 should only be initiated in women following failure of alternative treatment options and correction of modifiable risk factors.
Figure 1 provides a management algorithm to assist in making a diagnosis prior to initiating therapy. If the patient meets the treatment criteria, counselling as to the benefits and potential risks of testosterone therapy should be provided, including discussions on the lack of data on the safety of long-term use.
The baseline total testosterone concentration should be measured before commencement, with a repeat level 3-6 weeks after treatment initiation (see Monitoring).

Monitoring.

Adult men (18 years old and above).

Hypogonadal symptom control is the primary aim of testosterone therapy via achieving a serum testosterone concentration sufficient to restore physiological androgen status to that comparable with eugonadal men. Biochemistry is an adjunct indicator of treatment response together with the identification and monitoring of the man's leading symptom. Trough testosterone levels should be within the lower limit of the reference interval for eugonadal men.
Eugonadal serum testosterone concentrations are generally reached within 24 hours of a single dose of AndroForte 2 applied scrotally. Absorption is variable between individuals and will have a different pharmacokinetic profile for men changing from non-scrotal testosterone products. In order to adjust the testosterone dose for scrotal application it is recommended that two (2) serum testosterone concentrations be measured at 3 hours (peak) and 24 hours (trough) from prior application after the 15th day of starting treatment. Results of clinical and/or biochemical monitoring may prompt dose titration.

Adult women.

It is recommended that serum testosterone monitoring be used as an aid to treatment rather than as the primary measure of efficacy. The primary determinant of efficacy should be based on the improvement in sexual function considered relevant to each individual woman.
Baseline testosterone and sex hormone binding globulin (SHBG) levels should be obtained prior to initiation of testosterone therapy.
It is recommended that women should ideally attend the same laboratory for baseline testosterone biochemistry prior to and during treatment.
The patient should have a follow-up blood test taken three to six weeks after initiating treatment.
Optimally, the serum concentration of total testosterone should be maintained within the approximate physiological range for premenopausal women. The dose should be titrated as deemed clinically appropriate up to a maximum of 10 mg (0.5 mL). It is recommended that if the serum testosterone concentration exceeds the upper limit of the premenopausal range of the assay being used that clinical evaluation is needed to screen for evidence of hyperandrogenism and a dose reduction considered. Women with total testosterone concentrations greater than 50% above the upper limit of the premenopausal reference range for the assay being used should be advised to reduce the dose of the applied cream. Follow-up should occur at 12 weeks including a full assessment of treatment efficacy and safety then review of serum testosterone levels 6 monthly thereafter.
A dose of up to 10 mg daily is usually sufficient to provide adequate improvement in symptoms and should rarely be exceeded. If no benefit is experienced by 6 months, treatment should be ceased.
Women should be made aware prior to initiating testosterone treatment of the lack of long-term clinical trial safety data beyond 24 months associated with use of testosterone in physiological doses in women. Treatment with AndroForte 2 should include regular monitoring and it should be an informed decision between physician and patient if treatment is to be continued beyond 24 months.
Caution should be exercised when patients are taking products that may increase or decrease SHBG or free-testosterone levels (see Section 4.5 Interactions with Other Medicines and Other Forms of Interactions).

Paediatric use.

AndroForte 2 is not indicated for use in children and has not been evaluated clinically in males or females under 18 years of age.

4.3 Contraindications

AndroForte 2 is contraindicated in patients with known sensitivity to testosterone, tree nuts (almond oil) or any of the excipients listed in List of Excipients.
It is contraindicated in male and females with known or suspected carcinoma of the breast or prostate, known or suspected androgen-dependent neoplasia, nephrotic syndrome, history of thromboembolism or hypercalcaemia.
It is contraindicated in pregnancy and lactation.
It is contraindicated in women with normal reproductive function because of the potential for virilisation of a female fetus unless adequate contraceptive measures are being utilised.

4.4 Special Warnings and Precautions for Use

Androgens may accelerate the progression of sub-clinical prostate cancer and benign prostatic hyperplasia.
AndroForte 2 should not be used by women (other than for the treatment of hypoactive sexual desire dysfunction in postmenopausal women) or children due to possible virilising effects.
Prior to testosterone initiation in men, all patients must undergo a detailed examination in order to assess for pre-existing prostate cancer. Careful and regular monitoring of the prostate gland (digital rectal examination and estimation of serum PSA (Prostate Specific Antigen) and breast must be performed in accordance with recommended practice in patients receiving testosterone therapy at least once yearly and twice yearly in elderly and at-risk patients (those with clinical or familial risk-factors).
Testosterone supplementation in women must be monitored closely, especially at onset of treatment (see Section 4.2 Dose and Method of Administration, Monitoring).
Female testosterone requirements are between ten and twenty times less than that of males.
In men, testosterone should be used only if hypogonadism (hyper- and hypogonadotropic) has been demonstrated and if other aetiology, responsible for the symptoms, has been excluded before treatment is started. Testosterone insufficiency should be clearly demonstrated by clinical features (regression of secondary sexual characteristics, change in body composition, asthenia, reduced libido, erectile dysfunction etc.) and confirmed by two separate blood testosterone measurements.
Normal ranges for testosterone may vary between laboratories and between different assay methods, therefore all measures of testosterone should be carried out in the same laboratory.
In women, androgenic side-effects may occur if doses are too high, therefore individual assessment and monitoring needs to be implemented on a patient-by-patient basis. If unwanted androgenic side effects are experienced treatment should be halted and recommenced after reduced serum testosterone levels have been established. Levels typically return to baseline 2-5 days after ceasing treatment.
Testosterone concentrations in men should be monitored when switching the patient from another testosterone product to AndroForte 2 or when switching from upper body application to scrotal application and vice versa.
Modest elevations of serum dihydrotestosterone (DHT) concentrations are commonly observed after scrotal and non-scrotal administration of testosterone, however there is no evidence to suggest that high circulating DHT concentrations have a deleterious effect on the prostate and cardiovascular safety profile.
In addition to monitoring the testosterone concentrations in male patients on long-term androgen therapy the following laboratory parameters should be checked periodically: haemoglobin, haematocrit (to avoid the risk of polycythaemia), liver function tests, and lipid profile.
Increases in haematocrit in men may require reductions in dose or discontinuation of testosterone therapy. Increased haematocrit may increase the risk for a thromboembolic event. Changes in serum lipid profile may require dose adjustment or discontinuation of testosterone therapy.

Clotting disorders.

Testosterone should be used with caution in male 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.
With specific reference to AndroForte 2, erythrocytosis and skin reactions are at the lowest end of the risk scale when transdermal testosterone is the mode of delivery. If the patient develops a severe application site reaction, treatment should be assessed and discontinued if necessary.
Testosterone is not a treatment for male sterility or impotence in men with normal serum testosterone levels.
With large doses of exogenous androgens, spermatogenesis may be suppressed through feedback inhibition of pituitary follicle-stimulating hormone (FSH) which could possibly lead to adverse effects on semen parameters including sperm count.
Certain clinical signs: irritability, nervousness, weight gain, prolonged or frequent erections may indicate excessive androgen exposure requiring dosage adjustment.
In patients suffering from severe cardiac, hepatic, or renal insufficiency or ischemic heart disease, treatment with testosterone may cause severe complications characterised by oedema with or without congestive cardiac failure. In such case, treatment must be stopped immediately. There are no studies undertaken to demonstrate the efficacy and safety of AndroForte 2 in patients with renal or hepatic impairment.
Patients with pre-existing cardiac, hepatic, or renal diseases need to be monitored closely when undergoing androgen treatment. Because AndroForte 2 is not taken orally hepatotoxicity is not a risk factor.
Gynecomastia occasionally develops and occasionally persists in male patients being treated with androgens for hypogonadism.
There are published reports of increased risk of sleep apnoea in hypogonadal men treated with testosterone, especially those with risk factors such as obesity or chronic lung disease.
Testosterone should be used with caution in patients with epilepsy and migraine as these conditions may be aggravated.
Testosterone 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.
Testosterone may cause an increase in blood pressure and should be used with caution in patients with hypertension.
Changes in insulin sensitivity may occur in patients treated with androgens who achieve normal testosterone plasma concentrations following replacement therapy.
Athletes should be informed that AndroForte 2 contains an active substance (testosterone), which may give positive results in an anti-doping test.
Androgens are not indicated for enhancing muscular development in healthy individuals.

Potential for transfer.

Transdermal testosterone cream can be transferred to other persons by close skin to skin contact, resulting in increased testosterone serum levels and, with repeated contact, possibly adverse effects. In women, this may cause growth of facial and/or body hair, deepening of the voice, irregularities of the menstrual cycle.
Patients should be made aware of the consequences of making sustained long-term close physical contact with young children. Long-term continual exposure may result in passive absorption and may cause premature puberty and genital enlargement, in case of repeat contact (inadvertent androgenisation). If virilisation occurs, testosterone therapy should be promptly discontinued until the cause has been identified.
The physician should inform the patient carefully about the risk of testosterone transfer and about safety instructions (see below). AndroForte 2 should not be prescribed to patients with a major risk of non-compliance with safety instructions (e.g. severe alcoholism, drug abuse and severe psychiatric disorders).
The risk of transfer is substantially reduced by wearing clothes covering the application area. The majority of residual testosterone is removed from the skin surface by washing with soap and water prior to contact.

For the patient.

Wash hands thoroughly with soap and water after applying the cream.
Cover the application area with clothing once the cream has dried.
Wash before any situation in which skin-to-skin contact is foreseen.

For people not being treated with AndroForte 2.

In the event of contact with an application area which has not been washed or is not covered with clothing, wash the area of skin onto which testosterone may have been transferred as soon as possible, using soap and water.
Report the development of signs of excessive androgen exposure such as acne or hair modification.
To improve female partner safety men using scrotal application should shower or wash the genital area with a damp warm flannel before sexual intercourse.
Furthermore, it is recommended to wear clothing, covering the application site during contact periods with children in order to avoid transference to children.
Pregnant women must avoid any contact with AndroForte 2 application sites. In case of pregnancy of the partner, the patient must particularly be careful to avoid potential transfer.

Use in hepatic impairment.

No formal studies were conducted with AndroForte 2 involving patients with hepatic impairment. Lower doses may be required in hepatic impairment.

Use in renal impairment.

No formal studies were conducted with AndroForte 2 involving patients with renal impairment. Lower doses may be required in renal impairment.

Cardiovascular risk factors.

There are currently few data available assessing the long-term effect of testosterone supplementation in women on cardiovascular disease beyond 24 months or in a more "at risk" patient population. Testosterone should be used with caution in women at risk for or with current cardiovascular disease.

Lipid concentrations.

In clinical trials in women, transdermal testosterone does not significantly alter the serum concentrations of total cholesterol, LDL cholesterol, and triglyceride, however a small, but a statistically significant decreased the HDL concentration may be observed, particularly with higher doses.

Blood pressure.

In clinical trials a small mean increase in both systolic and diastolic blood pressure (≤ 3 mmHg) in postmenopausal women was observed after 4 years of treatment with transdermal testosterone. This change is not considered to be clinically significant.

Body weight.

In clinical trials a small mean increase in weight (1.52 kg, fat and muscle weight were not assessed separately) was observed in postmenopausal women who used a transdermal testosterone patch for 3 years.

Carbohydrate metabolism.

In clinical trials no significant difference in serum glucose or insulin was observed between transdermal testosterone and placebo in women treated for 24 months.

Effect on breast tissue.

Evidence for long-term effects of testosterone supplementation on breast cancer is limited. Testosterone should be used with caution in women at risk for breast cancer.
Clinical studies have found no statistically significant difference in the mean increase in the amount of dense breast tissue or area of dense breast was associated with testosterone supplementation in postmenopausal women. Testosterone has been shown to inhibit total breast cell proliferation in postmenopausal women using estrogen/progesterone hormone therapy. Epidemiology studies conducted for up to 5 years have found no statistically significant increase in breast cancer risk.
In women over 50 years of age the BreastScreen Australian recommendation for mammographic screen is every 2 years, unless there is an individual need e.g. family history. This applies to women using AndroForte 2 therapy.

Effect on endometrium.

Short-term treatment with testosterone does not appear to stimulate endometrial proliferation, however the longer-term effects of testosterone on endometrial proliferation and the risk of endometrial cancer are unknown. Testosterone should be used with caution in women at risk for or with current endometrial hyperplasia or cancer.

Use in the elderly.

There is limited experience of the use of testosterone in elderly patients over 65 years of age. Currently, there is no consensus about age specific testosterone reference values. However, it should be taken into account that physiological testosterone serum levels are lower with increasing age.

Paediatric use.

The safety and efficacy of AndroForte 2 in children and adolescents aged under 18 years of age has not been established.
The patient should be advised to wash their hands well with soap and water after AndroForte 2 has been applied in case of contact with children.

Effects on laboratory tests.

Androgens may decrease levels of thyroxine-binding globulin resulting in decreased total T4 serum levels and increased resin uptake of T3 and T4. Free thyroid hormone levels remain unchanged, however, and there is no clinical evidence of thyroid dysfunction.

4.5 Interactions with Other Medicines and Other Forms of Interactions

All oral estrogens (oral contraceptives and oral HRT) will result in an increase in SHBG which will bind testosterone and reduce bioavailability. Patients using oral estrogen should be changed to transdermal estrogen before being considered for testosterone therapy.
The concurrent use of tibolone or glucocorticoids with testosterone may result in elevated testosterone levels due to a decrease in SHBG.
Changes in insulin sensitivity, glucose tolerance, glycaemic control, blood glucose and glycosylated haemoglobin have been reported with androgens. In diabetic patients, medication requirements may change.
When androgens are used simultaneously with anti-coagulants, the anti-coagulant effects may be increased. More frequent monitoring of INR and prothrombin time is recommended in patients taking anticoagulants, especially at the initiation and termination of androgen therapy.
The concurrent use of testosterone with ACTH or corticosteroids may result in increased fluid retention and should be monitored, particularly in patients with cardiac, renal, or hepatic disease.
Concurrent administration of oxyphenbutazone and androgens may result in elevated serum levels of oxyphenbutazone.
In diabetic patients, the metabolic effects of androgens may decrease blood glucose levels, and therefore, insulin requirements.
Concurrent administration of testosterone and bupropion may result in a lowered seizure threshold.
Concurrent administration with ciclosporin may result in increased cyclosporin toxicity and elevated ciclosporin blood levels.
Theoretically, in general, any substance which affects liver function should not be taken with testosterone, although this may not be as problematic with transdermal preparations such as AndroForte 2. Examples of herbal products include: ancreamica dahurica, chapparal, comfrey, eucalyptus, germander tea, Jin Bu Huan, kava, penny royal oil, skullcap, and valerian.

4.6 Fertility, Pregnancy and Lactation

Effects on fertility.

AndroForte 2 has not been evaluated for possible effects on human fertility but fertility studies in animals have shown that treatment with testosterone can impair fertility by suppressing spermatogenesis in a dose dependent manner and has the potential to disrupt ovulation and impair fertility in females.
(Category D)
Testosterone is contraindicated in women who are or who anticipate becoming pregnant (see Section 4.3 Contraindications). Pregnant women must avoid any contact with AndroForte 2 application sites.
Studies with testosterone in pregnant animals indicate the potential for adverse effects on embryofetal development, including on the reproductive tract and cardiovascular system.
Exposure of a fetus to androgens may result in varying degrees of virilisation. In the event of contact, women are advised to wash with soap and water as soon as possible.
Testosterone should not be used by breast-feeding women. Testosterone suppresses prolactin in lactating females and may cause adverse effects in the infant. AndroForte 2 must not be used in breast-feeding women (see Section 4.3 Contraindications). 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

No studies on the effects on the ability to drive and use machines have been performed.

4.8 Adverse Effects (Undesirable Effects)

According to the literature, additional undesirable events that are possibly or probably related to testosterone use are shown in Table 1.
The following adverse events have been reported in clinical trials in postmenopausal women, using transdermal testosterone preparations providing similar systemic exposure to testosterone as AndroForte 2 when used as directed in Dose and Method of Administration. That is, when physiological testosterone concentrations for premenopausal women are approximated. See Table 2.
Headache, abdominal bloating, and constipation have been reported in association with AndroForte 2.
In women, the inhibitory action of androgens on the activity of the anterior pituitary may result in the suppression of ovarian activity and menstruation. Continued administration of large doses may produce symptoms of virilism, such as male-pattern hirsutism or baldness, deepening of the voice, atrophy of the breasts and endometrial tissue, oily skin, acne, hypertrophy of the clitoris and suppression of lactation.
Potential side effects from excessive testosterone doses may include: nausea, vomiting, jaundice or swelling of the ankles; increased body hair; increased acne; signs of virilisation; weight gain; persistent headaches; deepening of the voice; electrolyte disturbances; polycythemia.

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

For information on the management of overdose, contact the Poisons Information Centre on 13 11 26 (Australia).
No cases of overdose with AndroForte 2 have been reported in clinical trials.
Treatment of overdose would consist of discontinuation of AndroForte 2 together with appropriate symptomatic and supportive care. Wash the skin with soap and water.

5 Pharmacological Properties

5.1 Pharmacodynamic Properties

Mechanism of action.

AndroForte 2 is an androgen replacement therapy containing the hormone testosterone. Testosterone and its 5α-reduced metabolite dihydrotestosterone (DHT) activate the intracellular androgen receptor and modulate gene transcription. Testosterone is produced in the adrenal glands and the ovaries in females and testes in men.
In males, testosterone and its major metabolite dihydrotestosterone (DHT), are responsible for the normal growth and 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); for a general effect on protein anabolism; for development of skeletal muscle and body fat distribution; for a reduction in urinary nitrogen, sodium, potassium, chloride, phosphate and water excretion.
Testosterone does not produce testicular development: it reduces the pituitary secretion of gonadotropins.
In women androgens act directly via the androgen receptors in tissues, such as bone, skin fibroblasts, hair follicles and sebaceous glands. Testosterone is a precursor hormone for estrogen biosynthesis in the ovaries and at extragonadal sites - bone, brain, cardiovascular and adipose tissues. Testosterone exerts an influence on female sexuality and has a physiological role in bone development and maintenance of mineralisation.
The effects of testosterone in some target organs arise after peripheral conversion of testosterone to oestradiol, which binds to oestrogen receptors in the target cell nucleus e.g. the pituitary, fat, brain, bone and testicular Leydig cells.

Clinical trials.

A three-phase single-dose cross-over pharmacokinetic study of testosterone cream in endogenous testosterone suppressed healthy volunteers (n=11) described by Iyer 2017¹ demonstrated a nonlinear dose-dependent increase in serum testosterone C_max following scrotal administration of testosterone doses of 12.5 mg, 25 mg and 50 mg. Testosterone was rapidly absorbed from the scrotal skin with a mean T_max of 3.3-5.3 h. The mean C_max (± SEM) for the 12.5 mg, 25 mg and 50 mg testosterone doses was 19.8 ± 3.8, 21.9 ± 2.8 and 28.8 ± 3.8 nanomol/L, respectively. Serum testosterone concentrations were maintained within the physiological reference range of 1.8-7.8 nanogram/mL (6.2-26.9 nanomol/L) for at least 12 h at the lowest 12.5 mg dose and for over 16 h for the 25 mg and 50 mg dose levels. Serum DHT concentrations after scrotal testosterone administration were higher than the physiological reference range of 0.07-0.64 nanogram/mL (0.24-2.21 nanomol/L) and independent of dose with a mean C_max of 4.5-4.9 nanomol/L. Serum estradiol concentrations were independent of testosterone dose and remained within the physiological range of 15-68 picogram/mL (55-250 picomol/L) for 16 h post-dose. Testosterone cream was well tolerated when applied to the scrotum with no complaints of skin irritation or discomfort after application. See Figure 2.

The clinical efficacy of AndroForte 2 cream on female is supported by literature evidence consisting of four meta-analyses and/or systematic reviews and four individual clinical trials. Of these publications, the meta-analysis by Achilli 2017 and clinical trial by El-Hage 2007 are considered pivotal and are summarised below.
The meta-analysis Achilli 2017 was designed to systematically review and summarise the existing evidence related to the efficacy and safety of transdermal testosterone in postmenopausal women when used to treat hypoactive sexual desire disorder (HSDD).
The criteria used to select individual studies for analysis were, that they should be randomised clinical trials, and that they were performed in postmenopausal women who were either on estrogen ± progesterone hormone therapy (HT) or not on HT (both surgically and naturally postmenopausal women) with HSDD, and who were treated with transdermal testosterone. The study outcomes were compared with either placebo or no treatment. Transdermal testosterone therapy could be administered as a patch or gel formulation.
Seven studies were included enrolling 3,035 participants. The sample size per study varied across the trials and ranged from 76 to 814 participants. In total, 1,350 women were randomised to treatment with transdermal testosterone and 1,379 women were randomised to placebo.
The assessment of methodological quality for risk of bias was based on Cochrane risk of bias assessment tool which considers allocation (random sequence generation and allocation concealment), blinding of participants and personnel, blinding of outcome assessors, incomplete outcome data, selective reporting, and other bias. The overall risk of each source of bias affecting studies was generally rated as low, with the exception of attrition bias (incomplete outcome data).
Hypoactive Sexual Desire Disorder symptoms were assessed using the same instruments [Sexual Activity Log (SAL), Profile of Female Sexual Function (PFSF), and Personal Distress Score (PDS)] in all seven studies.
Compared to placebo, transdermal testosterone produced:
significantly more Satisfying Sexual Episodes (MD, 0.92; 95% CI, 0.65, 1.19; P < 0.00001);
significantly more desire (MD, 6.09; 95% CI, 4.51, 7.68; P < 0.00001);
significant reduction in personal distress scores (MD, -8.15; 95% CI, -10.60, -5.70; P < 0.00001);
no difference in plasma lipid profiles, carbohydrate metabolism, and renal and liver function as assessed by clinical chemistry and haematology indices.
El-Hage 2007 study is a placebo-controlled, double blind cross over trial comparing the safety and efficacy of 10 mg of testosterone cream to placebo in postmenopausal women with HSDD.
The primary hypothesis was that the BISF-W scores of menopausal women who have taken estrogen and testosterone cream for a period of 3 months will be significantly higher (20%) at 80% power (p < 0.05) than the scores of women using estrogen alone the BISF-W is a 22-item multiple-choice questionnaire that has been used in previous studies of menopausal women. It provides scores for sexual thoughts, arousal, frequency of sex, sexual receptivity, pleasure, satisfaction with their relationship and sexual problems. The total BISF-W score ranges from 16 (poor function) to +75 (maximal function).
The study consisted of two double-blind, 12-week treatment periods separated by a single blind, 4-week, washout period. Subjects were then randomised to either 10 mg testosterone or placebo cream, 1 mL daily applied to the non-blood collecting forearm for 12 weeks. At the end of the first period, all subjects stopped the test cream for 4 weeks (wash-out period), then proceeded to the second period where they received the alternate cream for another 12 weeks.
Participants were required to have undergone a hysterectomy, have decreased sexual motivation (a BISF-W score less than 33.6), be in a stable relationship for at least 6 months (assessed by the sex therapist), have a thyroid stimulating hormone (TSH) serum concentration of between 0.220 and 3.20 mIU/L (i.e. normal thyroid function) and record a postmenopausal follicle stimulating hormone (FSH) concentration of more than 30 U/L.
Participants were evaluated by a psychologist, who undertook a comprehensive psychosexual history, to exclude depression or underlying socio-sexual problems that may be contributing to their HSDD.
Thirty-six women were randomised and 33 completed the study. Their mean age was 54 years and average body mass index was 25.4 kg/m².
The mean (± standard deviation) BISF-W composite scores were similar for the two groups at the commencement of the study. After 12 weeks of treatment, no effect on the BISF-W scores was seen in the placebo group (21.05 ± 10.41 at baseline versus 21.52 ± 12.57 at week 12). In contrast, the testosterone active treatment saw a mean increase by 8.8 points (from 19.85 ± 10.67 to 28.45 ± 11.28; 44% increase, p=0.000). Table 3 summarises the findings in the seven domains contributing to the BISF-W score.

The mean serum total testosterone concentrations were similar between the testosterone (2.1 ± 1.2 nanomol/L) and placebo groups (1.6 ± 0.5 nanomol/L) at the commencement of the study. The normal reference range was taken to be < 2.6 nanomol/L.
The mean serum testosterone concentration in women on active treatment was 4.1 ± 1.8 nanomol/L at week 6 and 3.8 ± 2.5 nanomol/L at week 12. At the end of 12 weeks, the active treatment increased serum testosterone by an average of 1.8 nanomol/L. No such rise was seen for the placebo group. Serum estradiol and SHBG levels were similar in both groups and in all phases.

5.2 Pharmacokinetic Properties

Absorption.

Following percutaneous absorption, testosterone diffuses into the systemic circulation at relatively constant concentrations during the 24-hour cycle.
In men, serum testosterone concentrations increase from the first hour after an application of AndroForte 2, reaching eugonadal levels within 24 hours. Daily changes in testosterone concentrations are then of similar amplitude to those observed during the circadian rhythm of endogenous testosterone. The percutaneous route avoids blood peaks or the first pass effect of oral androgen therapy.
Administration of a single dose 1.25 mL of AndroForte 2 (25 mg testosterone) to the scrotum of healthy eugonadal volunteers with endogenous testosterone suppressed by administration of nandrolone decanoate produced a C_max serum testosterone concentration of 19.1 nanomol/L with a T_max around 2.8 hours after application.
The half-life of testosterone is controlled by skin permeation and not clearance/metabolism.
In women, after the single-dose application of 5 mg of AndroForte 2 cream to the upper thigh/ lower buttock at steady state (day 22), the mean peak level (C_max) of total testosterone (TT) was found to be 2.437 ± 1.668 nanomol/L (range 0.728 - 6.275 nanomol/L) and that of free testosterone (fT) was found to be 28.99 ± 22.99 picomol/L (range 10.47 - 88.40 picomol/L).
Across the 24-hour blood sampling period, the mean Cavg for TT and fT were 1.505 ± 0.856 nanomol/L (range 0.433 - 3.571 nanomol/L) and 17.34 ± 11.72 picomol/L (range 7.94 - 50.27 picomol/L), respectively.

Distribution.

The majority of testosterone binds to SHBG and albumin and is biologically inactive. Testosterone also circulates unbound as a free hormone and is considered biologically active.

Metabolism.

Testosterone is metabolised primarily in the liver and also in peripheral tissue. The major active metabolites of testosterone are DHT and oestradiol.
DHT is produced by reduction through the action of the enzyme 5-alpha reductase, which is present in genital tissue and skin. DHT is further metabolised to 3-alpha and 3-beta androstanediol. DHT binds with greater affinity to SHBG than does testosterone. E2 is produced by aromatisation of testosterone.

Excretion.

Testosterone is excreted, mostly in urine as glucuronide and sulphate conjugates of testosterone and its metabolites, and in faeces as conjugated testosterone metabolites.

5.3 Preclinical Safety Data

Genotoxicity.

The genotoxic potential of testosterone has not been fully investigated in a comprehensive battery of genotoxicity studies. However, testosterone was found not to be clastogenic when tested in vitro in assays with hamster lung fibroblasts or in mouse or hamster embryo fibroblasts, or in in vivo chromosome aberration assays in mouse bone marrow cells and spermatocytes. Testosterone was also negative in assays for unscheduled DNA synthesis in rat and human hepatocytes.

Carcinogenicity.

A relationship between androgen treatment and certain cancers has been found in laboratory animals. Experimental data in rats have shown increased incidences of prostate cancer after treatment with testosterone.
Sex hormones are known to 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 is also known to increase the number of tumours and decrease the degree of differentiation of chemically induced carcinomas of the liver in rats. Hepatocellular carcinoma has been reported in male patients receiving long-term therapy with androgens.
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

dl-alpha-tocopheryl acetate, almond oil, cetomacrogol 1000, cetostearyl alcohol, carbomer 940, trolamine, butylated hydroxytoluene, Phenonip (PI 10352) contains hydroxybenzoates, citric acid, purified water.

6.2 Incompatibilities

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

6.3 Shelf Life

In Australia, information on the 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

The tube should not be opened until immediately prior to application of the cream.
Store below 25°C. Do not freeze.
In-use storage: AndroForte 2 should be used within 125 days of opening.

6.5 Nature and Contents of Container

AndroForte 2 is supplied in a 50 mL sealed tube with a graduated syringe-style measuring device in a carton.

6.6 Special Precautions for Disposal

In Australia, any unused medicine or waste material should be disposed of by taking to your local pharmacy.

6.7 Physicochemical Properties

Chemical structure.

Testosterone is an androgen. Chemically testosterone is 17β-hydroxyandrost-4-en-3-one and has the following structural formula:

Chemical Formula: C₁₉H₂₈O₂.
Molecular Weight: 288.4 g/mol.
Testosterone is a white, crystalline powder, odourless or almost odourless produced semi synthetically from plant origin. It is practically insoluble in water, freely soluble in ethanol (96%); slightly soluble in ethyl oleate.

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