Consumer medicine information

AndroFeme 1

Testosterone

BRAND INFORMATION

Brand name

AndroFeme 1

Active ingredient

Testosterone

Schedule

What is in this leaflet?

This leaflet answers some of the common questions about ANDROFEME®. 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 ANDROFEME® against the benefits it can have for you. If you have any concerns about using ANDROFEME® talk to your doctor or pharmacist. Keep this leaflet with the medicine. You may need to read it again.

What ANDROFEME® is used for?

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

Prior to using ANDROFEME®

ANDROFEME® is only for use in women. ANDROFEME® cream should not be used if you are allergic to testosterone, ANDROFEME® or any of the ingredients contained within ANDROFEME®. These are listed at the end of this leaflet. This product contains almond oil. Do not use ANDROFEME® if you have cancer especially breast cancer, kidney disease, are pregnant, lactating 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 use as ANDROFEME® 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 ANDROFEME®. If you are taking other medications check with your doctor or pharmacist before starting ANDROFEME®. High level athletes need to be aware of the rules governing androgen use if prescribed ANDROFEME® cream. Do not use ANDROFEME® 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 ANDROFEME® if the foil seal at the top of the tube is damaged or broken. ANDROFEME® is not indicated for use in children.

How to use ANDROFEME®

Follow all directions given to you by your doctor or pharmacist carefully. They may differ from the information contained in this leaflet.

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

How much to use

The usual starting dose is 0.5 mL of cream by measured applicator per day. Your doctor or pharmacist will tell you exactly how much to use. You should not use more than 1.5 mL (15 mg testosterone) of cream per day without confirming this dose with your doctor. The dose 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.

Measuring the correct dose of ANDROFEME®

To open the tube remove the cap and peel off the foil seal. A measuring applicator (syringe style) in a sealed sleeve is enclosed in the ANDROFEME® box.

The applicator is marked with 0.5mL graduations for dosing accuracy.

To measure the correct dose of cream, gently squeeze the base of the ANDROFEME® tube until cream reaches the open nozzle of the tube. Insert the tip of the applicator into the open nozzle of ANDROFEME® cream so that the nozzle and the shoulder of the applicator are in contact. Invert the tube and the applicator so the cream will flow with gravity when squeezed.

Carefully squeeze the base of the ANDROFEME® tube and at the same time slowly withdraw the plunger of the applicator. The cream will flow into the barrel of the applicator.

Do not try to squeeze the cream into the syringe.

Fill to the required dose. For example: a 0.5 mL dose of ANDROFEME® (5 mg testosterone) needs the flat part of the plunger level with the 0.5 mL mark. If there are any air bubbles in the measured dose fill slightly past the required dose mark then depress the plunger so that the excess cream flows back into the tube. Stop at the required dose mark.

Remove the applicator from the nozzle of the tube and replace the cap firmly on the tube.

There is a Using the Application Syringe demonstration video at www.lawleydirect.com.au

Where to apply ANDROFEME® cream

Always apply ANDROFEME® directly onto clean, dry, healthy skin of either the lower torso or the upper outer thigh.

Massage the cream into the area until absorbed.

Typically this takes about 30 seconds.

No perfume, deodorant or moisturising creams / gels should be used on the area because this may interfere with ANDROFEME® from being absorbed. Never apply the cream to broken or damaged skin.

Do not use ANDROFEME® on the genital area, unless specifically directed to do so by your doctor.

ANDROFEME® cream should be applied at approximately the same time each day.

It is recommended that patients do not swim or shower until at least one hour after application of ANDROFEME® cream. Close skin contact with the area of application within an hour of application, by a partner or children should be avoided. This may result in the partner or child absorbing some testosterone through the skin contact. Cover the application area with clothing once applied.

Rinse the applicator in hot water after use and replace in box with ANDROFEME® cream ready for the next day's application.

Wash your hands thoroughly with soap and water after applying the cream.

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 Is due. Missing a dose will not create an undue disruption to your treatment.

If you use too much (overdose)

Because of the way ANDROFEME® is used, an unintentional overdose is unlikely.

If you think that you or anyone else may have used too much ANDROFEME®, immediately telephone your doctor or the 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 ANDROFEME® is accidentally swallowed or eaten contact a doctor.

During ANDROFEME® use

Do’s

Inform your doctor or pharmacist that you are using ANDROFEME® 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 ANDROFEME®.

It is very important that you have a follow-up blood test to measure your testosterone levels within three weeks of starting ANDROFEME®. This is to confirm that your starting dose is correct and ensure your testosterone levels are within the normal range for women.

Do Not's

Do not give ANDROFEME® 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 ANDROFEME® until you know how ANDROFEME® affects you. There is no evidence that ANDROFEME® will affect your ability to drive or to operate machinery.

Side-effects

Tell your doctor as soon as possible if you do not feel well while you are using ANDROFEME®.

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 are 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.
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

ANDROFEME® may stop you ovulating and affect your periods. Rarely-reported events associated with testosterone supplementation include:

Electrolyte imbalances in the blood
Changes to the tissue of the breast and endometrium (uterus)

Tell your doctor if you observe any other effects not listed above.

Do not be alarmed by this list of possible side-effects.

You most likely will not experience any of them.

ANDROFEME® has not been associated with these effects however because it contains testosterone there is a potential for side effects.

After using ANDROFEME®

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 within 12 weeks.

Keep medicines out of reach of children.

Disposal

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

Product description

ANDROFEME® cream is a white, opaque odorless cream in a sealed 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 a graduated measuring applicator.

Ingredients

Each 50 ml tube contains 500 milligrams (500mg) of testosterone. Each 1ml dose delivers 10mg of testosterone. Other ingredients in the cream include cetomacrogol 1000, cetostearyl alcohol, almond oil, dl-α-tocopherol acetate (Vitamin E acetate), butylated hydroxytoluene, anhydrous citric acid, triethanolamine, Carbomer 940, B&J Phenonip® and purified water.

ANDROFEME® 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 Street, 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: Jan 2014.

ANDROFEME® is a registered trademark.

Published by MIMS June 2019

BRAND INFORMATION

Brand name

AndroFeme 1

Active ingredient

Testosterone

Schedule

1 Name of Medicine

Testosterone.

2 Qualitative and Quantitative Composition

AndroFeme 1 contains 1% w/v testosterone (10 mg testosterone per 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.
AndroFeme 1 is a white, opaque, oil-in-water cream.

4 Clinical Particulars

4.1 Therapeutic Indications

AndroFeme 1 is indicated for the treatment of hypoactive sexual desire dysfunction (HSDD) in postmenopausal women.
Therapeutic intervention with AndroFeme 1 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

Dose.

The recommended starting dose is 5 mg testosterone (0.5 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 (1.0 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 graduated applicator and immediately apply to clean dry skin on the upper outer thigh or buttock. The cream should be massaged evenly until absorption is complete (typically around 30 seconds). The patient should be instructed to wash their hands with soap and water after each application.
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 genitalia or perineum.

Prior to prescribing.

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 AndroFeme 1 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.

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 (1 mL). It is recommended that if the serum testosterone concentration exceeds the upper limit of the premenopausal range of the assay being used, 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 AndroFeme 1 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).

4.3 Contraindications

AndroFeme 1 is contraindicated in patients with known sensitivity to testosterone, tree nuts (almond oil) or any of the excipients listed, see Section 6.1 List of Excipients.
AndroFeme 1 is contraindicated in females with known or suspected carcinoma of the breast, known or suspected androgen-dependent neoplasia, nephrotic syndrome, history of thromboembolism or hypercalcaemia.
AndroFeme 1 is contraindicated in pregnancy and lactation.
AndroFeme 1 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

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.
Normal ranges for testosterone may vary between laboratories and between different assay methods. 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.
All patients with pre-existing cardiac, hepatic or renal diseases need to be monitored closely when undergoing androgen treatment.
High level athletes need to be aware of the rules governing androgen use if prescribed AndroFeme 1 cream.

Potential for transfer.

It has been reported that high dose transdermal testosterone preparations used in men 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. While the recommended dose of testosterone in AndroFeme 1 is low by comparison to male doses, close skin contact with the area of application by a partner or child should be avoided.
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 have adverse effects, including virilisation, in young children.
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.
As a result, the following precautions are recommended:

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 women and children not being treated with AndroFeme 1.

In the event of sustained 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.
The patient must be particularly careful to avoid potential transfer to pregnant women.

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 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 AndroFeme 1 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.

This product is not suitable for children.
Care should be taken to ensure that children do not come into contact with AndroFeme 1 application sites. In the event of contact, wash with soap and water as soon as possible.

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.
Concurrent administration of testosterone and bupropion may result in a lowered seizure threshold.
Concurrent administration with ciclosporin may result in increased ciclosporin toxicity and elevated ciclosporin blood levels.

4.6 Fertility, Pregnancy and Lactation

Effects on fertility.

AndroFeme 1 has not been evaluated for possible effects on human fertility. Studies in animals have shown that testosterone 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 AndroFeme 1 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 suppresses prolactin in lactating females and may cause adverse effects in the infant. AndroFeme 1 must not be used in breastfeeding women (see Section 4.3 Contraindications).
Care should be taken by breast-feeding women to avoid any contact with AndroFeme 1. In the event of contact, wash with soap and water as soon as possible.

4.7 Effects on Ability to Drive and Use Machines

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

4.8 Adverse Effects (Undesirable Effects)

The following adverse events have been reported in clinical trials in postmenopausal women, using transdermal testosterone preparations providing similar systemic exposure to testosterone as AndroFeme 1 when used as directed, see Section 4.2 Dose and Method of Administration. That is, when physiological testosterone concentrations for premenopausal women are approximated. (See Table 1).
Headache, abdominal bloating, and constipation have been reported in association with AndroFeme 1.
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 AndroFeme 1 have been reported in clinical trials.
Treatment of overdose would consist of discontinuation of AndroFeme 1 together with appropriate symptomatic and supportive care. Wash the skin with soap and water.

5 Pharmacological Properties

5.1 Pharmacodynamic Properties

Mechanism of action.

Testosterone is the primary androgenic hormone. 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.
In males, testosterone is responsible for the normal growth and development of the male sex organs and for maintenance of secondary characteristics.
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.

Clinical trials.

The clinical efficacy of AndroFeme 1 cream 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 < .00001);
significantly more desire (MD, 6.09; 95% CI, 4.51, 7.68; P < .00001);
significant reduction in personal distress scores (MD, -8.15; 95% CI, -10.60, -5.70; P < .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 AndroFeme 1 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 AndroFeme 1 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 2 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.

After the single-dose application of 5 mg of AndroFeme 1 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 C_avg 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 in peripheral tissue. DHT and oestradiol (E₂) are products of testosterone metabolism.
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. E₂is produced by aromatisation of testosterone.

Excretion.

90% of testosterone is excreted in the urine as glucuronide and sulphate conjugates of testosterone and its 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.

6 Pharmaceutical Particulars

6.1 List of Excipients

Almond oil, butyl hydroxybenzoate, butylated hydroxytoluene, carbomer 940, cetomacrogol 1000, cetostearyl alcohol, citric acid, dl-alpha-tocopherol acetate, ethyl hydroxybenzoate, isobutyl hydroxybenzoate, methyl hydroxybenzoate, phenoxyethanol, propyl hydroxybenzoate, purified water, trolamine.

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.

AndroFeme 1 should be used within 125 days of opening.

6.5 Nature and Contents of Container

AndroFeme 1 is supplied in a 50 mL sealed tube with a dose applicator marked with 0.25 mL graduations 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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AndroFeme 1

Testosterone

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