Consumer medicine information

What is in this leaflet

This leaflet answers some common questions about Sandrena. It does not contain all the available information. It does not take the place to talking to your doctor or pharmacist.

Keep this information with the pack. You may wish to read it again.

General advice

1. This medicine has been prescribed only for your current medical problem. It should not be used for other medical conditions.
2. Never give your medicine to anyone else and do not use medicines meant for other people.
3. Tell every doctor treating you what medicines you are taking. Always carry a medical information card stating which medicines you are using. This can be very important if for example you are involved in an accident.
4. Return unused medicines to your pharmacy for disposal.
5. Make sure that other people who live with you or who look after you read this information.

A doctor's prescription is required to obtain this medicine.

What Sandrena is used for

During and after menopause the production of sex hormones produced by the body decreases. Women may then suffer from complaints such as hot flushes, night sweats, vaginal irritation, depression, and loss of sexual desire. Sandrena can be used for the short-term relief of menopausal complaints.

It can also relieve these symptoms in women who have had their ovaries removed. Relief of symptoms usually starts within a few weeks, but optimal results are obtained after three months of treatment. Sandrena is not intended for contraceptive use.

If you have not had a hysterectomy, your doctor will probably combine the Sandrena treatment with another hormone product, a progestogen.

Before you use it

Sandrena may not be suitable for you if you suffer from certain medical conditions.

Before you take it

Tell your doctor if you-

1. are pregnant or think you may be pregnant
2. have a tumour (e.g. a breast tumour or a tumour in your womb)
3. have or ever had heart disease or blood vessel problems
4. have or have ever had thrombosis (blood clots)
5. recently had unexpected vaginal bleeding
6. have or have ever had liver disease
7. have uterine fibroids. Careful examinations should be performed, by your doctor, at regular intervals during therapy
8. had heart failure, kidney problems or severe hypertension.

Also tell your doctor if:

• you have or have ever had too much cholesterol or other fatty substances in the blood
• you have been treated with other sex hormones recently.

Tell your doctor if you are or think you are allergic to any of the components of the gel. The ingredients are listed at the end of this leaflet. Note this product contains propylene glycol and may cause skin irritation.

Your doctor will conduct a complete gynaecological examination before commencement with Sandrena.

Breast cancer:
Before starting with hormone replacement therapy (HT) you have to inform your doctor of your personal and family medical history. You will get a general and gynaecological examination. You will also get periodic check-ups, especially examinations of the breasts. Every woman is at risk of getting breast cancer, whether or not she takes HT. Breast cancer has been found slightly more often in women using HT than in women of the same age who have never used HT.

It is not known whether Sandrena is associated with the same higher chance of having breast cancer diagnosed as other hormone replacement therapies.

Nevertheless, if you are concerned about the risk of breast cancer, discuss the risk compared to the benefits of treatment with your doctor.

Stroke:
There may be an increased risk of stroke when using this product.

Dementia:
There may be an increased risk of dementia when using this product.

Ovarian/Endometrial cancer:
Ovarian cancer (cancer of the ovaries) is very rare, but it is a serious condition. It can be difficult to diagnose, because there are often no obvious signs of the disease.

Evidence from studies suggests an increased risk in women taking oestrogen-only or combined oestrogen-progestogen HRT, which becomes apparent within 5 years of use and diminishes over time after stopping.

Some other studies, including the Women's Health Initiative (WHI) trial, suggest that use of combined HRTs may be associated with a similar risk.

Women who still have a uterus must take both estrogen and progestogen as part of HT. This is because estrogen stimulates the growth of the lining of the uterus (called the endometrium). Before menopause this lining is shed during your period through the action of a natural progestogen.

After menopause, taking estrogen on its own as HT may lead to irregular bleeding and a disorder of the uterus lining called endometrial hyperplasia, which can become endometrial cancer. Progestogens help protect the lining of the uterus from developing this disorder.

Also, clinical studies on similar products showed a possible increased risk of cardiovascular problems in the first year of use and no benefit thereafter.

Thrombosis (blood clots):
All women have a very small chance of having a blood clot in the veins of the leg, lung or other parts of the body whether or not they take HT. Using some forms of HT may slightly increase this small chance. Whether or not Sandrena may increase the chance of having a blood clot is not known.

You are more likely to have a blood clot (whether or not you use HT) if:

• you are very overweight;
• you have had a blood clot in the veins of your legs or in your lungs before;
• blood clots run in your family;
• you have systemic lupus erythematosus (a disease of your immune system);
• you are unable to move for long periods, for example after a long illness or major operation;
• may be also if you have varicose veins.

You should talk to your doctor about whether you should use Sandrena if any of these apply to you.

If you get a blood clot while you are using Sandrena you should stop taking it immediately and contact your doctor.

Warning signs to look out for are:

• unusual pains or swelling of your legs;
• pain in your chest or sudden shortness of breath.

Other medicines may influence the effects of Sandrena, or Sandrena may affect other medicines.

You must tell your doctor or pharmacist if you are taking (or intend to take) other medicines such as:

• anticonvulsants, barbiturates, carbamazepine and hydantoins (medicines for epilepsy or sleeplessness);
• rifampicin, rifabutin, nevirapine, efavirenz (medicines for infections);
• meprobamate and phenylbutazone
• ritonavir, nelfinavir;
• herbal preparations containing St John’s Wort.

These drugs may reduce the effects of Sandrena. Sandrena may also reduce the effectiveness of other medicines such as some oral hypoglycaemics (medicines which lower blood sugar), antihypertensives (medicines which lower blood pressure) and some anticoagulants (medicines which "thin" the blood). Let your pharmacist or doctor know if you are a diabetic, or are being treated for blood clotting or high blood pressure.

This is not a complete list of medicines which may interact with Sandrena.

Please talk to your doctor or pharmacist.

Do not use Sandrena if you are pregnant or breast-feeding, or think you may be pregnant.

Yearly medical checks are recommended. Additionally, the doctor may check with you on how the treatment is progressing every six months or so.

How to use it

Apply Sandrena as directed by your doctor. You should also read the instructions on the label of your medicine.

If you are not sure how to use Sandrena ask your doctor or pharmacist.

How much to use

The usual starting dose is one sachet per day. Your doctor or pharmacist will tell you exactly how much to use.

How to use it

Open the sachet(s). Rub the contents daily on the skin of your lower abdomen or thighs. The application surface area should be one to two times the size of the hand.

Sandrena should not be applied on the breasts, face or irritated skin.

Avoid contact with eyes. If Sandrena does get into your eyes, wash out thoroughly with water. Wash hands thoroughly immediately after application.

In clinical trials the use of Sandrena has infrequently caused irritation of the skin. The chance of skin reactions can be further decreased by changing the area of application daily (e.g. left and right side on alternate days).

Sandrena is used either cyclically or continuously, in individually adjusted doses.

If you have not had a hysterectomy, your doctor will probably prescribe a progestogen, to help prevent overgrowth of the tissues lining your womb.

What to do if you miss a dose

If you forget to apply the gel do so as soon as you remember, unless you are more than twelve hours late. If you are more than twelve hours late, do not apply the missed dose and just carry on with the next dose as normal.

While you are using it

Ability to drive or operate machinery. As far as is known, Sandrena has no effect on alertness and concentration.

Discuss with your doctor or pharmacist if you are unsure of any of the aspects of this product.

Side effects

Side effects, which may or may not be related to Sandrena are most common in the first months of the treatment. They are usually mild leading only seldom to discontinuation of the treatment.

Common (more than 1/100):

• breast pain or tension;
• headache;
• fatigue;
• nausea;
• vomiting;
• stomach cramps;
• flatulence;
• dizziness;
• palpitations;
• swelling from water retention;
• weight increase;
• varicose veins;
• vaginal discharge;
• lethargy;
• depression;
• nervousness;
• hot flushes;
• itch of application site;
• pain;
• increased sweating;
• unscheduled or breakthrough bleedings.

Uncommon (less than 1/100):

• skeletal pain;
• itching;
• muscle pain & cramps;
• nervousness;
• changes in mood or libido;
• migraine;
• benign breast or endometrial tumours;
• increased appetite;
• excessive growth of the cells of the uterus.

Tell your doctor if spotting occurs or if any side-effects become troublesome or continue.

It is also important to tell your doctor or pharmacist if you experience any other unusual or unexpected symptoms during treatment with Sandrena.

Seek advice before using other medications to deal with any side effects you may have.

You should stop using Sandrena and seek medical attention immediately if you experience any signs of:

• thrombosis (red, painful or swollen leg, difficulty breathing, chest pain, headache or pain elsewhere in your body, dizziness, fainting, disturbances in vision, swollen ankles);
• jaundice (yellowing of the eyes or skin).

Other side effects not listed above may also occur in some people.

Overdose

If someone has taken or used several sachets at once, there is no need for great concern. However, you should consult a doctor.

Symptoms that may arise are nausea and vomiting. Vaginal bleeding may occur after a few days.

After taking it

Storage

Keep your Sandrena gel in the original container in a safe place out of the reach of children.

Store below 25°C.

The expiry date (sometimes written as "exp") is also printed on the strip of sachets - do not use after this date.

Disposal

Return any unused medicine to your pharmacist

Product description

What it looks like

Sandrena is a smooth opalescent gel.

It is available in 0.5 g or 1 g sachets in packs containing28 or 91 sachets.

* Not all presentation and/or pack sizes are available.

Ingredients

Sandrena consists of 0.1% estradiol.

Each 1 g sachet of gel contains 1.0 mg of estradiol.

Each 0.5 g sachet of gel contains 0.5 mg of estradiol.

It also contains the following inactive ingredients:

• carbomer 934P;
• trolamine;
• propylene glycol;
• ethanol;
• purified water.

Sponsor

Orion Pharma (Aus) Pty Limited
Level 24, Tower 3
300 Barangaroo Avenue, Sydney,
NSW 2000, Australia
Telephone: 1800 861 913

AUST R: 93609 (1.0 g sachet)
AUST R: 93608 (0.5g sachet)

This leaflet was revised in July 2022.

Published by MIMS September 2022

1 Name of Medicine

Estradiol.

2 Qualitative and Quantitative Composition

Sandrena gel contains estradiol 1 mg/g.
Each 0.5 g sachet of gel contains 0.5 mg of estradiol.
Each 1 g sachet of gel contains 1 mg of estradiol.

Excipient with known effect.

3 Pharmaceutical Form

Gel.
The product is a smooth opalescent gel.

4 Clinical Particulars

4.1 Therapeutic Indications

Short-term treatment of climacteric symptoms after natural or surgical menopause. Wherever possible the lowest effective dose should be used.
Review the need for continuation of treatment after 6 months, taking into account the risk-benefit ratio for the individual user at that moment (including cardiovascular disease and breast cancer, see Section 5.1 Pharmacodynamic Properties, Clinical trials; Section 4.4 Special Warnings and Precautions for Use). Sandrena should only be continued for as long as the benefit outweighs the risks.

4.2 Dose and Method of Administration

Sandrena is a gel for transdermal use. Sandrena is used either cyclically or continuously, in individually adjusted doses of 0.5 g to 1.5 g per day, corresponding to 0.5 to 1.5 mg estradiol per day. Most patients usually start with a 1.0 mg estradiol dose daily. This can be adjusted after 2 to 3 cycles.
In patients with an intact uterus, it is necessary to combine Sandrena with an adequate dose of progestogen for adequate duration, at least 12-14 consecutive days per month/28 day cycle to oppose estrogen stimulated hyperplasia of the endometrium.
Unless there is a previous diagnosis of endometriosis, it is not recommended to add a progestogen in hysterectomised women.

Method of administration.

Monitoring advice.

4.3 Contraindications

Undiagnosed vaginal or genital bleeding.
Cerebrovascular disorders.
Active or recent arterial thromboembolic diseases (e.g. angina, myocardial infarction) or thrombophlebitis.
Acute liver disease, history of liver disease where liver function has failed to return to normal or severe hepatic disease (including Dubin-Johnson and Rotors' syndrome).
Known, past or suspected malignancy of the genitals or breasts.
Pregnancy.
Non hysterectomised women without concomitant progestogen.
Known or suspected estrogen-dependent malignant tumours (e.g. endometrial cancer).
Untreated endometrial hyperplasia.
Previous or current venous thromboembolism (deep venous thrombosis, pulmonary embolism).
Known thrombophilic disorders (e.g. protein C, protein S, or antithrombin deficiency).
Porphyria.
Hypersensitivity to the active substance or to any of the excipients listed in Section 6.1 List of Excipients.

4.4 Special Warnings and Precautions for Use

Identified precautions.

Check the following before use.

Reasons for immediate withdrawal of therapy.

Coronary artery disease (CAD).

Endometrial hyperplasia and carcinoma.

Breast cancer.

Combined estrogen-progestogen therapy.

Estrogen-only therapy.

Ovarian cancer.

Venous thromboembolism.

Ischaemic stroke.

Other conditions.

ALT elevations.

Potential estradiol transfer to children.

Excipients.

Use in the elderly.

Paediatric use.

Effects on laboratory tests.

4.5 Interactions with Other Medicines and Other Forms of Interactions

The metabolism of estrogens may be increased by concomitant use of substances, known to induce drug-metabolising enzymes, specifically cytochrome P450 enzymes such as anticonvulsants (e.g. phenobarbital, phenytoin, carbamazepine) and anti-infectives (e.g. rifampicin, rifabutin, nevirapine, efavirenz).
Ritonavir and nelfinavir, although known as strong inhibitors, by contrast exhibit inducing properties when used concomitantly with steroid hormones.
When co-administered with sex hormones, many combinations of HIV protease inhibitors and non-nucleoside reverse transcriptase inhibitors, including combinations with HCF inhibitors, can increase or decrease plasma concentrations of estrogen. The net effect of these changes may be clinically relevant in some cases.
Therefore, the prescribing information of concomitant medications including HIV/HCV antivirals should be consulted to identify potential interactions and any related recommendations.
Herbal preparations, containing St John's wort (Hypericum perforatum), may induce the metabolism of estrogens.
Clinically an increased metabolism of estrogens and progestins may lead to decreased effect and changes in the uterine bleeding profile.

Effect of HRT with oestrogens on other medicinal products.

Pharmacodynamic interactions.

4.6 Fertility, Pregnancy and Lactation

Effects on fertility.

4.7 Effects on Ability to Drive and Use Machines

Estrogens such as Sandrena do not affect the ability to drive or use machines.

4.8 Adverse Effects (Undesirable Effects)

Adverse events reported at an incidence of > 1% among patients treated with Sandrena during controlled trials are shown in Table 1.
In clinical trials dermal irritation has occurred in less than 4% of the patients.
Side effects are most common in the first months of the treatment. They are usually mild, only seldom leading to discontinuation of the treatment.

Estimates from postmarketing surveillance.

Common (≥ 1% - < 10%).

Uncommon (≥ 0.1% - < 1%).

Rare (> 0.01% - < 0.1%).

Breast cancer risk.

Largest meta-analysis of prospective epidemiological studies.

Endometrial cancer risk.

Postmenopausal women with a uterus.

Ovarian cancer.

Risk of venous thromboembolism.

Risk of coronary artery disease.

Risk of ischaemic stroke.

Reporting suspected adverse effects.

4.9 Overdose

For information on the management of overdose, contact the Poisons Information Centre on 13 11 26 (Australia).
Generally, estrogens are well tolerated even in massive doses. Possible symptoms include those listed under adverse drug reaction. Management is symptomatic.

5 Pharmacological Properties

5.1 Pharmacodynamic Properties

Mechanism of action.

Clinical trials.

5.2 Pharmacokinetic Properties

Sandrena is an alcohol based estradiol gel. When applied to the skin the gel evaporates rapidly and estradiol is absorbed through the skin into circulation. To some extent, however, the estradiol is stored in subcutaneous tissue from where it is released gradually into circulation.
Percutaneous administration naturally circumvents the hepatic first-pass metabolism.
Because of the change in composition, the new formulation was compared to the old formulation of Sandrena in a bioequivalence study. Twenty-seven study subjects were postmenopausal Caucasian females, 50-70 years of age, nonsmokers, their BMI was 19-30 kg/m² and they had normal gynaecological status. The study was a multiple dose, single blind, randomised, crossover trial without washout period. Both treatments consisted of application of 1 gram of the gel on a skin area of 400 cm² (thigh) once daily for 14 consecutive days. The new formulation was bioequivalent with the old formulation. The estimate for the ratio (the new/the old formulation) of extent of drug absorption, AUC_{(0-24 h)}, was 1.05. The associated 90% confidence interval (89.7 - 123%) was included within the bioequivalence range of 80-125%. The estimate for the ratio (the new/ the old formulation) of the rate of absorption, C_max, was 1.06. The associated 90% confidence interval (87.9-128%) was included. The wider confidence interval for C_max was justified because transdermal estradiol can be considered as a highly variable drug. See Table 7.
During Sandrena treatment the estradiol/estrone ratio remains at 0.7, while during peroral estrogen treatment it usually drops to less than 0.2. The steady-state bioavailability of Sandrena is 82 per cent compared to the equivalent oral dose of estradiol valerate.
Otherwise, the metabolism and excretion of transdermal estradiol follow the fate of natural estrogens.

5.3 Preclinical Safety Data

Genotoxicity.

Carcinogenicity.

Breast cancer.

6 Pharmaceutical Particulars

6.1 List of Excipients

Carbomer 934P, trolamine, propylene glycol, purified water and ethanol.

6.2 Incompatibilities

No incompatibilities have been found.

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

Store below 25°C.

6.5 Nature and Contents of Container

Sandrena is available in single-dose Al laminated with PVC/paper sachets.

Pack sizes.

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.

CAS number.

7 Medicine Schedule (Poisons Standard)

S4 - Prescription Only Medicine.

Summary Table of Changes