Consumer medicine information

Sandrena gel

Estradiol

BRAND INFORMATION

Brand name

Sandrena

Active ingredient

Estradiol

Schedule

S4

 

Consumer medicine information (CMI) leaflet

Please read this leaflet carefully before you start using Sandrena gel.

SUMMARY CMI

Sandrena gel

Consumer Medicine Information (CMI) summary

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

1. Why am I using Sandrena?

Sandrena contains the active ingredient estradiol. Sandrena is a Hormone Replacement Therapy (HRT).

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

2. What should I know before I use Sandrena?

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

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

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

3. What if I am taking other medicines?

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

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

4. How do I use Sandrena?

  • The usual starting dose is one 0.5 g or 1 g sachet per day
  • Sandrena should be rubbed gently on dry and clean skin. It should not be swallowed.

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

5. What should I know while using Sandrena?

Things you should do
  • Remind any doctor, dentist or pharmacist you visit that you are using Sandrena.
  • Attend your scheduled appointments and have periodic checkups, especially examinations of the breasts.
  • Cover the application area with clothing as soon as the gel has dried to prevent accidental transfer of the gel to others (e.g., child or spouse or pet).
Things you should not do
  • Do not stop using this medicine suddenly.
  • Do not give this medicine to anyone else, even if their signs of illness are the same as yours.
Driving or using machines
  • Sandrena is not expected to affect your ability to drive or use machines.
Looking after your medicine
  • Store below 25°C.

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

6. Are there any side effects?

All medicines can have side effects. If you do experience any side effects, most of them are minor and temporary. However, some side effects may need medical attention. Ask your doctor if you have any further questions about side effects. Tell your doctor if you experience any side effects, including those not listed in this leaflet.

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



FULL CMI

Sandrena gel

Active ingredient(s): estradiol


Consumer Medicine Information (CMI)

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

Where to find information in this leaflet:

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

1. Why am I using Sandrena?

Sandrena contains the active ingredient estradiol.

Sandrena is a Hormone Replacement Therapy (HRT). It is used for the short-term relief of menopausal complaints. 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.

2. What should I know before I use Sandrena?

Warnings

Do not use Sandrena if:

  • you have any unexplained vaginal bleeding
  • you have or ever had heart disease or blood vessel problems, such as a heart attack, stroke or angina
  • you have or have ever had a liver disease and your liver function tests have not returned to normal
  • you have a tumour (e.g., a breast tumour or a tumour in your womb), or if you are suspected of having it
  • you are pregnant or think you may be pregnant
  • you have excessive thickening of the womb lining (endometrial hyperplasia) that is not being treated
  • you have or have ever had a blood clot in a vein (thrombosis), such as in the legs (deep venous thrombosis) or the lungs (pulmonary embolism)
  • you have a blood clotting disorder (such as protein C, protein S, or antithrombin deficiency)
  • you have a rare blood problem called “porphyria” which is passed down in families (inherited)
  • you are allergic to estradiol or any of the other ingredients of this medicine Sandrena (listed in section 7).

Before you start using Sandrena:

Tell your doctor if you have ever had any of the following problems, as these may return or become worse during treatment with Sandrena. If so, you should see your doctor more often for check-ups:

  • fibroids inside your womb
  • growth of womb lining outside your womb (endometriosis) or a history of excessive growth of the womb lining (endometrial hyperplasia)
  • increased risk of developing blood clots
  • increased risk of getting an estrogen-sensitive cancer (such as having a mother, sister or grandmother who has had breast cancer)
  • high blood pressure
  • a liver disorder, such as a benign liver tumour
  • diabetes
  • gallstones
  • migraine or severe headaches
  • a disease of the immune system that affects many organs of the body (systemic lupus erythematosus, SLE)
  • epilepsy
  • asthma
  • a disease affecting the eardrum and hearing (otosclerosis)
  • a very high level of fat in your blood (triglycerides)
  • fluid retention due to cardiac or kidney problems
  • hereditary or acquired angioedema.

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

If you have had your womb removed (a hysterectomy), discuss with your doctor whether you can safely use Sandrena without a progestogen.

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

Pregnancy and breastfeeding

Do not use Sandrena if you are pregnant or think you may be pregnant, or breast-feeding. If you become pregnant, stop using Sandrena and contact your doctor.

Sandrena is not a contraceptive. If it is less than 12 months since your last menstrual period or you are under 50 years old, you may still need to use additional contraception to prevent pregnancy. Speak to your doctor for advice.

3. What if I am taking other medicines?

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

Some medicines may interfere with the effect of Sandrena. This might lead to irregular bleeding. This applies to the following medicines:

  • Medicines for epilepsy (such as phenobarbital, phenytoin and carbamazepine)
  • Medicines for tuberculosis (such as rifampicin, rifabutin)
  • Medicines for HIV infection (such as nevirapine, efavirenz, ritonavir and nelfinavir)
  • Herbal remedies containing St. John's wort (Hypericum perforatum).

HRT can affect the way some medicines work:

  • A medicine for epilepsy (lamotrigine), as this could increase frequency of seizures.
  • Medicines for Hepatitis C virus (HCV) (such as combination regimen ombitasvir/paritaprevir/ritonavir with or without dasabuvir as well as a regimen with glecaprevir/pibrentasvir) may cause increases in liver function blood test results (increase in ALT liver enzyme) in women using Combined Hormonal Contraceptives (CHCs) containing ethinylestradiol. Sandrena contains estradiol instead of ethinylestradiol. It is not known whether an increase in ALT liver enzyme can occur when using Sandrena with this HCV combination regimen. Your doctor will advise you.

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

4. How do I use Sandrena?

How much to use

The usual starting dose is one 0.5 g or 1 g sachet per day. Your doctor or pharmacist will tell you exactly how much to use.

If you have an intact womb, your doctor will normally also prescribe another medicine containing the hormone progestogen. This is normally for 12 to 14 days in each monthly cycle. After each course of progestogen, you will usually have a withdrawal bleed, like a period.

How to apply the gel

  • Sandrena should be rubbed gently on dry and clean skin. It should not be swallowed.

Where to apply the gel

  • Do not apply the gel to your breasts, face or on irritated skin.
  • Apply the gel to your lower body or thighs.
  • Apply the gel to a different side of your body each day.

Follow these instructions:

  1. Apply the gel once a day to the skin on your lower body or thighs.
  2. Spread the gel over an area 1–2 times the size of your hand.
  3. Allow the gel to dry for a few minutes.
  4. Wash your hands after applying the gel. Avoid contact of the gel with your eyes. The gel may irritate your eyes.
  5. Do not wash the area where you have applied the gel for at least one hour.

If you forget to use Sandrena

  • Apply the missed dose when you remember, unless you are more than 12 hours late.
  • If you are more than 12 hours late just skip the missed dose.
  • Missed doses may cause some bleeding between your periods. This is called breakthrough bleeding.

If you use too much Sandrena

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

You should immediately:

  • phone the Poisons Information Centre
    (by calling 13 11 26), or
  • contact your doctor, or
  • go to the Emergency Department at your nearest hospital.

You should do this even if there are no signs of discomfort or poisoning. You may feel bloated, anxious or irritable, or your breasts may feel tender. Nausea, vomiting and withdrawal bleeding may also occur in some women.

5. What should I know while using Sandrena?

Things you should do

  • Attend your scheduled appointments so that your doctor can check on your progress. Tell your doctor if you do not feel better or if you feel worse.
  • Regularly check your breasts for any changes. See your doctor if you notice any changes such as:
    - dimpling of the skin
    - changes in the nipple
    - any lumps you can see or feel
    Go for regular breast screening, as recommended by your doctor.
  • If you need a blood test, tell your doctor or the laboratory staff that you are using Sandrena, because this medicine can affect the results of some tests
  • If you are going to have surgery, tell the surgeon that you are using Sandrena. You may need to stop using Sandrena about 4 to 6 weeks before the operation to reduce the risk of a blood clot. Ask your doctor when you can start using Sandrena again.

Call your doctor straight away if:

  • you notice yellowing of your skin or the whites of your eyes (jaundice). These may be signs of a liver disease
  • swollen face, tongue and/or throat and/or difficulty swallowing or hives, together with difficulty breathing which are suggestive of an angioedema
  • a large rise in your blood pressure (symptoms may be headache, tiredness, dizziness)
  • migraine-like headaches which happen for the first time
  • if you become pregnant
  • if you notice signs of a blood clot, such as:
    - painful swelling and redness of the legs
    - sudden chest pain
    - difficulty in breathing

Remind any doctor, dentist or pharmacist you visit that you are using Sandrena.

Things you should not do

  • Do not stop using this medicine suddenly. Keep using Sandrena, even if you seem to be better. If you stop too early or too suddenly your problem may return.
  • Do not give this medicine to anyone else. It may harm them, even if their signs of illness are the same as yours.

Possible transfer of estradiol

During close skin contact estradiol gel may transfer to others (e.g. child, spouse, pets) if the application area has not been covered with clothing. Therefore, following precautions should be followed:

  • wash your hands with soap and water after application
  • cover the application area with clothing as soon as the gel has dried
  • shower the application site before skin contact with others.

If the gel has accidentally transferred to others, wash the exposed area with soap and water.

Contact your doctor or veterinarian in case of any symptoms of side-effects.

Driving or using machines

Sandrena is not expected to affect your ability to drive or use machines.

Looking after your medicine

  • Store below 25°C.

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

Store it in a cool dry place away from moisture, heat or sunlight; for example, do not store it:

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

Keep it where young children cannot reach it.

Getting rid of any unwanted medicine

If you no longer need to use this medicine or it is out of date, take it to any pharmacy for safe disposal.

Do not use this medicine after the expiry date.

6. Are there any side effects?

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

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

Less serious side effects

Less serious side effectsWhat to do
  • 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
Speak to your doctor if you have any of these less serious side effects and they worry you.

Serious side effects

Serious side effectsWhat to do
  • 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).
Call your doctor straight away, or go straight to the Emergency Department at your nearest hospital if you notice any of these serious side effects.

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

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

Reporting side effects

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

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

7. Product details

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

What Sandrena contains

Active ingredient
(main ingredient)
Estradiol
Other ingredients
(inactive ingredients)
Carbomer 934P, trolamine, propylene glycol, purified water and ethanol
Potential allergensContains 58.50% v/v alcohol

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

What Sandrena looks like

Sandrena is a smooth opalescent gel.

It is available in 0.5 g or 1 g sachets in packs containing 28 or 91 sachets.

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

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

Who distributes Sandrena

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

This leaflet was prepared in December 2023.

Published by MIMS February 2024

BRAND INFORMATION

Brand name

Sandrena

Active ingredient

Estradiol

Schedule

S4

 

1 Name of Medicine

Estradiol.

2 Qualitative and Quantitative Composition

Sandrena gel contains estradiol 1 mg/g.
Each sachet contains either 0.5 mg or 1.0 mg of estradiol.

Excipient with known effect.

Contains 58.50% v/v alcohol.
For the full list of excipients, see Section 6.1 List of Excipients.

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.

Apply on dry and clean skin.
One to two dose units (0.5 g or 1.0 g) of Sandrena (0.5 to 1.5 mg estradiol) are applied once daily on the skin of the lower trunk or the thigh. The application surface area should be one to two times the size of the hand. Sandrena should not be applied on the breasts, on the face or on irritated or broken skin. After application the gel should be allowed to dry for a few minutes and the application site should not be washed for one hour. Contact of the gel with the eyes should be avoided.
Hands should be washed thoroughly with soap and water after application.
As soon as the gel has dried after application, the application site should be covered with clothing.
Application site should be cleansed before situations where skin-to-skin contact with others is expected.
If another person (e.g. child or spouse) or pet accidentally touches the application site, that area of their skin should be washed with soap and water right away.
If no precautionary measures are taken, the estradiol gel can be accidentally transferred through close contact to others (e.g. child, spouse, pets). This may cause adverse effects if the gel is transferred. In case of any signs of symptoms of adverse effects, physician or veterinarian should be contacted.
Patients should be informed that children should not come in contact with the area of the body where estradiol gel was applied (see Section 4.4 Special Warnings and Precautions for Use).
In clinical trials the use of Sandrena has induced dermal irritation only very infrequently. The probability of topical irritation can be further decreased by changing the area of application daily (e.g. left and right side on alternate days).
If the patient forgets to apply a dose, it should be applied as soon as possible, unless the dose is more than 12 hours late. If the dose is more than 12 hours late, it should be skipped. Missed doses may induce breakthrough bleeding.
Improvement of symptoms generally occurs within a few weeks, but optimal results are obtained when therapy is continued for at least 3 months. Sandrena should be prescribed for the shortest duration consistent with treatment goals. Review the need for continuation of treatment after 6 months, taking into account the risk-benefit ratio for the individual user at that moment.

Monitoring advice.

As for all steroids with hormonal activity, yearly medical examination particularly of the breasts and pelvic areas is advisable. Review the need for continuation of treatment after 6 months (see Section 4.4 Special Warnings and Precautions for Use; Section 4.1 Therapeutic Indications).

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.

The benefits and risks of hormone treatment (HT), including Sandrena, must always be carefully weighed, including consideration of the emergence of risks as therapy continues. Sandrena should be used for the shortest duration consistent with treatment goals. The need for continued treatment should be reviewed after 6 months. Sandrena should only be continued for as long as the benefit outweighs the risks.
Do not use in combination with a progestogen in hysterectomised women.

Check the following before use.

Before therapy is initiated or reinstituted, a complete gynaecological examination should be performed and repeated at least once a year in long term replacement therapy. A careful appraisal of the risks and benefits should be undertaken before use and after 6 months, and Sandrena should only be continued as long as the benefit outweighs the risk.

Reasons for immediate withdrawal of therapy.

Therapy should be discontinued in case a contraindication is discovered and in the following situations: jaundice or deterioration in liver function, significant increase in blood pressure, new onset of migraine-type headache, pregnancy.

Coronary artery disease (CAD).

Hormone treatment should not be initiated or continued to prevent or treat cardiovascular disease. There is no evidence from randomised controlled trials of cardiovascular benefit with continuous combined conjugated estrogens and MPA. Large clinical trials showed a possible increased risk of cardiovascular morbidity in the first year of use and no benefit thereafter. For other HT products there are only limited data from randomised controlled trials examining benefit in cardiovascular morbidity or mortality. Therefore it is uncertain whether these findings also extend to other HT products.
The relative risk of CAD during use of combined estrogen+progestin hormone replacement therapy (HRT) is slightly increased. As the baseline absolute risk of CAD is strongly dependent on age, the number of extra cases of CAD due to estrogen+progestin use is very low in healthy women close to menopause, but will rise with more advanced age.
Randomised controlled data found no increased risk of CAD in hysterectomised women using estrogen-only therapy.

Endometrial hyperplasia and carcinoma.

The risks and benefits of treatment should be evaluated and close monitoring performed for patients with: endometriosis. Endometrial hyperplasia (simple glandular hyperplasia or hyperplasia glandularis cystica). Pre-existing uterine leiomyoma can increase in size under estradiol treatment. In these patients, careful examinations should be performed at regular intervals during therapy.
In women with an intact uterus the risk of endometrial hyperplasia and carcinoma is increased when estrogens are administered alone for prolonged periods. The reported increase in endometrial cancer risk among estrogen-only users varies from 2- to 12-fold greater compared with non-users, depending on the duration of treatment and estrogen dose. After stopping treatment risk may remain elevated for at least 10 years.
The addition of a progestin cyclically for at least 12 days per month/28 day cycle or continuous combined estrogen-progestin therapy in non-hysterectomised women prevents the excess risk associated with estrogen-only HRT.
Breakthrough bleeding and spotting may occur during the first months of treatment. If breakthrough bleeding or spotting appears after some time on therapy or continues after treatment has been discontinued, the reason should be investigated, which may include endometrial biopsy to exclude endometrial malignancy.
Unopposed estrogen stimulation may lead to premalignant or malignant transformation in the residual foci of endometriosis. Therefore, the addition of progestins to estrogen replacement therapy should be considered in women, who have undergone hysterectomy because of endometriosis, if they are known to have residual endometriosis.

Breast cancer.

The overall evidence shows an increased risk of breast cancer in women taking combined estrogen-progestogen or estrogen-only HRT, that is dependent on the duration of taking HRT.

Combined estrogen-progestogen therapy.

The randomised placebo-controlled trial, the Women's Health Initiative study (WHI), and a meta-analysis of prospective epidemiological studies are consistent in finding an increased risk of breast cancer in women taking combined estrogen-progestogen for HRT that becomes apparent after about 3 (1-4) years (see Section 4.8 Adverse Effects (Undesirable Effects)).

Estrogen-only therapy.

The WHI trial found no increase in the risk of breast cancer in hysterectomised women using estrogen-only HRT. Observational studies have mostly reported a small increase in risk of having breast cancer diagnosed that is lower than that found in users of estrogen-progestogen combinations (see Section 4.8 Adverse Effects (Undesirable Effects)).
Results from a large meta-analysis showed that after stopping treatment, the excess risk will decrease with time and the time needed to return to baseline depends on the duration of prior HRT use. When HRT was taken for more than 5 years, the risk may persist for 10 years or more.
Women on this therapy, in particular those with fibrocystic disease of the breast or a family history of breast cancer (first degree relatives), should have regular breast examinations and should be instructed in breast self examination. It is recommended that mammography be performed before the start of treatment and repeated at regular intervals. Mammographic density may be increased after the use of combined HT. This may have implications for the sensitivity and specificity of breast cancer screening.

Ovarian cancer.

Ovarian cancer is much rarer than breast cancer.
Epidemiological evidence from a large meta‐analysis suggests an increased risk in women taking estrogen‐only or combined estrogen‐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.

Venous thromboembolism.

Oral HT is associated with a higher relative risk of developing venous thromboembolism (VTE), i.e. deep vein thrombosis or pulmonary embolism. The studies found a two to threefold higher risk for users compared with nonusers, which for healthy women amounts to 1 to 2 additional cases of VTE in 10,000 patient years of treatment with HT. This increased risk may not apply for transdermal estrogens (see Section 5.1 Pharmacodynamic Properties, Clinical trials).
The occurrence of such an event is more likely in the first year of HT than later. Generally recognized risk factors for VTE include a personal history or family history, severe obesity (BMI > 30 kg/m2) and systemic lupus erythematosus (SLE). There is no consensus about the possible role of varicose veins in VTE. Patients with a history of VTE or known thrombophilic states have an increased risk of VTE. HT may add to this risk. Personal or strong family history of thromboembolism or recurrent spontaneous abortion should be investigated in order to exclude a thrombophilic predisposition. Until a thorough evaluation of thrombophilic factors has been made or anticoagulant treatment initiated, use of HT in such patients should be viewed as contraindicated. Those women already on anticoagulant treatment require careful consideration of the benefit/risk of use of HT. The risk of VTE may be temporarily increased with prolonged immobilization, major trauma or major surgery. As in all postoperative patients, scrupulous attention should be given to prophylactic measures to prevent VTE following surgery. Where prolonged immobilization is liable to follow elective surgery, particularly abdominal or orthopaedic surgery to the lower limbs, consideration should be given to temporarily stopping HT 4 to 6 weeks earlier, if possible. Treatment should not be restarted until the woman is completely mobilized.
If VTE develops after initiating therapy, the drug should be discontinued. Patients should be told to contact their doctors immediately when they are aware of a potential thromboembolic symptom (e.g. painful swelling of a leg, sudden pain in the chest, dyspnea).
The concurrent use of Sandrena and other estrogenic or partial estrogenic agents has not been studied and is, therefore, not recommended as its use may contribute to long-term risk.

Ischaemic stroke.

Combined estrogen-progestin and estrogen-only therapies are associated with an up to 1.5-fold increase in risk of ischaemic stroke. The relative risk does not change with age or time since menopause. However, as the baseline risk of stroke is strongly age-dependent, the overall risk of stroke in women, who use HRT, will increase with age.

Other conditions.

Some conditions may be aggravated during estrogen therapy. Women on estradiol treatment with one of the following conditions (or with a history thereof during previous pregnancy or hormone use) should therefore be closely monitored. These conditions include: hypertension, hypertriglyceridemia, migraine or severe headache, benign breast disease, liver function disturbances, cholestasis, cholelithiasis, diabetes mellitus with or without vascular involvement, asthma, otosclerosis, multiple sclerosis, galactorrhea, elevated prolactin levels, history of herpes gestationis, epilepsy and angioedema (hereditary or acquired), severe disturbance of the lipid metabolism, renal dysfunction, systemic lupus erythematosus, metabolic bone disease associated with hypercalcaemia.
Since estrogen may cause water retention, patients with heart failure, renal dysfunction or severe hypertension should be observed closely.
Women with pre-existing hypertriglyceridemia, should be followed closely during estrogen replacement or hormone replacement therapy, since rare cases of large increases of plasma triglycerides leading to pancreatitis have been reported with estrogen therapy in this condition.
Exogenous estrogens may induce or exacerbate symptoms of hereditary and acquired angioedema.
Estrogens increase thyroid binding globulin (TBG), leading to increased circulating total thyroid hormone as measured by protein bound iodine (PBI), T4 levels (by column or by radioimmunoassay) or T3 levels (by radioimmunoassay). T3 resin uptake is decreased, reflecting the elevated TBG. Free T4 and free T3 concentrations are unaltered. Other binding proteins may be elevated in serum, i.e. corticoid binding globulin (CBG), sex hormone binding globulin (SHBG), leading to increased circulating corticosteroids and sex steroids, respectively. Free or biological active hormone concentrations are unchanged. Other plasma proteins may be increased (angiotensinogen/renin substrate, alpha-1-antitrypsin, ceruloplasmin.
Chloasma may occasionally occur, especially in women with a history of chloasma gravidarum. Women with a tendency to chloasma should minimise exposure to the sun or ultraviolet radiation whilst taking HRT.
HRT does not improve cognitive function. There is some evidence of increased risk of probable dementia in women who start using continuous combined or estrogen-only HRT after the age of 65.
Sandrena is not a contraceptive and adequate non-hormonal contraception should be advised.

ALT elevations.

During clinical trials with patients treated for hepatitis C virus (HCV) infections with the combination regimen ombitasvir/paritaprevir/ritonavir with and without dasabuvir, ALT elevations greater than 5 times the upper limit of normal (ULN) were significantly more frequent in women using ethinylestradiol containing medicinal products such as CHCs. Additionally, also in patients treated with glecaprevir/pibrentasvir, ALT elevations were observed in women using ethinylestradiol containing medications such as CHCs. Women using medicinal products containing oestrogens other than ethinylestradiol, such as estradiol, had a rate of ALT elevation similar to those not receiving any oestrogens; however, due to the limited number of women taking these other oestrogens, caution is warranted for coadministration with the combination drug regimen ombitasvir/paritaprevir/ritonavir with or without dasabuvir and also the regimen glecaprevir/pibrentasvir. See Section 4.5 Interactions with Other Medicines and Other Forms of Interactions.

Potential estradiol transfer to children.

Estradiol gel can be accidentally transferred to children from the area of the skin where it was applied.
Post-marketing reports of breast budding and breast masses in prepubertal females, precocious puberty, gynaecomastia and breast masses in prepubertal males following unintentional secondary exposure to estradiol spray/gel have been reported. In most cases, the condition resolved with removal of estradiol exposure.
Patients should be instructed:
Not to allow others, especially children, to come into contact with the exposed area of the skin and to cover the application site with clothing if needed. In case of contact the child's skin should be washed with soap and water as soon as possible.
To consult a physician in case of signs and symptoms (breast development or other sexual changes) in a child that may have been exposed accidentally to estradiol gel.

Excipients.

This product contains propylene glycol and may cause skin irritation.
This product contains 271-835 mg alcohol (ethanol) in each dose of 0.5-1.5 g. It may cause burning sensation on damaged skin.

Use in the elderly.

No data is available.

Paediatric use.

No data is available.

Effects on laboratory tests.

No data is available.

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.

Hormone contraceptives containing oestrogens have been shown to significantly decrease plasma concentrations of lamotrigine when co-administered due to induction of lamotrigine glucuronidation. This may reduce seizure control. Although the potential interaction between hormone replacement therapy and lamotrigine has not been studied, it is expected that a similar interaction exists, which may lead to a reduction in seizure control among women taking both medicinal products together.

Pharmacodynamic interactions.

During clinical trials with the HCV combination drug regimen ombitasvir/paritaprevir/ritonavir with and without dasabuvir, ALT elevations greater than 5 times the upper limit of normal (ULN) were significantly more frequent in women using ethinylestradiol-containing medicinal products such as CHCs. Women using medicinal products containing oestrogens other than ethinylestradiol, such as estradiol, had a rate of ALT elevation similar to those not receiving any oestrogens; however, due to the limited number of women taking these other oestrogens, caution is warranted for coadministration with the combination drug regimen ombitasvir/paritaprevir/ritonavir with or without dasabuvir and also the regimen with glecaprevir/pibrentasvir (see Section 4.4 Special Warnings and Precautions for Use).

4.6 Fertility, Pregnancy and Lactation

Effects on fertility.

No data is available.
(Category B31)
Estrogens must not be used during pregnancy. If pregnancy occurs, treatment should be withdrawn immediately (see Section 4.3 Contraindications; Section 4.4 Special Warnings and Precautions for Use).
Estrogen administration to nursing mothers has been shown to decrease the quantity and quality of milk. Detectable amounts of estrogens and progestogens have been found in the milk of lactating mothers receiving these compounds, but the effects on the breastfed infant have not been determined. Estrogens must not be used during lactation.
1Australia Pregnancy Category B3: Drugs which have been taken by only a limited number of pregnant women and women of childbearing age, without an increase in the frequency of malformation or other direct or indirect harmful effects on the human fetus having been observed. Studies in animals have shown evidence of an increased occurrence of fetal damage, the significance of which is considered uncertain in humans.

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)

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.
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.

The experience of adverse drug reactions is overall expected in 76% of the patients. Undesirable effects according to system organ class associated with transdermal estradiol treatment are presented below:
Adverse events reported postmarketing with frequency not known (cannot be estimated from available data): uterine fibroids, exacerbation of hereditary angioedema, cerebral ischaemic events, abdominal pain, bloating (abdominal distension), cholestatic jaundice, contact dermatitis and eczema.

Common (≥ 1% - < 10%).

Skin irritation, myalgia, headache, dizziness, gastrointestinal symptoms (nausea, vomiting, stomach cramps, flatulence), oedema, weight increase, cardiac symptoms, varicose veins, mastalgia, vaginal spotting, vaginal discharge, disorder of vulvar/vagina, menstrual disorder, dysmenorrhoea, fatigue, depression, nervousness, lethargy, hot flushes, application site pruritus, pain and increased sweating.

Uncommon (≥ 0.1% - < 1%).

Itching, erythema, chloasma, myalgia, arthralgia, arthropathy, neurological disorders, anxiety, apathy, emotional lability, impaired concentration, changes in mood or libido, migraine, paraesthesia, palpitations, vision disturbances, tinnitus, sleep disorders (incl. insomnia), amnesia, hypertension, thrombosis and thrombophlebitis, urinary problems (incl. increased urinary frequency/urgency), constipation, pruritus genital, uterine fibroid, endocervical polyp, Ca adenopapillaris, corporis uteri, pelvic pain, leg pain, benign breast neoplasm, benign endometrial neoplasm, increased appetite, acne, alopecia, dry skin, joint disorders, muscle cramps, breast enlargement, breast tenderness and endometrial hyperplasia.

Rare (> 0.01% - < 0.1%).

Venous thromboembolism, alterations in liver function and biliary flow and rash.
Other adverse reactions have been reported in association with estrogen-progestin treatment:

Breast cancer risk.

An up to 2-fold increased risk of having breast cancer diagnosed is reported in women taking combined estrogen-progestogen therapy for more than 5 years.
The increased risk in users of estrogen-only therapy is lower than that seen in users of estrogen-progestogen combinations.
The level of risk is dependent on the duration of use (see Section 4.4 Special Warnings and Precautions for Use).
Absolute risk estimations based on results of the largest randomised placebo controlled trial (WHI-study) and the largest meta-analysis of prospective epidemiological studies are presented.

Largest meta-analysis of prospective epidemiological studies.

See Tables 2-4.

Endometrial cancer risk.

Postmenopausal women with a uterus.

The endometrial cancer risk is about 5 in every 1000 women with a uterus not using HRT.
In women with a uterus, use of estrogen-only HRT is not recommended because it increases the risk of endometrial cancer (see Section 4.4 Special Warnings and Precautions for Use).
Depending on the duration of estrogen-only use and estrogen dose, the increase in risk of endometrial cancer in epidemiology studies varied from between 5 and 55 extra cases diagnosed in every 1000 women between the ages of 50 and 65.
Adding a progestogen to estrogen-only therapy for at least 12 days per cycle can prevent this increased risk. In the Million Women Study the use of five years of combined (sequential or continuous) HRT did not increase risk of endometrial cancer (RR of 1.0 (0.8-1.2)).

Ovarian cancer.

Use of estrogen‐only or combined estrogen‐progestogen HRT has been associated with a slightly increased risk of having ovarian cancer diagnosed.
A meta‐analysis from 52 epidemiological studies reported an increased risk of ovarian cancer in women currently using HRT compared to women who have never used HRT (RR 1.43, 95% CI 1.31‐1.56). For women aged 50-54 years taking 5 years of HRT, this results in about 1 extra case per 2000 users. In women aged 50 to 54 years who are not taking HRT, about 2 women in 2000 will be diagnosed with ovarian cancer over a 5 year period.

Risk of venous thromboembolism.

HRT is associated with a 1.3-3-fold increased relative risk of developing venous thromboembolism (VTE), i.e. deep vein thrombosis or pulmonary embolism. The occurrence of such an event is more likely in the first year of using HT (see Section 4.4 Special Warnings and Precautions for Use). Results of the WHI studies are presented in Table 5:

Risk of coronary artery disease.

The risk of coronary artery disease is slightly increased in users of combined estrogen-progestogen HRT over the age of 60 (see Section 4.4 Special Warnings and Precautions for Use).

Risk of ischaemic stroke.

The use of estrogen-only and estrogen + progestogen therapy is associated with an up to 1.5 fold increased relative risk of ischaemic stroke. The risk of haemorrhagic stroke is not increased during use of HRT.
This relative risk is not dependent on age or on duration of use, but as the baseline risk is strongly age-dependent, the overall risk of stroke in women who use HRT will increase with age, see Section 4.4 Special Warnings and Precautions for Use. See Table 6.

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.

Sandrena is an alcohol based, percutaneously applied gel for hormone replacement therapy with estradiol as its active ingredient. The pharmacodynamics of Sandrena are similar to those of oral estrogens but the major difference to oral administration lies in the pharmacokinetic profile.
The clinical efficacy of Sandrena in the treatment of menopausal symptoms is comparable to that of peroral estrogen. Combined with medroxyprogesterone acetate, percutaneous estradiol treatment lowers total cholesterol without reducing the HDL cholesterol level.

Clinical trials.

Different adverse reaction rates have been reported with the use of different transdermal estrogen replacement therapy regimens. Depending on the formulation of the transdermal regimens, gel or patch, the rate of skin irritation varies and is considerably lower with the gel formulation.
In clinical trials with 0.5-1.5 g Sandrena (0.5-1.5 mg estradiol) 659 women have been treated for 1-2 years. Sandrena has been equally effective alleviating climacteric symptoms as oral estradiol valerate tablets or a transdermal patch. Sandrena treatment has also rendered an acceptable bleeding pattern compared with oral or other transdermal regimens.
In a clinical trial with 395 women only 3% discontinued the study due to adverse events. The adverse reaction profile and rate with Sandrena has been similar to that of oral and other transdermal regimens. In clinical trials with Sandrena less than 5% of the patients have reported skin irritation while the percentage with the comparative transdermal patch reached over 30%. The aforementioned studies were conducted prior to the WHI and Million Women studies. (See Section 4.1 Therapeutic Indications; Section 4.2 Dose and Method of Administration for recommended clinical use.)
In a large randomised trial involving women who received hormone replacement therapy for an average of 5.2 years using conjugated equine estrogens (0.625 mg/day) continuously combined with medroxyprogesterone acetate (2.5 mg/day), adverse effects on cardiovascular disease and the incidence of breast cancer were observed. The Women's Health Initiative study was designed to investigate the efficacy and safety of long-term hormone replacement therapy (HT) in preventing coronary heart disease in healthy postmenopausal women with an intact uterus.
The relative risk of coronary heart disease was 1.29 (95% confidence interval 1.02-1.63), corresponding to an increase in the absolute rate from 30 to 37 per 10,000 person years. The increased risk of breast cancer became apparent after 4 years on study medication. The relative risk of stroke was 1.41 (1.07-1.85), an increase in the absolute rate from 21 to 29 per 10,000 person years. The relative risk of VTE was 2.11 (1.58-2.82), an increase from 16 to 34 per 10,000 person years. The relative risk of breast cancer was 1.26 (1.00-1.59), an increase from 30 to 38 per 10,000 person years. The study was stopped prematurely because the preset criterion for invasive breast cancer was fulfilled and a global risk-benefit index supported risks exceeding benefits. In the estrogen only arm global risk-benefit index has not been exceeded, and that arm is continuing. The risks and benefits in women receiving treatment for the short-term management of climacteric symptoms of estrogen deficiency or for the management of premature menopause were not examined. In a randomised controlled subgroup of the WHI trial (referred to as the WHI Memory study, WHIMS), women of 65 years of age or older (n = 4,532, 50% older than 70) treated with conjugated equine estrogens (0.625 mg/day) continuously combined with medroxyprogesterone acetate (2.5 mg/day) were reported to have a two fold increase in the risk of developing probable dementia. After an average follow-up of 4 years the absolute risk of probable dementia was 45 per 10,000 in the estrogen plus progestogen group compared to 22 per 10,000 in the placebo group.
It is unknown if these findings apply to younger postmenopausal women.
An observational study of 1,084,110 women (the Million Women study) of whom 828,923 were postmenopausal has shown that, compared to never users, use of estrogen-progestogen combined HT is associated with a higher risk of breast cancer (RR = 2.00, 95% CI: 1.88-2.12) than use of estrogens alone (RR = 1.30, 95% CI: 1.21-1.40). In this study the magnitude of the increase in breast cancer risk was similar for all estrogen only preparations, irrespective of the type, dose or route of administration of the estrogen (oral RR = 1.32, 95% CI: 1.21-1.45; transdermal RR = 1.24, 95% CI: 1.11-1.39 and implanted RR = 1.65, 95% CI: 1.26-2.16). Likewise the magnitude of the increased risk was similar for all estrogen plus progestogen preparations, irrespective of the type of progestogen or the number of days of addition per cycle (sequential < 5 years RR = 1.77, 95% CI: 1.59-1.97 and ≥ 5 years RR = 2.12, 95% CI: 1.95-2.30; continuous < 5 years RR = 1.57, 95% CI: 1.37-1.79 and ≥ 5 years RR = 2.40, 95% CI: 2.15-2.67). For all HT, an excess risk becomes apparent within 1-2 years of starting treatment and increases with duration of use of HT but begins to decline when HT is stopped and by 5 years reaches the same level as in women who have never taken HT. The increase in risks applies to all women studied, although the relative risk in all current users of HT was significantly higher in those with a lean or normal body build (body mass index or BMI of < 25 kg/m2; RR = 1.97, 95% CI: 1.82-2.14) compared to those with a BMI of ≥ 25 kg/m2; RR = 1.46, 95% CI: 1.36-1.58 (see Section 4.4 Special Warnings and Precautions for Use).

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, Cmax, was 1.06. The associated 90% confidence interval (87.9-128%) was included. The wider confidence interval for Cmax 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.

Estradiol is a natural female hormone with an established clinical use, therefore no toxicological studies have been performed with Sandrena. The necessary studies on the irritant effects of the gel have been studied in rabbits and skin sensitisation in guinea pigs. Based on the results from these studies it can be concluded that Sandrena very infrequently could cause mild skin irritation. The frequency of the occurrence of dermal irritation can be reduced by daily change of the application site.
There is limited evidence available in the literature suggesting that estradiol may be weakly genotoxic. No evidence could be found for an increase in the rate of gene mutation in bacterial or mammalian cells, but there was some evidence for the induction of chromosomal aberrations and aneuploidy and an increased incidence of sister chromatid exchanges (indicative of DNA damage) in mammalian cells. None of these effects were induced by estradiol in human lymphocyte cultures. Importantly, there was no evidence of micronuclei formation in rodent bone marrow micronucleus assays.

Carcinogenicity.

Supraphysiological doses of estradiol have been associated with the induction of tumours in estrogen-dependent target organs in all rodent species tested. The relevance of these findings with respect to humans has not been established. Unopposed estrogen therapy is associated with an increased incidence of endometrial carcinoma, particularly with prolonged use.
Concurrent progestogen therapy for a minimum of 12 to 14 days reduces the risk of endometrial hyperplasia (see Section 4.2 Dose and Method of Administration). Usually, a withdrawal bleed resembling normal menstruation will occur after the progestin period. Unexpected or prolonged uterine bleeding during therapy should be reported to the physician and its cause clarified.

Breast cancer.

Epidemiological studies indicated a small or moderate increase in the probability of having breast cancer in women currently or recently using hormone treatment (HT). A large observational study, the Million Women study, has shown that compared to never users, use of estrogen-progestogen combined HT is associated with a higher risk of breast cancer (RR = 2.00, 95% CI: 1.88-2.12) than use of estrogens alone (RR = 1.30, 95% CI: 1.21-1.40). A large randomised clinical trial demonstrated that continuous combined HT is associated with an increase in breast cancer risk (RR 1.26, 95% CI:1.00-1.59) (see Section 5.1 Pharmacodynamic Properties, Clinical trials, Women's Health Initiative). In a separate arm of this trial no increased risk has so far been observed for estrogen-only therapy. The use of estrogens alone as well as combined/sequential estrogen and progestogen use is associated with an increased risk of breast cancer. This emerges towards the end of the first year of treatment (see Million Women study in Clinical trials).
Breast cancer can be fatal. Therefore, for all HT, the benefits and risks of treatment should be carefully considered (see Section 4.1 Therapeutic Indications). It is recommended that women are encouraged to report any changes in their breast to their doctor. Regular breast examinations and, where appropriate, mammography should be carried out, particularly in women with risk factors for breast cancer.
If prescribing HT, the potential for increased cardiovascular, thrombotic and neoplastic adverse events, and an increased incidence of probable dementia in older women, must be considered as part of the risk-benefit assessment (see Section 5.1 Pharmacodynamic Properties, Clinical trials). The need for continuation of treatment should be reviewed after 6 months.

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.

0.5 g sachets: 28 or 91 sachets.
1 g sachets: 7 (sample pack), 28 or 91 sachets.
Not all pack sizes may be marketed in Australia.

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.


Chemical name: 17β-estradiol; estra-1, 3, 5 (10)-triene-3, 17β-diol.
Molecular formula: C18H24O2. Molecular weight: 272.4.

CAS number.

50-28-2 (anhydrous).

7 Medicine Schedule (Poisons Standard)

S4 - Prescription Only Medicine.

Summary Table of Changes