Consumer medicine information

Ovestin Tablets

Estriol

BRAND INFORMATION

Brand name

Ovestin Tablets

Active ingredient

Estriol

Schedule

S4

 

Consumer medicine information (CMI) leaflet

Please read this leaflet carefully before you start using Ovestin Tablets.

SUMMARY CMI

Ovestin Tablets

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 Ovestin Tablets?

Ovestin Tablets contains the active ingredient estriol. Ovestin Tablets is used for relief of symptoms occurring after menopause.

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

2. What should I know before I take Ovestin Tablets?

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

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

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

3. What if I am taking other medicines?

Some medicines may interfere with Ovestin Tablets 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 take Ovestin Tablets?

  • Ovestin Tablets should be taken at the same time every day, to ensure it works effectively. Always use this medicine exactly as your doctor or pharmacist has told you.

More instructions can be found in Section 4. How do I take Ovestin Tablets? in the full CMI.

5. What should I know while taking Ovestin Tablets?

Things you should do
  • Remind any doctor, dentist or pharmacist you visit that you are using Ovestin Tablets.
  • If you become pregnant while using this medicine, stop using it and tell your doctor immediately.
  • Monitor your health and contact your doctor if you notice any changes.
  • Keep all of your doctor's appointments and go for regular check-ups
Things you should not do
  • Do not stop using this medicine suddenly without telling your doctor.
  • Do not give your medicine to anyone else, even if they have the same condition as you.
Driving or using machines
  • No effects on the ability to drive and use machines have been observed.
Looking after your medicine
  • Store Ovestin Tablets in a cool dry place, out of direct light, where the temperature is below 30°C.
  • Keep Ovestin Tablets in the original packaging, in a safe place, away from children.

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

6. Are there any side effects?

Side effects include local irritation or itching of skin in or around vagina, swelling and increased tenderness of the breasts, increased vaginal discharge, nausea, fluid retention in the tissues, usually marked by swollen ankles or feet or flu-like symptoms.

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

Ovestin Tablets

Active ingredient: estriol

Consumer Medicine Information (CMI)

This leaflet provides important information about using Ovestin Tablets. 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 Ovestin Tablets.

Where to find information in this leaflet:

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

1. Why am I using Ovestin Tablet?

Ovestin Tablet is a Hormone Replacement Therapy (HRT). It contains the active ingredient female hormone estriol (an estrogen).

Ovestin is used for relief of symptoms occurring after menopause. It is used in postmenopausal women with at least 12 months since their last natural period.

During menopause, the amount of estrogens produced by a woman's body gradually drops. If the ovaries are removed surgically (ovariectomy) before menopause, the decrease in estrogen production occurs very abruptly. In many cases the decrease in estrogen production leads to well-known menopausal complaints such as hot flushes and night sweating. The shortage of estrogens may cause the vaginal wall to become thin and dry. As a result sexual intercourse become painful and vaginal itching and infections may occur. Estrogen deficiency may also lead to symptoms like urinary incontinence and recurrent cystitis. Ovestin alleviates these symptoms after menopause. It may take several days or even weeks before you notice an improvement. You will only be prescribed Ovestin if your symptoms seriously hinder your daily life. In addition to the above uses, Ovestin Tablets may also be prescribed to treat certain forms of infertility, improve wound healing in postmenopausal women undergoing vaginal surgery or help assess cervical smears taken from postmenopausal women.

2. What should I know before I take Ovestin Tablets?

Warnings

Do not take Ovestin Tablets if:

  • you are allergic to estriol, or any of the ingredients listed at the end of this leaflet.
    Some of the symptoms of an allergic reaction may include:
    - shortness of breath
    - wheezing or troubled breathing
    - swelling of the face, lips, tongue or other parts of the body
    - rash, itching or hives on the skin.

Always check the ingredients to make sure you can use this medicine.

  • you have or have ever had anaphylactic reaction, angioedema or hypersensitivity to Ovestin
  • you have or have ever had breast cancer, or if you are suspected of having it.
  • you have or if it is suspected that you have cancer which is sensitive to estrogens, such as cancer of the lining of the womb.
  • you have any unexplained vaginal bleeding
  • you have excessive thickening of the lining of your womb (endometrial hyperplasia) that is not being treated.
  • you have or have had a blood clot in a vein (thrombosis) such as in the legs (deep vein thrombosis) or the lungs (pulmonary embolism)
  • you have a blood clotting disorder (such as protein C, protein S, or antithrombin deficiency)
  • you have or have had a disease caused by blood clots in the arteries such a heart attack, stroke or angina
  • you have or ever have had a liver disease and your liver function tests have not returned to normal
  • you have a rare blood problem called 'porphyria' (an inherited or acquired disorder in the production of blood pigment).

Check with your doctor if you:

  • have any other medical conditions
  • have allergies to any other medicines, foods, preservatives or dyes.
  • react badly to lactose or milk. Ovestin Tablets contain lactose.

Certain conditions may be made worse by HRT. If you have or have had any of the following conditions, tell your doctor before starting Ovestin Tablets as these may return or become worse during treatment with this medicine:

  • 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 (see “Blood clots in a vein (thrombosis)”)
  • increased risk of getting an estrogen-sensitive cancer (such as having a mother, sister or grandmother who has had breast cancer)
  • high blood pressure
  • heart disease
  • liver disorders
  • kidney disorders
  • diabetes
  • gallstones
  • migraine or (severe) headache
  • systemic lupus erythematosus (SLE, an immune disorder affecting the skin and other organs)
  • epilepsy
  • asthma
  • otosclerosis (inherited deafness)
  • fluid retention due to cardiac or kidney problems

Tell your doctor if you have Hepatitis C and you are taking the combination drug regimen ombitasvir/paritaprevir/ritonavir, with or without dasabuvir. Taking the combination of these drugs with some estrogen-containing products may cause increases in liver function blood test results (increase in ALT liver enzyme); the risk of this happening with Ovestin is currently unknown.

Before you start using Ovestin Tablets, your doctor should ask about your own and your family's medical history. Your doctor may decide to examine your breasts and/or your abdomen, and may do an internal examination. You will also have periodic check-ups, especially examinations of the breastsbreast screening. Your doctor will tell you how often these tests should be performed.

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 Ovestin if you are pregnant. Ovestin is for use in postmenopausal women only. If you become pregnant, stop using Ovestin and contact your doctor.

Do not breast-feed if you are using Ovestin. The active ingredient estriol passes into breast milk and there is a possibility that your baby may be affected.

HRT and cancer

Endometrial cancer

Every woman is at a small risk of getting endometrial cancer (cancer of the lining of the womb), whether or not HRT is used. The risk of cancer of the lining of the womb increases with the duration of treatment.

Breakthrough bleeding or spotting may occur during the first few months of using Ovestin.

Tell your doctor if the bleeding or spotting:

  • carries on for more than the first few months
  • starts after you have been on Ovestin for a while
  • carries on even after you have stopped using Ovestin.

Breast cancer

Women who have breast cancer, or have had breast cancer in the past, should not use Ovestin Tablets.

Taking estrogen or estrogen-progestogen combined HRT or Ovestin for several years slightly increases the risk of breast cancer. The risk increases with the duration of use and returns to normal within about five years after stopping HRT. Women using combined HRT have a slightly greater risk of developing breast cancer than women using estrogen-only HRT.

It is not known whether Ovestin 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.

Be sure to regularly check your breasts for any changes such as dimpling of the skin, changes in the nipple, or any lumps you can see or feel.

Ovarian 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. Some studies have indicated that taking estrogen-only HRT for more than 5 years may increase the risk of ovarian cancer. It is not yet known whether other kinds of HRT or Ovestin increase the risk in the same way.

Effects of HRT on heart or circulation

Blood clot (thrombosis)

All women have a very small chance of having a blood clot in the veins of the leg, lungs or other parts of the body. Using some forms of HRT may slightly increase this small chance. It is unknown if Ovestin increases the risk in the same way.

These blood clots are not always serious, but if one travels to the lungs, it can cause chest pain, breathlessness, collapse or even death. This condition is called pulmonary embolism.

You are more likely to get a blood clot in your veins as you get older and if any of the following applies to you. Inform your doctor if any of these situations applies to you:

  • you are pregnant or have recently had a baby
  • you have had one or more miscarriages
  • you use estrogens
  • you are seriously overweight
  • you have had a blood clot before in the leg, lung or another organ
  • blood clots run in your family
  • you have any blood clotting problem that needs treatment with a medicine such as warfarin
  • you have systemic lupus erythematosus (SLE)
  • you are unable to move for long periods, for example after a long illness or major operation
  • you have cancer.

Stroke

Recent research with one type of HRT (containing conjugated estrogen plus the progestogen MPA) has shown a slight increase in the risk of having a stroke.

If you have symptoms that might indicate that you have a stroke (such as unexplained migraine-type headaches, with or without disturbed vision), see a doctor as soon as possible. Do not use any more Ovestin until your doctor says you can.

Dementia

It is not known if there is an increased risk of dementia when using Ovestin.

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 Ovestin Tablets and affect how it works. This might lead to irregular bleeding. These include:

  • anticoagulants (medicines to stop blood clots);
  • corticosteroid hormones (includes many anti-asthmatic drugs);
  • succinylcholine (medicine for muscle relaxation);
  • theophyllines (medicine for asthma);
  • medicines for epilepsy (such as barbiturates (phenobarbital), hydantoins (phenytoin) and carbamazepine);
  • medicines for fungal or bacterial infections (such as griseofulvin, rifamycins (rifampicin, rifabutin); troleandomycin);
  • medicines for viral infections (eg. nevirapine, efavirenz, ritonavir, nelfinavir, ombitasvir, paritaprevir);
  • herbal preparations containing St John's Wort (Hypericum Perforatum).

Tell your doctor if you have Hepatitis C and aretaking the combination drug regimen ombitasvir/paritaprevir/ritonavir, with or without dasabuvir. Taking the combination of these drugs with some estrogen-containing products may cause increases in liver function blood test results (increase in ALT liver enzyme); the risk of this happening with Ovestin is currently unknown.

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

4. How do I take Ovestin Tablets?

How much to take

Your doctor will usually prescribe this product as a daily dosage of up to 4-8 mg daily. This dose is usually given in the first 5-7 days and can then be reduced to a maintenance level of 1-2 mg daily in the following 1-3 weeks depending on what your doctor thinks about your response to the treatment.

The score line is only there to help you break the tablet if you have difficulty swallowing it whole.

How long to take Ovestin Tablets

  • You would not normally take the tablets for more than 12 months.
  • If long-term use is required, your doctor will review your need to continue at least every 6 months.

When to take Ovestin Tablets

Ovestin Tablets should be taken orally with water. You should take your tablets at about the same time each day.

If you forget to take Ovestin Tablets

If you miss your dose at the usual time, take it as soon as you remember.

If it is more than 12 hours have lapsed, skip the dose you missed and take your next dose when you are meant to.

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

This may increase the chance of you getting an unwanted side effect.

If you take too much Ovestin Tablets

If you think that you have taken too much Ovestin Tablets, 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.

5. What should I know while taking Ovestin Tablets?

Things you should do

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

If you are about to be started on any new medicine, remind your doctor or pharmacist that you are taking Ovestin Tablets.

If you become pregnant while using Ovestin, stop using it and tell your doctor immediately.

If you are to be hospitalised or undergo surgery, tell your doctor and your surgeon that you are taking Ovestin. You may need to stop taking Ovestin about 4-6 weeks before the operation, to reduce the risk of a blood clot. Your doctors will tell you when you can start using Ovestin again.

Conduct monthly self-examination of your breasts. Your doctor or nurse can show you how to check your breasts properly. If you notice any changes to your breasts, see your doctor.

See your doctor for regular check-ups (at least once every year). At these check-ups, your doctor may discuss with you the benefits and risks of continuing to use Ovestin.

Thinks you should not do

  • Do not use Ovestin to treat any other complaints unless your doctor tells you to.
  • Do not give your medicine to anyone else, even if they have the same condition as you.
  • Do not stop using your medicine without checking with your doctor.

Driving or using machines

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

Looking after your medicine

Keep your Ovestin Tablets in the original package in a cool dry place where the temperature stays below 30°C, away from moisture, heat or sunlight; 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.

Do not use this medicine if it does not look quite right.

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.

Dependent on dosage and sensitivity of the patient, Ovestin may cause side effects as shown below, 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
  • irritation or itching of the skin in or around vagina
  • increased vaginal discharge
  • swelling and increased tenderness of the breasts
  • nausea
  • fluid retention in the tissues, usually marked by swollen ankles or feet
  • flu-like symptoms
In most patients these side effects will disappear after the first weeks of treatment.
Tell your doctor if vaginal bleeding occurs or if these side effects worry you.

Serious side effects

Serious side effectsWhat to do
  • signs of allergy such as rash, swelling of the face, lips, mouth, throat or other parts of the body, shortness of breath, wheezing or trouble breathing
  • yellowing of your skin or the whites of your eyes (jaundice)
  • sudden increase in blood pressure
  • migraine, or severe headaches
  • thrombosis (red, painful or swollen leg, difficulty breathing, chest pain, headache or pain elsewhere in your body, dizziness, fainting, disturbances in vision, swollen ankles.
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 Ovestin Tablets contains

Active ingredient
(main ingredient)		estriol, 1 mg
Other ingredients
(inactive ingredients)
  • magnesium stearate
  • potato starch
  • lactose monohydrate

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

What Ovestin Tablets look like

Packs contain one blister strip of 30 white round flat, scored tablets with bevelled edges. The tablets are marked 'DG' above '7' on one side (AUST R 14514).

Do not use the product if the pack or Tablets is damaged or appears unusual.

Who distributes Ovestin Tablets

Aspen Pharmacare Australia Pty Ltd
34-36 Chandos St
St Leonards, NSW 2065
Australia

This leaflet was prepared in August 2023.

Published by MIMS October 2023

BRAND INFORMATION

Brand name

Ovestin Tablets

Active ingredient

Estriol

Schedule

S4

 

1 Name of Medicine

Estriol.

2 Qualitative and Quantitative Composition

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

3 Pharmaceutical Form

Tablets, each containing 1 mg estriol.
Ovestin Tablets 1 mg are white, round, flat, scored tablets, with bevelled edges. All tablets are coded "DG" above "7" below the score line on one side. The score line is only to facilitate breaking for ease of swallowing and not to divide into equal doses.

4 Clinical Particulars

4.1 Therapeutic Indications

Short-term treatment of menopausal syndrome.
Review the need for continuation of treatment after 6 months treatment, taking into account the risk-benefit ratio for the individual user at that moment (including cardiovascular disease and breast cancer, see Section 4.4 Special Warnings and Precautions for Use). Ovestin Tablets should only be continued for as long as the benefit outweighs the risks.

4.2 Dose and Method of Administration

Ovestin is an estrogen-only product that may be given to women with or without a uterus.
Ovestin Tablets should be taken orally and swallowed with some water or other drink, preferably at the same time every day.
When initiating therapy, depending on the severity of the symptoms, a daily dosage of up to 4 mg (4 tablets) will usually be required. This dosage should be given in the first 5 to 7 days and can then be reduced to the maintenance level (1 to 2 mg daily, i.e. 1 to 2 tablets) in the course of the following 1 to 3 weeks depending on the degree of patient response. The lowest dose which will control the symptoms should be used.
Estriol tablets should be prescribed for the shortest duration consistent with treatment goals. Review the need for continuation of treatment at least every 6 months, taking into account the risk-benefit ratio for the individual user at that moment (see Section 4.4 Special Warnings and Precautions for Use; Section 4.1 Therapeutic Indications). Treatment should not be continued for more than 12 months.
Ovestin can be administered either continuously or intermittently. If preference is given to the latter treatment, a tablet free period of 5 to 7 days may be introduced after about each three weeks of treatment.
A missed dose should be taken as soon as remembered, unless it is more than 12 hours overdue. In the latter case the missed dose should be skipped and the next dose should be taken at the normal time.
In women not taking HRT or women who switch from a continuous combined HRT product, treatment with Ovestin Tablets may be started on any day. Women who switch from cyclic HRT regimen should start Ovestin treatment 1 week after completion of the cycle.

Monitoring advice.

As for all steroids with hormonal activity, yearly medical examination particularly of the breasts and pelvic areas is advisable.

4.3 Contraindications

Known, past or suspected breast cancer.
Known or suspected estrogen-dependent malignant tumours (e.g. endometrial cancer).
Untreated endometrial hyperplasia.
Pregnancy.
Undiagnosed genital bleeding.
Previous or current venous thromboembolism (deep venous thrombosis, pulmonary embolism).
Known thrombophilic disorders (e.g. protein C, protein S, or antithrombin deficiency, see Section 4.4 Special Warnings and Precautions for Use).
A history of recurrent venous thromboembolism (VTE) or known thrombophilic disease in a patient who is not already on anticoagulant treatment (see Section 4.4 Special Warnings and Precautions for Use).
Hypersensitivity to the active substances or to any of the excipients.
Active or recent arterial thromboembolic disease (e.g. angina, myocardial infarction).
Acute liver disease, or a history of liver disease as long as liver function tests failed to return to normal.
Porphyria.
Thrombophlebitis, or with a past history of this condition.
A history during pregnancy or previous use of steroids of a manifestation or deterioration of otosclerosis.
Endometriosis.
Hyperlipoproteinaemia, particularly in the presence of other risk factors which may indicate a predisposition to cardiovascular disorders.
Rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption.
See Section 4.6, Use in pregnancy, Use in lactation.

4.4 Special Warnings and Precautions for Use

Identified precautions.

For the treatment of postmenopausal symptoms, hormone replacement therapy (HRT) should only be initiated for symptoms that adversely affect quality of life. In all cases, a careful appraisal of the risks and benefits should be undertaken at least annually and HRT should only be continued as long as the benefit outweighs the risk. The benefits and risks of hormone treatment, including Ovestin Tablets must always be carefully weighed, including consideration of the emergence of risks as therapy continues. Ovestin Tablets should be used for the shortest duration consistent with treatment goals. The need for continued treatment should be reviewed after 6 months or earlier. Ovestin Tablets should only be continued for as long as the benefit outweighs the risks.
If prescribing HRT for long-term purposes (please note that Ovestin Tablets are not indicated for the prevention or treatment of bone loss), the potential for increased cardiovascular, thrombotic and neoplastic adverse events and an increased incidence of probable dementia in older women, must also be considered as part of the risk-benefit assessment. Breast cancer can be fatal. Hormone treatments should not be used for the long-term maintenance of general health, including the primary prevention of cardiovascular disease.

Medical examination/follow-up.

Before initiation or reinstituting HRT, a complete personal and family medical history should be taken, together with a thorough general and gynaecological examination. Physical (including pelvic and breast) examination should be guided by this and by the contraindications and warnings for use. During treatment, periodic check-ups are recommended of a frequency and nature adapted to the individual woman. Women should be advised what changes in their breast should be reported to their doctor or nurse (see 'Breast cancer' below). Investigations, including appropriate imaging tools e.g. mammography, should be carried out in accordance with current accepted practices, modified according to the clinical needs of the individual.

Conditions which need supervision.

If any of the following conditions are present, have occurred previously and/or have aggravated during pregnancy or previous hormone treatment, the benefits of treatment should be weighed against the possible risks. In these cases the patient should be closely supervised. It should be taken into account that these conditions may recur or be aggravated during treatment with Ovestin, in particular:
A history of, or the presence of risk factors for thromboembolic disorders (see below).
Liver disorders (e.g. liver adenoma).
Porphyria.
Diabetes mellitus with or without vascular involvement.
Hypertension.
Leiomyoma (uterine fibroids) or endometriosis.
Cholelithiasis.
Severe pruritus.
Migraine (or severe) headache.
Cholestatic jaundice.
Systemic lupus erythematosus.
Herpes gestationis.
Otosclerosis.
A history of endometrial hyperplasia (see below).
Epilepsy.
Asthma.
Risk factors for estrogen dependent tumours, e.g. first degree heredity for breast cancer.

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 headaches.
Pregnancy.

Endometrial hyperplasia and carcinoma.

Clinical studies showed that the use of divided daily doses and long-term use of high doses of estriol (more than 8 mg daily) may lead to endometrium stimulation. In addition, one epidemiological study has shown that long-term treatment with low doses of oral estriol may increase the risk for endometrial cancer. The risk increased with the duration of treatment and disappeared within one year after the treatment was stopped. The increased risk mainly concerned less invasive and highly differentiated tumours. In women with an intact uterus, the following precautions should be taken:
The total daily dose should be taken at one time.
The patient should be informed to contact a doctor if vaginal bleeding occurs. Vaginal bleeding during medication should always be investigated.
During long-term treatment, the endometrium should be monitored at least annually. Alternatively, a progestogen should be added, for at least 12-14 days of each calendar month.
The increased breast cancer risk associated with combined estrogen-progestogen treatment should be considered, when making decisions to either monitor the endometrium or add a progestogen. There are no indications that treatment with oral estriol alone increases the risk for breast cancer.

Breast cancer.

HRT may increase mammographic density. This may complicate the radiological detection of breast cancer. Clinical studies reported that the likelihood of developing increased mammographic density was lower in subjects treated with estriol than in subjects treated with other estrogens.
A randomized placebo-controlled trial, the Women's Health Initiative study (WHI), and a meta-analysis of prospective epidemiological studies, including the Million Women Study (MWS), have reported are consistent in finding an increased risk of breast cancer in women taking estrogens, estrogen-progestagen combinations or tibolone for HRT for several years (see Section 4.8 Adverse Effects (Undesirable Effects)).
For all HRT, an excess risk becomes apparent within a few years of use and increases with duration of intake but returns to baseline within a few (at most five) years after stopping treatment.
In the MWS, the relative risk of breast cancer with conjugated equine estrogens (CEE) or estradiol (E2) was greater when a progestagen was added, either sequentially or continuously, and regardless of type of progestagen. There was no evidence of a difference in risk between the different routes of administration.
In the WHI study, the continuous combined conjugated equine estrogen and medroxyprogesterone acetate (CEE + MPA) product used was associated with breast cancers that were slightly larger in size and more frequently had local lymph node metastases compared to placebo.
It is unknown whether Ovestin carries the same risk. In a population-based case-control study in 3,345 women with invasive breast cancer and 3,454 controls, estriol was found not to be associated with an increased risk of breast cancer, in contrast to other estrogens. However, the clinical implications of these findings are as yet unknown. Therefore, it is important that the risk of being diagnosed with breast cancer is discussed with the patient and weighed against the known benefits of HRT.

Venous thromboembolism.

HRT is associated with a higher relative risk of developing venous thromboembolism (VTE), i.e. deep vein thrombosis or pulmonary embolism. One randomized controlled trial and epidemiological studies found a 2-3 fold higher risk for users compared with non-users. For non-users it is estimated that the number of cases of VTE that will occur over a 5 year period is about 3 per 1,000 women aged 50-59 years and 8 per 1,000 women aged 60-69 years. It is estimated that in healthy women who use HRT for 5 years, the number of additional cases of VTE over a 5 year period will be between 2 and 6 (best estimate = 4) per 1,000 women aged 50-59 years and between 5 and 15 (best estimate = 9) per 1,000 women aged 60-69 years. The occurrence of such an event is more likely in the first year of HRT than later. These studies did not include Ovestin and, in the absence of data, it is unknown whether Ovestin carries the same risk.
Patients with known thrombophilic states have an increased risk of VTE and HRT may add to this risk. HRT is therefore contraindicated in these patients (see Section 4.3 Contraindications).
Generally recognised risk factors for VTE include use of estrogens, older age, major surgery, prolonged immobilization, a personal history or family history, obesity (body mass index > 30 kg/m2), pregnancy/ postpartum period, systemic lupus erythematosus (SLE) and breast cancer. There is no consensus about the possible role of varicose veins in VTE. The risk of VTE may be temporarily increased with prolonged immobilisation, major trauma or major elective or post-traumatic surgery. As in all post-operative patients, scrupulous attention should be given to prophylactic measures to prevent VTE following surgery. Where prolonged immobilisation is liable to follow elective surgery, particularly abdominal surgery or orthopaedic surgery to the lower limbs, consideration should be given to temporarily stopping HRT four to six weeks earlier, if possible.
Patients with a history of recurrent VTE or known thrombophilic states have an increased risk of VTE. HRT may add to this risk. Personal or strong family history of recurrent thromboembolism or recurrent spontaneous abortion should be investigated in order to exclude a thrombophilic predisposition. Until a definitive diagnosis has been made or anticoagulant treatment initiated, use of HRT in such patients should be viewed as contraindicated. Women already on anticoagulant treatment requires careful consideration of the benefit-risk of use of HRT.
In women with no personal history of VTE but with a first degree relative with a history of thrombosis at young age, screening may be offered after careful counseling regarding its limitations (only a proportion of thrombophilic defects are identified by screening). If a thrombophilic defect is identified which segregates with thrombosis in family members or if the defect is 'severe' (e.g. antithrombin, protein S, or protein C deficiencies or a combination of defects) HRT is contraindicated.
If VTE develops after initiating Ovestin therapy, Ovestin Tablets should be discontinued and/or adequate anticoagulant treatment should be given. 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, dyspnoea).

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. Two large clinical trials (WHI and HERS, i.e. Heart and Estrogen/ progestin Replacement Study) showed a possible increased risk of cardiovascular morbidity in the first year of use and no overall benefit. For other HRT products there are only limited data from randomised controlled trials examining effects in cardiovascular morbidity or mortality. Therefore it is uncertain whether these findings also extend to other HRT products.
It is suspected that estrogen replacement therapy in post-menopausal women may increase the risk of myocardial infarction. Women who use estrogens should therefore be strongly advised against smoking as it may further increase the risk of adverse cardiovascular effects.
Combined hormone replacement therapy should not be used for long-term maintenance of general health, including primary prevention of cardiovascular disease. Ovestin does not fall in to this category. The concurrent use of Ovestin and other estrogenic agents, or partial estrogenic agents has not been studied and is, therefore, not recommended as its use with other estrogenic agents, or partial estrogenic agonists, may contribute to long-term risk.

Ischaemic stroke.

One large randomised clinical trial (WHI-trial) found, as a secondary outcome, an increased risk of ischemic stroke in healthy women during treatment with continuous combined conjugated estrogens and MPA. For women who do not use HRT, it is estimated that the number of cases of stroke that will occur over a five year period is about 3 per 1,000 women aged 50-59 years and 11 per 1,000 women aged 60-69 years. It is estimated that for women who use CCE and MPA for five years, the number of additional cases will be between 0 and 3 (best estimate = 1) per 1,000 users aged 50-59 years and between 1 and 9 (best estimate = 4) per 1,000 women aged 60-69 years. It is unknown whether the increased risk also extends to other HRT products.

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.

Hereditary and acquired angioedema.

Exogenous estrogens may induce or exacerbate symptoms of hereditary and acquired angioedema. Consider whether the benefits of estrogen therapy, including Ovestin, outweigh the risks in such women.

Hepatitis C.

During clinical trials with the hepatitis C virus (HCV) 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 combined hormonal contraceptives (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 estrogens other than ethinylestradiol, such as estradiol, had a rate of ALT elevation similar to those not receiving any estrogens; however, due to the limited number of women taking these other estrogens, caution is warranted for co-administration 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.

Other conditions.

Estrogens may cause fluid retention, and therefore patients with cardiac or renal dysfunction should be carefully observed. Patients with terminal renal insufficiency should be closely observed, since it is expected that the level of circulating active ingredients in Ovestin is increased.
Estriol is a weak gonadotrophin inhibitor without other significant effects on the endocrine system.
Vaginal bleeding during medication should always be investigated. The patient should be informed to contact a doctor if vaginal bleeding occurs.
Treatment of long duration (exceeding 6 months) should be discontinued from time to time for a period of 2 to 3 weeks to see whether the patient remains symptom free, in which case treatment should be suspended.
Patients with myocardial or renal disease, or epilepsy or migraine should be followed carefully, since fluid retention has been observed during continued use of large doses of estrogens.
The following warnings are common to all estrogen preparations:
in women receiving post menopausal estrogens there may be a two to three fold increased risk of gall bladder disease similar to that noted after use of oral contraceptives for 2 years or more;
an increase in blood pressure has been reported during estrogen replacement therapy in the menopause. Blood pressure should therefore be monitored especially if high doses are used.
Estrogens may increase the size of uterine fibroids. The pathologist should be advised of estrogen therapy when relevant specimens are submitted.
Diabetic patients should be observed carefully during administration of estrogens.
Estrogens may be poorly metabolised in patients with impaired liver function and they should be administered with caution in such patients.
Patients with metabolic bone diseases or renal insufficiency should be treated with caution because of the effect of estrogens on calcium and phosphorus metabolism.
There is no conclusive evidence for improvement of cognitive function. There is some evidence from the WHI trial of increased risk of probable dementia in women who start using continuous combined CEE and MPA after the age of 65. It is unknown whether the findings apply to younger post-menopausal women on other HRT products.
Ovestin is not intended for contraceptive use.

Use in hepatic impairment.

No data is available.

Use in renal impairment.

No data is available.

Use in the elderly.

No data is available.

Paediatric use.

No data is available.

Effects on laboratory tests.

Large doses of estrogens may interfere with certain liver function tests and blood coagulation and endocrine tests including thyroid function and glucose tolerance (as for estrogen-containing oral contraceptives). If results are abnormal, tests should be repeated after withdrawing exogenous estrogens for one month.

4.5 Interactions with Other Medicines and Other Forms of Interactions

No examples of interactions between Ovestin and other medicines have been reported in clinical practice. Although data are limited, interactions between Ovestin and other medicinal products may occur. The following interactions have been described with use of combined oral contraceptives which may also be relevant for Ovestin.
The metabolism of estrogens may be increased by concomitant use of substances known to induce drug-metabolizing enzymes, specifically cytochrome P450 enzymes, such as anticonvulsants (e.g. hydantoins (phenytoin), barbiturates (phenobarbital), carbamazepine), and anti-infectives (e.g. griseofulvin, rifamycins (rifampicin, rifabutin), antiretroviral agents (nevirapine, efavirenz)).
Ritonavir and nelfinavir, although known as strong inhibitors, by contrast exhibit inducing properties when used concomitantly with steroid hormones.
Herbal preparations containing St John's wort (Hypericum perforatum) may induce the metabolism of estrogens.
Clinically, an increased metabolism of estrogens may lead to decreased effect and changes in the uterine bleeding profile.
Estriol may possibly increase the pharmacological effects of corticosteroids, succinylcholine, theophylline and troleandomycin. If necessary the dosage should be reduced. Estriol may possibly change the effectiveness of oral anticoagulants.

Other 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 estrogens other than ethinylestradiol, such as estradiol, had a rate of ALT elevation similar to those not receiving any estrogens; however, due to the limited number of women taking these other estrogens, caution is warranted for co-administration 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.

Ovestin Tablets can be used for the treatment of women with infertility due to cervical sterility. Estriol therapy is not expected to have post-natal consequences as administration ends before possible implantation occurs.
(Category B1)
Ovestin Tablets are contraindicated during pregnancy. If pregnancy occurs during medication with Ovestin, treatment should be withdrawn immediately. The results of most epidemiological studies to date relevant to inadvertent foetal exposure to estrogens indicate no teratogenic or fetotoxic effects.
 Ovestin is contraindicated during lactation. There are insufficient data on the use of this medicine during breastfeeding to assess the potential harm to the infant. Estriol is excreted in breast milk and may decrease milk production.

4.7 Effects on Ability to Drive and Use Machines

There is no information to suggest that Ovestin affects a patient's ability to drive or operate machinery.

4.8 Adverse Effects (Undesirable Effects)

From literature and safety surveillance monitoring, the following adverse effects have been reported (see Table 1).
These adverse effects are usually transient, but may also be indicative of too high a dose.
Other adverse effects have been reported in association with estrogen-only and estrogen-progestagen combined treatment. In the absence of data, it is unknown whether Ovestin is distinct in this regard.
Estrogen-dependent neoplasms benign and malignant, e.g. endometrial cancer and breast cancer. For further information see Section 4.3 Contraindications; Section 4.4 Special Warnings and Precautions for Use.
Venous thromboembolism, i.e. deep leg or pelvic venous thrombosis and pulmonary embolism, is more frequent among HRT users than among non-users. In the absence of data, it is unknown whether Ovestin is distinct in this regard. For further information see Section 4.3 Contraindications; Section 4.4 Special Warnings and Precautions for Use.
Myocardial infarction and stroke.
Gall bladder disease.
Skin and subcutaneous disorders: chloasma, erythema multiforme, erythema nodosum, vascular purpura.
Probable dementia over the age of 65 (see Section 4.4 Special Warnings and Precautions for Use).
Angioedema.

Breast cancer risk.

The increased risk in users of estrogen-only therapy is substantially lower than that seen in users of estrogen-progestagen combinations.
The level of risk is dependent on the duration of use (see Section 4.4 Special Warnings and Precautions for Use).

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.
According to evidence from a large number of epidemiological studies and one randomised placebo-controlled trial, the Women's Health Initiative (WHI), the overall risk of breast cancer increases with increasing duration of HRT use in current or recent HRT users.
For estrogen-only HRT, estimates of relative risk (RR) from a re-analysis of original from 51 epidemiological studies (which > 80% of HRT use was estrogen-only HRT) and from the epidemiological Million Women Study (MWS) are similar at 1.35 (95% CI: 1.21-1.49) and 1.30 (95% CI: 1.21-1.40) respectively.
For estrogen plus progestagen combined HRT, several epidemiological studies have reported an overall higher risk for breast cancer than with estrogens alone.
The WHI trial reported a risk estimate of 1.24 (95% CI 1.01-1.54) after 5.6 years of use of estrogen-progestagen combined HRT (CEE + MPA) in all users compared with placebo.
The absolute risks calculated from the MWS and the WHI trial is presented below.
The MWS has estimated, from the known average incidence of breast cancer in developed countries that:
for women not using HRT, about 32 in every 1,000 are expected to have breast cancer diagnosed between the ages of 50 and 64 years;
for 1,000 current or recent users of HRT, the number of additional cases during the corresponding period will be as follows.
For users of estrogen-only replacement therapy: between 0 and 3 (best estimate = 1.5) for 5 years' use; between 3 and 7 (best estimate = 5) for 10 years' use.
For users of estrogen plus progestagen combined HRT: between 5 and 7 (best estimate = 6) for 5 years' use; between 18 and 20 (best estimate = 19) for 10 years' use.
The WHI trial estimated that after 5.6 years of follow up of women between the ages of 50 and 79 years, an additional 8 cases of invasive breast cancer would be due to estrogen-progestagen combined HRT (CEE + MPA) per 10,000 women years.
According to calculations from the trial data, it is estimated that:
For 1,000 women in the placebo group, about 16 cases of invasive breast cancer would be diagnosed in 5 years.
For 1,000 women who used estrogen + progestagen combined HRT (CEE + MPA), the number of additional cases would be between 0 and 9 (best estimate = 4) for 5 years' use.
The number of additional cases of breast cancer in women who use HRT is broadly similar for women who start HRT irrespective of age at start of use (between the ages of 45-65). [See Section 4.4 Special Warnings and Precautions for Use.]

Ovarian cancer.

Use of estrogen‐only or combined estrogen‐progestogen HRT has been associated with an 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 (RR1.43, 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 50‐54 years who are not taking HRT, about 2 women in 2000 will be diagnosed with ovarian cancer over a 5 year period.

4.9 Overdose

For information on the management of overdose, contact the Poisons Information Centre on 13 11 26 (Australia).
The acute toxicity of estriol in animals is very low. Therefore, toxic symptoms are not expected to occur if several tablets are taken simultaneously. In cases of acute overdose, nausea, vomiting, and withdrawal bleeding in females may develop. No specific antidote is known. Symptomatic treatment can be given if necessary.

5 Pharmacological Properties

5.1 Pharmacodynamic Properties

Mechanism of action.

Ovestin contains the natural female hormone estriol. Unlike other estrogens, estriol is short acting since it has only a short retention time in the nuclei of endometrial cells. It substitutes for the loss of estrogen production in menopausal women and alleviates menopausal symptoms. Estriol is particularly effective in the treatment of urogenital symptoms. In case of atrophy of the lower urogenital tract estriol induces the normalization of the urogenital epithelium and helps to restore the normal microflora and the physiological pH in the vagina. As a result, it increases the resistance of the urogenital epithelial cells to infection and inflammation reducing vaginal complaints such as dyspareunia, dryness, itching, vaginal and urinary infections, micturition complaints and mild urinary incontinence.

Clinical trials.

No data is available.

5.2 Pharmacokinetic Properties

Absorption.

After oral administration estriol is rapidly and almost completely absorbed from the gastrointestinal tract. Peak plasma levels of unconjugated estriol are reached within 1 hour of administration. After oral administration of 8 mg estriol, Cmax is approximately 200 nanogram/mL; Cmin is approximately 20 nanogram/mL and Caverage approximately 40 nanogram/mL.

Distribution.

Nearly all (90%) estriol is bound to albumin in the plasma and in contrast with other estrogens hardly any estriol is bound to sex hormone-binding globulin.

Metabolism.

The metabolism of estriol consists principally of conjugation and deconjugation during the enterohepatic circulation.

Excretion.

Estriol, being a metabolic end product, is mainly excreted via the urine in the conjugated form. Only a small part (± 2%) is excreted via the faeces, mainly as unconjugated estriol.

5.3 Preclinical Safety Data

Genotoxicity.

No data is available.

Carcinogenicity.

Long term continuous administration of natural and synthetic estrogens in certain animal species increases the frequency of carcinoma of the breast, uterus, cervix, vagina, testis and liver. The relevance of these findings is uncertain.

6 Pharmaceutical Particulars

6.1 List of Excipients

Inactive ingredients: amylopectin, magnesium stearate, potato starch, lactose monohydrate.

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

Store in original package to protect from light. Store below 30°C.

6.5 Nature and Contents of Container

Ovestin Tablets are packed in push-through strips of PVC film backed by aluminium foil provided with heat seal coating on the side in contact with the tablets.
The following package is available: 1 push-through strip with 30 tablets.

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.

50-27-1.
Molecular formula: C18H24O3. Molecular weight: 288.4.
Chemical name: estra-1,3,5(10)- triene-3,16α-17β-triol.
Estriol, the active ingredient of Ovestin is a synthetic white odourless micronised powder. Like other estrogenic substances it is practically insoluble in water but is soluble in ethanol, chloroform, dioxane, ether and vegetable oils.
Pharmacotherapeutic group: natural and semisynthetic estrogens.
ATC code: G03C-A04.

7 Medicine Schedule (Poisons Standard)

Schedule 4 - Prescription Only Medicine.

Summary Table of Changes