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.

What is in this leaflet

This leaflet answers some common questions about Ovestin tablets.

It does not contain all the available information and it does not take the place of talking to your doctor or pharmacist.

All medicines have risks and benefits. Your doctor has weighed the risks of you taking Ovestin Tablets against the benefits they expect it will have for you.

If you have any concerns about taking this medicine, ask your doctor or pharmacist

Keep this leaflet. You may need to read it again.

What Ovestin tablets are used for

Ovestin tablets is a Hormone Replacement Therapy (HRT). It contains the female hormone oestriol (an oestrogen). Ovestin is used in postmenopausal women with at least 12 months since their last natural period. Ovestin is used for relief of symptoms occurring after menopause. During menopause, the amount of oestrogens produced by a woman's body gradually drops. If the ovaries are removed surgically (ovariectomy) before menopause, the decrease in oestrogen production occurs very abruptly. In many cases the decrease in oestrogen production leads to well-known menopausal complaints such as hot flushes and night sweating. The shortage of oestrogens may cause the vaginal wall to become thin and dry. As a result sexual intercourse become painful and vaginal itching and infections may occur. Oestrogen 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.

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

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

Before you take it

When you must not take it

Do not take Ovestin tablets if:

  • you have or have ever had breast cancer, or if you are suspected of having it.
  • you are pregnant or think you may be pregnant
  • you have or if it is suspected that you have cancer which is sensitive to oestrogens, such as cancer of the lining of the womb
  • you have any unexplained vaginal bleeding, which has not been evaluated by your doctor
  • 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 (thrombosis in the veins of 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 had an allergic reaction to oestriol, or any of the other ingredients of Ovestin
  • you have a rare blood problem called porphyria (an inherited or acquired disorder in the production of blood pigment).

Do not take Ovestin if you have an allergy to:

  • any medicine containing oestriol
  • 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.

Before you start to take it

Tell your doctor if you have allergies to any other medicines, foods, preservatives or dyes.

Take special care with Ovestin Tablets

As well as benefits, Ovestin Tablets have some risks which you need to consider when you are deciding to start or continue treatment.

Medical check-ups
Before you start taking Ovestin, 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 breasts. Your doctor will tell you how often these tests should be performed.

Once you have started taking Ovestin Tablets, you should 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 take Ovestin

Certain conditions may be made worse by hormone replacement therapy (HRT). If you have or have had any of the following conditions and/or which were worse during pregnancy or with previous use of hormones tell your doctor who will monitor you closely:

  • uterine (womb) fibroids
  • endometriosis
  • clots in the blood vessels (thrombosis, deep vein thrombosis, lung embolism) or an increased risk of developing this
  • if anyone in your family has ever had an oestrogen-dependent cancer, such as a close relative who has had breast cancer or cancer of the lining of the womb
  • 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)
  • endometrial hyperplasia (thickening of the lining of the womb)
  • epilepsy
  • asthma
  • otosclerosis (inherited deafness)

Tell your doctor if you notice any change in your condition while using Ovestin.

Reasons for immediately stopping Ovestin Tablets:

  • jaundice (your skin goes yellow)
  • a sudden increase in blood pressure
  • if you get a migraine, or severe headaches, for the first time
  • pregnancy

Effects on your risk of developing 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 taking 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 taking Ovestin.

Breast cancer

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

Taking oestrogen or oestrogen- 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 oestrogen-only HRT.

It is not known whether Ovestin is associated with the same higher risk of breast cancer as other HRT.

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 oestrogen-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 on your heart or circulation

Blood clots (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 have a blood clot if:

  • you are older
  • you are pregnant or have recently had a baby
  • you have one or more miscarriages
  • you use oestrogens
  • 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 (a disease of your immune system)
  • you are unable to move for long periods, for example after a long illness or major operation
  • you have cancer.

If any of these apply to you, you should talk to your doctor about whether you should use Ovestin Tablets.

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

See a doctor as soon as possible if you get:

  • painful swelling in your leg
  • sudden chest pain
  • difficulty breathing,

These may be signs of a blood clot.

Tell your doctor and your surgeon if you are to be hospitalized or undergo surgery. 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.

Heart disease

Ovestin is not recommended for women who have heart disease, or have had heart disease recently. If you have ever had heart disease, talk to your doctor to see if you should be taking Ovestin.

Ovestin will not help to prevent heart disease.

Studies with one type of HRT (containing conjugated oestrogen plus the progestogen MPA) have shown that women may be slightly more likely to get heart disease during the first year of taking the medication. For other types of HRT, the risk is likely to be similar, although this is not yet certain.

If you have symptoms that might indicate that you have a heart disease (such as pain in your chest that spreads to your arm or neck), see a doctor as soon as possible. Do not take any more HRT until your doctor says you can.

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 take any more Ovestin until your doctor says you can.

Dementia

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

Taking other medicines

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

Other medicines may influence the effects of oestriol, or oestriol may affect other medicines. 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 are pregnant. Ovestin Tablets should not be taken.

Tell your doctor if you are breast-feeding.Small amounts of the active Small amounts of the active oestriol can be excreted in the breast milk and milk production could also be reduced.

Tell your doctor if you react badly to lactose or milk before you start taking Ovestin. Ovestin Tablets contain lactose.

How to take it

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 it

If you require treatment for long periods then your doctor will review your need to continue at least every 6 months. You would not normally take the tablets for more than 12 months.

When to take it

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 it

If you forget to take a tablet, take it as soon as you remember, unless you are more than 12 hours late. In this case, 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 that you missed. This may increase the chance of you getting an unwanted side effect.

If you take too much (overdose)

If you think you or anyone else may have taken too much contact your doctor for advice. Overdose may cause nausea and vomiting. Vaginal bleeding in females may also occur after a few days.

While you are taking it

Things you must do

If you become pregnant while using Ovestin Tablets, tell your doctor immediately. It should not be used while you are pregnant.

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.

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

Tell any other doctor, dentist or pharmacist who treats you that you are taking Ovestin Tablets.

Things you must not do

Do not use Ovestin Tablets to treat any other complaints unless your doctor tells you to.

Do not give Ovestin Tablets to anyone else, even if their symptoms seem to be the same as yours.

Side effects

Tell your doctor or pharmacist as soon as possible if you do not feel well while you are taking Ovestin Tablets.

The medicine helps most women with menopausal symptoms, but it may have unwanted side effects in a few people. All medicines have side effects. Sometimes they are serious, most of the time they are not.

Do not be alarmed by the following lists of side effects. You may not experience any of them.

Dependent on dosage and sensitivity of the patient, Ovestin may cause side effects, such as:

  • swelling and increased tenderness of the breasts
  • vaginal bleeding
  • increased vaginal discharge
  • 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 any side effect becomes troublesome or persists.

Other side effects which may occur with HRT:

  • benign and malignant hormone- dependent tumours such as endometrial cancer
  • heart attack and stroke
  • gall bladder disease
  • skin problems such as rashes, discolouration or red patches on the skin
  • various skin diseases with blisters and nodules or bleeding into the skin
  • venous thromboembolism or deep leg or pelvic venous thrombosis and pulmonary embolism (see Before you take Ovestin Tablets)
  • using HRT for several years slightly increases the risk of breast cancer.

Tell your doctor or pharmacist if you notice any side effects not mentioned in this leaflet.

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

After taking it

Storage

Keep this medicine in a safe place out of the reach of children.

Keep your Ovestin tablets in the original package in a cool dry place where the temperature stays below 30°C.

Do not take after the expiry date stated on the blister and outer box.

Product description

What it looks 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.

Ingredients

Ovestin tablets contain 1 mg of estriol as the active ingredient.

They also contain:

  • amylopectin
  • magnesium stearate
  • potato starch
  • lactose monohydrate.

Do not use the product if the blister pack or tablets are damaged or appear unusual.

Distributor

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

AUST R 14514

This leaflet was revised in March 2021.

Published by MIMS May 2021

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 and 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.
Estrogen may increase plasma triglyceride levels, which is a risk factor for pancreatitis and other complications.
Caution should be exercised in patients with pre-existing hypertriglyceridaemia since rare cases of large increases of plasma triglycerides leading to pancreatitis have been reported with estrogen therapy in this population. Women with pre-existing hypertriglyceridaemia should be closely monitored during treatment.
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.

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.

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