Consumer medicine information

Ovestin Ovula

Estriol

BRAND INFORMATION

Brand name

Ovestin Ovula

Active ingredient

Estriol

Schedule

S4

 

Consumer medicine information (CMI) leaflet

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

SUMMARY CMI

Ovestin Ovula

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 Ovula?

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

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

2. What should I know before I use Ovestin Ovula?

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 Ovula? in the full CMI.

3. What if I am taking other medicines?

Some medicines may interfere with Ovestin Ovula and affect how it works.

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

4. How do I use Ovestin Ovula?

  • Ovestin Ovula is administered intravaginally. Always use this medicine exactly as your doctor or pharmacist has told you.

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

5. What should I know while using Ovestin Ovula?

Things you should do
  • Remind any doctor, dentist or pharmacist you visit that you are using Ovestin Ovula.
  • 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 Ovula in a cool dry place, out of direct light, where the temperature is below 30°C.
  • Avoid excessive heat: the pessary will melt at temperatures above 32°C.

For more information, see Section 5. What should I know while using Ovestin Ovula? 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 Ovula

Active ingredient: estriol

Consumer Medicine Information (CMI)

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

Where to find information in this leaflet:

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

1. Why am I using Ovestin Ovula?

Ovestin Ovula 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 he 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 Ovula 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 use Ovestin Ovula?

Warnings

Do not use Ovestin Ovula 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.

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 Ovula 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

Before you start using Ovestin Ovula, 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 Ovula.

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 Ovula 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 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.

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 Ovula.

4. How do I use Ovestin Ovula?

How much to use

For vaginal complaints:

  • the usual dosage is one pessary daily during the first weeks. Later on the dose is gradually decreased to, for instance, one pessary twice a week. For other conditions, a different dosage may be prescribed.
  • Your doctor may ask you to stop using Ovestin every 2 to 3 months for 4 weeks to check the need for further treatment.

For vulvo-vaginal complaints associated with menopause:

  • Initially one pessary per day for 3 weeks
  • Later you may only need one pessary twice a week.

Before vaginal surgery:

  • One pessary daily beginning 2 weeks before the operation

When having a Pap smear your doctor may recommend a daily insertion of 1 pessary for 7 days.

How to insert a pessary

The pessary should be inserted into the vagina before retiring at night.

You may need to moisten your first few pessaries with water before insertion if you are particularly dry and insertion feels uncomfortable.

  • Remove one pessary from its wrapper.
  • Either using a squatting position or lying on your back or side, insert the pessary deeply into the vagina.

If you forget to use Ovestin Ovula

If you miss your dose, use it as soon as you remember.

If it is almost time for your next dose, skip the dose you missed and use your next dose when you are meant to.

Do not use 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 use too much Ovestin Ovula

If you think you may have used more Ovestin than you should, 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 using Ovestin Ovula?

Things you should do

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

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

If you become pregnant while you are 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 using Ovestin. You may need to stop using 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 Ovula in the original package in a cool dry place where the temperature stays below 25°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.

Avoid excessive heat: the pessary will melt at temperatures above 32°C.

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
  • local irritation or itching of skin 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
  • flu-like symptoms.
Speak to your doctor 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)
  • a 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 Ovula contains

Active ingredient
(main ingredient)		Estriol, 0.5 mg
Other ingredients
(inactive ingredients)
  • hard fat
  • cetomacrogol 1000
  • glyceryl ricinoleate

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

What Ovestin Ovula looks like

Packs contain 3 blister strips, each strip contains 5 pessaries. Ovestin Ovula are white to light cream coloured, torpedo shaped pessaries (AUST R 35632).

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

Who distributes Ovestin Ovula

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 Ovula

Active ingredient

Estriol

Schedule

S4

 

1 Name of Medicine

Estriol.

2 Qualitative and Quantitative Composition

Each pessary contains 0.5 mg estriol.
For the full list of excipients, see Section 6.1 List of Excipients.

3 Pharmaceutical Form

White to light cream coloured torpedo shaped pessaries of uniform texture.

4 Clinical Particulars

4.1 Therapeutic Indications

Vulvo-vaginal complaints due to estrogen deficiency associated with the climacteric and the postmenopause or after ovariectomy.
Atrophic vaginitis.
Pruritus vulvae.
Dyspareunia due to vulvo-vaginal atrophy.
As auxiliary therapy in the treatment of vaginal infections.
As pre-operative therapy for vulvo-vaginal surgery and during subsequent convalescence.
Ulcers in cases of prolapse of the uterus or vagina.
To avoid misinterpretation of a cytological smear.

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 Ovula is intended for intravaginal administration, before retiring at night. Each pessary contains 0.5 mg estriol.
For initiation and continuation of treatment of postmenopausal symptoms, the lowest effective dose for the shortest duration of time should be used (see Section 4.4 Special Warnings and Precautions for Use).
Usual dosage for vulvo-vaginal complaints associated with the menopause: one pessary per day for 2-3 weeks initially.
As maintenance dosage, one pessary once or twice a week is recommended. Medication should be discontinued every 2 to 3 months for a period of 4 weeks to assess the necessity for further treatment.
Pre-surgery therapy (one pessary per day) should begin 2 weeks before the operation (see Section 4.4 Special Warnings and Precautions for Use).
In the case of a suspect cytological smear a daily application of 0.5 mg estriol for 7 days is recommended before re-evaluating the cytology.
A missed dose should be administered as soon as remembered, unless the missed dose is noticed at the day of the next dose. In the latter case the missed dose should be skipped and the regular dosing scheme continued. Two doses must never be administered on the same day.
In women not taking HRT or women who switch from a continuous combined HRT product, treatment with Ovestin may be started on any day. Women who switch from cyclic HRT regime should start Ovestin treatment 1 week after completion of the cycle.

Administration.

Patient instructions.

Ovestin pessaries should be inserted intravaginally before retiring at night.
Remove one pessary from its wrapper.
Either using a squatting position or lying on your back or side, insert the pessary deeply into the vagina.

4.3 Contraindications

Pregnancy.
Known past, or suspected breast cancer.
Known or suspected estrogen-dependent malignant tumours such as carcinoma of the endometrium.
Undiagnosed genital bleeding.
Previous or current active 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).
Active or recent arterial thromboembolic disease (e.g. angina, myocardial infarction).
Thrombophlebitis, or a past history of this condition.
A history during pregnancy or previous use of steroids of a manifestation or deterioration of otosclerosis.
Endometriosis.
Untreated endometrial hyperplasia.
Porphyria.
Severe liver dysfunction or a history of liver disease as long as liver function tests failed to return to normal.
Disturbed lipid metabolism, particularly in the presence of other risk factors which may indicate a predisposition to cardiovascular disorders.
Hypersensitivity to the active substances or to any of the excipients.

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.

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, in rare cases, recur or be aggravated during treatment with Ovestin.
Leiomyoma (uterine fibroids) or endometriosis.
A history of thromboembolic disorders or the presence of risk factors (see below).
Risk factors for estrogen dependent tumours, e.g. 1st degree heredity for breast cancer.
Hypertension.
Liver disorders (e.g. liver adenoma).
Diabetes mellitus with or without vascular involvement.
Cholelithiasis.
Migraine or (severe) headache.
Systemic lupus erythematosus.
A history of endometrial hyperplasia.
Epilepsy.
Asthma.
Otosclerosis.
Severe pruritus.
Cholestatic jaundice.
Herpes gestationis.

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.

In order to prevent endometrial stimulation, the daily dose should not exceed 1 application (0.5 mg estriol) nor should this maximum dose be used for longer than several weeks. One epidemiological study has shown that long-term treatment with low doses of oral estriol, but not vaginal estriol, may increase the risk for endometrial cancer. This risk increases with the duration of treatment and disappeared within one year after the treatment was terminated. The increased risk mainly concerned less invasive and highly differentiated tumours. Vaginal bleeding during medication should always be investigated. The patient should be informed to contact a doctor if vaginal bleeding occurs.
The following risks have been associated with systemic HRT and apply to a lesser extent for estrogen products for vaginal application of which the systemic exposure to the estrogen remains within the normal postmenopausal range. However, they should be considered in case of long term or repeated use of this product.

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 randomised placebo-controlled trial, the Women's Health Initiative study (WHI), and epidemiological studies, including the Million Women Study (MWS), have reported 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. Another, large observational study, the Million Women Study, has shown that compared to never-users, use of estrogen-progestogen combined HRT is associated with a higher risk of breast cancer (RR = 2.00, 95% CI: 1.88-2.12). In the small number of women using vaginal or other topical HRT preparations, no increased risk of breast cancer was observed (RR = 0.67, 95% CI: 0.30-1.49). For all HRT, including Ovestin, the benefits and risks of treatment should be carefully considered. It is recommended that women are encouraged to report any changes in their breasts to their doctor. Regular breast examinations and, where appropriate, mammography should be carried out, particularly in women with risk factors for breast cancer.

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- to 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 role of varicose veins in VTE. The risk of VTE may be temporarily increased with prolonged immobilisation, major trauma or major 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.
Use of HRT in patients with a history of recurrent VTE or known thrombophilic states already on anticoagulant treatment require careful consideration of the benefit-risk of use of HRT (also see Section 4.3 Contraindications). The presence of a 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 the drug should be discontinued. Patients should be told to contact their doctors immediately when they are aware of a potential thromboembolic symptom (e.g. painful swelling of a leg, sudden pain in the chest, dyspnoea).

Coronary artery disease (CAD).

There is no evidence from randomised controlled trials of cardiovascular benefit with continuous combined conjugated estrogens and medroxyprogesterone acetate (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 randomized 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 into 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 randomized 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 5-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 conjugated estrogens and MPA for 5 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 users aged 60-69 years. It is unknown whether the increased risk also extends to other HRT products.

Ovarian cancer.

Long-term (at least 5-10 years) use of estrogen-only HRT products in hysterectomised women has been associated with an increased risk of ovarian cancer in some epidemiological studies. It is uncertain whether long-term use of combined HRT or low potency estrogens (such as Ovestin) confers a different risk than estrogen-only products.

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.
Benign hepatic adenoma and hepato-cellular carcinoma appear to be associated with the use of oral contraceptives but such lesions have not been reported with the use of other estrogen preparations.
A two-fold increase has been reported in the risk of gall bladder disease in women receiving oral estrogen preparations (including oral contraceptives). However, there have been no reports of gall bladder disease in association with estriol tablets, cream or pessaries.
Susceptible women may experience a rise in blood pressure. Care should be exercised in prescribing estrogens for patients with hypertension; regular measurement of blood pressure and careful observation for progressive hypertension is recommended.
Because estrogens may increase the size of uterine fibroids, the pathologist should be advised of estrogen therapy when relevant specimens are submitted.
Patients with diabetes, severe migraine, epilepsy, asthma, fibrocystic mastopathy, significant cardiac or renal dysfunction should be observed carefully during administration of estrogens.
Patients with metabolic bone disease or renal insufficiency should be treated with caution because of the effect of estrogens on the metabolism of calcium and phosphorus.
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 or other HRT products.
Ovestin is not intended for contraceptive use.

Use in hepatic impairment.

Data is not available.

Use in renal impairment.

Data is not available.

Use in the elderly.

Data is not available.

Paediatric use.

Data is not available.

Effects on laboratory tests.

Unknown.

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 is intended for the treatment in postmenopausal (naturally and surgically induced) women only.
(Category B1)
Estrogen must not be used during pregnancy (see Section 4.3 Contraindications). 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.
 There are insufficient data on the use of this medicine during breastfeeding to assess potential harm to the infant. Estriol is excreted in breastmilk 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 operate machinery.

4.8 Adverse Effects (Undesirable Effects)

Reporting suspected adverse effects.

Reporting suspected adverse reactions after registration of the medicinal product is important. It allows continued monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions at www.tga.gov.au/reporting-problems.
From literature and safety surveillance monitoring, the following adverse effects have been reported (see Table 1).
As with any product that is to be applied to mucosal surfaces, Ovestin Ovula may cause local irritation or itching in very sensitive persons at the beginning of treatment. Breast tension or pain may occasionally occur (frequency 0.1-1%). In general, this is of a temporary nature, but may also be indicative of too high a dosage.
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, ovarian 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 purpure.
Probable dementia over the age of 65 (see Section 4.4 Special Warnings and Precautions for Use).
Angioedema.

Breast cancer risk.

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. Topical (vaginally administered) products were not included in the WHI study and there are limited data in the Million Women Study. At present, there is uncertainty whether these data apply to estriol.
For estrogen-only HRT, estimates of relative risk (RR) from a reanalysis of original data from 51 epidemiological studies (in 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 MWS reported that, compared to never users, the use of various types of estrogen-progestagen combined HRT was associated with a higher risk of breast cancer (RR = 2.00, 95% CI: 1.88-2.12) than use of estrogens alone (RR = 1.30, 95% CI: 1.21-1.40) or use of tibolone (RR = 1.45; 95% CI:1.25-1.68).
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 trials are 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 responding period will be:
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-progestogen 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 + progestogen 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).

4.9 Overdose

The acute toxicity of estriol in animals is very low. Overdose with Ovestin pessaries after vaginal administration is unlikely. However, in cases where large quantities of pessaries are ingested, nausea, vomiting and withdrawal bleeding in females may occur. No specific antidote is known. Symptomatic treatment can be given if necessary.
For information on the management of overdose, contact the Poisons Information Centre on 13 11 26 (Australia).

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.

Intravaginal administration of estriol ensures optimal availability at the site of action. Estriol is also absorbed into the general circulation, as is shown by a sharp rise in the plasma levels of unconjugated estriol. Systemic absorption of estriol from Ovestin Ovula can produce significant plasma levels. Furthermore, the initial circulation through the liver, which reduces the effectiveness of oral estriol by conjugation, is bypassed. However, with the doses recommended, absorption has not been sufficient to produce endometrial proliferation or any untoward systemic effect.
Following vaginal administration of 0.5 mg of estriol, plasma levels of unconjugated and conjugated estriol reach a maximum within 1 to 2 hours. After vaginal administration of 0.5 mg estriol, Cmax is approximately 100 picogram/mL (pg/mL), Cmin is approximately 25 picogram/mL and Caverage is approximately 70 picogram/mL of unconjugated, presumably biologically active estriol. The proportion of unconjugated hormone was similar to that reported during pregnancy about 10%. After 3 weeks of daily administration of 0.5 mg vaginal estriol, Caverage had decreased to 40 picogram/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.

In contrast to estradiol and estrone, apart from being conjugated, estriol is not metabolised before excretion. It is also less strongly protein-bound and thus more rapidly cleared from the plasma. The metabolism of estriol consists principally of conjugation and deconjugation during the enterohepatic circulation. Various conjugates of estriol are found in both the urine and the faeces. The half-life of estriol in plasma after vaginal administration has been estimated as approximately 5 to 7 hours.

Excretion.

Estriol, a metabolic end product, is mainly excreted via the urine in the conjugated form. Only a small fraction (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: hard fat, cetomacrogol 1000 and glyceryl ricinoleate.

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 below 25°C. Protect from light and moisture.
Avoid excessive heat: pessaries will melt at temperatures above 32°C.

6.5 Nature and Contents of Container

Ovestin Ovula are white, torpedo shaped pessaries packed in blisters of polyvinylchloride (PVC). Each blister contains 5 pessaries. Three blister strips are packed in a cardboard box.

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.
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.

Molecular formula.

C18H24O3.

Molecular weight.

288.4.

Chemical name.

Estra-1, 3, 5 (10)-triene-3,16α-17β-triol.

Pharmacotherapeutic group.

Natural and semisynthetic estrogens.
ATC code: G03C-A04.

7 Medicine Schedule (Poisons Standard)

Schedule 4 - Prescription Only Medicine.

Summary Table of Changes