Consumer medicine information

Progynova

Estradiol valerate

BRAND INFORMATION

Brand name

Progynova

Active ingredient

Estradiol valerate

Schedule

S4

 

Consumer medicine information (CMI) leaflet

Please read this leaflet carefully before you start using Progynova.

SUMMARY CMI

PROGYNOVA®

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.

WARNING: Important safety information is provided in a boxed warning in the full CMI. Read before using this medicine.

1. Why am I using PROGYNOVA®?

PROGYNOVA® contains the active ingredient estradiol valerate. PROGYNOVA® provides hormone replacement therapy (HRT) for the treatment of menopausal complaints after the cessation of monthly bleeding, after surgical removal of the ovaries (oophorectomy) or due to radiotherapy.

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

2. What should I know before I use PROGYNOVA®?

Do not use if you have ever had an allergic reaction to estradiol valerate 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 PROGYNOVA®? in the full CMI.

3. What if I am taking other medicines?

Some medicines may interfere with PROGYNOVA® 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 PROGYNOVA®?

Take one tablet at the same time each day. Swallow the tablets whole with a glass of water.

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

5. What should I know while using PROGYNOVA®?

Things you should do
  • Remind any doctor, dentist or pharmacist you visit that you are using PROGYNOVA®.
  • If you become pregnant while taking this medicine, tell your doctor immediately.
Things you should not do
  • Do not take PROGYNOVA® 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.
Driving or using machines
  • Be careful before you drive or use any machines or tools until you know how PROGYNOVA® affects you.
Drinking alcohol
  • Tell your doctor if you drink alcohol.
  • Excess intake of alcohol during use of HRT has an influence on the treatment.
Looking after your medicine
  • PROGYNOVA® 1 mg: Store below 30°C; PROGYNOVA® 2 mg: Store below 25°C.
  • Store it in a cool dry place away from moisture, heat or sunlight. Keep out of reach of children.

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

6. Are there any side effects?

All medicines can have side effects. If you do experience any side effects, most of them are minor and temporary. However, some side effects may need medical attention. Ask your doctor or pharmacist if you have any further questions about side effects.

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.

WARNING: The Women's Health Initiative (WHI) trial examined the health benefits and risks of combined estrogen plus progestogen therapy (n=16,608) and estrogen-alone therapy (n=10,739) in postmenopausal women aged 50 to 79 years.

The estrogen plus progestogen arm of the WHI trial indicated an increased risk of myocardial infarction (MI), stroke, invasive breast cancer, pulmonary embolism and deep vein thrombosis in postmenopausal women receiving treatment with combined conjugated equine estrogens (CEE, 0.625 mg/day) and medroxyprogesterone acetate (MPA, 2.5 mg/day) for 5.2 years compared to those receiving placebo.

The estrogen-alone arm of the WHI trial indicated an increased risk of stroke and deep vein thrombosis in hysterectomized women treated with CEE-alone (0.625 mg/day) for 6.8 years compared to those receiving placebo.

Other doses of oral conjugated estrogens with medroxyprogesterone acetate, and other combinations and dosage forms of estrogens and progestogens were not studied in the WHI clinical trials and, in the absence of comparable data, these risks should be assumed to be similar.

Therefore, the following should be given serious consideration at the time of prescribing:
• Estrogens with or without progestogens should not be prescribed for primary or secondary prevention of cardiovascular diseases.
• Estrogens with or without progestogens should be prescribed at the lowest effective dose for the approved indication.
• Estrogens with or without progestogens should be prescribed for the shortest period possible for the approved indication.
• For the prevention of osteoporosis, estrogen treatment should be considered in light of other available therapies.



FULL CMI

PROGYNOVA® (PRO.guy.no.va)

Active ingredient(s): estradiol valerate

Consumer Medicine Information (CMI)

This leaflet provides important information about using PROGYNOVA®. 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 PROGYNOVA®.

Where to find information in this leaflet:

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

1. Why am I using PROGYNOVA®?

PROGYNOVA® provides hormone replacement therapy (HRT) for the treatment of menopausal complaints after the cessation of monthly bleeding, after surgical removal of the ovaries (oophorectomy) or due to radiotherapy. PROGYNOVA® is only intended for short term use.

PROGYNOVA® contains the active ingredient estradiol valerate, a precursor of the hormone estradiol. During menopause, the estradiol production of the ovaries declines. Although menopause is natural, it often causes distressing symptoms, which are connected with the gradual loss of the hormones produced by the ovaries.

PROGYNOVA®replaces the hormone estradiol that the body no longer makes and prevents or relieves symptoms such as hot flushes, sweats, sleep disturbances, depressive moods, irritability, dizziness, headaches as well as vaginal dryness and burning.

If you have not had your uterus removed (hysterectomy) your doctor will prescribe another hormone progestogen to take with PROGYNOVA®.

PROGYNOVA® is not a contraceptive. It will not prevent you from falling pregnant.

2. What should I know before I use PROGYNOVA®?

Warnings

Do not use PROGYNOVA® if:

  • you are allergic to estradiol valerate, or any of the ingredients listed at the end of this leaflet. Always check the ingredients to make sure you can use this medicine.
  • undiagnosed vaginal bleeding
  • breast cancer or a suspicion of breast cancer
  • other tumours (including liver tumours) or a suspicion of other tumours
  • severe liver disease including jaundice (yellowing of the skin and/or eyes)
  • had a heart attack and/or stroke
  • a history of or are at a high risk of a blood clot in the blood vessels of the legs (deep venous thrombosis) or the lungs (pulmonary embolism)
  • high levels of fat in the blood (triglycerides)
  • hearing loss caused by an abnormal bone growth in the ear (otosclerosis), which worsens during pregnancy
  • severe diabetes

Do not take this medicine if you are under 18 years old.

Before you start to take it

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

Tell your doctor if:

  • you smoke
  • you are overweight
  • you or anyone in your immediate family has had blood clots (thrombosis)
  • you have any hospitalisation, surgery or prolonged immobilization

You have an increased risk of a blood clot if you have any of the above risk factors. In addition to these, there may be other risk factors. Talk to your doctor if you have any concerns.

Taking PROGYNOVA® may also increase your risk of coronary heart disease. Tell your doctor if you experience chest pain or discomfort.

Taking PROGYNOVA® may increase your risk of gall bladder disease. This is because estrogen stimulates the liver to remove more cholesterol from blood and divert it to the gall bladder.

Before starting PROGYNOVA®, your doctor should conduct a thorough medical and gynaecological examination (including the breasts). Your doctor should conduct this examination periodically. If you have liver disease, your doctor will also conduct liver function tests from time to time. Your doctor will also note your family medical history and exclude pregnancy.

Tell your doctor if you have or have had any of the following:

  • high blood pressure
  • liver disease including jaundice (yellowing of the skin and/or eyes)
  • thyroid disease and you are taking medication for it
  • heart or kidney disease
  • low calcium levels in the blood
  • endometriosis (the presence of tissue of the lining of the womb in places in the body where it is not normally found)
  • asthma
  • diabetes
  • epilepsy
  • migraine
  • porphyria (an inherited disease where the body cannot convert naturally occurring compounds into haem, which contains iron)
  • systemic lupus erythematosus (SLE; a chronic inflammatory disease)
  • an abnormal build-up of blood vessels in the liver (hepatic haemangioma)
  • tumours in your womb or pituitary gland
  • chloasma (yellow brown patches on the skin); if so, avoid too much exposure to the sun or ultraviolet radiation
  • lumpy or painful breasts (benign breast disease)
  • chorea minor (involuntary movement disorder)
  • hereditary angioedema (repeated episodes of severe swelling)

Tell your doctor if you are 65 years or older when HRT is initiated. The reason is that there is limited evidence from clinical studies that hormonal treatment may increase the risk of significant loss of intellectual abilities such as memory capacity (dementia).

If HRT is used in the presence of any of the conditions listed above you will need to be kept under close observation. Your doctor can explain this to you. Therefore, if any of these apply to you, tell your doctor before starting to take PROGYNOVA®.

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?

PROGYNOVA® contains lactose. If you have been told by your doctor that you have an intolerance to some sugars, contact your doctor before taking it. Some of the symptoms of an allergic reaction may include:

  • shortness of breath
  • wheezing or difficulty breathing
  • swelling of the face, lips, tongue or other parts of the body
  • rash, itching or hives on the skin.

Pregnancy and breastfeeding

Do not take this medicine if you are pregnant. It may affect your developing baby if you take it during pregnancy.

Do not breast-feed if you are taking this medicine. The active ingredient in PROGYNOVA® passes into breast milk and there is a possibility that your baby may be affected.

HRT and cancer

Endometrial cancer

The risk of cancer of the lining of the womb (endometrial cancer) increases when estrogens are used alone for prolonged periods. Taking a progestogen in addition to the estrogen lowers the increased risk.

Please inform your doctor if you frequently have bleeding irregularities or persistent bleeding during the treatment with PROGYNOVA®.

Breast cancer

Please inform your doctor if you have suffered from fibrocystic disease of the breasts (lumpy or painful breasts) or if you have first degree relatives (mother, sisters, daughters) who have had breast cancer.

Breast cancer has been diagnosed slightly more often in women who have used hormone replacement therapy (HRT) than in women of the same age who have never used HRT. The risk increases with duration of treatment. If you are concerned about this information you should discuss this with your doctor. It is recommended that yearly breast examinations are conducted and regular self-examination (monthly) should be carried out. HRT has been reported to result in an increased number of abnormal mammograms requiring further evaluation.

HRT increases the density of mammographic images. This may complicate the mammographic detection of breast cancer in some cases. Therefore your doctor may choose to use other breast cancer screening techniques as well.

Ovarian cancer

Some observational studies show a slightly increased overall risk of developing ovarian cancer in women who have used HRT compared to women who have never used HRT. In women currently using HRT, this risk was further increased. These associations have not been shown in all studies. There is no consistent evidence that the risk of developing ovarian cancer is related to the duration of use of HRT. However, the risk may be more relevant with long-term use (for several years).

Liver tumour

During or after the use of hormones such as those that are contained in PROGYNOVA®, benign liver tumours have rarely occurred, and malignant liver tumours even more rarely. In isolated cases, bleeding has occurred from such tumours into the abdominal cavity. Although such events are rare, you should inform your doctor about any pain in your upper abdomen that does not disappear within a short time.

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 and PROGYNOVA® may interfere with each other. These include:

  • medicines to treat high blood pressure, chest pain and/or irregular heartbeat such as ACE inhibitors, verapamil, diltiazem
  • medicines used to treat epilepsy such as hydantoins, barbiturates, primidone, carbamazepine, oxcarbazepine, topiramate, felbamate
  • rifampicin for the treatment of tuberculosis
  • macrolide antibiotics (e.g. clarithromycin, erythromycin)
  • herbal medicines containing St John's Wort
  • medicines used to treat HIV such as ritonavir or nevirapine
  • some medicines used to treat Hepatitis C Virus (HCV) such as boceprevir, telaprevir
  • medicines used to treat fungal infections such as ketoconazole, itraconazole, voriconazole, fluconazole
  • grapefruit juice
  • medicines used to treat pain and fever (e.g. paracetamol)
  • medicines used to treat diabetes, such as insulin or other anti-diabetic medications

These medicines may be affected by PROGYNOVA® or may affect how well it works. You may need different amounts of your medicines, or you may need to take different medicines.

If you are diabetic, your doctor may alter the dose of the diabetes medication.

Your doctor and pharmacist have more information on medicines to be careful with or avoid while taking this medicine.

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

4. How do I use PROGYNOVA®?

Follow all directions given to you by your doctor or pharmacist carefully. They may differ from the information contained in this leaflet.

If you do not understand the instructions printed on the pharmacist label, ask your doctor or pharmacist for help.

How much to take PROGYNOVA®

  • Take one tablet at the same time each day.
  • Swallow the tablets whole with a glass of water.
  • Follow the instructions provided and use PROGYNOVA® until your doctor tells you to stop.

Taking it at the same time each day will have the best effect. It will also help you remember when to take it. It does not matter if you take this medicine before or after food.

When you have finished each blister foil start the next one on the following day. Never leave a break between blister foils unless your doctor has advised you to. Tablet taking should be continuous.

How long to take PROGYNOVA®

PROGYNOVA® is only intended for short term use. Your doctor will advise you on how long to use PROGYNOVA®. Your doctor will discuss the risks of long term treatment with HRT with you. Some recent studies have shown that women using HRT have a small increase in breast cancer risk. The risk increases with the length of HRT use.

HRT is associated with a small increase in the risk of developing breast cancer, heart attacks, strokes, blood clots, including clots in the lungs, and dementia. However, the evidence is inconclusive. On the other hand the risk of hip fractures and bowel cancer may be reduced. Your doctor can discuss these risks and benefits with you, taking into account your particular circumstances.

If you forget to use PROGYNOVA®

PROGYNOVA® should be used regularly at the same time each day. If you are less than 24 hours late, take your tablet as soon as possible, and take the next one at the normal time. If you miss tablets for several days, irregular bleeding may occur.

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

If you use too much PROGYNOVA®

If you think that you have used too much PROGYNOVA®, 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 PROGYNOVA®?

Things you should do

If you are about to be started on any new medicine, remind your doctor and pharmacist that you are taking PROGYNOVA®.

Tell any other doctors, dentists, and pharmacists who treat you that you are taking this medicine.

If you become pregnant while taking this medicine, tell your doctor immediately.

If you are going to have surgery, tell the surgeon or anaesthetist that you are taking this medicine. It may affect other medicines used during surgery.

The use of HRT may affect the results of certain laboratory tests. If you are about to have any blood tests, tell your doctor that you are taking this medicine. It may interfere with the results of some tests.

Stop taking PROGYNOVA® immediately if

You should stop treatment at once and consult your doctor if you have any of the following conditions:

  • your very first attack of migraine (typically a throbbing headache and nausea preceded by visual disturbances)
  • worsening of pre-existing migraine, any unusually frequent or unusually severe headaches
  • sudden disturbances of vision or hearing
  • swollen veins (phlebitis)
  • itching of the whole body
  • unusual upper abdominal pain that do not disappear within a short period of time.

If you get a blood clot while you are taking PROGYNOVA® or there is a suspicion of this you should stop taking it immediately and contact your doctor. Warning signs to look out for are:

  • coughing blood
  • unusual pains or swelling of your arms or legs
  • sudden shortness of breath
  • fainting.

PROGYNOVA® must also be stopped at once if you develop jaundice (yellowing of the skin and/or eyes). Tell your doctor immediately if either occurs.

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

Things you should not do

Do not take PROGYNOVA® 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 taking your medicine without checking with your doctor.

If you stop taking it suddenly, your condition may worsen or you may have unwanted side effects.

Driving or using machines

Be careful before you drive or use any machines or tools until you know how PROGYNOVA® affects you.

Drinking alcohol

Tell your doctor if you drink alcohol.

Excess intake of alcohol during use of HRT has an influence on the treatment. Your doctor will advise you.

Looking after your medicine

  • PROGYNOVA® 1 mg: Store below 30°C.
  • PROGYNOVA® 2 mg: Store below 25°C.

Keep your tablets in the pack until it is time to take them. If you take the tablets out of the pack they may not keep well.

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

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

Keep it where young children cannot reach it.

Getting rid of any unwanted medicine

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

Do not use this medicine after the expiry date.

6. Are there any side effects?

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

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

Less serious side effects

Less serious side effectsWhat to do
Metabolism and nutrition disorders:
  • Changes in body weight
Psychiatric disorders:
  • feeling depressed and/or anxious
  • changes in sexual drive
Eye disorders:
  • visual disturbances such as partial or complete loss of vision, bulging eyes, double vision
  • intolerance to contact lenses
Musculoskeletal and connective tissue disorders:
  • muscle cramps
Reproductive system and breast disorders:
  • changes in vaginal bleeding pattern including spotting
  • painful menstrual periods
  • vaginal secretion
  • premenstrual-like syndrome such as mood swings, bloating, breast swelling and tenderness
  • breast pain
Gastrointestinal disorders:
  • indigestion
  • nausea
  • vomiting
  • stomach pain
  • increased appetite
Skin and subcutaneous tissue disorders:
  • rash
  • various skin disorders such as itching, hives, acne, excessive hairiness, hair loss or red, painful lumps
Nervous system disorders:
  • headache
  • migraine
  • dizziness
General disorders and administration site conditions:
  • swelling of the hands, ankles or feet
  • feeling tired
Speak to your doctor if you have any of these less serious side effects and they worry you.

Serious side effects

Serious side effectsWhat to do
Immune system disorders:
  • 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
Cardiac disorders:
  • irregular heartbeat
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 PROGYNOVA® contains

Active ingredient
(main ingredient)

PROGYNOVA® 1 mg:

  • 1 mg estradiol valerate

PROGYNOVA® 2 mg:

  • 2 mg estradiol valerate
Other ingredients
(inactive ingredients)

PROGYNOVA® 1 mg:

  • lactose
  • maize starch
  • povidone
  • purified talc
  • magnesium stearate
  • sucrose
  • macrogol 6000
  • calcium carbonate
  • glycerol
  • glycol montanate
  • titanium dioxide
  • iron oxide yellow

PROGYNOVA® 2 mg:

  • lactose
  • maize starch
  • povidone
  • purified talc
  • magnesium stearate
  • sucrose
  • macrogol 6000
  • calcium carbonate
  • glycol montanate

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

What PROGYNOVA® looks like

PROGYNOVA® 1 mg are small round beige sugar coated tablets packaged in calendar blister strips containing 28 tablets (Aust R 10708).

PROGYNOVA® 2 mg are small round white sugar coated tablets packaged in calendar blister strips containing 28 tablets (Aust R 323720).

Each pack contains 2 blister strips.

Who distributes PROGYNOVA®

Bayer Australia Ltd
ABN 22 000 138 714
875 Pacific Highway
Pymble NSW 2073
www.bayer.com.au

This leaflet was prepared in December 2021.

See TGA website (www.ebs.tga.gov.au) for latest Australian Consumer Medicine Information.

® Registered trademark

Published by MIMS March 2022

BRAND INFORMATION

Brand name

Progynova

Active ingredient

Estradiol valerate

Schedule

S4

 

1 Name of Medicine

Estradiol valerate.

2 Qualitative and Quantitative Composition

Progynova 1 mg.

Each tablet contains 1 mg estradiol valerate.

Progynova 2 mg.

Each tablet contains 2 mg estradiol valerate.
Contains lactose. For the full list of excipients, see Section 6.1 List of Excipients.

3 Pharmaceutical Form

Progynova 1 mg.

Yellow coloured tablets that contain 1 mg estradiol valerate.

Progynova 2 mg.

White coloured tablets that contain 2 mg estradiol valerate.

4 Clinical Particulars

4.1 Therapeutic Indications

Short-term treatment of climacteric complaints after the cessation of monthly bleeding, or deficiency symptoms after oophorectomy or radiological castration for noncarcinomatous diseases, such as hot flushes, outbreaks of sweat, sleep disturbances, depressive moods, irritability, headaches, dizziness.
Progynova also has a favourable influence on bladder irritation (a not infrequent occurrence in the climacteric), signs of cutaneous and mucosal involution (particularly in the genital region) which normally occur with advancing age.

4.2 Dose and Method of Administration

Hormone therapy should only be continued as long as the benefit in alleviation of severe symptoms outweighs the risk.
A complete medical history should be taken and a physical examination should be conducted prior to the initiation or reinstitution of HRT, guided by the Contraindications and Special Warnings and Precautions for Use and should be repeated periodically. The frequency and nature of these examinations should be based on established practice guidelines, 6 monthly reviews are generally considered appropriate, and be adapted to the individual woman, but should generally include pelvic organs, including routine cervical cytology, abdomen, breasts and blood pressure. The need for continued therapy should be reconsidered at each review.
Unless otherwise prescribed by the doctor, one Progynova tablet is taken daily (either one beige 1 mg tablet or one white 2 mg tablet) and the tablets are to be swallowed whole with some liquid. Each pack covers 28 days and treatment is continuous, which means that the next pack follows immediately without a break. It does not matter at what time of the day the patient takes her tablet, but once she has selected a particular time, she should keep to it every day. If she forgets to take a tablet at the usual time, she may take it within the following 12 to 24 hours. If the treatment is discontinued for longer, irregular bleeding may occur.
Treatment may be started at any time provided that pregnancy has been excluded.
High dosed and long-term use of unopposed estrogens during the climacteric may increase the incidence of endometrial carcinoma. Endometrial hyperplasia should be avoided in unopposed estrogen treatment. It is, therefore, mandatory to add a progestogen for the last 10-14 days of each month of therapy.
As a general rule, Progynova treatment should be discontinued every 6 months in order to verify the persistence of complaints requiring treatment. It is essential to adhere to the dosage scheme prescribed by the doctor and to keep the appointments made for gynaecological checkups.

4.3 Contraindications

HRT should not be started in the presence of any of the conditions listed below. Should any of the following conditions appear during HRT use, the product should be stopped immediately.
Pregnancy and lactation.
Undiagnosed vaginal bleeding.
Known or suspected cancer of the breast.
Known or suspected premalignant conditions or malignancies, if sex steroid influenced.
Presence or history of liver tumours (benign or malignant).
Severe hepatic disease.
Acute arterial thromboembolism (e.g. myocardial infarction, stroke).
Active deep vein thrombosis, thromboembolic disorders or a documented history of these conditions.
A high risk of venous or arterial thrombosis.
Severe hypertriglyceridaemia.
Idiopathic cholestatic jaundice of pregnancy or jaundice with prior combined oral contraceptive use or combined HRT use.
Otosclerosis with deterioration during pregnancy.
Severe diabetes with vascular changes.
Known hypersensitivity to any of the components of Progynova.

4.4 Special Warnings and Precautions for Use

The benefits and risks of HRT must be carefully weighed, including consideration of the emergence of risks as therapy continues. Estrogens with or without progestagens should be prescribed at the lowest effective doses and for the shortest duration consistent with the treatment goal and risks for the individual women.
If any of the conditions/risk factors mentioned below is present or deteriorates, an individual risk/benefit analysis should be done before HRT is started or continued.
The potential for an increased synergistic risk of thrombosis should be considered in women who possess a combination of risk factors or exhibit a greater severity of an individual risk factor. This increase risk may be greater than a simple cumulative risk of the factor. HRT should not be prescribed in case of a negative risk benefit assessment.

Cardiovascular disorders.

Estrogen and estrogen/progestogen therapy have been associated with an increased risk of cardiovascular events such as myocardial infarction and stroke, as well as venous thrombosis and pulmonary embolism (venous thromboembolism or VTE). Should any of these occur or be suspected, estrogens should be discontinued immediately.
Risk factors for arterial vascular disease (e.g. hypertension, diabetes mellitus, tobacco use, hypercholesterolaemia and obesity) and/or venous thromboembolism (e.g. personal history or family history of VTE, obesity, and systemic lupus erythematosus) should be managed appropriately.

Coronary heart disease and stroke.

In the estrogen alone substudy of the Women's Health Initiative (WHI) study, an increased risk of stroke was observed in women receiving 0.625 mg conjugated estrogens per day compared to women receiving placebo (44 vs 32 per 10,000 women years). The increase in risk was observed in year one and persisted (see Section 5.1 Pharmacodynamic Properties, Clinical trials).
In the estrogen plus progestogen substudy of WHI, an increased risk of coronary heart disease (CHD) events (defined as nonfatal myocardial infarction and CHD death) was observed in women receiving 0.625 mg conjugated estrogens plus 2.5 mg medroxyprogesterone acetate (CE/MPA) per day compared to women receiving placebo (37 vs 30 per 10,000 women-years). The increase in risk was observed in year one and persisted.
In the same estrogen plus progestogen substudy of WHI, an increased risk of stroke was observed in women receiving CE/MPA compared to women receiving placebo (29 vs 21 per 10,000 women years). The increase in risk was observed after the first year and persisted.
In postmenopausal women with documented heart disease (n = 2,763, average age 66.7 years) a controlled clinical trial of secondary prevention of cardiovascular disease (Heart and Estrogen/progestin Replacement Study; HERS) treatment with 0.625 mg conjugated estrogen plus 2.5 mg medroxyprogesterone acetate per day demonstrated no cardiovascular benefit. During an average follow-up of 4.1 years, treatment with 0.625 mg conjugated estrogens plus 2.5 mg medroxyprogesterone acetate did not reduce the overall rate of CHD events in postmenopausal women with established coronary heart disease. There were more CHD events in the 0.625 mg conjugated estrogens plus 2.5 mg medroxyprogesterone acetate treated group than in the placebo group in year 1, but not during the subsequent years. Two thousand three hundred and twenty one women from the original HERS trial agreed to participate in an open label extension of HERS, HERS II. Average follow-up in HERS II was an additional 2.7 years, for a total of 6.8 years overall. Rates of CHD events were comparable among women in the 0.625 mg conjugated estrogens plus 2.5 mg medroxyprogesterone acetate group and the placebo group in HERS, HERS II, and overall.

Venous thromboembolism (VTE).

In the estrogen alone substudy of the Women's Health Initiative (WHI) study, an increased risk of deep vein thrombosis was observed in women receiving 0.625 mg conjugated estrogens compared to placebo (21 vs 15 per 10,000 women years). The increase in VTE risk was observed during the first year (see Section 5.1 Pharmacodynamic Properties, Clinical trials).
In the estrogen plus progestogen substudy of WHI, a 2-fold greater rate of VTE, including deep venous thrombosis and pulmonary embolism, was observed in women receiving with 0.625 mg conjugated estrogens plus 2.5 mg medroxyprogesterone acetate compared to women receiving placebo. The rate of VTE was 34 per 10,000 women years in the 0.625 mg conjugated estrogens plus 2.5 mg medroxyprogesterone acetate group compared to 16 per 10,000 women years in the placebo group. The increase in VTE risk was observed during the first year and persisted.
If feasible, estrogens should be discontinued at least 4 to 6 weeks before surgery of the type associated with an increased risk of thromboembolism, or during periods of prolonged immobilisation.

Malignant neoplasms.

Endometrial cancer.

The use of unopposed estrogens in women with intact uteri has been associated with an increased risk of endometrial cancer. The reported endometrial cancer risk among unopposed estrogen users with an intact uterus is about 2 to 12-fold greater than in nonusers, and appears dependent on duration of treatment and on estrogen dose. Most studies show no significant increased risk associated with the use of estrogens for less than one year. The greatest risk appears associated with prolonged use, with increased risks of 15 to 24-fold for five to ten years or more, and this risk has been shown to persist for at least 8 to 15 years after estrogen therapy is discontinued.
Clinical surveillance of all women taking estrogen/progestogen combinations is important. Adequate diagnostic measures, including endometrial sampling when indicated, should be undertaken to rule out malignancy in all cases of undiagnosed persistent or recurring abnormal vaginal bleeding. There is no evidence that the use of natural estrogens results in a different endometrial risk profile than synthetic estrogens of equivalent estrogen dose. Adding a progestogen to postmenopausal estrogen therapy has been shown to reduce the risk of endometrial hyperplasia, which may be a precursor to endometrial cancer.

Addition of a progestogen when a woman has not had a hysterectomy.

Studies of the addition of a progestogen for 10 or more days of a cycle of estrogen administration, or daily with estrogen in a continuous regimen, have reported a lowered incidence of endometrial hyperplasia than would be induced by estrogen treatment alone. Endometrial hyperplasia may be a precursor to endometrial cancer.
There are, however, possible risks that may be associated with the use of progestogens with estrogens compared to estrogen alone regimens. These include a possible increased risk of breast cancer, adverse effects on lipoprotein metabolism (e.g. lowering HDL, raising LDL) and impairment of glucose tolerance.

Breast cancer.

In some studies, the use of estrogens and progestogens by postmenopausal women has been reported to increase the risk of breast cancer. The most important randomised clinical trial providing information about this issue is the Women's Health Initiative (WHI) trial of estrogen plus progestogen (see Section 5.1 Pharmacodynamic Properties, Clinical trials). The results from observational studies are generally consistent with those of the WHI clinical trial.
After a mean follow-up of 5.6 years, the WHI trial reported an increased risk of breast cancer in women who took estrogen plus progestogen. Observational studies have also reported an increased risk for estrogen/progestogen combination therapy, and a smaller increased risk for estrogen alone therapy, after several years of use. For both findings, the excess risk increased with duration of use, and decreases with time after stopping HRT (only the observational studies have substantial data on risk after stopping). In these studies, the risk of breast cancer was greater, and became apparent earlier, with estrogen/progestogen combination therapy as compared to estrogen alone therapy. However, these studies have not found significant variation in the risk of breast cancer among different estrogens or among different estrogen/progestogen combinations, doses, or routes of administration.
In the WHI trial of estrogen plus progestogen, 26% of the women reported prior use of estrogen alone and/or estrogen/progestogen combination hormone therapy. After a mean follow-up of 5.6 years during the clinical trial, the overall relative risk of invasive breast cancer was 1.24 (95% confidence interval, 1.01 to 1.54), and the overall absolute risk was 41 vs 33 cases per 10,000 women-years, for estrogen plus progestogen compared with placebo. Among women who reported prior use of hormone therapy, the relative risk of invasive breast cancer was 1.86, and the absolute risk was 46 vs 25 cases per 10,000 women-years, for estrogen plus progestogen compared with placebo. Among women who reported no prior use of hormone therapy, the relative risk of invasive breast cancer was 1.09, and the absolute risk was 40 vs 36 cases per 10,000 women-years, for estrogen plus progestogen compared with placebo. In the WHI trial, invasive breast cancers were larger and diagnosed at a more advanced stage in the estrogen plus progestogen group compared with the placebo group. Metastatic disease was rare with no apparent difference between the two groups. Other prognostic factors such as histologic subtype, grade and hormone receptor status did not differ between the groups.
The observational Million Women Study in Europe reported an increased risk of mortality due to breast cancer among current users of estrogens alone or estrogens plus progestogens compared to never users, while the estrogen plus progestogen substudy of WHI showed no effect on breast cancer mortality with a mean follow-up of 5.6 years.
The use of estrogen plus progestogen has been reported to result in an increase in abnormal mammograms requiring further evaluation. All women should receive yearly breast examinations by a healthcare provider and perform monthly breast self examinations. In addition, mammography examinations should be scheduled based on patient age, risk factors, and prior mammogram results.

Liver tumour.

In rare cases benign and in even rarer cases malignant liver tumours leading in isolated cases to life threatening intra-abdominal haemorrhage have been observed after the use of hormonal substances such as the one contained in Progynova. If severe upper abdominal complaints, liver enlargement or signs of intra-abdominal haemorrhage occur, a liver tumour should be included in the differential diagnostic considerations.

Dementia.

In the estrogen alone Women's Health Initiative Memory Study (WHIMS), a substudy of WHI, a population of 2,947 hysterectomised women aged 65 to 79 years was randomised to 0.625 mg conjugated estrogens or placebo. In the estrogen plus progestogen WHIMS substudy, a population of 4,532 postmenopausal women aged 65 to 79 years was randomised to 0.625 mg conjugated estrogens plus 2.5 mg medroxyprogesterone acetate or placebo.
In the estrogen alone substudy, after an average follow-up of 5.2 years, 28 women in the estrogen alone group and 19 women in the placebo group were diagnosed with probable dementia. The relative risk of probable dementia for 0.625 mg conjugated estrogens alone vs placebo was 1.49 (95% CI: 0.83-2.66). The absolute risk of probable dementia for 0.625 mg conjugated estrogens alone vs placebo was 37 vs 25 cases per 10,000 women-years.
In the estrogen plus progestogen substudy, after an average follow-up of 4 years, 40 women in the estrogen plus progestogen group and 21 women in the placebo group were diagnosed with probable dementia. The relative risk of probable dementia for estrogen plus progestogen vs placebo was 2.05 (95% CI: 1.21 to 3.48). The absolute risk of probable dementia for 0.625 mg conjugated estrogens plus 2.5 mg medroxyprogesterone acetate vs placebo was 45 vs 22 cases per 10,000 women-years.
Since both substudies were conducted in women aged 65 to 79 years, it is unknown whether these findings apply to younger postmenopausal women (see Section 4.4 Special Warnings and Precautions for Use, Use in the elderly).

Gallbladder disease.

A 2 to 4-fold increase in the risk of gallbladder disease requiring surgery in postmenopausal women receiving estrogens has been reported.

Hypercalcemia.

Estrogen administration may lead to severe hypercalcemia in patients with breast cancer and bone metastases. If hypercalcemia occurs, use of the drug should be stopped and appropriate measures taken to reduce the serum calcium level.

Visual abnormalities.

Retinal vascular thrombosis has been reported in patients receiving estrogens. Discontinue medication pending examination if there is sudden partial or complete loss of vision, or a sudden onset of proptosis, diplopia, or migraine. If examination reveals papilloedema or retinal vascular lesions, estrogens should be discontinued.

General precautions.

Elevated blood pressure.

In a small number of case reports, substantial increases in blood pressure have been attributed to idiosyncratic reactions to estrogens. In a large, randomised, placebo controlled clinical trial, a generalised effect of estrogen therapy on blood pressure was not seen. Blood pressure should be monitored at regular intervals during estrogen use.

Hypertriglyceridemia.

In patients with pre-existing hypertriglyceridemia, estrogen therapy may be associated with elevations of plasma triglycerides leading to pancreatitis and other complications.

Impaired liver function and past history of cholestatic jaundice.

Estrogens may be poorly metabolised in patients with impaired liver function. For patients with a history of cholestatic jaundice associated with past estrogen use or with pregnancy, caution should be exercised and in the case of recurrence, medication should be discontinued.

Hypothyroidism.

Estrogen administration leads to increased thyroid binding globulin (TBG) levels. Patients with normal thyroid function can compensate for the increased TBG by making more thyroid hormone, thus maintaining free T4 and T3 serum concentrations in the normal range. Patients dependent on thyroid hormone replacement therapy who are also receiving estrogens may require increased doses of their thyroid replacement therapy. These patients should have their thyroid function monitored in order to maintain their free thyroid hormone levels in an acceptable range.

Fluid retention.

Because estrogens may cause some degree of fluid retention, patients with conditions that might be influenced by this factor, such as cardiac or renal dysfunction, warrant careful observation when estrogens are prescribed.

Hypocalcemia.

Estrogens should be used with caution in individuals with severe hypocalcemia.

Ovarian cancer.

Ovarian cancer is less prevalent than breast cancer. A meta-analysis from 52 epidemiological studies reported that the overall risk of being diagnosed with ovarian cancer is slightly increased for users of estrogen only and combined HRT compared to women who have never used HRT (prospective studies: RR 1.20, 95% CI: 1.15-1.26; all studies combined: RR 1.14, 95% CI: 1.10-1.19). In women currently using HRT the risk of ovarian cancer was further increased (RR 1.43, 95% CI: 1.31-1.56). For women aged 50 to 54 years taking 5 years of HRT, this results in about 1 extra case per 2000 users. In women aged 50 to 54 who are not taking HRT, about 2 women in 2000 will be diagnosed with ovarian cancer over a 5 year period.
These associations were not shown in the WHI.
Furthermore, an effect of duration of exposure has not been consistently shown, but the risk may be more relevant with long-term use (several years).

Exacerbation of endometriosis.

Endometriosis may be exacerbated with administration of estrogen therapy.

Exacerbation of other conditions.

Estrogen therapy may cause an exacerbation of asthma, diabetes mellitus, epilepsy, migraine, porphyria, systemic lupus erythematosus and hepatic hemangiomas and should be used with caution in patients with these conditions.

Other conditions and product specific precautions.

Treatment should be stopped at once if migrainous or frequent unusually severe headaches occur for the first time, or if there are other symptoms that are possible premonitory signs of cerebrovascular occlusion.
Nonsevere disturbances of liver function, including hyperbilirubinemias such as Dubin-Johnson syndrome or Rotor syndrome, need closer supervision and liver function should be checked periodically. In case of deterioration of markers of liver function, use of HRT should be stopped.
Certain patients may develop undesirable manifestations of estrogenic stimulation under HRT such as abnormal uterine bleeding. Frequent or persistent abnormal uterine bleeding during treatment is an indication for endometrial assessment.
Uterine myomas may increase in size under the influence of estrogens. If this is observed, treatment should be discontinued.
Should there be a suspicion of a prolactinoma, this should be ruled out before starting treatment.
Chloasma may occasionally occur, especially in women with a history of chloasma gravidarum. Women with a tendency to chloasma should avoid exposure to the sun or ultraviolet radiation whilst taking HRT.
The following conditions have been reported to occur or deteriorate with HRT use. Although the evidence of an association with HRT use is inconclusive, women with these conditions and treated with HRT should be carefully monitored: benign breast disease, otosclerosis and chorea minor.
In women with hereditary angioedema, exogenous estrogens may induce or exacerbate symptoms of angioedema.

Use in hepatic impairment.

Progynova has not been studied in patients with hepatic impairment. Progynova is contraindicated in women with presence or history of liver tumours and with severe hepatic disease (see Section 4.3 Contraindications). For women with impaired liver function, close supervision is needed and in case of deterioration of markers of liver function, use of HRT should be stopped.

Use in the elderly.

Of the total number of subjects in the estrogen alone substudy of the Women's Health Initiative (WHI) study, 46% (n = 4,943) were 65 years and over, while 7.1% (n = 767) were 75 years and over. There was a higher relative risk (conjugated estrogens (CE) vs placebo) of stroke in women less than 75 years of age compared to women 75 years and over.
In the estrogen alone substudy of the Women's Health Initiative Memory Study (WHIMS), a substudy of WHI, a population of 2,947 hysterectomised women, aged 65 to 79 years, was randomised to CE (0.625 mg) or placebo. In the estrogen alone group, after an average follow-up of 5.2 years, the relative risk (CE vs placebo) of probable dementia was 1.49 (95% CI: 0.83-2.66).
Of the total number of subjects in the estrogen plus progestogen substudy of the Women's Health Initiative study, 44% (n = 7,320) were 65 years and over, while 6.6% (n = 1,095) were 75 years and over. There was a higher relative risk (CE/MPA vs placebo) of stroke and invasive breast cancer in women 75 and over compared to women less than 75 years of age.
In the estrogen plus progestogen substudy of WHIMS, a population of 4,532 postmenopausal women, aged 65 to 79 years, was randomised to CE/MPA (0.625 mg/2.5 mg) or placebo. In the estrogen plus progestogen group, after an average follow-up of 4 years, the relative risk (CE/MPA vs placebo) of probable dementia was 2.05 (95% CI: 1.21-3.48).
Pooling the events in women receiving CE or CE/MPA in comparison to those in women on placebo, the overall relative risk for probable dementia was 1.76 (95% CI: 1.19 to 2.60). Since both substudies were conducted in women aged 65 to 79 years, it is unknown whether these findings apply to younger postmenopausal women (see Section 4.4 Special Warnings and Precautions for Use, Dementia).
With respect to efficacy in the approved indications, there have not been sufficient numbers of elderly patients involved in studies utilising estrogens to determine whether those over 65 years of age differ from younger subjects in their response to estrogens.

Paediatric use.

Progynova is not indicated for use in children and adolescents.

Effects on laboratory tests.

The use of sex steroids may influence the results of certain laboratory tests, including biochemical parameters of liver, thyroid, adrenal and renal function, plasma levels of (carrier) proteins, e.g. corticosteroid binding globulin and lipid/lipoprotein fractions, parameters of carbohydrate metabolism, and parameters of coagulation and fibrinolysis. Changes generally remain within the normal laboratory range.

4.5 Interactions with Other Medicines and Other Forms of Interactions

The product information of concomitant medicines should be consulted to identify potential interactions.

Effects of other medicines on Progynova.

Interactions can occur with medicines that induce microsomal enzymes which can result in increased clearance of sex hormones and which may lead to changes in the uterine bleeding profile and/or reduction of the therapeutic effect.

Substances increasing the clearance of sex hormones (diminished efficacy by enzyme induction), e.g.

Phenytoin, barbiturates, primidone, carbamazepine, rifampicin and possibly also oxcarbazepine, topiramate, felbamate, griseofulvin and products containing St John's wort (Hypericum perforatum).
Enzyme induction can already be observed after a few days of treatment. Maximal enzyme induction is generally seen within a few weeks. After the cessation of drug therapy, enzyme induction may be sustained for about four weeks.

Substances with variable effects on the clearance of sex hormones.

When coadministered with sex hormones, many HIV/HCV protease inhibitors and non-nucleoside reverse transcriptase inhibitors can increase or decrease plasma concentrations of the estrogen. These changes may be clinically relevant in some cases.

Substances decreasing the clearance of sex hormones (enzyme inhibitors).

Strong and moderate CYP3A4 inhibitors such as azole antifungals (e.g. fluconazole, ketoconazole, itraconazole, voriconazole), verapamil, macrolides (e.g. clarithromycin, erythromycin), diltiazem and grapefruit juice can increase plasma concentrations of the estrogen.
Substances which undergo substantial conjugation (e.g. paracetamol) may increase the bioavailability of estradiol by competitive inhibition of the conjugation system during absorption.

Effect of Progynova on other medicines.

In individual cases, the requirement for oral antidiabetics or insulin can change as a result of the effect on glucose tolerance.

Interaction with alcohol.

Acute alcohol ingestion during use of HRT may lead to elevations in circulating estradiol levels.

4.6 Fertility, Pregnancy and Lactation

Effects on fertility.

No data available.
(Category B3)
Progynova is contraindicated during pregnancy (see Section 4.3 Contraindications). If pregnancy occurs during medication with Progynova, treatment must be discontinued immediately.
In animal studies, maternal administration of high doses of synthetic estrogens produced urogenital malformations in the offspring. However, the relevance of the animal findings for the clinical use of 17β-estradiol is uncertain.
 Progynova is contraindicated during lactation (see Section 4.3 Contraindications).

4.7 Effects on Ability to Drive and Use Machines

The effects of this medicine on a person's ability to drive and use machines were not assessed as part of its registration.

4.8 Adverse Effects (Undesirable Effects)

In addition to the adverse effects listed in the Contraindications and Special Warnings and Precautions for Use, the following undesirable effects have been reported in users of different oral HRT preparations by MedDRA system organ classes (MedDRA SOCs, version 8.1).

Immune system disorders.

Hypersensitivity reaction.

Metabolism and nutrition disorders.

Weight increase or weight decrease.

Psychiatric disorders.

Depressed mood, anxiety, libido decreased or libido increased.

Eye disorders.

Visual disturbances, contact lens intolerance.

Cardiac disorders.

Palpitations.

Musculoskeletal and connective tissue disorders.

Muscle cramps.

Reproductive system and breast disorders.

Uterine/vaginal bleeding including spotting, dysmenorrhoea, vaginal discharge, premenstrual-like syndrome, breast pain, breast tenderness, breast enlargement.

Gastrointestinal disorders.

Dyspepsia, bloating, nausea, vomiting, abdominal pain, increased appetite.

Skin and subcutaneous tissue disorders.

Rashes, various skin disorders (including pruritus, eczema, urticaria, acne, hirsutism, hair loss, erythema nodosum).

Nervous system disorders.

Headache, migraine, dizziness.

General disorders and administration site conditions.

Oedema, fatigue.

Malignancy.

Estrogen only and combined estrogen-progestogen HRT has been associated with a slightly increased risk of ovarian cancer in epidemiological studies. The risk may be more relevant with long-term use (several years) (see Section 4.4 Special Warnings and Precautions for Use).
In women with hereditary angioedema, exogenous estrogens may induce or exacerbate symptoms of angioedema.
The most serious adverse reactions associated with the use of Progynova are described under 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.

4.9 Overdose

Acute toxicity studies indicate that even in the case of inadvertent intake of a multiple of the therapeutic dose, no acute toxicity risk is to be expected. Overdosage may cause nausea and vomiting and withdrawal bleeding may occur in some women. There is no specific antidote and treatment should be symptomatic. 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.

Progynova contains estradiol valerate which is a prodrug of the natural human 17β-estradiol. Ovulation is not inhibited during the use of Progynova and the endogenous production of hormones is hardly affected.
During the climacteric, the reduction and finally loss of ovarian estradiol secretion can result in instability of thermoregulation, causing hot flushes associated with sleep disturbance and excessive sweating, and urogenital atrophy with symptoms of vaginal dryness, dyspareunia and urinary incontinence. Less specific but often mentioned as part of the climacteric syndrome are symptoms like anginal complaints, palpitations, irritability, nervousness, lack of energy and concentration abilities, forgetfulness, loss of libido and joint and muscle pain. Hormone replacement therapy (HRT) alleviates many of these symptoms of estradiol deficiency in the postmenopausal woman.
HRT reduces bone resorption and retards or halts postmenopausal bone loss. When HRT is discontinued, bone mass declines at a rate comparable to that in the immediate postmenopausal period. There is no evidence that HRT restores bone mass to premenopausal levels. HRT also has a positive effect on skin collagen content and skin thickness and can retard the process of skin wrinkling.
During estrogen replacement therapy, the addition of a progestogen for at least 10 days per cycle is recommended in women with an intact uterus. It reduces the risk of endometrial hyperplasia and the attendant risk of adenocarcinoma in these women.

Clinical trials.

Women's health initiative studies (WHI).

The Women's Health Initiative (WHI) enrolled a total of 27,000 predominantly healthy postmenopausal women to assess the risks and benefits of either the use of 0.625 mg conjugated estrogens (CE) per day alone or the use of 0.625 mg conjugated estrogens plus 2.5 mg medroxyprogesterone acetate (MPA) per day compared to placebo in the prevention of certain chronic diseases. The primary endpoint was the incidence of coronary heart disease (CHD) (nonfatal myocardial infarction and CHD death), with invasive breast cancer as the primary adverse outcome studied. A global index included the earliest occurrence of CHD, invasive breast cancer, stroke, pulmonary embolism (PE), endometrial cancer, colorectal cancer, hip fracture, or death due to other cause. The study did not evaluate the effects of CE or CE/MPA on menopausal symptoms.
The estrogen alone substudy was stopped early because an increased risk of stroke was observed and it was deemed that no further information would be obtained regarding the risks and benefits of estrogen alone in predetermined primary endpoints. Results of the estrogen alone substudy, which included 10,739 women (average age of 63 years, range 50 to 79; 75.3% white, 15% black, 6.1% Hispanic), after an average follow-up of 6.8 years are presented in Table 1.
For those outcomes included in the WHI global index that reached statistical significance, the absolute excess risk per 10,000 women-years in the group treated with CE alone were 12 more strokes while the absolute risk reduction per 10,000 women-years was 6 fewer hip fractures. The absolute excess risk of events included in the global index was a nonsignificant 2 events per 10,000 women-years. There was no difference between the groups in terms of all cause mortality (see Section 4.4 Special Warnings and Precautions for Use).
The estrogen plus progestogen substudy was also stopped early because, according to the predefined stopping rule, the increased risk of breast cancer and cardiovascular events exceeded the specified benefits included in the global index. Results of the estrogen plus progestogen substudy, which included 16,608 women (average age of 63 years, range 50 to 79; 83.9% white, 6.5% black, 5.5% Hispanic), after an average follow up of 5.2 years are presented in Table 2.
For those outcomes included in the WHI global index, the absolute excess risks per 10,000 women-years in the group treated with CE/MPA were 7 more CHD events, 8 more strokes, 8 more PEs and 8 more invasive breast cancers, while the absolute risk reductions per 10,000 women-years were 6 fewer colorectal cancers and 5 fewer hip fractures. The absolute excess risk of events included in the global index was 19 per 10,000 women-years. There was no difference between the groups in terms of all cause mortality (see Section 4.4 Special Warnings and Precautions for Use).

Women's health initiative memory study.

The estrogen alone Women's Health Initiative Memory Study (WHIMS), a substudy of WHI, enrolled 2,947 predominantly healthy postmenopausal women 65 years of age and older (45% were age 65 to 69 years, 36% were 70 to 74 years, and 19% were 75 years of age and older) to evaluate the effects of 0.625 mg conjugated estrogens on the incidence of probable dementia (primary outcome) compared with placebo.
After an average follow-up of 5.2 years, 28 women in the estrogen alone group (37 per 10,000 women-years) and 19 in the placebo group (25 per 10,000 women years) were diagnosed with probable dementia. The relative risk of probable dementia in the estrogen alone group was 1.49 (95% CI: 0.83 to 2.66) compared to placebo. It is unknown whether these findings apply to younger postmenopausal women (see Section 4.4 Special Warnings and Precautions for Use, Dementia, Use in the elderly).
The estrogen plus progestogen WHIMS substudy enrolled 4,532 predominantly healthy postmenopausal women 65 years of age and older (47% were age 65 to 69 years, 35% were 70 to 74 years, and 18% were 75 years of age and older) to evaluate the effects of 0.625 mg conjugated estrogens plus 2.5 mg medroxyprogesterone acetate on the incidence of probable dementia (primary outcome) compared with placebo.
After an average follow-up of 4 years, 40 women in the estrogen/progestogen group (45 per 10,000 women-years) and 21 in the placebo group (22 per 10,000 women-years) were diagnosed with probable dementia. The relative risk of probable dementia in the hormone therapy group was 2.05 (95% CI: 1.21 to 3.48) compared to placebo. Differences between groups became apparent in the first year of treatment. It is unknown whether these findings apply to younger postmenopausal women (see Section 4.4 Special Warnings and Precautions for Use, Dementia, Use in the elderly).

5.2 Pharmacokinetic Properties

Absorption.

Estradiol valerate is rapidly and completely absorbed. The steroid ester is cleaved into estradiol and valeric acid during absorption and the first liver passage. At the same time estradiol undergoes extensive further metabolism, e.g. into oestrone, oestriol and oestrone sulfate. About 3% of estradiol becomes bioavailable after oral administration of estradiol valerate. Food does not appear to affect the bioavailability of estradiol.

Distribution.

Maximum concentrations of estradiol in serum of approximately 15 picogram/mL (or 30 picogram/mL) are generally expected between 4-9 hours after tablet intake. Within 24 hours after tablet intake, serum levels of estradiol are expected to decline to concentrations of about 8 picogram/mL (or 15 picogram/mL). Estradiol binds to albumin and the sex hormone binding globulin (SHBG). The unbound fraction of estradiol in serum is about 1-1.5% and the SHBG bound fraction is in the range of 30-40%.
The apparent volume of distribution of estradiol after single intravenous administration is about 1 L/kg.

Metabolism.

After the ester cleavage of the exogenously administered estradiol valerate, the metabolism of the drug follows the biotransformation pathways of endogenous estradiol. Estradiol is mainly metabolised in the liver but also extrahepatically, e.g. in the gut, kidney, skeletal muscles and target organs. These processes involve the formation of oestrone, oestriol, catecholestrogens and sulfate and glucuronide conjugates of these compounds, which are all distinctly less estrogenic or even nonestrogenic.
There is a dynamic equilibrium between estradiol, oestrone and oestrone sulfate due to involvement of various enzymes including dehydrogenases, sulfotransferases, aryl sulfatases and glucuronosyltransferases and glucuronidases. Oxidation of oestrone and estradiol involves cytochrome P450 isoforms, mainly CYP1A2, CYP1A1 (extra hepatic), CYP3A4, CYP3A5, and CYP1B1 and CYP2C9 (see Section 4.5 Interactions with Other Medicines and Other Forms of Interactions).

Excretion.

The total serum clearance of estradiol following single intravenous administration, shows high variability in the range of 10-30 mL/minute/kg. A certain proportion of estradiol metabolites are excreted in the bile and undergo a so called enterohepatic circulation. Ultimately estradiol metabolites are mainly excreted as sulfates and glucuronides with the urine.

Steady-state conditions.

Compared to the single dose, approximately two times higher serum levels of estradiol are observed after multiple administration. On average, the concentration of estradiol varies between 15 picogram/mL (or 30 picogram/mL) (minimum levels) and 30 picogram/mL (or 60 picogram/mL) (maximum levels). Oestrone, as a less estrogenic metabolite, reaches about 8-times higher concentrations in serum, oestrone sulfate reaches approximately 150 times higher concentrations. After stopping the treatment, pretreatment levels of estradiol and oestrone are reached within 2-3 days.

5.3 Preclinical Safety Data

Genotoxicity.

There is limited evidence available in the literature suggesting that 17β-estradiol may be weakly genotoxic at high doses. No evidence could be found for an increase in the rate of gene mutation in bacterial or mammalian cells, but there was some evidence for the induction of chromosomal aberrations and aneuploidy in mammalian cells, and two groups reported an increase incidence of sister chromatid exchanges, indicative of DNA damage. Neither of these latter effects were induced by 17β-estradiol in human lymphocyte cultures. Importantly, there was no evidence of micronuclei formation in well controlled rodent bone marrow assays.

Carcinogenicity.

Supraphysiological doses of 17β-estradiol have been associated with the induction of tumours in estrogen dependent target organs in all rodent species tested. The relevance of these findings with respect to humans has not been established.

6 Pharmaceutical Particulars

6.1 List of Excipients

Progynova 1 mg tablets.

Lactose monohydrate, maize starch, povidone 25000, magnesium stearate, purified talc, sucrose, povidone 700000, macrogol 6000, calcium carbonate, glycerol, titanium dioxide, iron oxide yellow and glycol montanate.

Progynova 2 mg tablets.

Lactose monohydrate, maize starch, povidone 25000, magnesium stearate, purified talc, sucrose, povidone 700000, macrogol 6000, calcium carbonate and glycol montanate.

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

Progynova 1 mg.

Store below 30°C.

Progynova 2 mg.

Store below 25°C.
Store all medicines according to the storage conditions listed on the pack and keep them out of reach of children. Do not take the tablets after the expiry date listed on the pack.

6.5 Nature and Contents of Container

Progynova 1 mg.

Blister strips with 28 yellow coloured tablets, each tablets containing 1 mg estradiol valerate. Packs contain two blister strips.

Progynova 2 mg.

Blister strips with 28 white coloured tablets, each tablet containing 2 mg estradiol valerate. Packs contain two blister strips.

6.6 Special Precautions for Disposal

In Australia, any unused medicine or waste material should be disposed of by taking to your local pharmacy.

6.7 Physicochemical Properties

Chemical structure.


Chemical name: 1,3,5(10)-estratriene-3,17β-diol-17-valerate.
Molecular formula: C23H32O3.
Molecular weight: 356.5.
Estradiol valerate exists as white to yellowish white crystals or crystalline powder. The substance is freely soluble in acetone and dichloromethane, soluble in ethanol, methanol, dioxane and diethylether, very slightly soluble in n-hexane and practically insoluble in petroleum ether and water. The melting point is 143 to 150°C.

CAS number.

979-32-8.

7 Medicine Schedule (Poisons Standard)

S4 - Prescription Only Medicine.

Summary Table of Changes