Consumer medicine information

Angeliq 1/2

Estradiol; Drospirenone

BRAND INFORMATION

Brand name

Angeliq 1/2

Active ingredient

Estradiol; Drospirenone

Schedule

S4

 

Consumer medicine information (CMI) leaflet

Please read this leaflet carefully before you start using Angeliq 1/2.

WHAT IS IN THIS LEAFLET

This leaflet answers some of the common questions about Angeliq 1/2 tablets. It does not contain all of the available information. It does not take the place of talking to your doctor or pharmacist.

All medicines have risks and benefits. Your doctor has weighed the risks of you taking Angeliq 1/2 against the benefits they expect it will have for you.

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

Keep this leaflet with the medicine. You may need to read it again.

WHAT ANGELIQ 1/2 IS USED FOR

Angeliq 1/2 provides hormone replacement therapy (HRT) for the treatment of menopausal complaints in postmenopausal women. It is also used to treat symptoms due to decreased activity from the sexual organs (hypogonadism), after removal of the ovaries (ovariectomy) or when the ovaries do not work (primary ovarian failure). Angeliq 1/2 is only intended for short term use.

Angeliq 1/2 tablets contain estradiol, an oestrogen hormone and drospirenone, a progestogen hormone. 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.

Angeliq 1/2 replaces the hormones that the body no longer makes and prevents or relieves symptoms such as hot flushes, sweats, sleep disturbances and nervousness.

Angeliq 1/2 should only be used by women who have not had their uterus removed (hysterectomy). If you have had a hysterectomy, your doctor will prescribe another form of oestrogen therapy.

Angeliq 1/2 is not a contraceptive. It will not prevent you from falling pregnant.

Ask your doctor if you have any questions about why this medicine has been prescribed for you. Your doctor may have prescribed it for another reason.

BEFORE YOU TAKE ANGELIQ 1/2

When you must not take it

Do not take Angeliq 1/2 if you have an allergy to:

  • estradiol and/or drospirenone, the active ingredients in Angeliq 1/2
  • 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 difficulty breathing
  • swelling of the face, lips, tongue or other parts of the body
  • rash, itching or hives on the skin.

Do not take Angeliq 1/2 if you have:

  • 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
  • a history of or have severe renal disease
  • 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)

If any of these conditions appear for the first time while taking Angeliq 1/2, stop taking it at once and consult your doctor.

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 Angeliq 1/2 passes into breast milk and there is a possibility that your baby may be affected.

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

Do not take this medicine after the expiry date printed on the pack and blister. The expiry date is printed on the carton and on each blister after “EXP” (e.g. 11 13 refers to November 2013). The expiry date refers to the last day of that month. If it has expired return it to your pharmacist for disposal.

Do not take this medicine if the packaging is torn or shows signs of tampering. If the packaging is damaged, return it to your pharmacist for disposal.

If you are not sure whether you should start taking this medicine, talk to your doctor.

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 are overweight
  • you have varicose veins
  • you or anyone in your immediate family has had blood clots in the legs (thrombosis)
  • you have any hospitalisation, surgery or prolonged immobilisation

If you have any of the above risk factors, you have an increased risk of a blood clot while you are taking Angeliq 1/2. The risk also increases with age.

Taking Angeliq 1/2 may increase your risk of coronary heart disease. Tell your doctor if you experience chest pain or discomfort.

Taking Angeliq 1/2 may increase your risk of gall bladder disease. This is because oestrogen stimulates the liver to remove more cholesterol from blood and divert it to the gall bladder.

Before starting Angeliq 1/2, 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 any of the following medical conditions:

  • high blood pressure
  • kidney or liver disease
  • jaundice (yellowing of the skin and/or eyes) during pregnancy or while on other hormone treatments
  • high levels of fat in the blood
  • diabetes
  • abnormal vaginal bleeding
  • tumours in your womb or pituitary gland
  • endometriosis (the presence of tissue of the lining of the womb in places in the body where it is not normally found)
  • chloasma (yellow brown patches on the skin)
  • epilepsy
  • lumpy or painful breasts (benign breast disease)
  • asthma
  • porphyria (an inherited disease where the body cannot convert naturally occurring compounds into haem, which contains iron)
  • hearing loss caused by an abnormal bone growth in the ear (otosclerosis)
  • systemic lupus erythematosus (SLE; a chronic inflammatory 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 Angeliq 1/2.

HRT and cancer

Endometrial cancer
The risk of cancer of the lining of the womb (endometrial cancer) increases when oestrogens are used alone for prolonged periods. The progestogen in Angeliq 1/2 opposes this risk.

Please inform your doctor if you have frequent bleeding irregularities or persistent bleeding during the treatment with Angeliq 1/2.

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) for several years 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 breast 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 have shown 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 Angeliq 1/2, 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 unusual pain in your upper abdomen that does not disappear within a short time.

If you have not told your doctor about any of the above, tell him/her before you start taking Angeliq 1/2.

Taking other medicines

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

Some medicines and Angeliq 1/2 may interfere with each other. These include:

  • medicines to treat high blood pressure, chest pain and/or irregular heart beats such as ACE inhibitors, verapamil, diltiazem
  • medicines used to treat epilepsy such as hydantoins, barbituates, primidone, carbamazepine
  • 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
  • anticoagulants, medicines used to thin blood and to treat or prevent blood clots
  • medicines used to treat fungal infections such as ketoconazole, itraconazole, voriconazole, fluconazole
  • medicines used to treat pain and inflammation (e.g. ibuprofen, diclofenac)
  • grapefruit juice

These medicines may be affected by Angeliq 1/2 or may affect how well it works. You may need different amounts of your medicines, or you may need to take different medicines.

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

HOW TO TAKE ANGELIQ 1/2

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 to take it

Take one tablet daily at about the same time each day.

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.

Swallow the tablets whole with a full glass of water.

When to take it

If you are using HRT for the first time or if you change from a continuous combination HRT product (each of the tablets contains the same ingredients), you may begin taking Angeliq 1/2 at any time.

If you are changing from a sequential combined HRT treatment (tablets differ in their ingredients, which is made visible with different colours), you should start Angeliq 1/2 at the end of the scheduled bleeding.

How long to take it

Angeliq 1/2 is only intended for short term use. Your doctor will advise you on how long to use Angeliq 1/2. Your doctor should discuss with you the risks and benefits with extended use of this product and your treatment with hormone therapy should also be re-evaluated at regular intervals.

You may have an increased risk of developing breast cancer, heart disease, stroke, blood clots including clots in the lungs, and dementia. 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 take it

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.

If you take too much (overdose)

Immediately telephone your doctor or the Poisons Information Centre on 13 11 26 for advice, or go to Accident and Emergency at the nearest hospital, if you think that you or anyone else may have taken too much Angeliq 1/2.

Do this even if there are no signs of discomfort or poisoning. You may need urgent medical attention.

If your bleeding pattern seems different

Angeliq 1/2 has been made to provide you with hormone replacement therapy without cyclical bleeding. You may, however, get some bleeding during the first few months of treatment. It could occur at any time but it is unlikely to be heavy. Bleeding episodes should eventually get less and finally stop. If significant bleeding continues or if at any time bleeding or spotting becomes unacceptable for you, ask your doctor whether you should discontinue treatment or change to a sequential therapy.

WHILE YOU ARE TAKING ANGELIQ 1/2

Things you must do

If you are about to be started on any new medicine, remind your doctor and pharmacist that you are taking Angeliq 1/2.

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.

See your doctor at least once a year for a check-up. Some women will need to go more often. Your doctor will:

  • check your breasts and order a mammogram at regular intervals
  • check your uterus and cervix and do a pap smear at regular intervals
  • monitor your blood pressure

Check your breasts each month and report any changes promptly to your doctor. Your doctor or nurse can show you how to check your breasts properly.

Stop taking it immediately

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)
  • if you have existing benign tumours in your womb, your doctor will organise scans to monitor your tumours as Angeliq 1/2 can increase the size of tumours.

If you get a blood clot while you are taking Angeliq 1/2 or if you suspect this has happened, 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.

Angeliq 1/2 must also be stopped at once if you develop jaundice (yellowing of the skin and/or eyes). Tell your doctor immediately if this occurs.

If bleeding occurs after a prolonged interval of not having period like bleeding, talk to your doctor, as this may need to be investigated.

Things you must not do

Do not take Angeliq 1/2 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.

What to be careful of

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

SIDE EFFECTS

Tell your doctor or pharmacist as soon as possible if you do not feel well while you are taking Angeliq 1/2.

All medicines can have side effects. Sometimes they are serious, most of the time they are not. You may need medical attention if you get some of the side effects.

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

Ask your doctor or pharmacist to answer any questions you may have.

During the first few months of treatment you may experience some vaginal bleeding at unexpected times (breakthrough bleeding and spotting). These are usually temporary and normally subside with continued use. If they do not, contact your doctor. Breast pain was a very common symptom.

Tell your doctor or pharmacist if you notice any of the following and they worry you:

  • abdominal pain
  • bloating
  • unusual tiredness or weakness
  • pain in the limbs
  • nausea
  • headache
  • mood swings
  • hot flushes
  • nervousness
  • benign breast tumour
  • breast enlargement
  • tumours in the womb enlarged
  • tumour of the neck of the uterus (cervix)
  • white vaginal discharge
  • urinary tract infections or incontinence (uncontrollable, involuntary passing of urine).

Tell your doctor immediately, or go to Accident and Emergency department at your nearest hospital if you notice any of the following:

  • 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
  • coughing blood, unusual pains or swelling of your arms or legs, sudden shortness of breath, fainting
  • lumpy breasts
  • tingling, prickling or numbness of the skin
  • chest pain

Rarely, skin disorders have been reported in women receiving hormone replacement therapy. Tell your doctor if you notice itchy, reddish, painful lumps (erythema nodosum, erythema multiforme, haemorrhagic dermatitis) or yellow-brown patches on the skin (chloasma).

Occurrences of inflammatory bowel disease (an inflammatory disease that can affect any part of the gastrointestinal tract) have been reported in a study with women using HRT. However, based on current scientific knowledge, there is no clear evidence if HRT use causes inflammatory bowel disease.

Tell your doctor or pharmacist if you notice anything that is making you feel unwell. Other side effects not listed above may also occur in some people.

Also tell your doctor if you have any of the symptoms listed under “While you are taking Angeliq 1/2 - stop taking it immediately”.

AFTER TAKING ANGELIQ 1/2

Storage

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.

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

Do not store it or any other medicine in the bathroom, near a sink, or on a window-sill.

Do not leave it in the car. Heat and dampness can destroy some medicines.

Keep it where children cannot reach it. A locked cupboard at least one-and-a half metres above the ground is a good place to store medicines.

Disposal

If your doctor tells you to stop taking this medicine or the expiry date has passed, ask your pharmacist what to do with any medicine that is left over.

Return any unused medicine to your pharmacist.

PRODUCT DESCRIPTION

What it looks like

Angeliq 1/2 is available in a calendar pack consisting of 7 or 28 red coloured tablets. Each tablet is marked with “DL” in a regular hexagon on one side.

Ingredients

Active ingredients per tablet:

  • Angeliq 1/2 -1 mg of estradiol and 2 mg of drospirenone

Inactive ingredients:

  • Lactose monohydrate
  • maize starch
  • pregelatinised maize starch
  • povidone
  • magnesium stearate
  • hypromellose
  • macrogol 6000
  • purified talc
  • titanium dioxide
  • iron oxide red

Supplier

Made in Germany for:

Bayer Australia Ltd
ABN 22 000 138 714
875 Pacific Highway
Pymble NSW 2073

Australian Registration Number

AUST R 114816

Date of preparation

February 2020

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

® Registered trademark of the Bayer group, Germany

© Bayer Australia Ltd

All rights reserved.

Published by MIMS May 2020

BRAND INFORMATION

Brand name

Angeliq 1/2

Active ingredient

Estradiol; Drospirenone

Schedule

S4

 

1 Name of Medicine

Estradiol and drospirenone.

2 Qualitative and Quantitative Composition

Angeliq 1/2 is a hormone replacement therapy (HRT) preparation containing the estrogen estradiol and the progestogen drospirenone. Each red film-coated tablet contains: estradiol 1.0 mg, drospirenone 2.0 mg.
Contains lactose monohydrate.
For the full list of excipients, see Section 6.1 List of Excipients.

3 Pharmaceutical Form

The tablets are film-coated tablets - small, round, red tablet, one side embossed with the letters DL in a regular hexagon.

4 Clinical Particulars

4.1 Therapeutic Indications

Hormone replacement therapy (HRT) for use in the short-term treatment in postmenopausal women with an intact uterus of the climacteric syndrome caused by deficient endogenous estrogen production due to natural menopause, hypogonadism, castration or primary ovarian failure.

4.2 Dose and Method of Administration

HRT should only be continued as long as the benefit in alleviation of severe symptoms outweighs the risk.

How to start Angeliq 1/2.

Women who do not take estrogens or women who change from a continuous combination product may start treatment at any time. Patients changing from a sequential combined HRT treatment should be started at the end of the scheduled bleeding.

Dosage.

One tablet is taken daily. Each blister pack is for 28 days of treatment.

Administration.

The tablets are to be swallowed whole with some liquid irrespective of food intake. Treatment is continuous, which means that the next pack follows immediately without a break. The tablets should preferably be taken at the same time every day. In case a tablet is forgotten, it should be taken as soon as possible. If more than 24 hours have elapsed no extra tablet needs to be taken. If several tablets are forgotten, bleeding may occur.

4.3 Contraindications

HRT should not be started in the presence of any of the conditions listed below. Should any of the conditions appear during HRT use, the product should be stopped immediately.
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.
Presence or history of severe renal disease as long as renal function values have not returned to normal.
Acute arterial thromboembolism (e.g. myocardial infarction, stroke).
Active deep venous thrombosis, thromboembolic disorders, or a documented history of these conditions.
A high risk of venous or arterial thrombosis.
Severe hypertriglyceridaemia.
Pregnancy or lactation.
Known hypersensitivity to the active substances or to any of the excipients.

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. HRT should be used only in women with menopausal symptoms and ordinarily not for long-term use. Estrogens with or without progestogens should be prescribed at the lowest effective doses and for the shortest duration consistent with the treatment goal and risks for the individual women.
Combination HRT, such as Angeliq 1/2, should not be used in hysterectomised women.
Angeliq 1/2 cannot be used as a contraceptive.
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 increased risk may be greater than a simple cumulative risk of the factors. HRT should not be prescribed in case of a negative risk benefit assessment.

Venous thromboembolism.

Both randomised controlled and epidemiological studies have suggested an increased relative risk of developing venous thromboembolism (VTE), i.e. deep venous thrombosis or pulmonary embolism. Risk/benefit should, therefore, be carefully weighed in consultation with the patient when prescribing HRT to women with a risk factor for VTE (see Section 5.1 Pharmacodynamic Properties, Clinical trials).
Scarabin and others reported the results of a case control study conducted during 1999-2002 in France. The investigators recruited 155 consecutive cases with a first documented episode of VTE of unknown cause (92 with pulmonary embolisms and 63 with deep vein thrombosis), and 381 controls (women admitted to hospital for other reasons) matched for centre, age, and time of recruitment. Overall, 32 (21%) cases and 27 (7%) controls were current users of oral estrogen replacement therapy (this was defined in this study as estrogen only therapy or combined HRT), whereas 30 (19%) cases and 93 (24%) controls were current users of transdermal estrogen replacement therapy. After adjustment for potential confounding variables, the odds ratio for VTE in current users of oral and transdermal estrogen replacement therapy compared with nonusers was 3.5 (95% CI 1.8-6.8) and 0.9 (0.5-1.6), respectively. Estimated risk for VTE in current users of oral estrogen replacement therapy compared with transdermal estrogen therapy users was 4.0 (1.9-8.3). These results may be interpreted as meaning that (i) the higher risk of VTE as shown in the WHI study has been further supported; and (ii) current but not past use was a risk factor for VTE. Use in the first year was also more risky than later use, a finding that is also consistent with the WHI study.
Generally recognised risk factors for VTE include a personal history, a family history (the occurrence of VTE in a direct relative at a relatively early age may indicate genetic disposition) and severe obesity. The risk of VTE also increases with age. There is no consensus about the possible role of varicose veins in VTE.
The risk of VTE may be temporarily increased with prolonged immobilisation, major elective or post-traumatic surgery, or major trauma. Depending on the nature of the event and the duration of the immobilisation, consideration should be given to a temporary discontinuation of HRT.
Treatment should be stopped at once if there are symptoms of a thrombotic event or suspicion thereof.

Arterial thromboembolism.

Two large clinical trials with continuous combined conjugated estrogens (CEE) and medroxyprogesterone acetate (MPA) showed a possible increased risk of coronary heart disease (CHD) in the first year of use and no benefit thereafter. One large clinical trial with CEE alone showed a potential reduction of CHD rates in women aged 50-59 and no overall benefit in the total study population. As a secondary outcome, in two large clinical trials with CEE alone or combined with MPA, a 30-40% increased risk of stroke was found. It is uncertain whether these findings also extend to other HRT products or nonoral routes of administration (also see Section 5.1 Pharmacodynamic Properties, Clinical trials).
In a study by Hodis et al., of a double blind, randomised, placebo controlled trial in 226 menopausal women who had at least one coronary artery lesion, estradiol with or without medroxyprogesterone acetate was administered. The primary efficacy endpoint was the average per participant change between baseline and follow-up coronary angiograms in the percent stenosis via quantitative angiography. The study showed that, in women with established coronary artery disease, estradiol with or without medroxyprogesterone acetate had no significant effect on the progression of atherosclerosis. See Table 1.

Gall bladder disease.

Estrogens are known to increase the lithogenicity of the bile. Some women are predisposed to gall bladder disease during estrogen therapy.

Dementia.

The Women's Health Initiative Memory study (WHIMS), included 4532 women 65 years of age and older that were followed up for an average of 4 years. 71% were 65-74 (3726) while 18% (806) were 75 and over and most women (80%) had no prior HRT use. Women treated with 0.625 mg conjugated estrogens, plus 2.5 mg medroxyprogesterone acetate were reported to have a twofold increase in the risk of developing probable dementia (DSM-IV criteria). This evidence from clinical studies (WHIMS) with conjugated estrogen (CEE) containing preparations suggests that hormonal treatment may increase the risk of probable dementia if initiated in women aged 65 or older. The risk may be decreased if treatment is initiated in early menopause, as observed in other studies. It is unknown whether these findings also extend to other HRT products.

Breast cancer.

A meta-analysis from 51 epidemiological studies has reported an increased risk of having breast cancer diagnosed in women who have used HRT for several years. The findings may be due to an earlier diagnosis, the biological effects of HRT or a combination of both. The relative risk increases with duration of treatment (by 2.3% per year of use). This is comparable to the increased risk of breast cancer observed in women with every year of delay of natural menopause (2.8% per year of delay). The excess risk decreases with time after stopping HRT. Breast cancers found in women using HRT are more likely to be localised to the breast than those found in nonusers.
The increased risk of having breast cancer diagnosed in women who have used HRT for several years was confirmed in the WHI study (see Section 5.1 Pharmacodynamic Properties, Clinical trials).
In the Million Women study this increased risk emerged towards the end of the first year of treatment (see Section 5.1 Pharmacodynamic Properties, Clinical trials).
HRT increases the density of mammographic images which may adversely affect radiological detection of breast cancer in some cases.

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).

Endometrial cancer.

Prolonged exposure to unopposed estrogens increases the risk of development of endometrial hyperplasia or carcinoma. Studies have suggested that the appropriate addition of progestogens to the regimen eliminates this increase in risk. The addition of drospirenone opposes the development of endometrial hyperplasia caused by estrogens.

Liver tumours.

In rare cases benign, and even more rarely, malignant liver tumours have been observed after the use of hormonal substances such as those contained in HRT products. In isolated cases, these tumours led to life threatening intra-abdominal haemorrhage. A hepatic tumour should be considered in the differential diagnosis if upper abdominal pain, enlarged liver or signs of intra-abdominal haemorrhage occur.

Other conditions.

Treatment should be stopped at once if migrainous or frequent and unusually severe headaches occur for the first time, or if there are other symptoms that are possible premonitory signs of cerebrovascular occlusion.
A general association between HRT use and development of clinical hypertension has not been established. Small increases in blood pressure have been reported in women taking HRT, clinically relevant increases are rare. However, if in individual cases a sustained clinically significant hypertension develops during the use of HRT then withdrawing the HRT may be considered.
Potassium excretion capacity may be limited in patients with renal insufficiency. In a clinical study, drospirenone intake did not show an effect on the serum potassium concentration in patients with mild or moderate renal impairment. A theoretical risk for hyperkalemia can be assumed only for patients whose pretreatment serum potassium is in the upper reference range, and who are additionally using potassium sparing drugs.
Nonsevere disturbances of liver function, including hyperbilirubinemias such as Dubin-Johnson syndrome or Rotor syndrome, need close supervision and liver function should be checked periodically. In case of deterioration of markers of liver function, use of HRT should be stopped.
Recurrence of cholestatic jaundice or cholestatic pruritus which occurred first during pregnancy or during previous use of sex steroids necessitates the immediate discontinuation of HRT.
Women with moderately elevated levels of triglycerides need special surveillance. HRT in these women may be associated with a further increase in triglyceride levels bearing the risk of acute pancreatitis.
Although HRT may have an effect on peripheral insulin resistance and glucose tolerance, there is generally no need to alter the therapeutic regimen in diabetics using HRT. However, diabetic women should be carefully monitored while taking HRT.
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 fibroids may increase in size under the influence of estrogens. If this is observed, treatment should be discontinued.
Should endometriosis be reactivated under treatment, discontinuation of therapy is recommended.
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: epilepsy, benign breast disease, asthma, migraine, porphyria, otosclerosis, systemic lupus erythematosus and chorea minor.
In women with hereditary angioedema, exogenous estrogens may induce or exacerbate symptoms of angioedema.

Use in hepatic impairment.

In women with mild or moderate hepatic impairment, drospirenone is well tolerated (see Section 5.2 Pharmacokinetic Properties). Angeliq 1/2 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 renal impairment.

In women with mild or moderate renal impairment, a slight increase of drospirenone exposure was observed but is not expected to be of clinical relevance (see Section 5.2 Pharmacokinetic Properties). Angeliq 1/2 is contraindicated in women with severe renal disease (see Section 4.3 Contraindications).

Use in the elderly.

See Section 5.1 Pharmacodynamic Properties, Clinical trials.

Paediatric use.

Angeliq 1/2 is not indicated for use in children or adolescents.

Medical examination/consultation.

A complete medical history should be taken and a physical examination should be conducted prior to the initiation or reinstitution of HRT, guided by Contraindications and Precautions and should be repeated periodically. The frequency and nature of these examinations should be based on established practice guidelines and be adapted to the individual woman, but should generally include pelvic organs, including routine cervical cytology, abdomen, breasts and blood pressure.

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. sex hormone binding globulin and lipid/lipoprotein fractions and parameters of coagulation and fibrinolysis. Changes generally remain within the reference range. Glucose tolerance was not compromised by the use of Angeliq 1/2.

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 Angeliq 1/2.

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.
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, e.g.

When coadministered with sex hormones, many HIV/HCV protease inhibitors and nonnucleoside reverse transcriptase inhibitors can increase or decrease plasma concentrations of estrogen or progestin or both. 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. ketoconazole, itraconazole, voriconazole, fluconazole), verapamil, macrolides (e.g. clarithromycin, erythromycin), diltiazem and grapefruit juice can increase plasma concentrations of the progestin or the estrogen or both.
The clinical relevance of potential interactions with enzyme inhibitors remains unknown.

Interaction with alcohol.

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

Effect of Angeliq 1/2 on other medicines.

In vitro, drospirenone has demonstrated a capacity to inhibit CYP1A1, CYP2C9 and CYP2C19 and CYP3A4.
Based on in vitro inhibition studies drospirenone showed 50% inhibition of CYP1A1, 2C9, 2C19 and 3A4 at concentrations which were about two to three orders of magnitude higher than the maximum free drospirenone serum concentrations at steady state after administration of Angeliq 1/2.
In a clinical drug-drug interaction study in 24 postmenopausal women [12 women with homozygous (wild type) CYP2C19 genotype, extensive metabolisers (EM) and 12 women with heterozygous CYP2C19 genotype, intermediate metabolisers (IM)] who received oral doses of 3 mg drospirenone for 14 days and omeprazole, 40 mg once before and once on the last day of the 14 days of drospirenone treatment, no significant influence from drospirenone coadministration on the AUC of the CYP2C19 substrate OMP and the CYP2C19 enzyme product 5-OHOMP was observed. There was no significant influence from drospirenone coadministration on AUC of the CYP3A4 enzyme product OMPSO in either IM or EM groups. Thus the results of this study did not demonstrate an inhibition of the enzymes CYP2C19 and CYP3A4 by drospirenone at clinically relevant steady-state exposure at 3 mg/day dosing regimen.
Based on in vivo interaction studies in female volunteers using simvastatin or midazolam as marker substrates, a clinically relevant interaction of drospirenone at doses of 3 mg with the CYP enzyme mediated metabolism of other medicines is unlikely.
Antagonism of the effectiveness of anticoagulants may occur.

Pharmacodynamic interaction with antihypertensive medicines.

Women treated with Angeliq 1/2 and antihypertensive medications may experience an additional decrease in blood pressure. Concomitant use of Angeliq 1/2, nonsteroidal anti-inflammatory medicines and antihypertensive medications may cause a small increase in serum potassium, more pronounced in diabetic women.

4.6 Fertility, Pregnancy and Lactation

Effects on fertility.

See Section 5.1 Pharmacodynamic Properties, Mechanism of action.
(Category B3)
Drospirenone and/or its metabolites crossed the placenta and entered the fetus when administered orally to pregnant rats and rabbits. No data are available for the combination of estradiol and drospirenone but treatment of pregnant rats with a combination of drospirenone and ethinylestradiol resulted in a dose dependent increased incidence of embryolethality due to increased preimplantation and postimplantation losses. There was no indication of teratogenic effects of drospirenone in rats or rabbits.
Dose dependent feminisation of male fetuses and virilisation of female fetuses were seen following administration of a combination of drospirenone and ethinylestradiol to female rats in the last third of pregnancy. Feminising effects in male fetuses were consistent with drospirenone's antiandrogenic activity and were observed at an estimated systemic exposure approximately 12 to 20-fold that anticipated clinically (based on AUC). Virilisation of female fetuses was seen following systemic drospirenone exposure of approximately 3 to 8-fold that anticipated clinically (based on AUC). This effect has previously been described for estrogens in rats. When pregnant monkeys received a combination of drospirenone and ethinylestradiol by daily oral administration during the major period of organogenesis and sexual organ differentiation, abortion rates were increased in a dose dependent manner. However, there were no indications of teratogenicity.
The potential risk for humans is unknown. Epidemiological studies to date have not revealed a teratogenic effect when women were inadvertently exposed to estrogen/progestogen combinations during early pregnancy.
Angeliq 1/2 should not be used during pregnancy (see Section 4.3 Contraindications). Pregnancy should be ruled out before the start of therapy. If pregnancy occurs during medication with Angeliq 1/2, treatment should be discontinued promptly.
 Angeliq 1/2 should not be used during lactation (see Section 4.3 Contraindications). Small amounts of drospirenone and estrogen are excreted with the milk. Estrogen administration to breastfeeding mothers has been shown to decrease the quantity and quality of milk.

4.7 Effects on Ability to Drive and Use Machines

No effects on the ability to drive and use machines have been observed.

4.8 Adverse Effects (Undesirable Effects)

Serious undesirable effects associated with the use of HRT are also mentioned under Special Warnings and Precautions for Use.
Serious adverse reactions are arterial and venous thromboembolic events, and breast cancer. For venous and arterial thromboembolic events, breast cancer and migraine, see Section 4.3 Contraindications; Section 4.4 Special Warnings and Precautions for Use.
Table 2 (HARTS Body System and Dictionary Term) attributes frequencies to the undesirable effects of Angeliq 1/2. These frequencies are based on the frequencies of adverse events, which were recorded in 4 phase III clinical studies (n = 1532 women at risk) and considered at least possibly related to Angeliq 1/2 treatment (containing 1, 2 or 3 mg drospirenone).
During the first few months of treatment, bleeding and spotting can occur. These are usually temporary and normally disappear after continued treatment (see Section 5.1 Pharmacodynamic Properties). The frequency of bleeding decreases with the duration of treatment. Breast pain was a very common symptom, reported in approximately one out of five women.
In exceptional cases erythema nodosum, erythema multiforme, chloasma and haemorrhagic dermatitis have been reported in women receiving HRT.
In a post hoc analysis of the prospective cohort of the Nurses' Health study, occurrences of inflammatory bowel disease have been reported in HRT users. Based on current scientific knowledge, there is no clear evidence for a causal relationship between HRT use and inflammatory bowel disease.
Adverse reactions with delayed onset of symptoms which are considered to be related to the group of continuous combined products for HRT are listed below (see Section 4.4 Special Warnings and Precautions for Use).

Tumours.

Liver tumours (benign and malignant).
Sex steroid influenced malignancies and premalignant conditions (if such a condition is known, this constitutes a contraindication for the use of Angeliq 1/2).
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).

Other conditions.

Gall bladder disease (see Section 4.4 Special Warnings and Precautions for Use).
Dementia (see Section 4.4 Special Warnings and Precautions for Use).
Endometrial cancer (see Section 4.4 Special Warnings and Precautions for Use).
Hypertension (see Section 4.4 Special Warnings and Precautions for Use).
Disturbances of liver function.
Hypertriglyceridaemia (see Section 4.4 Special Warnings and Precautions for Use).
Changes in glucose tolerance or effect on peripheral insulin resistance.
Increase in size of uterine fibroids.
Reactivation of endometriosis.
Prolactinoma (risk of aggravation of hyperprolactinaemia or induction of tumour growth).
Chloasma.
Jaundice and/or pruritus related to cholestasis.
Occurrence or deterioration of conditions for which association with HRT use is not conclusive: epilepsy, benign breast disease, asthma, porphyria, systemic lupus erythematosus, otosclerosis, chorea minor.
In women with hereditary angioedema, exogenous estrogens may induce or exacerbate symptoms of angioedema.
Hypersensitivity (incl. symptoms such as rash and urticaria).

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

In clinical studies, up to 100 mg of drospirenone and estrogen/progestogen preparations containing 4 mg estradiol were well tolerated. 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.

Angeliq 1/2 contains 17β-estradiol, which is chemically and biologically identical to endogenous human estradiol, and the synthetic progestogen, drospirenone. 17β-estradiol provides hormone replacement during and after the climacteric.
The addition of drospirenone helps to provide bleeding control and opposes the development of endometrial hyperplasia caused by estrogens.
Effects of estradiol. The loss of the ovarian function, accompanied by a depletion of estrogen and progesterone production, leads to the menopausal syndrome, characterised by vasomotor and organic symptoms. HRT is indicated to eliminate these complaints.
Of all physiological estrogens, estradiol is the most potent one with the highest affinity to the estrogen receptor. Estrogen target organs include, in particular, uterus, hypothalamus, pituitary, vagina, breast and bones (osteoclasts).
Other effects of estrogens include reduction of insulin and blood glucose concentrations, local vasoactive effects mediated by receptors, and receptor independent effects on vascular smooth muscle. Estrogen receptors have been identified in the heart and coronary arteries.
HRT has also a positive effect on skin collagen and skin thickness and can retard the process of skin wrinkling.
Estrogen monotherapy exerts a dose dependent stimulating effect on mitosis and proliferation of the endometrium and thus increases the frequency of endometrial hyperplasia and hence the risk of endometrial carcinoma. In order to avoid endometrial hyperplasia, a combination with a progestogen is necessary.
Effects of drospirenone. Drospirenone exerts pharmacodynamic effects very similar to natural progesterone.

Progestogenic activity.

Drospirenone is a progestogen with a central inhibitory effect on the hypothalamic pituitary gonadal axis. In fertile women, drospirenone exerts a contraceptive effect; ovulation is inhibited when drospirenone is administered as a monosubstance. The threshold dose of drospirenone for ovulation inhibition is 2 mg/day. Complete transformation of an estrogen primed endometrium occurs following a dose of 4 or 6 mg/day for 10 days (= 40 to 60 mg per cycle).
Angeliq 1/2 is a continuous combined HRT given with the intent of avoiding the regular withdrawal bleeding associated with cyclic or sequential HRT. During the first months of treatment bleeding and spotting are quite common but decrease with time. With Angeliq 1/2 (2 mg drospirenone), the amenorrhea rate rapidly increased to 81% already in cycle 6, 86% in cycle 12, and 91% in cycle 24.
Drospirenone in Angeliq 1/2 opposes the development of estrogen induced endometrial hyperplasia effectively. After 12 months of treatment with Angeliq (drospirenone doses 0.5, 1, 2, or 3 mg) an atrophic/inactive endometrium was achieved in 71-77% of the women.

Antimineralocorticoid activity.

Drospirenone displays antimineralocorticoid activity (similar to progesterone and spironolactone) affecting the renin angiotensin aldosterone system. A dose of 1 mg drospirenone was found to be as potent as about 7 mg spironolactone. Thus, increases in sodium and water excretion are observed due to aldosterone antagonistic effects. Unfavorable estrogen effects such as increases in blood pressure in susceptible women and sodium and fluid retention resulting in oedema are counterbalanced.
In clinical trials (pooled data from research report nos. AR99, AU18 and A02827 where data was obtained over a period of at least 1 year), the mean systolic and diastolic blood pressure were slightly decreased. After 12 weeks of treatment the mean systolic blood pressure was reduced by -2 mmHg whereas the diastolic blood pressure was reduced by -2 mmHg (n = 428). With few exceptions, decreases in blood pressure were greater for combinations of estradiol and drospirenone compared with estradiol alone. A post hoc performed analysis showed that the effects on blood pressure was more pronounced in patients with borderline hypertension, with a greater decrease observed in mean systolic (-11 mmHg) than diastolic values (-6 mmHg) (n = 71).
In clinical trials with Angeliq 1/2 the mean bodyweight was either unchanged (1 mg drospirenone) or decreased during the treatment period of 12 months by 1.1-1.2 kg (3 or 2 mg drospirenone daily) whereas an increase of 0.5 kg was observed in patients treated with estradiol alone.

Antiandrogenic activity.

Like natural progesterone, drospirenone has antiandrogenic properties.

Effects on carbohydrate metabolism.

Drospirenone has no glucocorticoid or antiglucocorticoid activity and has no effect on glucose tolerance and insulin resistance. Glucose tolerance is not compromised by the use of Angeliq 1/2.

Other properties.

Drospirenone is devoid of estrogenic activity.

Clinical trials.

The efficacy and safety of Angeliq 1/2 was examined in 4 phase II/III clinical trials. The women enrolled in these studies were postmenopausal, i.e. had their last natural menstrual bleeding at least 6 months prior and serum estradiol level ≤ 20 picogram/mL and serum follicle stimulating hormone ≥ 50 U/L. The exclusion criteria for these studies were typical for evaluation of hormone replacement therapies. The pivotal results are presented below.

Research report no. AR98.

The pivotal phase III study (research report no. AR98) was a randomised, double blind, placebo controlled study examining the efficacy of Angeliq 1/2 and two other estradiol/drospirenone combinations (1 mg estradiol with either 1 mg or 3 mg drospirenone) in the prevention of hot flushes and other climacteric symptoms over 16 weeks of treatment. The primary efficacy variable was the frequency and severity of hot flushes, while secondary variables included the frequency and severity of other climacteric complaints, occurrence and severity of vaginal bleeding and safety related parameters. The results for the primary variable are provided in Table 3.

Research report no. AR99.

A double blind, placebo controlled study (research report no. AR99) examining the efficacy of Angeliq 1/2 and two other estradiol/drospirenone combinations (1 mg estradiol with either 1 mg or 3 mg drospirenone) on the prevention of bone mineral density loss over 2 years of treatment was conducted. The primary efficacy variable was hip bone mineral density after 104 weeks of treatment while the secondary variables included hip bone mineral density after 12, 28, 52 and 80 weeks, bone mineral density of lumbar spine, midshaft of the radius and total body. This study was conducted prior to awareness of the ethical implications of the Women's Health Initiative (WHI) study and Million Women studies (see below). The results for each treatment group after 6 months (28 weeks) are presented in Tables 4 and 5.

Research report no. A02827 and A17844.

A double blind, randomised study (research report no. A02827) comparison of Angeliq 1/2 and three other estradiol/drospirenone combinations (1 mg estradiol with either 0.5 mg, 1 mg or 3 mg drospirenone) with estradiol (1 mg) to examine effects on the endometrium after 1 year of treatment (13 cycles).
A re-evaluation of the endometrial biopsy samples from report no. A02827 was conducted (report no. A17844). The results are presented in Table 6.

Women's Health Initiative (WHI) study.

Two subsets of the Women's Health Initiative (WHI) enrolled a total of 27,000 predominantly healthy postmenopausal women to assess the risks and benefits of either long-term estrogen replacement therapy (ERT) or HRT (conjugated estrogens alone [0.625 mg per day] and conjugated estrogens in combination with medroxyprogesterone acetate [0.625 mg/2.5 mg per day]) compared to placebo in the prevention of certain chronic diseases. The study did not evaluate the effects of HRT on menopausal symptoms.
In 8506 postmenopausal women who received oral HRT using a continuous combined regimen of conjugated equine estrogens (conjugated estrogens) 0.625 mg/day plus medroxyprogesterone acetate 2.5 mg/day and 8102 women who received placebo for an average of 5.2 years, adverse effects on the cardiovascular system and the incidence of breast cancer were observed. The Women's Health Initiative (WHI) study was designed to investigate the efficacy and safety of long-term HRT in preventing coronary heart disease (CHD) in healthy postmenopausal women with an intact uterus. A global index summarising the balance of risks and benefits included an analysis of the primary outcomes CHD and primary adverse outcome, invasive breast cancer, and the following secondary outcomes: stroke, pulmonary embolism (PE), endometrial cancer, colorectal cancer, hip fracture and death due to other causes. The women enrolled in the study had a mean age at entry of 63.3 years. On average they were overweight (mean body mass index [BMI] = 28.5) and one-third were obese (BMI = ≥ 30), 50% were previous or current smokers, one-third had received treatment for high blood pressure and over 10% had raised cholesterol levels requiring medication.
After a mean of 5.2 years of follow-up, the study was stopped because the preset criterion for invasive breast cancer was fulfilled and the global index supported risks exceeding benefits. Estimated hazard ratios (HRs) (nominal 95% confidence intervals [CIs]) were as follows: CHD, 1.29 (1.02-1.63); breast cancer, 1.26 (1.00-1.59); stroke, 1.41 (1.07-1.85); PE, 2.13 (1.39-3.25); colorectal cancer, 0.63 (0.43-0.92); endometrial cancer, 0.83 (0.47-1.47); hip fracture, 0.66 (0.45-0.98), and death due to other causes, 0.92 (0.74-1.14). Corresponding HRs (nominal 95% CIs) for composite outcomes were 1.22 (1.09-1.36) for total cardiovascular disease (arterial and venous disease), 1.03 (0.90-1.17) for total cancer and 1.15 (1.03-1.28) for the global index. The HR for total fractures was 0.76 (0.69-0.85) while total mortality was unchanged [0.98 (0.82-1.18)].
In this study, the absolute excess risks per 10,000 person years attributable to estrogen plus progestin were small, i.e. 7 more cases of CHD (37 vs 30), 8 more strokes (29 vs 21), 8 more pulmonary emboli (15 vs 7) and 8 more invasive breast cancers (38 vs 30), while the absolute risk reductions per 10,000 person years were 6 fewer colorectal cancers (10 vs 16), 1 less endometrial cancer (5 vs 6), 5 fewer hip fractures (10 vs 15), 44 total fractures (147 vs 191) and one less death (52 vs 53), than in women not using that form of HRT.
The risks and benefits in women receiving treatment for the short-term management of menopausal symptoms of estrogen deficiency or for the management of premature menopause were not examined in the WHI study. As well, the study did not include other formulations, dosage regimens or routes of administration of HRT, such as Angeliq 1/2 containing estradiol and drospirenone.

Estrogen only arm of WHI study.

In 5310 postmenopausal women who received oral estrogen replacement therapy using conjugated equine estrogens (conjugated estrogens) 0.625 mg/day and 5429 women who received placebo for an average of 6.8 years, adverse effects on the cardiovascular system and the incidence of breast cancer were observed. This Women's Health Initiative (WHI) study was designed to investigate the efficacy and safety of long-term ERT in preventing coronary heart disease (CHD) in healthy postmenopausal women with hysterectomy. A global index summarising the balance of risks and benefits included an analysis of the primary outcomes CHD and primary adverse outcome, invasive breast cancer, and the following secondary outcomes: stroke, pulmonary embolism (PE), colorectal cancer, hip fracture and death due to other causes. The women enrolled in the study had a mean age at entry of 63.6 years. On average they were overweight (mean body mass index [BMI] = 30.1) and 45% were obese (BMI = ≥ 30), 50% were previous or current smokers, almost 50% had received treatment for high blood pressure and 15% had raised cholesterol levels requiring medication.
After a mean of 6.8 years of follow-up, the study was stopped because CEE did not appear to negatively affect the risk of heart disease or breast cancer but an increased risk of stroke was found. Estimated hazard ratios (HRs) (nominal 95% confidence intervals [CIs]) were as follows: CHD, 0.91 (0.75-1.12); breast cancer, 0.77 (0.59-1.01); stroke, 1.39 (1.10-1.77); PE, 1.34 (0.87-2.06); colorectal cancer, 1.08 (0.75-1.55); hip fracture, 0.61 (0.41-0.91), and death due to other causes, 1.08 (0.88-1.32). Corresponding HRs (nominal 95% CIs) for composite outcomes were 1.12 (1.01-1.24) for total cardiovascular disease (arterial and venous disease), 0.93 (0.81-1.07) for total cancer and 1.01 (0.91-1.12) for the global index. The HR for total fractures was 0.70 (0.63-0.79) while total mortality was unchanged [1.04 (0.88-1.22)].
In this study, the absolute excess risks per 10,000 person years attributable to estrogen were small, i.e. 12 more strokes (44 vs 32), 3 more pulmonary emboli (13 vs 10), 1 more colorectal cancer (17 vs 16) and 3 more deaths (81 vs 78), while the absolute risk reductions per 10,000 person years were 5 fewer cases of CHD (49 vs 54), 7 fewer invasive breast cancers (26 vs 33), 6 fewer hip fractures (11 vs 17), 56 fewer total fractures (139 vs 195), than in women not using that form of HRT.

Million women study.

The results of this study were based on follow-up of one million, eighty four thousand, one hundred and ten (1,084,110) women. The average age of the women at recruitment was 55.9 years and the average period of follow-up was 2.6 years for analyses of the cancer incidence and 4.1 years for analyses for mortality. Overall, 50% of the study population had used HRT at some point. There were nine thousand, three hundred and sixty four (9364) newly diagnosed cases of invasive breast cancer and six hundred and thirty seven (637) deaths from breast cancers. The current users of HRT at recruitment were more likely to develop breast cancer and to die from it. Past users of HRT were not at an increased risk of newly diagnosed or fatal disease. The incidence was significantly increased for current users of preparations containing estrogen only, estrogen/progestogen and tibolone but the magnitude of the associated risk was greater for the combined treatment than for any other preparation. See Table 7.
An important finding of the Million Women study was that the relative risks of breast cancer were separated from oral, transdermal and implanted estrogen only formulations.
In terms of absolute risk, after ten years' use of HRT, it is estimated that there would be 5 (95% CI 3-7) additional breast cancers per 1000 users of estrogen only preparations and 19 (95% CI 15-23) additional cancers per 1000 users of estrogen/progestogen combinations. The elevated risk reduces after discontinuation of HRT and is effectively lost after 5 years.

5.2 Pharmacokinetic Properties

Drospirenone.

Absorption.

Orally administered drospirenone is rapidly and almost completely absorbed. Maximum serum concentrations of about 21.9 and 35.9 nanogram/mL are reached about 1 hour after single and multiple ingestion of Angeliq 1/2. Pharmacokinetics of drospirenone are dose proportional within the dose range of 1 to 4 mg. Bioavailability is between 76 and 85%. The effect of food on absorption of drospirenone was not studied with Angeliq 1/2 tablets. However, a food effect study with another estrogen/drospirenone combination tablet showed that the extent of absorption (bioavailability) of drospirenone is not affected by concomitant food intake.

Distribution.

After oral administration, postmaximum serum drospirenone levels decrease in two phases with a mean terminal half-life of about 35-39 hours. Drospirenone is bound to serum albumin and does not bind to sex hormone binding globulin (SHBG) or corticoid binding globulin (CBG). Only 3-5% of the total serum drug concentrations are present as free steroid. The mean apparent volume of distribution of drospirenone is 3.7-4.2 L/kg.

Metabolism.

Drospirenone is extensively metabolised after oral administration. The major metabolites in the plasma are the acid form of drospirenone, generated by opening of the lactone ring, and the 4,5-dihydro-drospirenone-3-sulfate, formed by reduction and subsequent sulfation. Based on general knowledge of steroid metabolism, the enzymes 5α-reductase, 3-hydroxysteroid dehydrogenase and 3-hydroxysteroid sulfotransferase are involved in the formation of 4,5-dihydro-drospirenone-3-sulfate. The opening of the lactone ring is presumably catalysed by nonspecific esterases. Drospirenone is also subject to oxidative metabolism catalysed by cytochrome P450 (CYP) 3A4.

Excretion.

The total clearance of drospirenone from serum is 1.2-1.5 mL/min/kg. Drospirenone is excreted only in trace amounts in unchanged form. The metabolites of drospirenone are excreted with the faeces and urine at a ratio (faeces vs urine) of about 1.2 to 1.4. The half-life of metabolite excretion with the urine and faeces is about 40 hours.

Steady-state conditions.

Steady-state conditions are reached after about 10 days of daily treatment with Angeliq 1/2. Serum drospirenone levels accumulated by a factor of about 2 to 3 as a consequence of the ratio of terminal half-life and dosing interval.

Estradiol.

Absorption.

Following oral administration, estradiol is rapidly and completely absorbed. During the absorption and the first liver passage, estradiol undergoes extensive metabolism, thus reducing the absolute bioavailability of estrogen after oral administration to about 5% of the dose. Maximum concentrations of about 22 picogram/mL were reached 6-8 hours after single oral administration of Angeliq 1/2. The effect of food on absorption of estradiol was not studied with Angeliq 1/2 tablets. However, studies with other estradiol/progestin combination tablets showed that the bioavailability of estradiol is not affected by concomitant food intake.

Distribution.

Following oral administration of Angeliq 1/2 only gradually changing serum levels of estradiol are observed within an administration interval of 24 hours. Because of the large circulating pool of estrogen sulfates and glucuronides on the one hand and the enterohepatic recirculation on the other hand, the terminal half-life of estradiol represents a composite parameter that is dependent on all of these processes and is in the range of about 13-20 hours after oral administration.
Estradiol is bound nonspecifically to serum albumin and specifically to SHBG. Only about 1-2% of the circulating estradiol is present as free steroid, 40-45% is bound to SHBG. The apparent volume of distribution of estradiol after single intravenous administration is about 1 L/kg.

Metabolism.

Estradiol is rapidly metabolised and, besides estrone and estrone sulfate, a large number of other metabolites and conjugates are formed. Estrone and estriol are known as pharmacologically active metabolites of estradiol; only estrone occurs in relevant concentrations in plasma. At the cellular level estrogenic potency is highest for estradiol > estrone > estriol. Estrone reaches about 6-fold higher serum than estradiol. The serum levels of the estrone conjugates are about 26 times higher than the corresponding concentrations of free estrone. The formation of estrone is catalysed by 17β-hydroxysteroid dehydrogenase and estrone is further converted to estrone sulfate by 3-hydroxysteroid sulfotransferase. Several hydroxylation reactions at positions 2, 4 and 16, including the formation of estriol are catalysed by CYP enzymes of the 3A and 1A families.
Ethnic differences in the metabolism of estradiol in Caucasian women as compared to Asian or African American women were reported based on a significantly increased 16α-hydroxylation of estrone observed in Oriental or African American women.
Estradiol is mainly metabolised in the liver but in part also in the gut wall after oral administration and the target organs.

Excretion.

The total clearance has been reported to be in the range of 10 to 30 mL/min/kg, indicating that estradiol is in part also metabolised extrahepatically. Estradiol and its metabolites are excreted via urine and bile with a half-life of about 1 day.

Steady-state conditions.

Following daily oral administration of Angeliq 1/2, estradiol concentrations reached a steady state after about five days. Serum estradiol levels accumulate approximately 2-fold. With a dosing interval of 24 hours, mean steady-state serum levels of estradiol fluctuate in the range of 20-43 picogram/mL following administration of Angeliq 1/2.

Pharmacokinetics in special populations.

Hepatic dysfunction.

The pharmacokinetics of a single oral dose of 3 mg drospirenone in combination with 1 mg estradiol was evaluated in 10 female patients with moderate hepatic impairment (Child-Pugh B) and 10 healthy female subjects matched for age, weight and smoking history. Mean serum drospirenone concentration time profiles were comparable in both groups of women during the absorption/distribution phases with similar Cmax and Tmax values, suggesting that the rate of absorption was not affected by the hepatic impairment. The mean terminal half-life was about 1.8 times greater and an about 50% decrease in apparent oral clearance (CL/f) was seen in volunteers with moderate hepatic impairment as compared to those with normal liver function.

Renal insufficiency.

The effect of renal insufficiency on the pharmacokinetics of drospirenone (3 mg daily for 14 days) were investigated in female subjects with normal renal function (n = 11) and mild (n = 10) and moderate (n = 7) renal impairment. At steady state of drospirenone treatment, serum drospirenone levels in the group with mild renal impairment (creatinine clearance Clcr, 50-80 mL/min) were comparable to those in the group with normal renal function (Clcr > 80 mL/min). The serum drospirenone levels were on average 37% higher in the group with moderate renal impairment (Clcr, 30-50 mL/min) compared with those in the group with normal renal function. Linear regression analysis of the drospirenone AUC(0-24 h) values in relation to the creatinine clearance revealed a 3.5% increase with a 10 mL/min reduction of creatinine clearance. This slight increase is not expected to be of clinical relevance.

5.3 Preclinical Safety Data

Genotoxicity.

There is limited evidence available in the literature suggesting that 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 estradiol in human lymphocyte cultures. Importantly, there was no evidence of micronuclei formation in well controlled rodent bone marrow assays.
Although interactions between drospirenone and DNA of liver cells which indicate a genotoxic potential were found in vitro and in vivo studies in rats, no such finding was observed in human liver cells in vitro. Furthermore, mutagenicity tests gave no indication of a mutagenic potential of the compound. Genotoxic potential of the estradiol drospirenone combination has not been investigated.

Carcinogenicity.

Carcinogenicity studies have not been performed with the combination of drospirenone and estradiol. However, studies have been performed for estradiol and drospirenone, the active components of Angeliq 1/2. Supraphysiological doses of estradiol have been associated with the induction of tumours in estrogen dependent target organs in all rodent species tested. The relevance of these findings with respect to humans has not been established. However, it must be borne in mind that sex steroids can promote the growth of certain hormone dependent tissues and tumours.
In long-term oral carcinogenicity studies in mice and rats, drospirenone alone did not increase the incidence of neoplastic lesions. Exposure to drospirenone (based on AUC) was up to ~ 5-fold (mice) and 12-fold (rats) that anticipated in humans at the recommended clinical dose.

6 Pharmaceutical Particulars

6.1 List of Excipients

Angeliq 1/2 tablets contain the following excipients: Lactose monohydrate, maize starch, pregelatinised maize starch, povidone 25 000, magnesium stearate, hypromellose, macrogol 6000, purified talc, titanium dioxide and iron oxide red.

6.2 Incompatibilities

Incompatibilities were either not assessed or not identified as part of the registration of this medicine.

6.3 Shelf Life

The expiry date is marked on the pack.

6.4 Special Precautions for Storage

Store all medicines properly, according to the storage conditions printed on the pack and keep them out of reach of children. Store below 30°C.

6.5 Nature and Contents of Container

Transparent polyvinyl film (250 microm)/aluminium foil (20 microm) blister strips of 28 tablets.
Calendar-pack containing 1 x 7, 1 x 28, 2 x 28, 3 x 28 and 4 x 28 tablets.
Not all pack sizes may be marketed.

6.6 Special Precautions for Disposal

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

6.7 Physicochemical Properties

Estradiol.

Chemical structure.

Estradiol is estra-1,3,5(10)-triene-3, 17β-diol, the major estrogenic hormone produced by the human ovary and it has the following chemical structure:
Chemical formula: C18H24O2.
Molecular weight: 281.4.

CAS number.

50-28-2.
Estradiol exists mostly as the hemihydrate, which is a nonhygroscopic, stable solid. Estradiol is a white to almost white, crystalline powder and is practically insoluble in water. The melting point is between 173 and 180°C.

Drospirenone.

Chemical structure.

Drospirenone is a progestogen. The chemical name for drospirenone is 6β, 7β, 15β, 16β-dimethylene-3-oxo-17α-pregn-4-ene-21, 17-carbolactone and it has the following chemical structure:
Chemical formula: C24H30O3.
Molecular weight: 366.50.

CAS number.

67392-87-4.
Drospirenone is a white to off-white crystalline powder. It is freely soluble in methylene chloride, soluble in acetone, methanol, sparingly soluble in ethylacetate and ethanol 96% (v/v) and practically insoluble in hexane and water.

7 Medicine Schedule (Poisons Standard)

S4 - Prescription Only Medicine.

Summary Table of Changes