Consumer medicine information

Bijuva 1/100

Estradiol; Progesterone

BRAND INFORMATION

Brand name

Bijuva 1/100

Active ingredient

Estradiol; Progesterone

Schedule

S4

 

Consumer medicine information (CMI) leaflet

Please read this leaflet carefully before you start using Bijuva 1/100.

SUMMARY CMI

BIJUVA® 1/100

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 BIJUVA 1/100?

BIJUVA 1/100 contains the active ingredient estradiol (as hemihydrate) and progesterone. BIJUVA 1/100 is used during continuous combined hormone replacement therapy (HRT) for estrogen deficiency symptoms in postmenopausal women who still have a uterus with at least 12 months (1 year) since their last natural period.

For more information, see Section 1. Why am I using BIJUVA 1/100? in the full CMI.

2. What should I know before I use BIJUVA 1/100?

Do not use if you have ever had an allergic reaction to BIJUVA 1/100 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. BIJUVA 1/100 is only for use in postmenopausal women who still have a uterus.

For more information, see Section 2. What should I know before I use BIJUVA 1/100? in the full CMI.

3. What if I am taking other medicines?

Some medicines may interfere with BIJUVA 1/100 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 BIJUVA 1/100?

  • BIJUVA 1/100 should be taken at the same time every day in the evening, to ensure it works effectively. Follow all instructions given to you by your doctor.

More instructions can be found in Section 4. How do I use BIJUVA 1/100? in the full CMI.

5. What should I know while using BIJUVA 1/100?

Things you should do
  • Remind any doctor, dentist or pharmacist you visit that you are using BIJUVA 1/100.
  • Monitor your health and contact your doctor if you notice any changes.
  • Keep all of your doctor's appointments and go for regular check-ups.
Things you should not do
  • Do not stop using this medicine suddenly without telling your doctor.
Driving or using machines
  • BIJUVA 1/100 is not expected to affect your ability to drive or operate machinery. If you experience any side effects which impact your ability to drive or operate machinery when taking this medicine, act appropriately and contact your doctor.
Drinking alcohol
  • Alcohol is not expected to interact with BIJUVA 1/100. If you drink alcohol, talk to your doctor about the possible effects of taking alcohol with this medicine.
Looking after your medicine
  • Store BIJUVA 1/100 in a cool dry place, out of direct light, where the temperature is below 25°C.
  • Keep BIJUVA 1/100 in the original packaging, in a safe place, away from children.

For more information, see Section 5. What should I know while using BIJUVA 1/100? in the full CMI.

6. Are there any side effects?

The most common side effects are breast tenderness, headache, vaginal bleeding, vaginal discharge, and pelvic pain. Serious side effects include heart attack, stroke, blood clots, breast cancer, ovarian cancer, cancer of the womb, gall bladder disease and dementia.

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 hysterectomised 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

BIJUVA® 1/100

Active ingredient(s): estradiol (as hemihydrate) and progesterone

Consumer Medicine Information (CMI)

This leaflet provides important information about using BIJUVA 1/100. 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 BIJUVA 1/100.

Where to find information in this leaflet:

1. Why am I using BIJUVA 1/100?
2. What should I know before I use BIJUVA 1/100?
3. What if I am taking other medicines?
4. How do I use BIJUVA 1/100?
5. What should I know while using BIJUVA 1/100?
6. Are there any side effects?
7. Product details

1. Why am I using BIJUVA 1/100?

BIJUVA 1/100 contains the active ingredients estradiol (as hemihydrate) and progesterone. BIJUVA 1/100 is a Hormone Replacement Therapy (HRT).

BIJUVA 1/100 is used during continuous combined hormone replacement therapy (HRT) for estrogen deficiency symptoms in postmenopausal women who still have a uterus with at least 12 months (1 year) since their last natural period.

BIJUVA 1/100 contains two types of female hormones, an estrogen and a progestogen. During menopause, the amount of estrogen produced by a woman's body drops. This can cause symptoms such as hot face, neck and chest (“hot flushes”). BIJUVA 1/100 alleviates these symptoms after menopause.

2. What should I know before I use BIJUVA 1/100?

Warnings

Do not use BIJUVA 1/100 if:

  • you are allergic to estradiol or progesterone, or any of the ingredients listed in Section 7. Always check the ingredients to make sure you can use this medicine.
  • you have or have ever had breast cancer, or if you are suspected of having it
  • you have cancer which is sensitive to estrogens, such as cancer of the womb lining (endometrium), or if you are suspected of having it
  • you have any unexplained vaginal bleeding
  • you have excessive thickening of the womb lining (endometrial hyperplasia) that is not being treated
  • you have or have ever had a blood clot in a vein (thrombosis), such as in the legs (deep venous thrombosis) or the lungs (pulmonary embolism)
  • you have a blood clotting disorder (such as protein C, protein S, or antithrombin deficiency)
  • you have or recently have had a disease caused by blood clots in the arteries, such as a heart attack, stroke, or angina
  • you have or have ever had a liver disease and your liver function tests have not returned to normal
  • you have a rare blood problem called “porphyria” which is passed down in families (inherited)

If any of the above conditions appear for the first time while taking BIJUVA 1/100, stop taking it at once and consult your doctor immediately.

Check with your doctor if you:

  • have any other medical conditions
  • take any medicines for any other condition

If you have had any of the following conditions, tell your doctor before starting BIJUVA 1/100 as these may return or become worse during treatment with this medicine:

  • fibroids inside your womb
  • growth of womb lining outside your womb (endometriosis) or a history of excessive growth of the womb lining (endometrial hyperplasia)
  • increased risk of developing blood clots (see “Blood clots in a vein (thrombosis)”)
  • increased risk of getting an estrogen-sensitive cancer (such as having a mother, sister or grandmother who has had breast cancer)
  • high blood pressure
  • a liver disorder, such as a benign liver tumour
  • diabetes
  • gallstones
  • migraine or severe headaches
  • a disease of the immune system that affects many organs of the body (systemic lupus erythematosus, SLE)
  • epilepsy
  • asthma
  • a disease affecting the eardrum and hearing (otosclerosis)
  • a very high level of fat in your blood (triglycerides)
  • fluid retention due to cardiac or kidney problems
  • hereditary or acquired angioedema.

During treatment, you may be at risk of developing certain side effects. It is important you understand these risks and how to monitor for them. See additional information under Section 6. Are there any side effects?

Pregnancy and breastfeeding

BIJUVA 1/100 is for use in postmenopausal women only. If you become pregnant, stop taking BIJUVA 1/100 and contact your doctor.

HRT and cancer

Excessive thickening of the lining of the womb (endometrial hyperplasia) and cancer of the lining of the womb (endometrial cancer)

  • Taking estrogen-only HRT will increase the risk of excessive thickening of the lining of the womb (endometrial hyperplasia) and cancer of the womb lining (endometrial cancer).
  • The progestogen in BIJUVA 1/100 protects you from this extra risk.

Irregular bleeding

You may have irregular bleeding or drops of blood (spotting) during the first 3-6 months of taking BIJUVA 1/100. However, if the irregular bleeding:

  • carries on for more than the first 6 months
  • starts after you have been taking BIJUVA 1/100 for more than 6 months
  • carries on after you have stopped taking BIJUVA 1/100

See your doctor as soon as possible.

Breast cancer

Evidence shows that taking combined estrogen-progestogen or estrogen-only hormone-replacement-therapy (HRT) increases the risk of breast cancer. The extra risk depends on how long you use HRT. The additional risk becomes clear within 3 years of use. After stopping HRT, the extra risk will decrease with time, but the risk may persist for 10 years or more if you have used HRT for more than 5 years.

Compare

Women aged 50 to 54 who are not taking HRT, on average, 13 to 17 in 1000 will be diagnosed with breast cancer over a 5-year period.

For women aged 50 who start taking estrogen-only HRT for 5 years, there will be 16-17 cases in 1000 users (i.e., an extra 0 to 3 cases).

For women aged 50 who start taking estrogen-progestogen HRT for 5 years, there will be 13 to 21 cases in 1000 users (i.e., an extra 4 to 8 cases).

Women aged 50 to 59 who are not taking HRT, on average, 27 in 1000 will be diagnosed with breast cancer over a 10-year period.

For women aged 50 who start taking estrogen-only HRT for 10 years, there will be 34 cases in 1000 users (i.e., an extra 7 cases)

For women aged 50 who start taking estrogen-progestogen HRT for 10 years, there will be 48 cases in 1000 users (i.e., an extra 21 cases).

Regularly check your breasts. See your doctor if you notice any changes such as:

  • dimpling of the skin
  • changes in the nipple
  • any lumps you can see or feel

Additionally, you are advised to join mammography screening programs when offered to you. For mammogram screening, it is important that you inform the nurse/healthcare professional who is actually taking the x-ray that you use HRT, as this medication may increase the density of your breasts which may affect the outcome of the mammogram. Where the density of the breast is increased, mammography may not detect all lumps.

Ovarian cancer

Ovarian cancer is much rarer than breast cancer. The use of estrogen-only or combined estrogen-progestogen HRT has been associated with a slightly increased risk of ovarian cancer. The risk of ovarian cancer varies with age. For example, 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. For women who have been taking HRT for 5 years, there will be about 3 cases per 2000 users (i.e., about 1 extra case).

Effect of HRT on heart and circulation Blood clots in a vein (thrombosis)

The risk of blood clots in the veins is about 1.3 to 3 times higher in HRT users than in non-users, especially during the first year of taking it. Blood clots can be serious, and if one travels to the lungs, it can cause chest pain, breathlessness, fainting or even death.

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

  • you are unable to walk for a long time because of major surgery, injury, or illness
  • you are seriously overweight (BMI >30 kg/m2)
  • you have any blood clotting problem that needs long-term treatment with a medicine used to prevent blood clots
  • if any of your close relatives has ever had a blood clot in the leg, lung, or any other organ
  • you have systemic lupus erythematosus (SLE)
  • you have cancer

Compare

Looking at women in their 50s who are not taking HRT, on average, over a 5-year period, 4 to 7 in 1000 would be expected to get a blood clot in a vein.

For women in their 50s who have been taking estrogen-progestogen HRT for over 5 years, there will be 9 to 12 cases in 1000 users (i.e., an extra 5 cases).

Stroke

The risk of having a stroke is about 1.5 times higher in HRT users than in non-users. The number of extra cases of stroke due to use of HRT will increase with age.

Compare

Looking at women in their 50s who are not taking HRT, on average, 8 in 1000 would be expected to have a stroke over a 5-year period.

For women in their 50s who are taking HRT, there will be 11 cases in 1000 users, over 5 years (i.e., an extra 3 cases).

3. What if I am taking other medicines?

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

Some medicines may interfere with BIJUVA 1/100 and affect how it works. This may lead to irregular bleeding. This applies to the following medicines:

  • medicines for epilepsy (such as phenobarbital, phenytoin, and carbamazepine)
  • medicines for tuberculosis (such as rifampicin, rifabutin)
  • medicines for HIV infection (such as nevirapine, efavirenz, ritonavir and nelfinavir)
  • herbal remedies containing St John's Wort (Hypericum perforatum)
  • bromocriptine used for problems with the pituitary gland or Parkinsons disease
  • ketoconazole, griseofulvin (used for fungal infections)
  • ciclosporin (used to suppress the immune system)
  • lamotrigine (used to control seizures)

Check with your doctor or pharmacist if you are not sure about what medicines, vitamins or supplements you are taking and if these affect BIJUVA 1/100.

4. How do I use BIJUVA 1/100?

How much to take

  • Take one capsule every day in the evening.
  • Follow the instructions provided and use BIJUVA 1/100 until your doctor tells you to stop.

Your doctor will aim to prescribe the lowest dose to treat your symptom for as short as necessary. Speak to your doctor if you think this dose is too strong or not strong enough.

When to take BIJUVA 1/100

  • BIJUVA 1/100 should be taken every day in the evening.

How to take BIJUVA 1/100

  • Capsules should be taken with food and swallowed with water.

If you forget to use BIJUVA 1/100

BIJUVA 1/100 should be used regularly at the same time each day. If you miss your dose at the usual time, take it as soon as you remember.

If more than 12 hours have lapsed, skip the missed dose.

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

If you use too much BIJUVA 1/100

If you think that you have used too much BIJUVA 1/100, 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 BIJUVA 1/100?

Things you should do

Keep all of your doctor's appointments and become familiar with potential risks associated when taking combined hormone replacement therapy.

Call your doctor straight away if you:

  • have yellowing of your skin or the whites of your eyes (jaundice). These may be signs of a liver disease
  • have swelling in your face, tongue and/or throat and/ or difficulty swallowing or hives, together with difficulty breathing as this is suggestive of an angioedema
  • have a large rise in your blood pressure (symptoms may be headache, tiredness, dizziness)
  • have migraine-like headaches which happen for the first time
  • become pregnant
  • notice signs of a blood clot, such as:
    - painful swelling and redness of the legs;
    - sudden chest pain;
    - difficulty in breathing;
    For more information, see Blood clots in a vein (thrombosis)
  • have a very high level of fat in your blood (triglycerides)
  • have fluid retention due to cardiac or kidney problems

Remind any doctor or dentist you visit that you are using BIJUVA 1/100.

Things you should not do

  • Do not take BIJUVA 1/100 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.

Driving or using machines

Be careful before you drive or use any machines or tools until you know how BIJUVA 1/100 affects you.

BIJUVA 1/100 is not expected to affect your ability to drive or operate machinery. If you experience any side effects which impact your ability to drive or operate machinery when taking this medicine, act appropriately and contact your doctor.

Drinking alcohol

Tell your doctor if you drink alcohol.

Alcohol is not expected to interact with BIJUVA 1/100. If you drink alcohol, talk to your doctor about the possible effects of taking alcohol with this medicine.

Looking after your medicine

Follow the instructions in the carton on how to take care of your medicine properly.

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

Store BIJUVA 1/100 in a cool dry place below 25°C, 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
  • irregular vaginal bleeding or spotting (if bleeding is heavy, check with your doctor as soon as possible)
  • tender, painful, or swollen breasts or painful nipples
  • vaginal itching, burning sensation, inflammation, or fluid discharge (white or yellowish discharge)
  • infection of the ear
  • swelling of the lower legs, ankles, fingers, or abdomen due to fluid retention
  • muscle spasms or pain, pain in extremities or joints
  • nausea (feeling sick), abdominal cramps, vomiting, heartburn, wind, diarrhoea, constipation
  • loss of smell or taste
  • weakness or dizziness
  • headaches
  • hair loss or excessive growth of hair (hirsutism)
  • back pain, pain in the pelvic region
  • hot flushes
  • change in sex drive
  • depression, nervousness, changes in mood, difficulty sleeping or abnormal dreams
  • disturbance in attention, memory loss
  • loss of coordination
  • visual impairment, blurred vision
  • numbness or tingling in an arm or leg
  • benign breast or uterine tumour (cysts in uterus),
  • vertigo
  • excessive eating
  • weight gain or weight loss
  • acne, itchy or dry skin, skin discolouration
  • dry mouth
  • rash or appearance of red lines on the skin
  • pain in extremity (e.g. back pain, arms, legs, wrists, ankles)
  • high blood pressure
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
  • sudden signs of allergy such as rash, itching or hives on the skin, swelling of face, lips, tongue or other parts of the body, shortness of breath, wheezing or trouble breathing
  • pain or tenderness in the abdomen, which may be accompanied by fever, loss of appetite, nausea, and vomiting
  • blood clots in the veins of the legs or lungs (venous thromboembolism)
  • breast cancer
  • stroke
  • slurred speech
  • itching, dark coloured urine
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 BIJUVA 1/100 contains

Active ingredient
(main ingredient)		Estradiol (as hemihydrate) and progesterone
Other ingredients
(inactive ingredients)		Capsule content contains:
  • Mono di-glycerides
  • Lauroyl Macrogolglycerides

Capsule shell contains:

  • Gelatin
  • Hydrolyzed gelatin
  • Glycerol
  • Opatint® Red DG-15001(PI-141454)
  • Opatint® Concentrated Colour Dispersion G-18006 (PI-140158)

Printing ink:

  • Opacode® WB water based Monogramming Ink NSP-78-18022 White (PI 3883)

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

What BIJUVA 1/100 looks like

BIJUVA 1/100 1 mg/100 mg capsules

BIJUVA 1/100 is presented in PVC/PE/PCTFE Aluminium backed blister strips containing either 14 or 28 soft gel capsules.

The blister strips are packed in a carton to protect BIJUVA 1/100 from light.

  • The 28-pack carton contains either 1 blister strip with 28 soft gel capsules or 2 blister strips each containing 14 soft gel capsules.
  • The 84-pack carton contains either 3 blister strips each containing 28 soft gel capsules or 6 blister strips each containing 14 soft gel capsules.

All packs contain a Consumer Medicines Information leaflet.

BIJUVA 1/100 soft gel capsules are opaque, light pink on one side and dark pink on the other, imprinted with “1C1” in white ink. Capsules are approximately 5.2-6 mm in size.

Australian Registration Number

AUST R 367690

Who distributes BIJUVA 1/100

Theramex Australia Pty Ltd
Level 22, 60 Margaret Street,
Sydney NSW 2000
1800 THERAMEX or 1800 843 726

This leaflet was updated in August 2024

Published by MIMS October 2024

BRAND INFORMATION

Brand name

Bijuva 1/100

Active ingredient

Estradiol; Progesterone

Schedule

S4

 

1 Name of Medicine

Estradiol (as hemihydrate) and progesterone.

2 Qualitative and Quantitative Composition

Each soft capsule contains 1 mg of estradiol (as hemihydrate) and 100 mg of progesterone.
For the full list of excipients, see Section 6.1 List of Excipients.

3 Pharmaceutical Form

Soft capsule.
Bijuva 1/100 soft capsules are oval and opaque, light pink on one side and dark pink on the other side with the marking "1C1" printed in white ink.
Capsules are oval and approximately 5.2 - 6 mm in size.

4 Clinical Particulars

4.1 Therapeutic Indications

Bijuva 1/100 is indicated for use during continuous combined hormone replacement therapy (HRT) for estrogen deficiency symptoms in postmenopausal women with an intact uterus and with at least 12 months since last menses.

4.2 Dose and Method of Administration

Bijuva 1/100 is a combined HRT. The recommended oral dose for the initiation and continuation of treatment of postmenopausal symptoms should be the lowest effective dose, taken for the shortest duration (also see Section 4.4 Special Warnings and Precautions for Use). Take one capsule each evening with food.
Continuous combined treatment may be started with Bijuva 1/100 depending on the time since menopause and severity of symptoms. Women experiencing a natural menopause should commence treatment with Bijuva 1/100 12 months after their last natural menstrual bleed. For surgically induced menopause, treatment may start immediately. Patients changing from a continuous sequential or cyclical preparation should complete the 28-day cycle and then change to Bijuva 1/100.

Management of missed capsules.

If a dose has been forgotten, it should be taken as soon as possible. If more than 12 hours have elapsed, treatment should be continued with the next capsule without taking the forgotten capsule. The likelihood of breakthrough bleeding or spotting may be increased.

Special patient groups.

Patients changing from another continuous combined preparation may start therapy at any time.
Bijuva 1/100 is not indicated for use in children.
Experience in treating women > 65 years with Bijuva 1/100 is limited.

4.3 Contraindications

Bijuva 1/100 is contradicted in patients with:
known, past or suspected breast cancer;
known or suspected estrogen-dependent malignant tumours (e.g. endometrial cancer);
undiagnosed genital bleeding;
untreated endometrial hyperplasia;
previous or current venous thromboembolism (deep vein thrombosis, pulmonary embolism);
known thrombophilic disorders (e.g. protein C, protein S, or antithrombin deficiency, see Section 4.4 Special Warnings and Precautions for Use);
active or recent arterial thromboembolic disease (e.g. angina, myocardial infarction);
acute liver disease or a history of liver disease as long as liver function tests have failed to return to normal;
porphyria;
known hypersensitivity to the active substances or to any of the excipients.

4.4 Special Warnings and Precautions for Use

General.

Bijuva 1/100 is indicated for the treatment of postmenopausal symptoms, HRT should only be initiated for symptoms that adversely affect quality of life. In all cases, a careful appraisal of the risks and benefits should be undertaken at least annually, and HRT should only be continued if the benefit outweighs the risk.
Evidence regarding the risks associated with HRT in the treatment of premature menopause is limited. Due to the low level of absolute risk in younger women, however, the balance of benefits and risks for these women may be more favourable than in older women.

Identified precautions.

Medical examination/follow up. Before initiating or reinstituting HRT, a complete personal and family medical history should be taken. Physical (including pelvic and breast) examination should be guided by this and by the contraindications and warnings for use. During treatment, periodic check-ups are recommended of a frequency and nature adapted to the individual woman. Women should be advised what changes in their breasts should be reported to their doctor or nurse (see Breast cancer risk below). Investigations, including appropriate imaging tools, e.g. mammography, should be carried out in accordance with currently accepted screening practices, modified to the clinical needs of the individual.
Conditions requiring supervision. If any of the following conditions are present, have occurred previously, and/or have been aggravated during pregnancy or previous hormone treatment, the patient should be closely supervised. It should be taken into account that these conditions may recur or be aggravated during treatment with Bijuva 1/100, in particular: leiomyoma (uterine fibroids) or endometriosis; risk factors for thromboembolic disorders (see below); risk factors for estrogen-dependent tumours (e.g. 1st degree heredity for breast cancer); hypertension; liver disorders (e.g. liver adenoma); diabetes mellitus with or without vascular involvement; cholelithiasis; migraine or (severe) headache; systemic lupus erythematosus; a history of endometrial hyperplasia (see below); epilepsy; asthma; otosclerosis.
Reasons for immediate withdrawal of therapy. Therapy should be discontinued in cases where a contraindication is discovered and in the following situations:
Jaundice or deterioration in liver function; significant increase in blood pressure; new onset of migraine-type headache; pregnancy.
Endometrial hyperplasia and carcinoma. In women with an intact uterus the risk of endometrial hyperplasia and carcinoma is increased when estrogens are administered alone for prolonged periods. The reported increase in endometrial cancer risk among estrogen-only users varies from 2- to 12-fold greater compared with non-users, depending on the duration of treatment and estrogen dose (see Section 4.8, Endometrial cancer). After stopping treatment risk may remain elevated for at least 10 years.
The addition of a progestogen cyclically for at least 12 days per month/28-day cycle or continuous combined estrogen-progestogen therapy in non-hysterectomised women prevents the excess risk associated with estrogen-only HRT.
Break-through bleeding and spotting may occur during the first months of treatment. If break-through bleeding or spotting appears after some time on therapy, or continues after treatment has been discontinued, the reason should be investigated, which may include endometrial biopsy to exclude endometrial malignancy.
Breast cancer. The overall evidence shows an increased risk of breast cancer in women taking combined estrogen-progestogen or also estrogen-only HRT, that is dependent on the duration of taking HRT.

Combined estrogen-progestogen therapy.

The randomised placebo-controlled trial the (Women's Health Initiative study (WHI), and a meta-analysis of prospective epidemiological studies are consistent in finding an increased risk of breast cancer in women taking combined estrogen-progestogen for HRT that becomes apparent after about 3 (1-4) years (see Section 4.8, Breast cancer risk).
In a one year trial, among 1,684 women who received a combination of estradiol plus progesterone (1 mg estradiol plus 100 mg progesterone or 0.5 mg estradiol plus 100 mg progesterone or 0.5 mg estradiol plus 50 mg progesterone or 0.25 mg estradiol plus 50 mg progesterone) or placebo (n = 151), six new cases of breast cancer were diagnosed, two of which occurred among the group of 424 women treated with Bijuva (estradiol and progesterone) capsules, 0.5 mg/100 mg, and two of which occurred among the group of 415 women treated with Bijuva (estradiol and progesterone) capsules, 1 mg/100 mg. No new cases of breast cancer were diagnosed in the group of 151 women treated with placebo.

Estrogen-only therapy.

The WHI trial found no increase in the risk of breast cancer in hysterectomised women using estrogen-only HRT. Observational studies have mostly reported a small increase in risk of having breast cancer diagnosed that is lower than that found in users of estrogen-progestogen combinations (see Section 4.8, Breast cancer risk).
Results from a large meta-analysis showed that after stopping treatment, the excess risk will decrease with time and the time needed to return to baseline depends on the duration of prior HRT use. When HRT was taken for more than 5 years, the risk may persist for 10 years or more.
HRT, especially estrogen-progestogen combined treatment, increases the density of mammographic images which may adversely affect the radiological detection of breast cancer.
Ovarian cancer. Ovarian cancer is much rarer than breast cancer. Epidemiological evidence from a large meta-analysis suggests a slightly increased risk in women taking estrogen-only or combined estrogen-progestogen HRT, which becomes apparent within 5 years of use and diminishes over time after stopping. Some other studies including the WHI trial suggest that use of combined HRTs may be associated with a similar or slightly smaller risk (see Section 4.8, Ovarian cancer).
Venous thromboembolism. HRT is associated with a 1.3 to 3-fold risk of developing venous thromboembolism (VTE), i.e. deep vein thrombosis or pulmonary embolism. The occurrence of such an event is more likely in the first year of HRT than later.
Patients with known thrombophilic states have an increased risk of VTE and HRT may add to this risk. HRT is therefore contraindicated in these patients (see Section 4.3 Contraindications).
Generally recognised risk factors for VTE include, use of estrogens, older ages, major surgery, prolonged immobilisation, obesity (BMI > 30 kg/m2), pregnancy/postpartum period, systemic lupus erythematosus (SLE), and cancer. There is no consensus about the possible role of varicose veins in VTE.
As in all postoperative patients, prophylactic measures need to be considered to prevent VTE following surgery. If prolonged immobilisation is to follow elective surgery temporarily stopping HRT 4 to 6 weeks earlier is recommended. Treatment should not be restarted until the woman is completely mobilised.
In women with no personal history of VTE but with a first degree relative with a history of thrombosis at young age, screening may be offered after careful counselling regarding its limitations (only a proportion of thrombophilic defects are identified by screening). If a thrombophilic defect is identified which segregates with thrombosis in family members or if the defect is 'severe' (e.g. antithrombin, protein S, or protein C deficiencies or a combination of defects) HRT is contraindicated.
Women already on chronic anticoagulant treatment require careful consideration of the benefit-risk use of HRT.
If VTE develops after initiating therapy, the drug should be discontinued. Patients should be told to contact their doctors immediately when they are aware of a potential thromboembolic symptom (e.g. painful swelling of a leg, sudden pain in the chest, dyspnoea).
Coronary artery disease (CAD). There is no evidence from randomised controlled trials of protection against myocardial infarction in women with or without existing CAD who received combined estrogen-progestogen or estrogen-only HRT.

Combined estrogen-progestogen therapy.

The relative risk of CAD during use of combined estrogen and progestogen HRT is slightly increased. As the baseline absolute risk of CAD is strongly dependent on age, the number of extra cases of CAD due to estrogen and progestogen use is very low in healthy women close to menopause but will rise with more advanced age.

Estrogen-only.

Randomised controlled data found no increased risk of CAD in hysterectomised women using estrogen-only therapy.
Ischaemic stroke. Combined estrogen-progestogen and estrogen-only therapy are associated with an up to 1.5-fold increase in risk of ischaemic stroke. The relative risk does not change with age or time since menopause. However, as the baseline risk of stroke is strongly age-dependent, the overall risk of stroke in women who use HRT will increase with age (see Section 4.8, Risk of ischaemic stroke).
Thyroid hormone levels. Estrogens increase thyroid binding globulin (TBG), leading to increased circulating total thyroid hormone, as measured by protein-bound iodine (PBI), T4 levels (by column or by radioimmunoassay) or T3 levels (by radioimmunoassay). T3 resin uptake is decreased, reflecting the elevated TBG. Serum concentrations of free T4 and T3 are unaltered. Other binding proteins may be elevated in serum, i.e. corticoid binding globulin (CBG), sex-hormone-binding globulin (SHBG) leading to increased circulating corticosteroids and sex steroids, respectively. Free or biological active hormone concentrations are unchanged. Other plasma proteins may be increased (angiotensinogen/renin substrate, alpha-1-antitrypsin, ceruloplasmin).

Other conditions.

Exogenous estrogens may induce or exacerbate symptoms of hereditary and acquired angioedema.

Use in renal impairment.

Estrogens may cause fluid retention, and therefore patients with cardiac or renal dysfunction should be carefully observed. Women with pre-existing hypertriglyceridemia should be followed closely during estrogen replacement or hormone replacement therapy, since rare cases of large increases of plasma triglycerides leading to pancreatitis have been reported with estrogen therapy in this condition.

Use in the elderly.

Clinical experience is limited in patients above 65 years of age. HRT use does not improve cognitive function. There is some evidence of increased risk of developing dementia in women who start using continuous combined or estrogen-only HRT after the age of 65.

Paediatric use.

Bijuva 1/100 is not indicated for use in paediatric populations, therefore, the safety and efficacy of estrogen and progesterone in patients under the age of 18 years have not been established.

Effects on laboratory tests.

No formal studies on the effects on laboratory tests have been conducted with Bijuva 1/100. The use of sex steroids may influence the results of certain laboratory tests, including biochemical parameters of liver, thyroid, adrenal, endocrine 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

No formal drug interaction studies have been conducted with Bijuva 1/100. However, the drug-drug interactions of estradiol and progesterone have been extensively studied and are well established. Both estrogens and progesterone are metabolised via cytochrome P450 (CYP450).

Effects of other medicinal products on Bijuva 1/100.

The metabolism of estrogens and progestogens may be increased by concomitant use of substances known to induce drug-metabolizing enzymes, specifically cytochrome P450 enzymes, such as anticonvulsants (e.g. phenobarbital, phenytoin, carbamazepine) and e.g. rifampicin, rifabutin, nevirapine, efavirenz, and griseofulvin. Herbal preparations containing St John's wort (Hypericum perforatum) may induce the metabolism of estrogens and progestogens.
Ritonavir and nelfinavir, although known as strong inhibitors, by contrast exhibit inducing properties when used concomitantly with steroid hormones.
Clinically, an increased metabolism of estrogens and progestogens may lead to decreased effect and changes in the uterine bleeding profile.
Ketoconazole and other inhibitors of CYP450-3A4 may increase bioavailability of progesterone. Such interactions may increase the incidence of adverse effects such as nausea, breast tenderness, headaches associated with progesterone.

Effects of Bijuva 1/100 on other medicinal products.

Hormone contraceptives containing estrogens have been shown to significantly decrease plasma concentrations of lamotrigine when co-administered due to induction of lamotrigine glucuronidation. This may reduce seizure control. Although the potential interaction between hormone replacement therapy and lamotrigine has not been studied, it is expected that a similar interaction exists, which may lead to a reduction in seizure control among women taking both medicinal products together.
Progesterone may raise the plasma concentration of ciclosporin.

4.6 Fertility, Pregnancy and Lactation

Effects on fertility.

Bijuva 1/100 is not indicated for use in women with childbearing potential.
(Category D)
Bijuva 1/100 is not indicated during pregnancy. If pregnancy occurs during medication with Bijuva 1/100 treatment should be withdrawn immediately.
In animal studies, maternal administration of high doses of estrogens has produced urogenital malformations in the offspring. The relevance of these animal findings for the clinical use of estradiol is uncertain, but is considered likely to be low. Animal studies have also shown that high doses of progestogens can cause masculinisation of the female fetus.
The results of most epidemiological studies to date relevant to inadvertent fetal exposure to combinations of estrogens and progestogens indicate no teratogenic or fetotoxic effect.
There are no adequate data from the use of estradiol/progesterone in pregnant women.
 Bijuva 1/100 is not indicated for use during lactation.

4.7 Effects on Ability to Drive and Use Machines

Bijuva 1/100 does not affect the patient's ability to drive or operate machinery. Patients experiencing medicine-related symptoms should be advised not to drive or use machines until symptoms resolve completely.

4.8 Adverse Effects (Undesirable Effects)

Summary of the safety profile.

The most reported related adverse drug reactions for Bijuva 1/100 in clinical trials were breast tenderness (10.4%), headache (3.4%), nausea (2.2%), pelvic pain (3.1%), vaginal haemorrhage (3.4%), and vaginal discharge (3.4%) (see Table 1).

Tabulated list of adverse reactions.

Clinical trial data.

The safety of estradiol and progesterone capsules was assessed in a 1-year, Phase 3 trial that included 1,835 postmenopausal women (1684 were treated with estradiol and progesterone capsules once daily and 151 women received placebo). Most women (~70%) in the active treatment groups were treated for ≥ 326 days (see Table 2).

Breast cancer risk.

An up to 2-fold increased risk of having breast cancer diagnosed is reported in women taking combined estrogen-progestogen therapy for more than 5 years (see Table 4 and Table 5).
The increased risk in users of estrogen-only therapy is lower than that seen in users of estrogen-progestogen combinations (see Table 3).
The level of risk is dependent on the duration of use (see Section 4.4 Special Warnings and Precautions for Use).

Endometrial cancer.

Postmenopausal women with a uterus.

The endometrial cancer risk is about 5 in every 1000 women with a uterus not using HRT.
In women with a uterus, use of estrogen-only HRT is not recommended because it increases the risk of endometrial cancer (see Section 4.4 Special Warnings and Precautions for Use).
Depending on the duration of estrogen-only use and estrogen dose, the increase in risk of endometrial cancer in epidemiology studies varied from between 5 and 55 extra cases diagnosed in every 1000 between the ages of 50 and 65.
Adding a progestogen to estrogen-only therapy for at least 12 days per cycle can prevent this increased risk. In the Million Women Study the use of five years of combined (sequential or continuous) HRT did not increase risk of endometrial cancer (R.R of 1.0 (0.8-1.2)).
Endometrial hyperplasia (a possible precursor of endometrial cancer) has been reported to occur at a rate of approximately 1 percent or less with Bijuva 1/100 (estradiol and progesterone) capsules, 1 mg/100 mg (see Section 5.1 Pharmacodynamic Properties).

Ovarian cancer.

Use of estrogen-only or combined estrogen-progestogen HRT has been associated with a slightly increased risk of having ovarian cancer diagnosed (see Section 4.4 Special Warnings and Precautions for Use).
A meta-analysis from 52 epidemiological studies reported an increased risk of ovarian cancer in women currently using HRT compared to women who have never used HRT (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.

Risk of venous thromboembolism.

HRT is associated with a 1.3-3-fold increased relative risk of developing venous thromboembolism (VTE), i.e. deep vein thrombosis or pulmonary embolism. The occurrence of such an event is more likely in the first year of using HRT (see Section 4.4 Special Warnings and Precautions for Use). Results of the WHI studies are presented in Table 6.

Risk of coronary artery disease.

The risk of coronary artery disease is slightly increased in users of combined estrogen-progestogen HRT over the age of 60 (see Section 4.4 Special Warnings and Precautions for Use).

Risk of ischaemic stroke.

The use of estrogen-only and estrogen + progestogen therapy is associated with an up to 1.5-fold increased relative risk of ischaemic stroke. The risk of haemorrhagic stroke is not increased during use of HRT (see Table 7).
This relative risk is not dependent on age or on duration of use, but as the baseline risk is strongly age-dependent, the overall risk of stroke in women who use HRT will increase with age (see Section 4.4 Special Warnings and Precautions for Use).

Other adverse reactions.

Other adverse effects have been reported in association with oestrogen/progestagen treatment:
Gall bladder disease.
Skin and subcutaneous disorders: chloasma, erythema multiforme, erythema nodosum, vascular purpura.
Probable dementia over the age of 65 (see Section 4.4 Special Warnings and Precautions for Use).
Exacerbation of symptoms of angioedema in women with hereditary and acquired angioedema.

Reporting suspected adverse events.

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

There is little experience with overdose in human clinical trials. Both estradiol and progestogen are substances with low toxicity. Symptoms such as nausea, vomiting, breast tenderness, dizziness, abdominal pain, drowsiness/fatigue, and withdrawal bleeding could occur in cases of overdosing. It is unlikely that any specific or symptomatic treatment will be necessary.
Treatment of overdose should consist of general supportive measures.
For information on the management of overdose, contact the Poisons Information Centre on 13 11 26 (Australia).

5 Pharmacological Properties

5.1 Pharmacodynamic Properties

The ATC code is G03FA04 progesterone and estrogen.

Mechanism of action.

Estradiol.

The active ingredient, synthetic 17β-estradiol, is chemically and biologically identical to endogenous human estradiol. It substitutes for the loss of estrogen production in menopausal women and alleviates menopausal symptoms.

Progesterone.

The active ingredient, progesterone is a natural progestogen, that is chemically and biologically identical to endogenous human progesterone. As estrogens promote the growth of the endometrium, unopposed estrogens increase the risk of endometrial hyperplasia and cancer. The addition of a progestogen greatly reduces the estrogen-induced risk of endometrial hyperplasia in non-hysterectomised women.

Clinical trials.

The effectiveness and safety of Bijuva 1/100 (estradiol and progesterone) capsules, 1 mg/100 mg, on moderate to severe vasomotor symptoms (hot flushes) due to menopause were examined in a 12-week randomized, double-blind, placebo-controlled substudy of a single 52-week safety study. A total of 726 postmenopausal women were randomized to multiple dose combinations of estradiol and progesterone, and placebo; these women were 40 to 65 years of age (mean 54.6 years) and had at least 50 moderate to severe vasomotor symptoms per week at baseline. The mean number of years since last menstrual period was 5.9 years, with all women undergoing natural menopause. The primary efficacy population consisted of women who self-identified their race as: White (67%), Black/African American (31%), and "Other" (2.1%). In the substudy evaluating effects on moderate to severe vasomotor symptoms, a total of 141 women received Bijuva 1/100 (estradiol and progesterone) capsules, 1 mg/100 mg, and 135 women received placebo.
The evaluated co-primary efficacy endpoints included: 1. mean weekly reduction in frequency of moderate to severe vasomotor symptoms with Bijuva 1/100 compared to placebo at Weeks 4 and 12; a clinically meaningful threshold for the reduction in frequency of vasomotor symptoms, defined as 14 vasomotor symptoms per week above placebo, was applied, and 2. mean weekly reduction in severity of moderate to severe vasomotor symptoms with Bijuva 1/100 compared to placebo at Weeks 4 and 12.
Overall, Bijuva 1/100 (estradiol and progesterone) capsules, 1 mg/100 mg, statistically significantly reduced both the frequency and severity of moderate to severe vasomotor symptoms from baseline compared with placebo at Weeks 4 and 12. A clinically meaningful threshold of a reduction of 14 vasomotor symptoms per week above placebo was not demonstrated for Bijuva 1/100 (estradiol and progesterone) capsules, 1 mg/100 mg, until Week 5. The change from baseline in the frequency and severity of vasomotor symptoms observed and the difference from placebo are shown in Table 8 and Table 9, respectively.
Adjusting for potential confounders such as BMI, smoking, alcohol use, and baseline estradiol level, treatment with Bijuva 1/100 (estradiol and progesterone) capsules, 1 mg/100 mg, did not demonstrate statistically significant reductions in both frequency and severity of moderate to severe vasomotor symptoms by Week 12 in women who self-identified as Black/African Americans (data not shown).

Relief of oestrogen-deficiency symptoms and bleeding patterns.

Relief of menopausal symptoms was achieved during the first few weeks of treatment. In a 12-week study, 1 mg estradiol/100 mg progesterone significantly reduced the number and severity of hot flushes compared to placebo at Weeks 4 and 12.
In this study, amenorrhea was reported in 82.6% of the women who received 1 mg estradiol/100 mg progesterone during months 10 to 12. Bleeding and/or spotting was reported in the 1 mg estradiol/100 mg progesterone group by 30.1% of women during the first 3 months of treatment and by 17.4% of women during months 10 to 12.

Endometrial safety.

The effects of 1 mg estradiol/100 mg progesterone (Bijuva 1/100) on the endometrium was assessed in the 52-week safety trial. During the trial, assessments of endometrial biopsies taken at 12 months or at early trial discontinuation revealed 1 case of simple endometrial hyperplasia without atypia and no endometrial cancer in women who received Bijuva 1/100 (1 mg estradiol/100 mg progesterone capsules (N = 1/268, 0.37%; upper 2-sided 95% CI: 1.83%).
Four (4) cases of disordered proliferative endometrium were also reported for Bijuva 1/100 1 mg estradiol/100 mg progesterone) capsules (see Table 10).

5.2 Pharmacokinetic Properties

Absorption.

The oral absorption of both estradiol and progesterone is subject to first pass metabolism.

Food effect.

Concomitant food ingestion increased the extent of absorption (AUC) and peak plasma concentration (Cmax) of the progesterone component of Bijuva 1/100 relative to a fasting state when administered at a dose of 100 mg. Concomitant food ingestion had no effect on the AUC of the estradiol component of Bijuva 1/100, but the rate of estradiol absorption was faster under fasting conditions compared to the fed state. Food increased the Cmax and AUC of the progesterone by 82% and 2.7-fold, respectively, relative to the fasting state.
After multiple doses of Bijuva 1/100 (estradiol and progesterone) capsules, 1 mg/100 mg taken under fed conditions, the tmax (the time at which the maximum concentration is attained) for estradiol is approximately 5 hours and approximately 3 hours for progesterone (see Table 11). Steady state for both estradiol and progesterone components of Bijuva 1/100, as well as estradiol's main metabolite, estrone, is achieved within seven days.
Following repeat dosing with Bijuva 1/100 (estradiol and progesterone) capsules, 1 mg/100 mg, the half-life of estradiol was approximately 26 hours. The half-life of progesterone, following repeat dosing was approximately 10 hours.

Estradiol.

Estradiol is extensively metabolised in the gastrointestinal mucosa during oral absorption and in the liver. Oral estradiol undergoes extensive first-pass metabolism in the liver and has an absolute bioavailability of 5% to 10% of the administered dose. Oral oestradiol exhibits dose-proportional pharmacokinetics over the dose range of up to 4 mg.

Micronized progesterone.

Progesterone administered orally undergoes extensive first-pass metabolism in the liver. The absolute bioavailability of micronized progesterone is not known; the relative bioavailability of the oral progesterone compared with intramuscular progesterone is approximately 10%.
Micronized progesterone exhibits dose proportional exhibited pharmacokinetics 100 and 300 mg.

Distribution.

Estradiol.

Estradiol is highly protein bound (approximately 95% to 98%), loosely to albumin or tightly to sex hormone-binding globulin, the major binding protein.

Progesterone.

Progesterone is extensively bound to serum proteins (approximately 97%). About 17% of the circulating progesterone is bound with high affinity to transcortin (corticosteroid-binding globulin, CBG) and 80% with low affinity to albumin.

Metabolism.

Estradiol.

Estradiol undergoes rapid hepatic biotransformation and is converted primarily to estrone and estriol. There is a dynamic mutual conversion system between estradiol, estrone, and estrone sulfate and estradiol sulfate, which can be regarded as both metabolites and precursors.
Estrogens also undergo enterohepatic recirculation via sulfate and glucuronide conjugation in the liver, biliary secretion of conjugates into the intestine, and hydrolysis in the gut followed by reabsorption.

Progesterone.

Progesterone is metabolised primarily by the liver largely to pregnanediols and pregnanolones. Pregnanediols and pregnanolones are conjugated in the liver to glucuronide and sulfate conjugates.

Excretion.

Estradiol.

Estradiol, estrone, and estriol are excreted in the urine along with glucuronide and sulfate conjugates.

Progesterone.

The glucuronide and sulfate conjugates of progesterone metabolites are eliminated in the urine.

5.3 Preclinical Safety Data

Genotoxicity.

No genotoxicity studies have been conducted with combination of estradiol (hemihydrate)/progesterone.
There is limited evidence available in the literature suggesting that estradiol may be weakly genotoxic. 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 and an increased incidence of sister chromatid exchanges (indicative of DNA damage) in mammalian cells. None of these effects were induced by estradiol in human lymphocyte cultures. Importantly, there was no evidence of clastogenicity in rodent bone marrow micronucleus assays.
Progesterone did not induce chromosomal aberrations or sister chromatid exchanges in cultured human cells nor chromosomal aberrations or DNA strand breaks in rodent cells. Progesterone did not induce dominant lethal mutations in mice or chromosomal aberrations in the bone marrow of rats in vivo although in vivo studies for chromosome damage have yielded positive results in mice at oral doses of 1000 mg/kg and 2000 mg/kg. Weak clastogenic activity was found for progesterone in the rat hepatocyte micronucleus test after treatment with a high oral dose (100 mg/kg). Studies on transformation of rodent cells in vitro were inconclusive. Variable results were obtained in the mouse lymphoma tk assay. Progesterone was not mutagenic to bacteria.

Carcinogenicity.

No carcinogenicity studies have been conducted with combination of estradiol (hemihydrate)/progesterone.
Long-term, continuous administration of natural and synthetic estrogens in laboratory animal species increases the frequency of carcinomas of the breast, uterus, cervix, vagina, testis, and liver. Carcinogenicity by estradiol may involve gene mutation induced by reactive metabolites or the activation of estrogen receptor-mediated signalling pathways that sustain the growth and survival of preneoplastic and malignant cells.
Progesterone has not been tested for carcinogenicity in animals by the oral route of administration. Progesterone has been shown to induce/promote the formation of ovarian, uterine, mammary, and genital tract tumours in animals. The clinical relevance of these findings is unknown. Literature data provides no indication of potential carcinogenicity in humans.
When implanted into female mice, progesterone produced mammary carcinomas, ovarian granulosa cell tumours and endometrial stromal sarcomas. In dogs, long-term intramuscular injections produced nodular hyperplasia and benign and malignant mammary tumours.
Subcutaneous or intramuscular injections of progesterone decreased the latency period and increased the incidence of mammary tumours in rats previously treated with a chemical carcinogen.

6 Pharmaceutical Particulars

6.1 List of Excipients

Mono and di-glycerides, lauroyl macrogolglycerides, gelatin, hydrolysed gelatin, glycerol; Opatint Red DG-15001 (PI-141454), Opatint Concentrated Color Dispersion G-18006 (PI-140158), Opacode WB water based Monogramming Ink NSP-78-18022 White (PI 3883).

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

This medicinal product does not require any special temperature storage conditions. Keep the blister in the outer carton in order to protect from light.

6.5 Nature and Contents of Container

Bijuva 1/100 is available in PVC/PE/PCTFE aluminium backed blister packs, containing 28 or 84 soft capsules.
Not all pack sizes may be marketed or available.

6.6 Special Precautions for Disposal

The release of medicines into the environment should be minimised. Medicines should not be disposed of via wastewater and disposal through household waste should be avoided. The hormonal active compounds in the capsule may have harmful effects if it reaches the aquatic environment. In Australia, any unused medicine or waste material should be disposed of by taking to your local pharmacy.

6.7 Physicochemical Properties

Chemical structure.

Estradiol hemihydrate.


Chemical name: estra-1,3,5(10)-triene-3,17β-diol (as hemihydrate). Estradiol has 5 chiral centres.
Molecular formula: C18H24O2.
Molecular weight: 281.39.

CAS number.

Estradiol hemihydrate: 35380-71-3.

Progesterone.


Chemical name: pregn-4-ene-3,20-dione.
Molecular formula: C21H30O2.
Molecular weight: 314.5.

CAS number.

Progesterone: 57-83-0.

7 Medicine Schedule (Poisons Standard)

Schedule 4 - Prescription Only Medicine.

Summary Table of Changes