Consumer medicine information

Duavive 0.45/20

Conjugated estrogens; Bazedoxifene

BRAND INFORMATION

Brand name

Duavive

Active ingredient

Conjugated estrogens; Bazedoxifene

Schedule

What is in this leaflet

This leaflet answers some common questions about DUAVIVE. It does not contain all 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 DUAVIVE 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 DUAVIVE is used for

This medicine is used for the treatment of symptoms, such as "hot flushes" and sweating, which are associated with menopause in women who still have their uterus (womb).

How DUAVIVE works

This medicine contains two active substances called conjugated estrogens and bazedoxifene. Conjugated estrogens belong to a group of medicines called menopausal hormone therapy (MHT), also known as hormone replacement therapy (HRT). Bazedoxifene belongs to a group of non-hormonal medicines called selective estrogen receptor modulators (SERMs).

Menopause occurs naturally in women, typically between the ages of 45 and 55. During menopause, your body produces less estrogen than it did beforehand. This can cause symptoms such as "hot flushes".

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.

This medicine is not addictive.

This medicine is available only with a doctor's prescription.

Before you take DUAVIVE

When you must not take it

DUAVIVE should only be taken if you have been fully informed of the risks.

The decision to take DUAVIVE should be based on your particular needs and health and made after a careful medical evaluation.

Talk regularly with your doctor about whether you still need treatment with DUAVIVE.

Do not take DUAVIVE if you have an allergy to:

any medicine containing conjugated estrogens or bazedoxifene
any of the ingredients listed at the end of this leaflet
any other similar medicines.

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 DUAVIVE if you have, or have had, any of the following medical conditions:

breast cancer or suspected breast cancer
estrogen-dependent cancers or suspected estrogen-dependent cancers. Examples include endometrial cancer
recent unexplained vaginal bleeding
excessive thickening of the womb lining (endometrial hyperplasia) that is not being treated
blood clot in a vein (thrombosis), such as in the legs (deep vein thrombosis, DVT), the lungs (pulmonary embolism) or eyes
blood clotting disorder (such as protein C, protein S, or antithrombin deficiency)
disease caused by blood clots in the arteries, such as a heart attack, stroke or angina
liver disease or where your liver function tests have not returned to normal
rare blood problem called porphyria, which is passed down in families (inherited).

This medicine is for use only by postmenopausal women with a uterus. Do not take this medicine if you are pregnant, or if you think you might be pregnant. Do not take this medicine if you are breast-feeding.

Do not give DUAVIVE to a child. This medicine is not suitable for use in children.

Do not take this medicine after the expiry date (EXP) printed on the pack or if the packaging is torn or shows signs of tampering. If it has expired or the package 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

You must have a thorough medical check-up before starting DUAVIVE for the first time or if you are taking it again after a break.

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

Tell your doctor if you are taking other menopausal hormonal therapy (e.g., other estrogens, progestogens) or other SERMS e.g., raloxifene (a medicine used to prevent or treat osteoporosis), clomiphene or tamoxifen.

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

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
have or are at increased risk of getting an estrogen-sensitive cancer (such as having a mother, sister or grandmother who has had breast cancer)
high blood pressure
any problems with your liver
diabetes
gallstones
migraine or severe headaches
a rare disease of the immune system that affects many organs of the body (systemic lupus erythematosus, SLE)
seizures (epilepsy)
asthma
a disease affecting the eardrum and hearing (otosclerosis)
a high level of fat in your blood (triglycerides)
fluid retention due to heart or kidney problems.
problems with your parathyroid gland
angioedema (a condition where fluid build-up causes swelling under the skin particularly on the face, hands, feet, eyes and lips)

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

If you have been told by your doctor that you have an intolerance to some sugars, contact your doctor before taking this medicine. This medicine contains lactose monohydrate, sucrose, sorbitol, glucose (in maltitol liquid, a type of sugar).

There is no experience in treating women with premature menopause (due to ovarian failure or surgery).

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, naturopath or health food shop. In particular, other menopausal hormonal therapy (e.g., other estrogens, progestogens) or other SERMS e.g., raloxifene (a medicine used to prevent or treat osteoporosis), clomiphene or tamoxifen.

Some medicines and DUAVIVE may interfere with each other. These include:

medicines to treat epilepsy such as phenobarbital, phenytoin, carbamazepine
some antibiotics and anti-infectives such as rifampicin, rifabutin, erythromycin, clarithromycin
anti-fungal agents such as ketoconazole and itraconazole
anti-virals such as ritonavir, efavirenz and nevirapine
St John's Wort (Hypericum perforatum).

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

Avoid grapefruit juice as it may also affect how well DUAVIVE works.

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

How to take DUAVIVE

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 on the box, ask your doctor or pharmacist for help.

How much to take

The recommended dose is one tablet taken once daily.

How to take it

Swallow the tablet whole with a full glass of water. Do not divide, crush, chew, or dissolve the tablet in your mouth.

When to take it

Take your medicine 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.

How long to take it

Continue taking your medicine for as long as your doctor tells you.

DUAVIVE should be taken for the shortest time possible and only for as long as treatment is needed. You and your doctor should talk regularly about whether you still need treatment with DUAVIVE.

If you forget to take it

If you forget to take a tablet, take it as soon as you remember.

If it is almost time to take your next tablet, skip the tablet you missed and take your next tablet when you are meant to.

Do not take a double dose to make up for the dose that you missed. This may increase the chance of you getting an unwanted side effect.

If you are not sure what to do, ask your doctor or pharmacist.

If you have trouble remembering to take your medicine, ask your pharmacist for some hints.

If you take too much (overdose)

Immediately telephone your doctor or the Poisons Information Centre (telephone Australia 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 DUAVIVE.

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

Symptoms of an overdose may include:

feeling sick or vomiting
breast tenderness
dizziness
stomach pain
feeling sleepy or tired
a short period of vaginal bleeding.

While you are taking DUAVIVE

Things you must do

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

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

If you are going to have surgery (or your movement is restricted), tell the surgeon or anaesthetist that you are taking this medicine. You may need to stop taking DUAVIVE about 4 to 6 weeks before the operation, to reduce the risk of a blood clot. Ask your doctor when you can start taking this medicine again.

If you become pregnant while taking this medicine, tell your doctor immediately. DUAVIVE should not be taken while you are pregnant.

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.

Keep all of your doctor's appointments so that your progress can be checked.

Once you have started this medicine you should see your doctor for regular check-ups (at least once a year). During these check-ups, discuss with your doctor the benefits and risks of continuing with DUAVIVE. You are advised to:

go for regular breast screening (mammograms), pelvic exams and cervical smear (pap) tests, as recommended by your doctor.
regularly check your breasts for any changes such as dimpling of the skin, changes in the nipple, or any lumps you can see or feel.

Tell your doctor right away if you get any unusual vaginal bleeding while you are taking DUAVIVE.

Vaginal bleeding after menopause may be a warning sign of cancer of the uterus (womb).

Things you must not do

Do not take DUAVIVE 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 or lower the dosage without checking with your doctor.

Things to be careful of

Be careful driving or operating machinery until you know how DUAVIVE affects you.

This medicine may cause drowsiness, blurred vision or a reduction in the sharpness of your vision in some people. If you have any of these symptoms, do not drive, operate machinery or do anything else that could be dangerous.

If this problem continues or gets worse, talk to your doctor.

Side effects

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

This medicine helps most people with menopausal symptoms, but it may have unwanted side effects in a few people. 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 list of side effects. You may not experience any of them.

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

Go to hospital if...

Stop taking DUAVIVE and tell your doctor immediately or go to Accident and Emergency at your nearest hospital, if you notice any of the following:

any of the conditions mentioned under the section 'Do not take DUAVIVE...' above
a severe allergic reaction - symptoms may include sudden wheezing and chest pain or tightness, swelling of the eyelids, face, lips, mouth, tongue or throat, difficulty breathing, collapse
if you have swelling of the eyes, nose, lips, mouth, tongue or throat, difficulty in breathing, severe dizziness or fainting, skin rash (symptoms of angioedema)
a large increase in your blood pressure (symptoms may be headache, tiredness, dizziness)
you notice signs of a blood clot, such as painful swelling and redness of the legs, sudden chest pain, or difficulty in breathing.
loss of vision, pain and swelling of the eye or eyelid, especially if sudden.

The above list includes very serious side effects. You may need urgent medical attention or hospitalisation. These side effects are rare.

Tell your doctor as soon as possible if...

Tell your doctor as soon as possible if you notice any of the following:

yellowing of your skin or the whites of your eyes (jaundice). These may be signs of liver disease.
blurred vision
reduction in the sharpness of your vision
dry eyes
difficulty in opening your eyes.
you see a halo around lights, sparks or lights when your eyes are closed.

The above list includes serious side effects that may require medical attention. Serious side effects are uncommon.

Tell your doctor if...

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

abdominal pain (stomach ache)
muscle spasms
constipation
diarrhoea
nausea
thrush (vaginal yeast infection).

The above list includes the more common side effects of your medicine.

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

Some of these side effects (for example, changes in thyroid function, blood pressure or cholesterol level) can only be found when your doctor does tests from time to time to check your progress.

After taking DUAVIVE

Storage

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

After opening the blister pouch, use all tablets within 60 days.

Keep your tablets in a cool dry place where the temperature stays below 25°C.

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

Product description

What it looks like

The DUAVIVE 0.45 mg/20 mg modified-release tablet is a pink, oval-shaped, tablet marked on one side with "0.45/20".

The tablets are provided in PVC/Aclar®/PVC/Al blister packs containing 28 tablets.

Ingredients

DUAVIVE contains 0.45 mg of conjugated estrogens and bazedoxifene acetate equivalent to 20 mg bazedoxifene as active ingredients.

It also contains:

lactose monohydrate
microcrystalline cellulose
powdered cellulose
hypromellose
magnesium stearate
calcium phosphate
sucrose
hyprolose
macrogol 400
sucrose palmitate
ascorbic acid
Opadry pink
Opaglos 2 clear
Opacode black ink.

Supplier

DUAVIVE is supplied in Australia by:

Pfizer Australia Pty Ltd
Sydney, NSW.
Toll Free Number: 1800 675 229.
www.pfizermedicalinformation.com.au/

Australian registration number

AUST R 262525.

Date of preparation

This leaflet was prepared in January 2024.

® Registered Trademark.

Published by MIMS March 2024

BRAND INFORMATION

Brand name

Duavive

Active ingredient

Conjugated estrogens; Bazedoxifene

Schedule

1 Name of Medicine

Conjugated estrogens/bazedoxifene.

2 Qualitative and Quantitative Composition

Each Duavive 0.45/20 modified release tablet contains 0.45 mg of conjugated estrogens (CE) and bazedoxifene acetate equivalent to 20 mg of bazedoxifene.

Excipient(s) with known effect.

Each tablet contains 96.9 mg sucrose (includes 0.7 mg sucrose as sucrose palmitate), 59.8 mg lactose monohydrate and 0.2 mg maltitol solution (a component of Opaglos 2 clear) (see Section 4.4 Special Warnings and Precautions for Use, Other conditions).
For the full list of excipients, see Section 6.1 List of Excipients.

3 Pharmaceutical Form

Modified release tablet.
Duavive 0.45 mg/20 mg is a pink, oval shaped, tablet marked on one side with "0.45/20".

4 Clinical Particulars

4.1 Therapeutic Indications

Duavive is indicated for treatment of moderate to severe vasomotor symptoms associated with menopause in women with a uterus.
Duavive should be used for the shortest duration consistent with treatment goals and risks for the individual woman.
Experience in women older than 65 years is limited.

4.2 Dose and Method of Administration

Dosage.

The recommended dose is as a single tablet, once daily.
For initiation and continuation of treatment of postmenopausal symptoms, the lowest effective dose for the shortest duration (see Section 4.4 Special Warnings and Precautions for Use) should be used.
Women taking Duavive should not take additional progestogens, estrogens or selective estrogen receptor modulators (SERMS) (see Section 4.4 Special Warnings and Precautions for Use).

Method of administration.

Orally.
Duavive may be given at any time of day, with or without food. Tablets should be swallowed whole. Tablets should not be chewed, crushed or broken.

Dosage adjustment.

Renal impairment.

The pharmacokinetics of CE/ bazedoxifene have not been evaluated in patients with renal impairment. Use in this population is therefore not recommended (see Section 4.4 Special Warnings and Precautions for Use, Use in renal impairment; Section 5.2 Pharmacokinetic Properties, Renal impairment).

Hepatic impairment.

The safety and efficacy of CE/ bazedoxifene have not been evaluated in patients with hepatic impairment. Use in this population is contraindicated (see Section 4.3 Contraindications; Section 5.2 Pharmacokinetic Properties, Hepatic impairment).

Elderly.

The experience treating women older than 65 years is limited.
In 224 women included in clinical trials, aged between 65 and 75 years, no dosage adjustment was required (see Section 5.2 Pharmacokinetic Properties, Elderly). Duavive has not been studied in women over 75 years of age.

Paediatric use.

There is no relevant use of Duavive in the paediatric population (see Section 4.4 Special Warnings and Precautions for Use, Paediatric use).

4.3 Contraindications

Hypersensitivity to the active substances or to any of the excipients (see Section 6.1 List of Excipients).
Known, suspected, or past history of breast cancer.
Known, past or suspected estrogen dependent malignant tumours (e.g. endometrial cancer).
Undiagnosed genital bleeding.
Untreated endometrial hyperplasia.
Active or past history of venous thromboembolism (e.g. deep venous thrombosis, pulmonary embolism, and retinal vein thrombosis).
Known thrombophilic disorders (e.g. protein C, protein S, or antithrombin deficiency, see Section 4.4 Special Warnings and Precautions for Use).
Active or past history of arterial thromboembolic disease (e.g. myocardial infarction, stroke).
Acute liver disease or a history of liver disease as long as liver function tests have failed to return to normal.
Pregnancy, women who may become pregnant, and nursing mothers (see Section 4.6 Fertility, Pregnancy and Lactation, Use in pregnancy, Use in lactation).
Porphyria.

4.4 Special Warnings and Precautions for Use

For the treatment of postmenopausal symptoms, Duavive 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 treatment should only be continued as long as the benefit outweighs the risk.
Women taking Duavive should not be taking progestogens, additional estrogens or SERMs (see Section 4.2 Dose and Method of Administration).
Duavive has not been studied in the treatment of premature menopause.

Medical examination/ follow-up.

Before initiating or reinstituting treatment with Duavive, 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 later in this section). 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 which need 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 Duavive, in particular.
Leiomyoma (uterine fibroids) or endometriosis.
Risk factors for thromboembolic disorders (see Venous thromboembolism (VTE)).
Risk factors for estrogen dependent tumours, e.g. 1^st degree heredity for breast cancer.
Hypertension.
Liver disorders e.g. hepatic adenoma, hepatic haemangiomas.
Diabetes mellitus with or without vascular involvement.
Cholelithiasis.
Migraine or severe headache.
Systemic lupus erythematosus.
A history of endometrial hyperplasia (see Endometrial hyperplasia and carcinoma).
Epilepsy.
Asthma.
Otosclerosis.

Reasons for immediate withdrawal of therapy.

Therapy should be discontinued where a contraindication to therapy presents, e.g. venous thromboembolism, stroke, pregnancy, jaundice or deterioration in liver function, significant increase in blood pressure, new onset of migraine type headache.

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 nonusers, depending on duration of treatment and estrogen dose. After stopping treatment, risk may remain elevated for at least 10 years. Women taking Duavive should not take additional estrogens as this may increase the risk of endometrial hyperplasia and endometrial carcinoma.
The addition of bazedoxifene in Duavive reduces the risk of endometrial hyperplasia, which may be a precursor of endometrial carcinoma (see Section 4.8 Adverse Effects (Undesirable Effects), Description of selected adverse reactions, Endometrial cancer risk; Section 5.1 Pharmacodynamic Properties, Clinical trials, Effects on the endometrium).
Breakthrough bleeding and spotting may occur during treatment. If breakthrough 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 effect of Duavive on the risk of breast cancer is unknown.
The overall evidence suggests a possible increased risk of breast cancer in women taking estrogen only therapy that is dependent on the duration of therapy and age at initiation of therapy.
The Women's Health Initiative (WHI) trial found no increase in the risk of breast cancer in hysterectomised women using estrogen only therapy (see Section 4.8 Adverse Effects (Undesirable Effects), Description of selected adverse reactions, Breast cancer risk).
Observational studies have mostly reported a small increase in risk of having breast cancer diagnosed in women treated with estrogens alone therapy that is substantially lower than that found in users of estrogen-progestogen combinations (see Section 4.8 Adverse Effects (Undesirable Effects), Description of selected adverse reactions, Breast cancer risk). The excess risk becomes apparent within a few years of use but returns to baseline within a few (at most five) years after stopping treatment.

Ovarian cancer.

The effect of Duavive on the risk of ovarian cancer is unknown.
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 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 Adverse Effects (Undesirable Effects), Description of selected adverse reactions, Ovarian cancer).

Venous thromboembolism (VTE).

In clinical trials of up to 2 years duration in postmenopausal women with CE/ bazedoxifene, cases of VTE have been reported (see Section 4.8 Adverse Effects (Undesirable Effects), Description of selected adverse reactions, Risk of venous thromboembolism). Should a VTE event occur or be suspected, Duavive should be discontinued immediately.
SERMs (including bazedoxifene) and estrogens individually increase the risk of VTE (see Section 4.8 Adverse Effects (Undesirable Effects), Description of selected adverse reactions, Risk of venous thromboembolism).
Hormone replacement therapy (HRT) is associated with a 1.3-3-fold risk of developing VTE. The occurrence of such an event is more likely in the first year of HRT than later (see Section 4.8 Adverse Effects (Undesirable Effects), Description of selected adverse reactions, Risk of venous thromboembolism).
Patients with known thrombophilic states have an increased risk of VTE and hormone therapy may add to this risk. Duavive is contraindicated in these patients (see Section 4.3 Contraindications).
Generally recognised risk factors for VTE include, use of estrogens, older age, 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 be considered to prevent VTE following surgery. If prolonged immobilisation is to follow elective surgery temporarily stopping Duavive 4 to 6 weeks earlier is recommended. Treatment should not be restarted until the woman is completely mobilised. In addition, women taking Duavive should be advised to move about periodically during travel involving prolonged immobilisation.
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) hormone therapy is contraindicated.
Women already on chronic anticoagulant treatment require careful consideration of the benefit/ risk of use of hormone therapy.
If VTE develops after initiating therapy, or is suspected, Duavive should be discontinued immediately. Women 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).

The effect of Duavive on the risk of CAD is unknown.
There is no evidence from randomised controlled trials of protection against myocardial infarction in women with or without existing CAD who received estrogen only therapy. Randomised controlled data found no increased risk of CAD in hysterectomised women using estrogen only therapy.

Stroke.

The effect of Duavive on the risk of stroke is unknown.
Estrogen only therapy is associated with an up to 1.5-fold increase in risk of 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 Adverse Effects (Undesirable Effects), Description of selected adverse reactions, Risk of stroke).
Should a stroke occur or be suspected, Duavive should be discontinued immediately (see Section 4.3 Contraindications).

Visual abnormalities.

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

Gallbladder disease.

Cases (< 1%) of cholecystitis have been reported in CE/ bazedoxifene clinical trials. A 2 to 4-fold increase in the risk of gall bladder disease requiring surgery in postmenopausal women receiving estrogens has been reported (see Section 4.8 Adverse Effects (Undesirable Effects)).

Elevated blood pressure.

In a small number of case reports in women receiving estrogens, substantial increases in blood pressure have been attributed to idiosyncratic reactions to estrogens. In a large, randomised, placebo controlled clinical study, a generalised effect of estrogens on blood pressure was not seen.

Hypertriglyceridaemia.

Women with pre-existing hypertriglyceridaemia should be followed closely during treatment with estrogens, since rare cases of large increases of plasma triglycerides leading to pancreatitis have been reported with estrogen therapy in this condition. CE/ bazedoxifene has not been studied in women with baseline triglyceride levels > 3.4 mmol/L. In clinical trials of up to 2 years duration, CE/ bazedoxifene was associated with an increase from baseline in the concentration of serum triglycerides of approximately 16% at month 12 and 20% at month 24. Annual monitoring of serum triglyceride levels should therefore be considered.

Impaired liver function and past history of cholestatic jaundice.

CE/ bazedoxifene has not been studied in patients with impaired liver function or history of cholestatic jaundice. Estrogens may be poorly metabolised in women with impaired liver function. For women with a history of cholestatic jaundice associated with past estrogen use or with pregnancy, caution should be exercised, and in the case of recurrence, Duavive should be discontinued (see Section 4.2 Dose and Method of Administration, Dosage adjustment, Hepatic impairment; Section 5.2 Pharmacokinetic Properties, Hepatic impairment).

Fluid retention.

Estrogens may cause fluid retention, and therefore patients with cardiac or renal impairment should be carefully monitored when being treated with Duavive, since it is expected that the level of circulating estrogens components of Duavive will be increased. Use in this population is not recommended (see Section 4.2 Dose and Method of Administration, Dosage adjustment, Renal impairment; Section 5.2 Pharmacokinetic Properties, Renal impairment).

Dementia.

The effect of Duavive on the risk of dementia is unknown.
Estrogen therapy use does not improve cognitive function. The Women's Health Initiative Memory Study (WHIMS), a substudy of WHI, reported increased risk of probable dementia in women who start using continuous estrogen only therapy after the age of 65.

Hypothyroidism.

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

Hypocalcemia.

Estrogen therapy should be used with caution in women with hypoparathyroidism as estrogen induced hypocalcaemia may occur.

Hereditary and acquired angioedema.

Exogenous estrogens may exacerbate symptoms of angioedema in women with hereditary and acquired angioedema.

Other conditions.

Duavive contains lactose, sucrose, glucose (in the polydextrose and maltitol liquid components of Opaglos 2 clear) and sorbitol (in the polydextrose component of Opaglos 2 clear). Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency, fructose intolerance, glucose-galactose malabsorption or sucrase-isomaltase insufficiency should not take this medicine.

Use in hepatic impairment.

The safety and efficacy of CE/ bazedoxifene have not been evaluated in patients with hepatic impairment. Use in this population is contraindicated (see Section 4.4 Special Warnings and Precautions for Use, Impaired liver function and past history of cholestatic jaundice; Section 5.2 Pharmacokinetic Properties, Hepatic impairment).

Use in renal impairment.

The pharmacokinetics of CE/ bazedoxifene have not been evaluated in patients with renal impairment. Use in this population is, therefore, not recommended (see Section 5.2 Pharmacokinetic Properties, Renal impairment).
Patients with renal impairment should be closely monitored since it is expected that the level of circulating estrogens components of Duavive will be increased. Use in this population is not recommended (see Section 4.2 Dose and Method of Administration, Dosage adjustment, Renal impairment; Section 5.2 Pharmacokinetic Properties, Renal impairment).

Use in the elderly.

Duavive has not been studied in women over 75 years of age. Of the total number of women in phase 3 clinical trials who received CE/ bazedoxifene 20 mg, 2.4% (n = 77) were aged ≥ 65 years. No overall differences in safety or effectiveness were observed between women aged > 65 years and younger women, but greater sensitivity of some older individuals cannot be ruled out (see Section 5.2 Pharmacokinetic Properties, Elderly).

Paediatric use.

There is no relevant use of Duavive in the paediatric population.

Effects on laboratory tests.

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. Free T4 and free T3 concentrations 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).

4.5 Interactions with Other Medicines and Other Forms of Interactions

Results from a clinical drug-drug interaction study conducted with Duavive and from interaction studies with CE or bazedoxifene monotherapy are summarised below.

Cytochrome P450.

In vitro and in vivo studies have shown that estrogens are partially metabolised by cytochrome P450 enzymes, including CYP3A4. However, in a clinical drug-drug interaction study, repeat administration of 200 mg itraconazole, a strong CYP3A4 inhibitor, had minimal impact on the pharmacokinetics of CE (as measured by estrone and equilin) and bazedoxifene when administered with a single dose of CE 0.45 mg/ bazedoxifene 20 mg.
The metabolism of estrogens may be increased by concomitant use of substances known to induce drug metabolising enzymes, such as anticonvulsants (e.g. phenobarbital, phenytoin, carbamazepine) and anti-infectives (e.g. rifampicin, rifabutin, nevirapine, efavirenz). Ritonavir and nelfinavir, although known as strong inhibitors, by contrast exhibit inducing properties when used concomitantly with steroid hormones. Herbal preparations containing St John's wort (Hypericum perforatum) may induce the metabolism of estrogens. Clinically, an increased metabolism of estrogens may lead to decreased effect and changes in the uterine bleeding profile.
Inhibitors of CYP3A4, such as erythromycin, clarithromycin, ketoconazole, ritonavir and grapefruit juice, may increase plasma concentrations of estrogens and may result in adverse reactions.
Bazedoxifene undergoes little or no cytochrome P450 (CYP)-mediated metabolism. Bazedoxifene does not inhibit the activities of major CYP isoenzymes at clinically relevant systemic concentrations. Bazedoxifene does not induce the activities of the major CYP isoenzymes.

Uridine diphosphate glucuronosyltransferase (UGT).

Bazedoxifene undergoes metabolism by UGT enzymes in the intestinal tract, kidney and liver (see Section 5.2 Pharmacokinetic Properties). The metabolism of bazedoxifene may be increased by concomitant use of substances known to induce UGTs, such as rifampicin, phenobarbital, carbamazepine, and phenytoin, potentially leading to decreased systemic concentrations of bazedoxifene. A reduction in bazedoxifene exposure may be associated with an increased risk of endometrial hyperplasia. If breakthrough 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 (see Section 4.4 Special Warnings and Precautions for Use).

Ibuprofen.

The pharmacokinetics of bazedoxifene and ibuprofen are not significantly altered when the drugs are coadministered.

Atorvastatin.

Concomitant administration of bazedoxifene (40 mg daily) and atorvastatin (20 mg, single dose) to healthy postmenopausal women did not affect the pharmacokinetics of bazedoxifene, atorvastatin or its active metabolites.

Azithromycin.

The pharmacokinetics of bazedoxifene were not significantly altered when coadministered with azithromycin.

Aluminium and magnesium hydroxide.

There was no clinically relevant pharmacokinetic interaction of antacids containing aluminium and magnesium hydroxide with bazedoxifene.

Drugs highly bound to plasma proteins.

Based on in vitro bazedoxifene plasma protein binding characteristics, interactions with warfarin, digoxin or diazepam are unlikely.

4.6 Fertility, Pregnancy and Lactation

Effects on fertility.

Fertility studies with CE/ bazedoxifene have not been conducted. The following data are based on the findings in studies with bazedoxifene.
Female rats were administered oral daily dosages of 0.3 to 30 mg/kg (yielding 0.03 to 10 times the plasma AUC in patients at the maximum recommended human dose of 20 mg/day) prior to and during mating with untreated males. Estrous cycles and fertility were adversely affected in all bazedoxifene treated female groups. The potential risk for humans is unknown.
(Category D)
Duavive is only for use in postmenopausal women, and is contraindicated in women who are or may become pregnant (see Section 4.3 Contraindications). There are no data from the use of Duavive in pregnant women. If pregnancy occurs during treatment with Duavive, it should be withdrawn immediately.
Treatment of pregnant rats with bazedoxifene at oral doses ≥ 1 mg/kg/day (yielding ≥ 0.3 times the human exposure based on plasma AUC) resulted in increased postimplantation loss, reduced numbers of live fetuses, reduced fetal weight, increased fetal vascular variations and impaired fetal ossification. In rabbit studies with bazedoxifene, abortion and increased incidences of fetal heart malformation (ventricular septal defect) and fetal skeletal system anomalies (ossification delays, misshapen or misaligned bones, primarily of the skull and spine) were observed at oral doses ≥ 0.5 mg/kg/day (≥ 1.7 times the human exposure). Adverse effects on embryofetal development in animals occurred at maternally toxic doses but at exposure levels below or only slightly above that of patients. The animal studies suggest a potential risk to the human fetus.
Duavive is contraindicated during breastfeeding (see Section 4.3 Contraindications). It is not known whether bazedoxifene is excreted in human milk. Detectable amounts of estrogens have been identified in the milk of mothers receiving CE. Estrogen administration to breastfeeding mothers has been shown to decrease the quantity and quality of the milk.

4.7 Effects on Ability to Drive and Use Machines

Duavive has a minor influence on the ability to drive and use machines.
In clinical trials with bazedoxifene monotherapy, somnolence was reported as an adverse reaction, and patients should be advised on the potential effect on driving and using machines.
In patients receiving bazedoxifene monotherapy there have been post-marketing reports of visual symptoms such as visual acuity disturbance or blurred vision. If such symptoms occur, patients should avoid driving or use of machines that requires accurate visual perception until symptoms have resolved, or until they have received medical advice that it is safe to do so (see Section 4.8 Adverse Effects (Undesirable Effects), Post-marketing experience).

4.8 Adverse Effects (Undesirable Effects)

The safety of CE/ bazedoxifene was evaluated in 4,868 postmenopausal women who participated in the five phase 3 trials. Among these, 1,585 women were treated with CE 0.45 mg/ bazedoxifene 20 mg and 1,241 received placebo. Long-term exposure to CE/ bazedoxifene for up to 2 years was evaluated; 3,322 women were exposed to CE/ bazedoxifene for at least 1 year, and 1,999 women were exposed for 2 years.
In the five phase 3 placebo controlled, randomised clinical trials, 8.4% of the 3,168 women treated with CE/ bazedoxifene discontinued treatment due to an adverse event, compared with 10.2% of the 1,241 women who received placebo. The most common reasons leading to discontinuation were abdominal pain and nausea in the treatment arms and continuing hot flushes in the placebo arms.
Table 1 lists the adverse events (regardless of causality) occurring in ≥ 1% of women treated with Duavive in double blind, placebo controlled phase 3 studies of up to 2 years duration.

Adverse reactions observed with CE/ bazedoxifene.

Table 2 lists the adverse reactions observed with both CE 0.45 mg/ bazedoxifene 20 mg and CE 0.625 mg/ bazedoxifene 20 mg treatment groups (n = 3,168) in placebo controlled clinical trials. Adverse reactions were categorised as very common, common, uncommon or rare.

Description of selected adverse reactions.

Breast cancer risk. Breast cancer risk associated with the use of estrogens alone is represented by several studies. Any increased risk to users of estrogen only therapy is substantially lower than that seen in users of estrogen-progestogen combinations. The level of risk is dependent on duration of use (see Section 4.4 Special Warnings and Precautions for Use). Results of the largest randomised placebo controlled trial (WHI-study) and largest epidemiological study (Million Women study) are presented in Table 3 and Table 4.

Endometrial cancer risk.

Postmenopausal women with a uterus.

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, Endometrial hyperplasia and carcinoma; Section 5.1 Pharmacodynamic Properties, Clinical trials, Effects on the endometrium). Depending on the duration of estrogen only use and estrogen dose, the increase in risk of endometrial cancer in epidemiology studies varied from 5 to 55 extra cases diagnosed in every 1,000 women between the ages of 50 and 65 years.
Duavive contains bazedoxifene, which reduces the risk of endometrial hyperplasia that can occur with estrogen only use (see Section 4.4 Special Warnings and Precautions for Use, Endometrial hyperplasia and carcinoma; Section 5.1 Pharmacodynamic Properties, Clinical trials, Effects on the endometrium). Endometrial hyperplasia may be a precursor to endometrial cancer.
Ovarian cancer. Use of estrogen only 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 2,000 users. In women aged 50 to 54 who are not taking HRT, about 2 women in 2,000 will be diagnosed with ovarian cancer over a 5 year period.
Risk of venous thromboembolism (VTE). In the bazedoxifene osteoporosis treatment trial (mean age = 66.5 years), the VTE rate per 1,000 women years through the 3 year study period was 2.86 in the bazedoxifene (20 mg) group and 1.76 in the placebo group and through the 5 year study period was 2.34 in the bazedoxifene 20 mg group and 1.56 in the placebo group. After 7 years, the VTE rate per 1,000 women years was 2.06 in the bazedoxifene 20 mg group and 1.36 in the placebo group.
Estrogens are known to increase the risk of VTE (see Section 4.4 Special Warnings and Precautions for Use, Venous thromboembolism (VTE)). The occurrence of such a reaction is more likely in the first year of treatment. The data from the largest randomised trial are summarised in Table 5.

Risk of stroke. The use of estrogen only therapy is associated with an up to 1.5-fold increased relative risk of stroke. 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 estrogen therapy will increase with age (see Section 4.4 Special Warnings and Precautions for Use, Stroke). The additional risk of stroke over five years of use was assessed in the largest randomised trial in women without a uterus (WHI) from 50-59 years of age (see Table 6).

Post-marketing experience.

In patients receiving bazedoxifene monotherapy there have been post-marketing reports of ocular events other than retinal vein thrombosis. These reports include visual acuity reduced, blurred vision, photopsia, visual field defect, visual impairment, dry eye, eyelid oedema, blepharospasm, eye pain and eye swelling. The underlying nature of these events is uncertain. If ocular symptoms occur, patients should be advised to seek medical attention.
Hereditary and acquired angioedema.

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/reportingproblems.

4.9 Overdose

In case of overdose of Duavive, there is no specific antidote, and the treatment should reflect the symptoms.
Symptoms of overdose of estrogen containing medicinal products in adults and children may include nausea, vomiting, breast tenderness, dizziness, abdominal pain, drowsiness/ fatigue; withdrawal bleeding may occur in females.
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.

Duavive pairs CE with the selective estrogen receptor modulator (SERM), bazedoxifene; this pairing is defined as a tissue selective estrogen complex (TSEC). The active ingredients of CE are primarily the sulfate esters of estrone, equilin sulfates and 17α/β-estradiol which demonstrate tissue selective estrogen receptor agonist activity. These substitute for the loss of estrogen production in menopausal women, and alleviate menopausal symptoms. As estrogens promote the growth of the endometrium, unopposed estrogens increase the risk of endometrial hyperplasia and cancer. The addition of bazedoxifene, acting as an estrogen receptor antagonist in the uterus, greatly reduces the estrogen induced risk of endometrial hyperplasia in nonhysterectomised women.

Clinical trials.

The safety and efficacy of CE/ bazedoxifene as a treatment for moderate to severe vasomotor symptoms (VMS) associated with menopause was established in a randomised, double blind, placebo controlled study. The Selective Estrogens, Menopause, and Response to Therapy (SMART) 2 trial enrolled a total of 318 women, age 42-64 (mean age of 53 years), who had at least 7 moderate to severe hot flushes per day or at least 50 per week at baseline. The mean number of years since menopause was 4.5 years with all women undergoing natural menopause. A total of 127 women were assigned to CE 0.45 mg/ bazedoxifene 20 mg and 63 women were assigned to placebo.
In the SMART 2 trial, CE 0.45 mg/ bazedoxifene 20 mg significantly reduced the number and severity of moderate to severe hot flushes, as measured by the daily severity score, compared with placebo at weeks 4 and 12. The change from baseline in the number and severity of moderate to severe hot flushes observed and the difference from placebo are shown in Table 7.

Effects on the endometrium. Effects of CE/ bazedoxifene on endometrial hyperplasia and endometrial malignancy were assessed in SMART 1, a 24 month, double blind, randomised, placebo and active controlled trial and SMART 5, a 12 month, double blind, randomised, placebo and active controlled trial. The efficacy evaluable population included patients who had taken at least one dose of CE/ bazedoxifene, had baseline and post baseline endometrial biopsies, or had been diagnosed with hyperplasia. The incidence of endometrial hyperplasia for CE/ bazedoxifene was below 1% in both trials (see Table 8).

Effects on uterine bleeding or spotting. Cumulative amenorrhoea (uterine bleeding or spotting) was a key secondary endpoint evaluated in two clinical trials (SMART 1 and SMART 5). In SMART 1, cumulative amenorrhoea at year 1 was 83% and 85% in women treated with CE 0.45 mg/ bazedoxifene 20 mg and placebo respectively. In SMART 5, cumulative amenorrhoea at year 1 was 88% in women treated with CE 0.45 mg/bazedoxifene 20 mg, 82% with bazedoxifene 20 mg and 84% in women who received placebo. For women treated with CE 0.45 mg/medroxyprogesterone 1.5 mg, the cumulative amenorrhoea was 54%.
Effects on breast.

Breast pain.

The effect of CE/ bazedoxifene on breast pain was evaluated as a key secondary endpoint in SMART 1, 2 and 5. In SMART 1, the rates for CE 0.45 mg/bazedoxifene 20 mg and placebo were 9% and 6% respectively. The rates in SMART 2 were 10% and 5% respectively and in SMART 5, the rates were 6% and 5% respectively. For bazedoxifene 20 mg, the breast pain rate was 7%. In SMART 5, the rate for CE 0.45 mg/medroxyprogesterone acetate 1.5 mg was 24%.

Breast density.

The effect of CE/ bazedoxifene on mammographic density was a key secondary endpoint in the SMART 1 and SMART 5 studies.
In SMART 5, the change in mammographic density in postmenopausal women (mean age = 54 years) treated with CE 0.45 mg/ bazedoxifene 20 mg (n = 186) or bazedoxifene 20 mg (n = 97) was not different from placebo (n = 181). In women treated with CE 0.45 mg/ medroxyprogesterone 1.5 mg (n = 68), mammographic density was increased compared to placebo. Supplemental evaluation of mammograms from the SMART 1 trial yielded results consistent with SMART 5.
In an ancillary study, mammographic breast density changes at 2 years for the bazedoxifene 20 mg group were (-1.45 percentage points), while no changes were observed in the placebo group (-0.15 percentage points).
Effects on bone mineral density (BMD). BMD changes at the lumbar spine was a key secondary endpoint, assessed in the SMART 5 study. In this study, women treated with CE 0.45 mg/bazedoxifene 20 mg showed a change from baseline in lumbar spine BMD (+ 1.52%) at month 12 compared to placebo. In the same study, the change in BMD with bazedoxifene 20 mg alone and CE 0.45 mg/medroxyprogesterone 1.5 mg was + 1.35%, + 2.58%, respectively.

5.2 Pharmacokinetic Properties

Pharmacokinetic studies for CE/ bazedoxifene were conducted in healthy postmenopausal women who were naturally postmenopausal or who had undergone bilateral oophorectomy.
Following multiple doses of CE 0.45 mg/bazedoxifene 20 mg, the mean steady-state pharmacokinetic parameters for CE (baseline adjusted for total estrone) and bazedoxifene are summarised in Table 9.

Absorption.

After a single dose of CE/ bazedoxifene, bazedoxifene and baseline adjusted total estrone were absorbed with a t_max of approximately 2 hours and 8.5 hours, respectively. When single doses of CE 0.625 mg/bazedoxifene 20 mg were administered with a high fat meal, bazedoxifene C_max was unaffected, but AUC increased by approximately 25%. Food had little or no effect on the exposure of CE.
CE/ bazedoxifene can be administered with or without food.
Following administration of bazedoxifene alone, a linear increase in plasma concentrations for single doses from 0.5 mg up to 120 mg and multiple daily doses from 1 mg to 80 mg was observed. The absolute bioavailability of bazedoxifene is approximately 6%.
CE are soluble in water and are well absorbed from the gastrointestinal tract after release from the medicinal product formulation. Estrogen dose proportionality was assessed in two studies of CE. Dose proportional increases in both AUC and C_max were observed across the dose range from 0.3 mg to 0.625 mg of CE for total (conjugated plus unconjugated) equilin, total estrone adjusted for baseline, and unconjugated estrone adjusted for baseline.

Distribution.

The distribution of CE and bazedoxifene after administration of CE/ bazedoxifene has not been studied.
Following intravenous administration of a 3 mg dose of bazedoxifene alone, the volume of distribution is 14.7 ± 3.9 L/kg. Bazedoxifene is highly bound (approximately 99%) to plasma proteins at therapeutic concentrations in vitro, but does not appear to bind to sex hormone binding globulin (SHBG).
The distribution of exogenous estrogens is similar to that of endogenous estrogens. Estrogens are widely distributed in the body and are generally found in higher concentrations in the sex hormone target organs. Estrogens circulate in the blood largely bound to SHBG and albumin.

Metabolism.

The metabolic disposition of CE and bazedoxifene, after administration of CE/ bazedoxifene, has not been studied.
Exogenous estrogens are metabolised in the same manner as endogenous estrogens. Circulating estrogens exist in a dynamic equilibrium of metabolic interconversions. 17β-estradiol is converted reversibly to estrone, and both can be converted to estriol, which is the major urinary metabolite. In postmenopausal women, a significant proportion of the circulating estrogens exists as sulfate conjugates, especially estrone sulfate, which serves as a circulating reservoir for the formation of more active estrogens.
The metabolic disposition of bazedoxifene in postmenopausal women has been determined following oral administration of 20 mg of radiolabelled bazedoxifene. Bazedoxifene is extensively metabolised in women. Glucuronidation is the major metabolic pathway. In vitro studies indicated that this occurs in the liver, kidney and intestines, and principally involves UGT1A1 and UGT1A10 with a smaller role for UGT1A9. Little or no cytochrome P450-mediated metabolism is evident. Bazedoxifene-5-glucuronide is the major circulating metabolite, and retains some pharmacological activity. The concentrations of this glucuronide are approximately 10-fold higher than those of unchanged bazedoxifene in plasma.

Excretion.

After a single dose of CE/ bazedoxifene, baseline adjusted total estrone (representing CE) is eliminated with a half-life of approximately 17 hours. Bazedoxifene is eliminated with a half-life of approximately 30 hours. Steady-state concentrations are achieved by the second week of once daily administration.
CE components, 17β-estradiol, estrone, and estriol are excreted in the urine, along with glucuronide and sulfate conjugates.
The clearance of bazedoxifene is 0.4 ± 0.1 L/h/kg based on IV administration. The major route of excretion of radiolabelled bazedoxifene is the faeces, and less than 1% of the dose is eliminated in urine.