English
A B C D E F G H I J K L M N O P Q R S T U V W X Y Z

Duavive (oestrogens conjugated / bazedoxifene) – Summary of product characteristics - G03CX

Updated on site: 06-Oct-2017

Medication nameDuavive
ATC CodeG03CX
Substanceoestrogens conjugated / bazedoxifene
ManufacturerPfizer Limited

1.NAME OF THE MEDICINAL PRODUCT

DUAVIVE 0.45 mg/20 mg modified-release tablets

2.QUALITATIVE AND QUANTITATIVE COMPOSITION

Each modified-release tablet contains 0.45 mg of conjugated oestrogens and bazedoxifene acetate equivalent to 20 mg bazedoxifene.

Excipients with known effect:

Each modified-release tablet contains 96.9 mg sucrose (includes 0.7 mg sucrose as sucrose monopalmitate), 59.8 mg lactose (as monohydrate) and 0.2 mg maltitol liquid.

For the full list of excipients, see section 6.1.

3.PHARMACEUTICAL FORM

Modified-release tablet.

Pink, oval-shaped, modified-release tablet of 12 mm printed on one side with “0.45/20”.

4.CLINICAL PARTICULARS

4.1Therapeutic indications

DUAVIVE is indicated for:

Treatment of oestrogen deficiency symptoms in postmenopausal women with a uterus (with at least 12 months since the last menses) for whom treatment with progestin-containing therapy is not appropriate.

The experience treating women older than 65 years is limited.

4.2Posology and method of administration

Posology

For initiation and continuation of treatment of postmenopausal symptoms, the lowest effective dose for the shortest duration (see also section 4.4) should be used.

The recommended dose for DUAVIVE is 0.45 mg conjugated oestrogens (CE) and 20 mg bazedoxifene taken as a single oral tablet, once daily.

If a tablet is forgotten, it should be taken as soon as the patient remembers. Therapy should then be continued as before. If more than one tablet has been forgotten, only the most recent tablet should be taken, the patient should not take double the usual dose to make up for missed tablets.

Special populations

Elderly population

DUAVIVE has not been studied in women over 75 years of age. Based on available data no dosage adjustment is necessary based on age (see section 5.2). The experience treating women older than 65 years is limited.

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 sections 4.4 and 5.2).

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 sections 4.3, 4.4 and 5.2).

Paediatric population

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

Method of administration

Oral use.

DUAVIVE may be taken at any time of day, without regard to meals (see section 5.2). Tablets should be swallowed whole.

4.3Contraindications

-Hypersensitivity to the active substances or to any of the excipients listed in section 6.1.

-Known, suspected, or past history of breast cancer.

-Known, past or suspected oestrogen-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).

-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.

-DUAVIVE is only indicated for use in postmenopausal women and must not be taken by women of childbearing potential (see sections 4.6 and 5.3).

-Porphyria.

4.4Special 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 progestins, additional oestrogens or selective oestrogen receptor modulators (SERMs).

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’ 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 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 below)

Risk factors for oestrogen-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 case a contraindication is discovered (e.g., venous thromboembolism, stroke, and pregnancy) and in the following situations:

-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 oestrogens are administered alone for prolonged periods. The reported increase in endometrial cancer risk among oestrogen-only users varies from 2- to 12-fold greater compared with non-users, depending on duration of treatment and oestrogen dose. After stopping treatment, risk may remain elevated for at least 10 years. Women taking DUAVIVE should not take additional oestrogens 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.

Break-through bleeding and spotting may occur during 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 suggests a possible increased risk of breast cancer in women taking oestrogen- only therapy that is dependent on the duration of therapy.

The Women’s Health Initiative (WHI) trial found no increase in the risk of breast cancer in hysterectomised women using oestrogen-only therapy.

Observational studies have mostly reported a small increase in risk of having breast cancer diagnosed that is substantially lower than that found in users of oestrogen-progestagen combinations (see section 4.8). 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.

The effect of DUAVIVE on the risk of breast cancer is unknown.

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 oestrogen-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).

The effect of DUAVIVE on the risk of ovarian cancer is unknown.

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). Should a VTE event occur or be suspected, DUAVIVE should be discontinued immediately.

SERMs (including bazedoxifene) and oestrogens individually increase the risk of VTE (see section 4.8).

Hormone therapy 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).

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).

Generally recognised risk factors for VTE include, use of oestrogens, 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)

There is no evidence from randomised controlled trials of protection against myocardial infarction in women with or without existing CAD who received oestrogen-only therapy. Randomised controlled data found no increased risk of CAD in hysterectomised women using oestrogen-only therapy.

Ischaemic stroke

Oestrogen-only therapy is 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 hormone therapy will increase with age (see section 4.8).

The effect of DUAVIVE on the risk of stroke is unknown.

Should a stroke occur or be suspected, DUAVIVE should be discontinued immediately (see section 4.3).

Other conditions

-Oestrogens may cause fluid retention, and therefore patients with cardiac or renal dysfunction should be carefully monitored when being treated with DUAVIVE.

-Patients with terminal renal insufficiency should be closely monitored, since it is expected that the level of circulating oestrogens components of DUAVIVE will be increased. Use in this population is not recommended (see sections 4.2 and 5.2).

-Women with pre-existing hypertriglyceridaemia should be followed closely during treatment with oestrogens, since rare cases of large increases of plasma triglycerides leading to pancreatitis have been reported with oestrogen therapy in this condition. CE/bazedoxifene has not been studied in women with baseline triglyceride levels >300 mg/dL (>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.

-CE/bazedoxifene has not been studied in patients with impaired liver function (see sections 4.2 and 5.2) or history of cholestatic jaundice. Oestrogens may be poorly metabolised in women with impaired liver function. For women with a history of cholestatic jaundice associated with past oestrogen use or with pregnancy, caution should be exercised, and in the case of recurrence, DUAVIVE should be discontinued.

-Cases (<1%) of cholecystitis have been reported in CE/bazedoxifene clinical trials. A 2 to 4-fold increase in the risk of gallbladder disease requiring surgery in postmenopausal women receiving oestrogens has been reported (see section 4.8).

-Oestrogens 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 radio-immunoassay). 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).

Oestrogen therapy use does not improve cognitive function. There is some evidence of increased risk of probable dementia in women who start using continuous oestrogen-only therapy after the age of 65.

The effect of DUAVIVE on the risk of dementia is unknown.

DUAVIVE contains lactose, sucrose, glucose (in polydextrose and maltitol liquid) and sorbitol (in polydextrose). 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.

4.5Interaction with other medicinal products and other forms of interaction

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

Conjugated oestrogens

In vitro and in vivo studies have shown that oestrogens are partially metabolized 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 oestrogens 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 oestrogens. Clinically, an increased metabolism of oestrogens may lead to decreased effect and changes in the uterine bleeding profile.

Bazedoxifene

Bazedoxifene undergoes metabolism by uridine diphosphate glucuronosyltransferase (UGT) enzymes in the intestinal tract and liver (see section 5.2). 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 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 (see section 4.4).

Bazedoxifene undergoes little or no cytochrome P450 (CYP)-mediated metabolism. Bazedoxifene does not induce or inhibit the activities of major CYP isoenzymes, and is unlikely to interact with co- administered medicinal products via CYP-mediated metabolism.

There were no significant pharmacokinetic interactions between bazedoxifene and the following medicinal products: ibuprofen, atorvastatin and azithromycin or an antacid containing aluminium and

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

4.6Fertility, pregnancy and lactation

Pregnancy

DUAVIVE is only for use in postmenopausal women, and is contraindicated in women who are or may become pregnant (see section 4.3). There are no data from the use of DUAVIVE in pregnant women. If pregnancy occurs during treatment with DUAVIVE, it should be withdrawn immediately.

The results of most epidemiological studies to date relevant to inadvertent foetal exposure to oestrogens indicate no teratogenic or foetotoxic effects.

In studies conducted in rabbits, bazedoxifene alone has shown reproductive toxicity (see section 5.3). The potential risk for humans is unknown.

Breast-feeding

DUAVIVE is contraindicated during breast-feeding (see section 4.3). It is not known whether bazedoxifene is excreted in human milk. Detectable amounts of oestrogens have been identified in the milk of mothers receiving CE. Oestrogen administration to breast-feeding mothers has been shown to decrease the quantity and quality of the milk.

Fertility

No studies were performed on animals to evaluate the effects on reproduction with the CE/bazedoxifene combination.

Studies in rats with bazedoxifene have shown adverse effects on fertility (see section 5.3). The potential risk for humans is unknown.

4.7Effects 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.

4.8Undesirable effects

Summary of the safety profile

The safety of CE/bazedoxifene was evaluated in 4,868 post-menopausal women who participated in 5 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.

The most commonly reported adverse event is abdominal pain, occurring in more than 10% of patients in clinical trials.

Serious venous thromboembolic events may occur rarely (less than 1 case per 1,000 patients).

Tabulated list of adverse reactions

The table below lists the adverse reactions observed with CE/bazedoxifene (n = 3,168) in placebo- controlled clinical trials. Adverse reactions were categorised as very common ( 1/10), common ( 1/100 to < 1/10), uncommon ( 1/1,000 to < 1/100) or rare ( 1/10,000 to < 1/1,000).

System organ

 

Frequency of occurrence of adverse reactions

class

 

 

 

 

 

Very common

 

Common

Uncommon

Rare

 

 

 

 

 

 

Infections and

 

 

Vulvovaginal

 

 

infestations

 

 

candidiasis

 

 

Vascular disorders

 

 

 

 

Venous

 

 

 

 

 

thromboembolic

 

 

 

 

 

events (including,

 

 

 

 

 

pulmonary

 

 

 

 

 

embolism, retinal

 

 

 

 

 

vein thrombosis,

 

 

 

 

 

deep vein

 

 

 

 

 

thrombosis and

 

 

 

 

 

thrombophlebitis)

Gastrointestinal

Abdominal pain

 

Constipation;

 

 

disorders

 

 

diarrhoea; nausea

 

 

Hepatobiliary

 

 

 

Cholecystitis

 

disorders

 

 

 

 

 

Musculoskeletal

 

 

Muscle spasms

 

 

and connective

 

 

 

 

 

tissue disorders

 

 

 

 

 

Investigations

 

 

Blood triglycerides

 

 

 

 

 

increased

 

 

Description of selected adverse reactions

 

 

Breast cancer risk

Breast cancer risk associated with the use of oestrogens alone is represented by several studies. Any increased risk to users of oestrogen-only therapy is substantially lower than that seen in users of oestrogen–progestagen combinations. The level of risk is dependent on duration of use (see

section 4.4). Results of the largest randomised placebo-controlled trial (WHI-study) and largest epidemiological study (MWS) are presented.

US WHI Oestrogen only (ET) arm – additional risk of breast cancer after 5 years use

 

Incidence per 1,000

 

Additional cases per

Age range

women in placebo arm

Risk ratio & 95% CI

1,000 ET users over 5

(years)

over 5 years

 

years (95% CI)

 

CE Oestrogen only

 

50-79

0.8 (0.7-1.0)

-4 (-6 – 0)*

*WHI study in women with no uterus, which did not show an increase in risk of breast cancer

Million women study (Estradiol only arm) – estimated additional risk of breast cancer after 5 years use

 

Additional cases per

Risk ratio#

Additional cases per

Age range

1,000 never-users of HRT

1,000 ET users over 5

(years)

over a 5 year period*

 

years (95%CI)

 

 

 

 

 

Estradiol only

 

 

 

 

 

50-65

9-12

1.2

1-2 (0-3)

* Taken from baseline incidence rates in developed countries

#Overall risk ratio. The risk ratio is not constant but will increase with increasing duration on use.

Endometrial cancer risk

Postmenopausal women with a uterus

The endometrial cancer risk is about 5 in every 1,000 women with a uterus not using HRT.

In women with a uterus, use of oestrogen-only HRT is not recommended because it increases the risk of endometrial cancer (see section 4.4). Depending on the duration of oestrogen-only use and oestrogen 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 oestrogen-only use (see section 4.4). Endometrial hyperplasia may be a precursor to endometrial cancer.

Ovarian cancer

Use of oestrogen-only HRT has been associated with a slightly increased risk of having ovarian cancer diagnosed (see section 4.4).

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

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.

Oestrogens are known to increase the risk of VTE (see section 4.4). The occurrence of such a reaction is more likely in the first year of treatment. The data from the largest randomised trial are summarised below:

WHI studies oestrogen only arm – additional risk of VTE over 5 years’ use

Age range (years)

Incidence per 1,000 women

Risk ratio & 95%CI

Additional cases per

 

in placebo arm over 5 years

 

1,000 ET users

 

Oral oestrogen-only*

 

50-59

1.2 (0.6-2.4)

1 (-3-10)

*study in women with no uterus

Risk of ischaemic stroke

The use of oestrogen-only therapy is associated with an up to 1.5 fold increased relative risk of ischaemic 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 oestrogen therapy will increase with age (see section 4.4). The additional risk of ischaemic 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.

WHI Studies combined – Additional risk of ischaemic stroke* over 5 years use

Age range (years)

Incidence per 1,000 women

Risk ratio & 95%CI

Additional cases per

 

in placebo arm over 5 years

 

1,000 HRT users

 

 

 

over 5 years

50-59

1.3 (1.1-1.6)

3 (1-5)

*no differentiation was made between ischaemic and haemorrhagic stroke.

Adverse reactions reported with CE and/or bazedoxifene monotherapy

Adverse reactions were categorized as very common (( 1/10), common ( 1/100 to < 1/10), uncommon ( 1/1,000 to < 1/100), rare ( 1/10,000 to < 1/1,000), very rare (< 1/10,000) or not known (cannot be estimated from available data).

Adverse reactions that have been observed with CE monotherapy

System organ class

 

Frequency of occurrence of adverse reactions

 

 

 

 

 

 

 

Common

 

Uncommon

Rare

Very rare

 

 

 

 

 

 

Infections and

 

 

Vaginitis

 

 

infestations

 

 

 

 

 

Neoplasms benign,

 

 

 

Growth

Enlargement of

malignant and

 

 

 

potentiation of

hepatic

unspecified (incl.

 

 

 

benign

haemangiomas

cysts and polyps)

 

 

 

meningioma;

 

 

 

 

 

fibrocystic

 

 

 

 

 

breast disease

 

Immune system

 

 

Hypersensitivity

Angioedema;

 

disorders

 

 

 

anaphylactic/ana

 

 

 

 

 

phylactoid

 

 

 

 

 

reactions;

 

 

 

 

 

urticaria

 

Metabolism and

 

 

 

Glucose

Exacerbation of

nutrition disorders

 

 

 

intolerance;

porphyria;

 

 

 

 

 

hypocalcaemia (in

 

 

 

 

 

patients with

 

 

 

 

 

disease that can

 

 

 

 

 

predispose to

 

 

 

 

 

severe

 

 

 

 

 

hypocalcaemia)

Psychiatric disorders

 

 

Dementia;

Irritability

 

 

 

 

depression; mood

 

 

 

 

 

altered; changes

 

 

 

 

 

in libido

 

 

Nervous system

 

 

Migraine;

Exacerbation of

Exacerbation of

disorders

 

 

headache;

epilepsy

chorea

 

 

 

dizziness;

 

 

 

 

 

nervousness

 

 

Eye disorders

 

 

Intolerance to

 

 

 

 

 

contact lenses

 

 

 

 

 

 

 

 

Cardiac disorders

 

 

 

Myocardial

 

 

 

 

 

infarction

 

Respiratory, thoracic

 

 

 

Exacerbation of

 

and mediastinal

 

 

 

asthma

 

disorders

 

 

 

 

 

System organ class

 

 

 

Frequency of occurrence of adverse reactions

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

Common

 

Uncommon

 

Rare

 

 

Very rare

 

 

 

 

 

 

 

 

 

 

 

 

Gastrointestinal

 

 

 

 

Nausea

 

Pancreatitis;

 

 

disorders

 

 

 

 

 

 

ischemic

colitis;

 

 

 

 

 

 

 

 

 

vomiting

 

 

 

 

Skin and

 

Alopecia

 

Hirsutism; rash;

 

 

 

 

erythema

 

subcutaneous tissue

 

 

 

 

pruritus;

 

 

 

 

multiforme;

 

disorders

 

 

 

 

chloasma

 

 

 

 

erythema

 

 

 

 

 

 

 

 

 

 

 

nodosum

 

 

 

 

 

 

 

 

 

 

 

 

 

Musculoskeletal and

 

Arthralgia; leg

 

 

 

 

 

 

 

 

connective tissue

 

cramps

 

 

 

 

 

 

 

 

disorders

 

 

 

 

 

 

 

 

 

 

 

Reproductive system

 

Breast pain,

 

Change in

 

Pelvic pain

 

 

and breast disorders

 

tenderness,

 

cervical ectropion

 

 

 

 

 

 

 

enlargement,

 

and secretion

 

 

 

 

 

 

 

 

discharge;

 

 

 

 

 

 

 

 

 

 

leucorrhoea

 

 

 

 

 

 

 

 

Investigations

 

Changes in

 

 

 

 

 

 

Increases in blood

 

 

 

weight (increase

 

 

 

 

 

pressure

 

 

 

or decrease)

 

 

 

 

 

 

 

 

Adverse reactions that have been observed with bazedoxifene monotherapy

 

 

 

 

 

 

 

 

 

 

 

 

System organ class

 

 

 

Frequency of occurrence of adverse reactions

 

 

 

 

 

 

 

 

 

 

 

Very common

 

Common

Uncommon

 

 

Not known

 

 

 

 

 

 

 

 

 

 

 

 

Immune system

 

 

 

Hypersensitivity

 

 

 

 

 

 

disorders

 

 

 

 

 

 

 

 

 

 

 

Nervous system

 

 

 

Somnolence

 

 

 

 

 

 

disorders

 

 

 

 

 

 

 

 

 

 

 

Eye disorders

 

 

 

 

 

Retinal vein

 

 

 

 

 

 

 

 

 

 

thrombosis

 

 

 

 

Cardiac disorders

 

 

 

 

 

 

 

 

 

Palpitations

 

Vascular disorders

Hot flush

 

 

 

Deep vein

 

 

 

 

 

 

 

 

 

 

thrombosis,

 

 

 

 

 

 

 

 

 

 

thrombophlebitis

 

 

 

 

 

 

 

 

superficial

 

 

 

 

Respiratory,

 

 

 

 

 

Pulmonary

 

 

 

 

thoracic and

 

 

 

 

 

embolism

 

 

 

 

mediastinal

 

 

 

 

 

 

 

 

 

 

 

disorders

 

 

 

 

 

 

 

 

 

 

 

Gastrointestinal

 

 

 

Dry mouth

 

 

 

 

 

 

disorders

 

 

 

 

 

 

 

 

 

 

 

Skin and

 

 

 

Urticaria, rash,

 

 

 

 

 

 

subcutaneous tissue

 

 

 

pruritus

 

 

 

 

 

 

disorders

 

 

 

 

 

 

 

 

 

 

 

Musculoskeletal

Muscle

 

 

 

 

 

 

 

 

 

and connective

spasms

 

 

 

 

 

 

 

 

 

tissue disorders

(includes leg

 

 

 

 

 

 

 

 

 

 

cramps)

 

 

 

 

 

 

 

 

 

General disorders

Oedema

 

 

 

 

 

 

 

 

 

and administration

peripheral

 

 

 

 

 

 

 

 

 

site conditions

 

 

 

 

 

 

 

 

 

 

 

System organ class

 

Frequency of occurrence of adverse reactions

 

 

 

 

 

 

Very common

Common

Uncommon

Not known

 

 

 

 

 

Investigations

 

Blood triglycerides

 

 

 

 

increased, alanine

 

 

 

 

aminotransferase

 

 

 

 

increased; aspartate

 

 

 

 

aminotransferase

 

 

 

 

increased

 

 

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.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation 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 via the national reporting system listed in Appendix V.

4.9Overdose

In case of overdose of DUAVIVE, there is no specific antidote, and the treatment should reflect the symptoms.

Symptoms of overdose of oestrogen-containing medicinal products in adults and children may include nausea, vomiting, breast tenderness, dizziness, abdominal pain, drowsiness/fatigue; withdrawal bleeding may occur in females.

5.PHARMACOLOGICAL PROPERTIES

5.1Pharmacodynamic properties

Pharmacotherapeutic group: Sex hormones and modulators of the genital system; estrogens, combinations with other drugs; ATC code: G03CC07

Mechanism of action

DUAVIVE pairs CE with the selective oestrogen receptor modulator (SERM), bazedoxifene, which is defined as a tissue selective oestrogen complex (TSEC). The active ingredients of CE are primarily the sulphate esters of estrone, equilin sulphates and 17α/β- estradiol. These substitute for the loss of oestrogen production in menopausal women, and alleviate menopausal symptoms. As oestrogens promote the growth of the endometrium, unopposed oestrogens increase the risk of endometrial hyperplasia and cancer. The addition of bazedoxifene, acting as an oestrogen receptor antagonist in the uterus, greatly reduces the oestrogen-induced risk of endometrial hyperplasia in non-hysterectomised women.

Clinical trial information

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, CE 0.45 mg/bazedoxifene 20 mg significantly reduced the number and severity of hot flushes compared to placebo at weeks 4 and 12.

In one study, amenorrhea was reported in 97% of the women who received CE 0.45 mg/bazedoxifene 20 mg during months 10 to 12. Irregular bleeding and/or spotting was reported in the CE 0.45 mg/ bazedoxifene 20 mg group by 7% of women during the first 3 months of treatment and by 3% of women during months 10 to 12.

In another study, amenorrhea was reported in 95% of the women who received CE

0.45 mg/bazedoxifene 20 mg during months 10 to 12. Irregular bleeding and/or spotting was reported in the CE 0.45 mg/ bazedoxifene 20 mg group by 6% of women during the first 3 months of treatment and by 5% of women during months 10 to 12.

Breast density

CE 0.45 mg/bazedoxifene 20 mg demonstrated similar changes in mammographic breast density compared to placebo over 1 year of treatment.

Effects on bone mineral density (BMD)

In a 1 year study, CE 0.45 mg/bazedoxifene 20 mg showed a significant difference from baseline in lumbar spine BMD (+1.52%) at Month 12 compared to placebo. This change in BMD was similar to that shown with bazedoxifene 20 mg alone (+1.35%) and less than that seen with CE 0.45 mg/ medroxyprogesterone 1.5 mg (+2.58%) in the same study.

Elderly population

CE/bazedoxifene has not been studied in women aged 75 years or older. 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.

Paediatric population

The European Medicines Agency has waived the obligation to submit the results of studies with DUAVIVE in all subsets of the paediatric population for the conditions ‘treatment of oestrogen deficiency symptoms in postmenopausal women’ (see section 4.2).

5.2Pharmacokinetic 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 and bazedoxifene (baseline adjusted for total estrone) are summarised below.

Mean ± SD Steady-State Pharmacokinetic Parameters (n=24)

 

Cmax

Tmax

AUCss

 

(ng/mL)

(hr)

(ng hr/mL)

Bazedoxifene

6.9 ± 3.9

2.5 ± 2.1

71 ± 34

Baseline-adjusted total estrone

2.6 ± 0.8

6.5 ± 1.6

35 ± 12

Absorption

After a single dose of CE/bazedoxifene, bazedoxifene and baseline-adjusted total estrone were absorbed with a tmax 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 Cmax 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. Oestrogen dose proportionality was assessed in two studies of CE. Dose-proportional increases in both AUC and Cmax 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 (98% - 99%) to plasma proteins in vitro, but does not bind to sex hormone binding globulin (SHBG).

The distribution of exogenous oestrogens is similar to that of endogenous oestrogens. Oestrogens are widely distributed in the body and are generally found in higher concentrations in the sex hormone target organs. Oestrogens circulate in the blood largely bound to SHBG and albumin.

Biotransformation

The metabolic disposition of CE and bazedoxifene, after administration of CE/bazedoxifene, has not been studied.

Exogenous oestrogens are metabolised in the same manner as endogenous oestrogens. Circulating oestrogens 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 oestrogens exists as sulfate conjugates, especially estrone sulfate, which serves as a circulating reservoir for the formation of more active oestrogens.

The metabolic disposition of bazedoxifene in postmenopausal women has been determined following oral administration of 20 mg of radiolabeled bazedoxifene. Bazedoxifene is extensively metabolised in women. Glucuronidation is the major metabolic pathway. Little or no cytochrome P450-mediated metabolism is evident. Bazedoxifene-5-glucuronide is the major circulating metabolite. The concentrations of this glucuronide are approximately 10-fold higher than those of unchanged bazedoxifene in plasma.

Elimination

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 radiolabeled bazedoxifene is the faeces, and less than 1% of the dose is eliminated in urine.

Special populations

Elderly

The pharmacokinetics of CE/bazedoxifene have not been evaluated in women over 75 years of age. The pharmacokinetics of a 20 mg single dose of bazedoxifene were evaluated in a study in 26 healthy postmenopausal women. On average, compared to women 51 to 64 years of age (n=8), women 65 to 74 years of age (n=8) showed a 1.5-fold increase in AUC, and women 75 years of age (n=8) showed a 2.6-fold increase in AUC. This increase is most likely attributable to age-related changes in hepatic function.

Renal impairment

The pharmacokinetics of CE/bazedoxifene have not been evaluated in patients with renal impairment. Limited clinical data (n=5) for bazedoxifene are available in subjects with moderate renal impairment (creatinine clearance 50 ml/min). A single 20 mg dose of bazedoxifene was administered to these subjects. Negligible ( 1%) amounts of bazedoxifene are eliminated in urine. Impaired renal function showed little or no influence on bazedoxifene pharmacokinetics.

Hepatic impairment

The pharmacokinetics of CE/bazedoxifene have not been evaluated in women with hepatic impairment.

The disposition of a single 20 mg dose of bazedoxifene was compared in women with hepatic impairment (Child-Pugh Class A [n=6], B [n=6], and C [n=6]) and subjects with normal hepatic function (n=18). On average, women with hepatic impairment showed a 4.3-fold increase in AUC compared with controls. Safety and efficacy have not been evaluated further in women with hepatic insufficiency. Use of CE/bazedoxifene in this population is contraindicated (see sections 4.2, 4.3 and 4.4).

Body mass index (BMI)

In a pharmacokinetic study (n=24) BMI appeared to have little impact on systemic exposure to CE and bazedoxifene.

5.3Preclinical safety data

Carcinogenicity, mutagenicity, and impairment of fertility studies with CE/bazedoxifene have not been conducted. The following data are based on the findings in studies with bazedoxifene.

In 6-month carcinogenicity studies in transgenic mice, there was an increased incidence of benign, ovarian granulosa-cell tumours in female mice given 150 or 500 mg/kg/day. Systemic exposure (AUC) to bazedoxifene in these groups was 35 and 69 times that in postmenopausal women administered 20 mg/day for 14 days.

In a 2-year carcinogenicity study in rats, an increased incidence of benign, ovarian granulosa-cell tumours was observed in female rats at dietary concentrations of 0.03% and 0.1%. Systemic exposure (AUC) of bazedoxifene in these groups was 2.6 and 6.6 times that observed in postmenopausal women administered 20 mg/day for 14 days.

The observation of benign, ovarian granulosa-cell tumours in female mice and rats administered bazedoxifene is a class effect of SERMs related to its pharmacology in rodents when treated during their reproductive lives, when their ovaries are functional and responsive to hormonal stimulation.

Bazedoxifene caused corticomedullar nephrocalcinosis and enhanced spontaneous chronic progressive nephropathy (CPN) in male rats. Urine parameters were pathologically changed. In long-term studies, renal tumours (adenomas and carcinomas) were observed at all doses tested, most likely as a consequence of this chronic renal damage. Since chronic progressive nephropathy and corticomedullar nephrocalcinosis are most likely rat-specific nephropathies, these findings are presumably not relevant for humans. In the 2-year carcinogenicity study, bazedoxifene, administered orally in the diet to rats at dosages of 0%, 0.003%, 0.01%, 0.03%, or 0.1%, resulted in exposure ratios of 0.05 to 4 in males and 0.26 to 6.61 times in females respectively. In addition, based on surface area (mg/m2) dose ratios resulted in approximately 0.6 to 22 times and 1.0 to 29 times in males and females, respectively, the clinical dose of 20 mg.

Renal cell carcinomas were observed in an 18-month bone efficacy study in aged ovariectomized cynomolgus monkeys. These tumours are considered as spontaneous renal cell carcinomas that are known to occur in aged nonhuman primates and are unlikely to be relevant to humans. Bazedoxifene, administered orally to monkeys at dosages of 0, 0.2, 0.5, 1, 5, or 25 mg/kg/day, resulted in exposure ratios of 0.05 to 16.3 times, and dose ratios, based on surface area (mg/m2), of approximately 0.2 to 24 times the clinical dose of 20 mg, respectively.

Bazedoxifene was not genotoxic or mutagenic in a battery of tests, including in vitro bacterial reverse mutation assay, in vitro mammalian cell forward mutation assay at the thymidine kinase (TK /-) locus in L5178Y mouse lymphoma cells, in vitro chromosome aberration assay in Chinese hamster ovary (CHO) cells, and in vivo mouse micronucleus assay.

Reproductive toxicity and impairment of fertility studies with CE/bazedoxifene have not been conducted. The following data are based on the findings in studies with bazedoxifene.

In rabbit studies with bazedoxifene, abortion and an increased incidence of heart (ventricular septal defect) and skeletal system (ossification delays, misshapen or misaligned bones, primarily of the spine and skull) anomalies in the fetuses were present at maternally toxic dosages of 0.5 mg/kg/day

(1.5 times the human exposure). Treatment of rats with bazedoxifene at maternally toxic

dosages 1 mg/kg/day ( 0.4 times the human dose based on body surface area) resulted in reduced numbers of live foetuses and/or reductions in foetal body weights. No foetal developmental anomalies were observed.

Female rats were administered daily dosages of 0.3 to 30 mg/kg (0.15 to 14.6 times the human dose based on body surface area, mg /m2 [20 mg/kg dosage in humans is 12.3 mg/m2]) prior to and during mating with untreated males. Oestrous cycles and fertility were adversely affected in all bazedoxifene- treated female groups.

6.PHARMACEUTICAL PARTICULARS

6.1List of excipients

Conjugated oestrogens tablet core

Lactose monohydrate

Microcrystalline cellulose

Powdered cellulose

Hypromellose 2208 (100,000 mPa•s)

Magnesium stearate

Calcium phosphate

Inert filler coating

Sucrose

Microcrystalline cellulose

Hydroxypropylcellulose

Hypromellose 2910 (6 mPa•s) (E464)

Hypromellose 2910 (15 mPa•s)

Macrogol 400

Bazedoxifene active coating

Sucrose

Hypromellose 2910 (3 mPa•s)

Sucrose monopalmitate

Ascorbic acid

Colour coating

Hypromellose 2910 (6 mPa•s)

Titanium dioxide (E171)

Macrogol 400

Iron oxide red (E172)

Clear coating

Hydroxyethylcellulose

Povidone (E1201)

Polydextrose (E1200)

Maltitol liquid

Poloxamer 188

Printing ink

Iron oxide black (E172)

Isopropyl alcohol

Propylene glycol (E1520)

Hypromellose 2910 (6 mPa•s)

6.2Incompatibilities

Not applicable.

6.3Shelf life

3 years

After opening the blister pouch, use within 60 days.

6.4Special precautions for storage

Do not store above 25ºC.

Store in the original package in order to protect from moisture.

6.5Nature and contents of container

UPVC/ Monochlorotrifluorethylene blister packs containing 28 modified-release tablets.

6.6Special precautions for disposal

No special requirements for disposal.

7.MARKETING AUTHORISATION HOLDER

Pfizer Ltd

Ramsgate Road

Sandwich

Kent CT13 9NJ

United Kingdom

8.MARKETING AUTHORISATION NUMBER(S)

EU/1/14/960/001

9.DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

Date of first authorisation: 16 December 2014

10.DATE OF REVISION OF THE TEXT

Detailed information on this medicinal product is available on the website of the European Medicines Agency http://www.ema.europa.eu/.

Comments

A B C D E F G H I J K L M N O P Q R S T U V W X Y Z
  • Help
  • Get it on Google Play
  • About
  • Info on site by:

  • Presented by RXed.eu

  • 27558

    prescription drugs listed