Duavive - summary of medicine characteristics

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), 62.9 mg lactose (as monohydrate), 0.2 mg maltitol liquid, 0.0176 mg glucose, and 0.0088 mg sorbitol

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 PARTICULARS4.1 Therapeutic indications

DUAVIVE is indicated for the 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.

4.2 Posology and method of administration

Posology

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

The recommended dose is 0.45 mg conjugated oestrogens (CE) and 20 mg bazedoxifene (BZA) 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

CE/BZA 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/BZA 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/BZA 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 CE/BZA in the paediatric population.

Method of administration

Oral use.

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

4.3 Contraindications

• – 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.

• – CE/BZA must not be taken by women of childbearing potential, or breast-feeding women (see sections 4.6 and 5.3).

• – Porphyria.

4.4 Special warnings and precautions for use

For the treatment of postmenopausal symptoms, CE/BZA 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 CE/BZA should not be taking progestins, additional oestrogens or selective oestrogen receptor modulators (SERMs).

DUAVIVE (CE/BZA) has not been studied in the treatment of premature menopause.

Medical examination/follow-up

Before initiating or reinstituting treatment with CE/BZA, 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 precautions 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 CE/BZA, 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 CE/BZA should not take additional oestrogens as this may increase the risk of endometrial hyperplasia and endometrial carcinoma.

The addition of bazedoxifene in CE/BZA 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 shows an increased risk of breast cancer in women taking oestrogen-only HRT that is dependent on the duration of taking HRT.

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 in oestrogen only users diagnosed that is lower than that found in users of oestrogen-progestagen combinations (see section 4.8).

Results from a large meta-analysis showed that after stopping treatment, the excess risk will decrease with time and the time needed to return to baseline depends on the duration of prior HRT use. When HRT was taken for more than 5 years, the risk may persist for 10 years or more.

An observational study with an average follow-up time of 22 months showed that the risk of breast cancer among users of CE/BZA might be in the same range as among users of oestrogen-progestin combination hormone therapy. The long-term effect of CE/BZA on the risk of breast cancer remains unknown (see section 5.1).

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 Hormone Replacement Therapy (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 CE/BZA 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/BZA, cases of VTE have been reported (see section 4.8). Should a VTE event occur or be suspected, CE/BZA 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. CE/BZA 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 CE/BZA 4 to 6 weeks earlier is recommended. Treatment should not be restarted until the woman is completely mobilised. In addition, women taking CE/BZA 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, CE/BZA 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).

An observational study with an average follow-up time of 10–11 months showed that the risk of stroke among users of CE/BZA might be in the same range as among users of oestrogen-progestin combination hormone therapy. The long-term effect of CE/BZA on the risk of stroke remains unknown (see section 5.1).

Should a stroke occur or be suspected, CE/BZA 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 CE/BZA.

• – Patients with terminal renal insufficiency should be closely monitored, since it is expected that the level of circulating oestrogens components of CE/BZA 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/BZA 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/BZA 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/BZA 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, CE/BZA should be discontinued.

• – 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). Patients treated with CE/BZA should be monitored carefully for signs of development of gallbladder disease.

• – 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).

4.5 Interaction with other medicinal products and other forms of interaction

Results from a clinical drug-drug interaction study conducted with CE/BZA 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 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/BZA 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

The metabolism of bazedoxifene may be increased by concomitant use of substances known to induce uridine diphosphate glucuronosyltran­sferases (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 (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.

4.6 Fertility, pregnancy and lactation

Pregnancy

CE/BZA 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 CE/BZA in pregnant women. If pregnancy occurs during treatment with CE/BZA, 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

CE/BZA 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/BZA combination.

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

4.7 Effects on ability to drive and use machines

CE/BZA 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.

4.8 Undesirable effects

Summary of the safety profile

The most commonly reported adverse reaction 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/BZA (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 class	Frequency of occurrence of adverse reactions
	Very common	Common	Uncommon	Rare
Infections and infestations		Vulvovaginal candidiasis
Vascular disorders				Venous thromboembolic events (including, pulmonary embolism, retinal vein thrombosis, deep vein thrombosis and thrombophlebitis)
Gastrointestinal disorders	Abdominal pain	Constipation; diarrhoea; nausea
Hepatobiliary disorders			Cholecystitis
Musculoskeletal and connective tissue disorders		Muscle spasms

System organ class	Frequency of occurrence of adverse reactions
	Very common	Common	Uncommon	Rare
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. The increased risk to users of oestrogen-only therapy is lower than that seen in users of oestrogenproges­tagen combinations. The level of risk is dependent on duration of use (see section 4.4). Absolute risk estimations based on the results of the largest randomised placebo-controlled trial (WHI-study) and the largest meta-analysis of prospective epidemiological studies are presented.

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

Age range (years)	Incidence per 1,000 women in placebo arm over 5 years	Risk ratio & 95% CI	Additional cases per 1,000 ET users over 5 years (95% CI)
CE Oestrogen only
50–79	21	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

Largest meta-analysis of prospective epidemiological studies

Estimated additional risk of breast cancer after 5 years’ use in women with BMI 27 (kg/m2)

Age at start HRT (years)	Incidence per 1,000 never-users of HRT over a 5 year period (50–54 years)	Risk ratio	Additional cases per 1,000 HRT users after 5 years
Oestrogen only
50	13.3	1.2	2.7

Taken from baseline incidence rates in England in 2015 in women with BMI 27

Note: Since the background incidence of breast cancer differs by EU country, the number of additional cases of breast cancer will also change proportionately.

Estimated additional risk of breast cancer after 10 years’ use in women with BMI 27 (kg/m2)

Age at start HRT (years)	Incidence per 1,000 never-users of HRT over a 10 year period (50–59 years)	Risk ratio	Additional cases per 1,000 HRT users after 10 years
Oestrogen only
50	26.6	1.3	7.1

Taken from baseline incidence rates in England in 2015 in women with BMI 27

Note: Since the background incidence of breast cancer differs by EU country, the number of additional cases of breast cancer will also change proportionately.

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.

CE/BZA 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 in placebo arm over 5 years	Risk ratio & 95%CI	Additional cases per 1,000 ET users
Oral oestrogen-only*
50–59	7	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 in placebo arm over 5 years	Risk ratio & 95%CI	Additional cases per 1,000 HRT users over 5 years
50–59	8	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 categorised 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 infestations		Vaginitis
Neoplasms benign, malignant and unspecified (incl. cysts and polyps)			Growth potentiation of benign meningioma; fibrocystic breast disease	Enlargement of hepatic haemangiomas
Immune system disorders		Hypersensitivity	Angioedema; anaphylactic/ana phylactoid reactions; urticaria
Metabolism and nutrition disorders			Glucose intolerance	Exacerbation of porphyria; hypocalcaemia (in patients with disease that can predispose to severe hypocalcaemia)
Psychiatric disorders		Dementia; depression; mood altered; changes in libido	Irritability
Nervous system disorders		Migraine; headache; dizziness; nervousness	Exacerbation of epilepsy	Exacerbation of chorea
Eye disorders		Intolerance to contact lenses
Cardiac disorders			Myocardial infarction
Respiratory, thoracic and mediastinal disorders			Exacerbation of asthma
Gastrointestinal disorders		Nausea	Pancreatitis; ischaemic colitis; vomiting
Skin and subcutaneous tissue disorders	Alopecia	Hirsutism; rash; pruritus; chloasma		Erythema multiforme; erythema nodosum
Musculoskeletal and connective tissue disorders	Arthralgia; leg cramps

System organ class	Frequency of occurrence of adverse reactions
	Common	Uncommon	Rare	Very rare
Reproductive system and breast disorders	Breast pain, tenderness, enlargement, discharge; leucorrhoea	Change in cervical ectropion and secretion	Pelvic pain
Investigations	Changes in weight (increase or decrease)			Increases in blood pressure

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 disorders		Hypersensitivity
Nervous system disorders		Somnolence
Eye disorders			Retinal vein thrombosis	Visual acuity reduced, blurred vision, photopsia, visual field defect, visual impairment, dry eye, eyelid oedema, blepharospasm, eye pain and eye swelling
Cardiac disorders				Palpitations
Vascular disorders	Hot flush		Deep vein thrombosis, thrombophlebitis superficial
Respiratory, thoracic and mediastinal disorders			Pulmonary embolism
Gastrointestinal disorders		Dry mouth
Skin and subcutaneous tissue disorders		Urticaria, rash, pruritus
Musculoskeletal and connective tissue disorders	Muscle spasms (includes leg cramps)
General disorders and administration site conditions	Oedema peripheral

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

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.

4.9 Overdose

There is no specific antidote. In case of overdose it is recommended that the patient be monitored for any signs or symptoms of adverse reactions and appropriate symptomatic treatment be instituted immediately.

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 PROPERTIES5.1 Pharmacodynamic properties

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

Mechanism of action

CE/BZA pairs CE with the selective oestrogen receptor modulator (SERM), BZA, 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 17a/p-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 efficacy and safety

CE/BZA was evaluated in 4,868 postmeno­pausal women who participated in 5 phase 3 trials. Among these, 1,585 women were treated with CE 0.45 mg/BZA 20 mg and 1,241 received placebo. Longterm exposure to CE/BZA for up to 2 years was evaluated; 3,322 women were exposed to CE/BZA for at least 1 year, and 1,999 women were exposed for 2 years.

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/BZA 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/BZA 20 mg during months 10 to 12. Irregular bleeding and/or spotting was reported in the CE 0.45 mg/BZA 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 96% of the women who received CE 0.45 mg/BZA 20 mg during months 10 to 12. Irregular bleeding and/or spotting was reported in the CE 0.45 mg/BZA 20 mg group by 8% of women during the first 3 months and by 4% of women during months 10 to 12.

Breast density

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

Risk of Breast Cancer

In an observational study of new users from five large US insurance claims databases with an average follow-up time of 22 months, the incidence rate of breast cancer among users of CE/BZA was 27.21/10,000 person-years (95% CI: 19.91, 34.51) based on 55 cases. The incidence rate among users of oestrogen-progestin combination hormone therapy was 36.33/10,000 person-years (95% CI: 30.42, 42.24) based on 231 cases. The long-term effect of CE/BZA on the risk of breast cancer remains unknown.

Risk of stroke

In an observational study of new users from five large US insurance claims databases with an average follow-up time of 10–11 months, the incidence rate of stroke among users of CE/BZA was 14.04/10,000 person-years (95% CI: 1.03, 27.05) based on 15 cases. The incidence rate among users of oestrogen-progestin combination hormone therapy was 13.36/10,000 person-years (95% CI: 7.11, 19.61) based on 41 cases. The long-term effect of CE/BZA on the risk of stroke remains unknown.

Effects on bone mineral density (BMD)

In a 1 year study, CE 0.45 mg/BZA 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

Of the total number of women in phase 3 clinical trials who received CE/BZA 20 mg, 2.4% (n=77) were aged >65 years. No overall differences in safety or efficacy 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 CE/BZA in all subsets of the paediatric population in the ‘treatment of oestrogen deficiency symptoms in postmenopausal women’ (see section 4.2 for information on paediatric use).

5.2 Pharmacokinetic properties

Pharmacokinetic studies for CE/BZA were conducted in healthy postmenopausal women who were naturally postmenopausal or who had undergone bilateral oophorectomy.

Following multiple doses of CE 0.45 mg/BZA 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 (ng/mL)	Tmax (hr)	AUCss (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/BZA, 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/BZA 20 mg were administered with a high-fat meal, bazedoxifene Cmax was unaffected, but Area Under Curve (AUC) increased by approximately 25%. Food had little or no effect on the exposure of CE.

CE/BZA can be administered with or without food.

Following administration of BZA 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 BZA 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/BZA has not been studied.

Following intravenous administration of a 3 mg dose of BZA alone, the volume of distribution is 14.7 ±3.9 l/kg. BZA 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 BZA, after administration of CE/BZA, has not been studied.

Circulating oestrogens exist in a dynamic equilibrium of metabolic interconversions. 17p—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 BZA. BZA 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 BZA in plasma.

Elimination

After a single dose of CE/BZA, baseline-adjusted total estrone (representing CE) is eliminated with a half-life of approximately 17 hours. BZA 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, 17p-estradiol, estrone, and estriol are excreted in the urine, along with glucuronide and sulfate conjugates.

The clearance of BZA is 0.4 ±0.1 L/h/kg based on intravenous administration. The major route of excretion of radiolabeled BZA is the faeces, and less than 1% of the dose is eliminated in urine.

Special populations

Elderly

The pharmacokinetics of CE/BZA have not been evaluated in women over 75 years of age.

The pharmacokinetics of a 20 mg single dose of BZA 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/BZA have not been evaluated in patients with renal impairment.

Limited clinical data (n=5) for bazedoxifene monotherapy are available in subjects with moderate renal impairment (creatinine clearance <50 ml/min). A single 20 mg dose of BZA was administered to these subjects. Negligible (<1%) amounts of BZA are eliminated in urine. Impaired renal function showed little or no influence on bazedoxifene pharmacokinetics.

Hepatic impairment

The pharmacokinetics of CE/BZA 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/BZA 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 BZA.

5.3 Preclinical safety data

Carcinogenicity, mutagenicity, and impairment of fertility studies with CE/BZA 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 elicited male rat-specific nephropathies (corticomedullar nephrocalcinosis and enhanced spontaneous chronic progressive nephropathy) and associated adenomas and carcinomas at exposure ratios of 0.05 to 4 times, and dose ratios, based on surface area (mg/m2), of approximately 0.6 to 22 times the clinical dose of 20 mg. These findings are considered rat-specific and presumably not relevant in humans. Renal cell carcinomas were observed in an 18-month bone efficacy study in aged ovariectomised cynomolgus monkeys at 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. These tumours are known to occur in aged nonhuman primates and were considered spontaneous in the aged monkeys and irrelevant to humans.

BZA 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/BZA have not been conducted. The following data are based on the findings in studies with BZA.

In rabbit studies with BZA, 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 BZA 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 PARTICULARS6.1 List of excipients

Conjugated oestrogens tablet core

Lactose monohydrate

Microcrystalline cellulose

Powdered cellulose

Hypromellose 2208 (100,000 mPa^s) (E464)

Magnesium stearate

Calcium phosphate

Inert filler coating

Sucrose

Microcrystalline cellulose

Hydroxypropyl­cellulose

Hypromellose 2910 (6 mPa^s) (E464)

Hypromellose 2910 (15 mPa^s) (E464)

Macrogol (400)

Bazedoxifene active coating

Sucrose

Hypromellose 2910 (3 mPa^s) (E464)

Sucrose monopalmitate

Ascorbic acid

Colour coating

Hypromellose 2910 (6 mPa^s) (E464)

Titanium dioxide (E171)

Macrogol (400)

Red Iron oxide (E172)

Clear coating

Hydroxyethylce­llulose

Povidone (E1201)

Polydextrose (E1200) (contains glucose and sorbitol)

Maltitol liquid

Poloxamer 188

Printing ink

Black Iron oxide (E172)

Propylene glycol (E1520)

Hypromellose 2910 (6 mPa^s)

6.2 Incompatibilities

Not applicable.

6.3 Shelf life

3 years

After opening the blister pouch, use within 60 days.

6.4 Special precautions for storage

Do not store above 25°C.

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

6.5 Nature and contents of container

PVC/Aclar/PVC blister packs containing 28 modified-release tablets.

6.6 Special precautions for disposal

No special requirements for disposal.

7. MARKETING AUTHORISATION HOLDER

Pfizer Europe MA EEIG

Boulevard de la Plaine 17

1050 Bruxelles

Belgium

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

Date of latest renewal: 11 November 2019