Duavive

HOS-096036 · has-adverse-reaction-information · PDF-Seite 9

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). 9  System organ Frequency of occurrence of adverse reactions class Very common Common Uncommon Rare Infections and Vulvovaginal infestations candidiasis Vascular Venous disorders 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. The increased risk to users of oestrogen-only therapy is lower than that seen in users of oestrogen– progestagen combinations. The level of risk

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HOS-096032 · has-contraindication-information · PDF-Seite 3

- 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.

HOS-096031 · has-indication-information · PDF-Seite 2

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.

HOS-096034 · has-interaction-information · PDF-Seite 7

Results from a clinical drug-drug interaction study conducted with CE/BZA and from interaction studies with CE or bazedoxifene monotherapy are summarised below. 7 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. Effect of HRT with oestrogens on other medicinal products Hormone contraceptives containing oestrogens have been shown to significantly decrease plasma concentrations of lamotrigine when co-administered due to induction of lamotrigine glucuronidation. This may reduce seizure control. Although the potential interaction between hormone replacement therapy and lamotrigine has not been studied, it is expected that a similar interaction exists, which may lead to a reduction in seizure control among women taking both medicinal products together. 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 med

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HOS-096035 · has-pregnancy-information · PDF-Seite 8

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. 8 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.

HOS-096033 · has-warning-information · PDF-Seite 3

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 3 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 deteriorat

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