Raloxifene Teva · 4.8 Undesirable effects · 1

HOS-154602 · has-adverse-reaction-information · PDF-Seite 5

a. Summary of the safety profile The clinically most important adverse reactions reported in postmenopausal women treated with Raloxifen were venous thromboembolic events (see section 4.4), which occurred in less than 1% of treated patients. b. Tabulated summary of adverse reactions The table below gives the adverse reactions and frequencies observed in treatment and prevention studies involving over 13,000 postmenopausal women along with adverse reactions arising from postmarketing reports. The duration of the treatment in these studies ranged from 6 to 60 months. The majority of adverse reactions have not usually required cessation of therapy. The frequencies for postmarketing reports were calculated from placebo-controlled clinical trials (comprising a total of 15,234 patients, 7,601 on raloxifene 60 mg and 7,633 on placebo) in postmenopausal women with osteoporosis, or established coronary heart disease (CHD) or increased risk for CHD, without comparison to the frequencies of adverse events in the placebo assignment groups. In the prevention population discontinuations of therapy due to any adverse reaction occurred in 10.7 % of 581 raloxifene treated patients and 11.1 % of 584 placebo-treated patients. In the treatment population discontinuations of therapy due to any clinical adverse event occurred in 12.8 % of 2,557 raloxifene treated patients and 11.1 % of 2,576 placebo treated patients. The following convention has been used for the classification of the adverse reactions: 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), not known (cannot be estimated from the available data). Blood and lymphatic system disorders Uncommon: Thrombocytopeniaa Nervous system disorders Common: Headache, including migrainea Uncommon: Fatal strokes Vascular disorders Very common: Vasodilation (hot flushes) Uncommon: Venous thromboembolic events, including deep vein thrombosis, pulmonary embolism, retinal vein thrombosis, superficial vein thrombophlebitis, Arterial thromboembolic reactionsa Gastrointestinal disorders Very common: Gastrointestinal symptomsa such as nausea, vomiting, abdominal pain, dyspepsia Skin and subcutaneous tissue disorders Common: Rasha Musculoskeletal and connective tissue disorders 5  Common: Leg cramps Reproductive system and breast disorders Common: Mild breast symptomsa such as p

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HOS-154598 · has-contraindication-information · PDF-Seite 3

Hypersensitivity to the active substance or to any of the excipients listed in section 6.1. Must not be used in women with child bearing potential. Active or past history of venous thromboembolic events (VTE), including deep vein thrombosis, pulmonary embolism and retinal vein thrombosis. Hepatic impairment including cholestasis. Severe renal impairment. Unexplained uterine bleeding. Raloxifene should not be used in patients with signs or symptoms of endometrial cancer as safety in this patient group has not been adequately studied.

HOS-154597 · has-indication-information · PDF-Seite 2

Raloxifene is indicated for the treatment and prevention of osteoporosis in postmenopausal women. A significant reduction in the incidence of vertebral, but not hip fractures has been demonstrated. When determining the choice of raloxifene or other therapies, including oestrogens, for an individual postmenopausal woman, consideration should be given to menopausal symptoms, effects on uterine and breast tissues, and cardiovascular risks and benefits (see section 5.1).

HOS-154600 · has-interaction-information · PDF-Seite 4

Concurrent administration of either calcium carbonate or aluminium and magnesium-hydroxide containing antacids do not affect the systemic exposure of raloxifene. Co-administration of raloxifene and warfarin does not alter the pharmacokinetics of either compound. However, modest decreases in the prothrombin time have been observed, and if raloxifene is given concurrently with warfarin or other coumarin derivatives, the prothrombin time should be monitored. Effects on prothrombin time may develop over several weeks if raloxifene treatment is started in patients who are already on coumarin anticoagulant therapy. Raloxifene has no effect on the pharmacokinetics of methylprednisolone given as a single dose. Raloxifene does not affect the steady-state AUC of digoxin. The Cmax of digoxin increased by less than 5 %. The influence of concomitant medication on raloxifene plasma concentrations was evaluated in the prevention and treatment trials. Frequently co-administered medicinal products included: paracetamol, non-steroidal anti-inflammatory drugs (such as acetylsalicylic acid, ibuprofen, and naproxen), oral antibiotics, H1 antagonists, H2 antagonists, and benzodiazepines. No clinically relevant effects of the co-administration of the agents on raloxifene plasma concentrations were identified. Concomitant use of vaginal oestrogen preparations was allowed in the clinical trial programme, if necessary to treat atrophic vaginal symptoms. Compared to placebo there was no increased use in raloxifene treated patients. In vitro, raloxifene did not interact with the binding of warfarin, phenytoin, or tamoxifen. Raloxifene should not be co-administered with cholestyramine (or other anion exchange resins), which significantly reduces the absorption and enterohepatic cycling of raloxifene. Peak concentrations of raloxifene are reduced with co-administration with ampicillin. However, since the overall extent of absorption and the elimination rate of raloxifene are not affected, raloxifene can be concurrently administered with ampicillin. Raloxifene modestly increases hormone-binding globulin concentrations, including sex steroid binding globulins (SHBG), thyroxine binding globulin (TBG), and corticosteroid binding globulin (CBG), with corresponding increases in total hormone concentrations. These changes do not affect concentrations of free hormones.

HOS-154601 · has-pregnancy-information · PDF-Seite 4

Pregnancy Raloxifene is only for use in postmenopausal women. 4 Raloxifene must not be taken by women of child bearing potential. Raloxifene may cause foetal harm when administered to a pregnant woman. If this medicinal product is used mistakenly during pregnancy or the patient becomes pregnant while taking it, the patient should be informed of the potential hazard to the foetus (see section 5.3). Breast-feeding It is not known whether raloxifene is excreted in human milk. Its clinical use, therefore, cannot be recommended in breast-feeding women. Raloxifene may affect the development of the baby.

HOS-154599 · has-warning-information · PDF-Seite 3

Raloxifene is associated with an increased risk for venous thromboembolic events that is similar to the reported risk associated with current use of hormone replacement therapy. The risk-benefit balance should be considered in patients at risk of venous thromboembolic events of any aetiology. Raloxifene should be discontinued in the event of an illness or a condition leading to a prolonged period of immobilisation. Discontinuation should happen as soon as possible in case of the illness, or from 3 days before the immobilisation occurs. Therapy should not be restarted until the initiating condition has resolved and the patient is fully mobile. In a study of postmenopausal women with documented coronary heart disease or at increased risk for coronary events, raloxifene did not affect the incidence of myocardial infarction, hospitalized acute coronary syndrome, overall mortality, including overall cardiovascular mortality, or stroke, compared to placebo. However, there was an increase in death due to stroke in women assigned to raloxifene. The incidence of stroke mortality was 1.5 per 1000 women per year for placebo versus 2.2 per 1000 women per year for raloxifene. This finding should be considered when prescribing raloxifene for postmenopausal women with a history of stroke or other significant stroke risk factors, such as transient ischemic attack or atrial fibrillation. There is no evidence of endometrial proliferation. Any uterine bleeding during raloxifene therapy is unexpected and should be fully investigated by a specialist. The two most frequent diagnoses associated with uterine bleeding during raloxifene treatment were endometrial atrophy and benign endometrial polyps. In postmenopausal women who received raloxifene treatment for 4 years, benign endometrial polyps were reported in 0.9 % compared to 0.3 % in women who received placebo treatment. Raloxifene is metabolised primarily in the liver. Single doses of raloxifene given to patients with cirrhosis and mild hepatic impairment (Child-Pugh class A) produced plasma concentrations of raloxifene which were approximately 2.5 times the controls. The increase correlated with total bilirubin concentrations. Until safety and efficacy have been evaluated further in patients with hepatic insufficiency, the use of raloxifene is not recommended in this patient population. Serum total bilirubin, gamma-glutamyl transferase, alkaline phosphatase, ALT and AST should be closely monitored during treatment if ele

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