Silapo · 4.1 Therapeutic indications · 1

HOS-094640 · has-adverse-reaction-information · PDF-Seite 15

Summary of the safety profile The most frequent adverse drug reaction during treatment with epoetin alfa is a dose-dependent increase in blood pressure or aggravation of existing hypertension. Monitoring of the blood pressure should be performed, particularly at the start of therapy (see section 4.4). The most frequently occurring adverse drug reactions observed in clinical trials of epoetin alfa are diarrhoea, nausea, vomiting, pyrexia and headache. Influenza-like illness may occur especially at the start of treatment. Respiratory tract congestion, which includes events of upper respiratory tract congestion, nasal congestion and nasopharyngitis, have been reported in studies with extended interval dosing in adult patients with renal insufficiency not yet undergoing dialysis. An increased incidence of thrombotic vascular events (TVEs) has been observed in patients receiving ESAs (see section 4.4). Tabulated list of adverse reactions Of a total 3 417 subjects in 25 randomised, double-blinded, placebo or standard of care controlled studies, the overall safety profile of epoetin alfa was evaluated in 2 094 anaemic subjects. Included were 228 epoetin alfa-treated CRF subjects in 4 chronic renal failure studies (2 studies in predialysis [N = 131 exposed CRF subjects] and 2 in dialysis [N = 97 exposed CRF subjects]); 1 404 exposed cancer subjects in 16 studies of anaemia due to chemotherapy; 147 exposed subjects in 2 studies for autologous blood donation; 213 exposed subjects in 1 study in the perisurgical period, and 102 exposed subjects in 2 MDS studies. Adverse drug reactions reported by ≥1% of subjects treated with epoetin alfa in these trials are shown in the table below. Frequency estimate: 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). 15  MedDRA System Organ Adverse Reaction (Preferred Term Frequency Classification (SOC) Level) Blood and lymphatic system Pure red cell aplasia3, Rare disorders Thrombocythemia Metabolism and nutrition Hyperkalaemia1 Uncommon disorders Immune system disorders Hypersensitivity3 Uncommon

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HOS-094636 · has-contraindication-information · PDF-Seite 10

Hypersensitivity to the active substance or to any of the excipients listed in section 6.1. Patients who develop pure red cell aplasia (PRCA) following treatment with any erythropoietin should not receive Silapo or any other erythropoietin (see section 4.4 - Pure Red Cell Aplasia (PRCA)). Uncontrolled hypertension. All contraindications associated with autologous blood predonation programmes should be respected in patients being supplemented with Silapo. The use of Silapo in patients scheduled for major elective orthopaedic surgery and not participating in an autologous blood predonation programme is contraindicated in patients with severe coronary, peripheral arterial, carotid or cerebral vascular disease, including patients with recent myocardial infarction or cerebral vascular accident. Surgery patients who for any reason cannot receive adequate antithrombotic prophylaxis.

HOS-094635 · has-indication-information · PDF-Seite 3

Silapo is indicated for the treatment of symptomatic anaemia associated with chronic renal failure (CRF): • in adults and paediatrics aged 1 to 18 years on haemodialysis and adult patients on peritoneal dialysis (see section 4.4). 3 • in adults with renal insufficiency not yet undergoing dialysis for the treatment of severe anaemia of renal origin accompanied by clinical symptoms in patients (see section 4.4). Silapo is indicated in adults receiving chemotherapy for solid tumours, malignant lymphoma or multiple myeloma, and at risk of transfusion as assessed by the patient's general status (e.g. cardiovascular status, pre-existing anaemia at the start of chemotherapy) for the treatment of anaemia and reduction of transfusion requirements. Silapo is indicated in adults in a predonation programme to increase the yield of autologous blood. Treatment should only be given to patients with moderate anaemia (haemoglobin [Hb] concentration range between 10 and 13 g/dL [6.2 and 8.1 mmol/L], no iron deficiency) if blood saving procedures are not available or insufficient when the scheduled major elective surgery requires a large volume of blood (4 or more units of blood for females or 5 or more units for males). Silapo is indicated for non-iron deficient adults prior to major elective orthopaedic surgery having a high perceived risk for transfusion complications to reduce exposure to allogeneic blood transfusions. Use should be restricted to patients with moderate anaemia (e.g. haemoglobin concentration range between 10 and 13 g/dL or 6.2 and 8.1 mmol/L) who do not have an autologous predonation programme available and with expected moderate blood loss (900 to 1 800 mL). Silapo is indicated for the treatment of symptomatic anaemia (haemoglobin concentration of ≤10 g/dL) in adults with low- or intermediate-1-risk primary myelodysplastic syndromes (MDS) who have low serum erythropoietin (<200 mU/mL).

HOS-094638 · has-interaction-information · PDF-Seite 14

No evidence exists that indicates that treatment with erythropoietin alters the metabolism of other medicinal products. Medicinal products that decrease erythropoiesis may decrease the response to Silapo. Since ciclosporin is bound by RBCs there is potential for a drug interaction. If Silapo is given concomitantly with ciclosporin, blood levels of ciclosporin should be monitored and the dose of ciclosporin adjusted as the haematocrit rises. No evidence exists that indicates an interaction between Silapo and G-CSF or GM-CSF with regard to haematological differentiation or proliferation of tumour biopsy specimens in vitro. In female adult patients with metastatic breast cancer, subcutaneous co-administration of 40 000 IU/mL epoetin alfa with trastuzumab 6 mg/kg had no effect on the pharmacokinetics of trastuzumab.

HOS-094639 · has-pregnancy-information · PDF-Seite 14

14 Pregnancy There are no adequate and well-controlled studies in pregnant women. Studies in animals have shown reproduction toxicity (see section 5.3). Consequently, epoetin zeta should be used in pregnancy only if the potential benefit outweighs the potential risk to the foetus. The use of epoetin zeta is not recommended in pregnant surgical patients participating in an autologous blood predonation. Breast-feeding It is not known whether exogenous epoetin zeta is excreted in human milk. Epoetin zeta should be used with caution in nursing women. A decision on whether to continue/discontinue breast-feeding or to continue/discontinue therapy with epoetin zeta should be made taking into account the benefit of breast-feeding to the child and the benefit of epoetin zeta therapy to the woman. The use of epoetin zeta is not recommended in lactating surgical patients participating in an autologous blood predonation programme. Fertility There are no studies assessing the potential effect of epoetin zeta on male or female fertility.

HOS-094637 · has-warning-information · PDF-Seite 10

Traceability In order to improve the traceability of biological medicinal products, the name and the batch number of the administered product should be clearly recorded. 10 General In all patients receiving Silapo, blood pressure should be closely monitored and controlled as necessary. Silapo should be used with caution in the presence of untreated, inadequately treated or poorly controllable hypertension. It may be necessary to add or increase anti-hypertensive treatment. If blood pressure cannot be controlled, Silapo treatment should be discontinued. Hypertensive crisis with encephalopathy and seizures, requiring the immediate attention of a physician and intensive medical care, have occurred also during epoetin alfa treatment in patients with previously normal or low blood pressure. Particular attention should be paid to sudden stabbing migraine-like headaches as a possible warning signal (see section 4.8). Silapo should be used with caution in patients with epilepsy, history of seizures, or medical conditions associated with a predisposition to seizure activity such as CNS infections and brain metastases. Silapo should be used with caution in patients with chronic liver failure. The safety of Silapo has not been established in patients with hepatic dysfunction. An increased incidence of thrombotic vascular events (TVEs) has been observed in patients receiving ESAs (see section 4.8). These include venous and arterial thrombosis and embolism (including some with fatal outcomes), such as deep venous thrombosis, pulmonary emboli, retinal thrombosis, and myocardial infarction. Additionally, cerebrovascular accidents (including cerebral infarction, cerebral haemorrhage and transient ischaemic attacks) have been reported. The reported risk of these TVEs should be carefully weighed against the benefits to be derived from treatment with Silapo particularly in patients with pre-existing risk factors for TVE, including obesity and prior history of TVEs (e.g., deep venous thrombosis, pulmonary embolism, and cerebral vascular accident). In all patients, haemoglobin levels should be closely monitored due to a potential increased risk of thromboembolic events and fatal outcomes when patients are treated at haemoglobin levels above the concentration range for the indication of use. There may be a moderate dose-dependent rise in the platelet count within the normal range during treatment with Silapo. This re

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