SILAPO Solution for injection in pre-filled syringe Ref.[49811] Active ingredients: Epoetin zeta

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 regresses during the course of continued therapy. In addition, thrombocythaemia above the normal range has been reported. It is recommended that the platelet count is regularly monitored during the first 8 weeks of therapy.

All other causes of anaemia (iron, folate or Vitamin B12 deficiency, aluminium intoxication, infection or inflammation, blood loss, haemolysis and bone marrow fibrosis of any origin) should be evaluated and treated prior to initiating therapy with Silapo, and when deciding to increase the dose. In most cases, the ferritin values in the serum fall simultaneously with the rise in packed cell volume. In order to ensure optimum response to Silapo, adequate iron stores should be assured and iron supplementation should be administered if necessary (see section 4.2):

• For chronic renal failure patients, iron supplementation, (elemental iron 200 to 300 mg/day orally for adults and 100 to 200 mg/day orally for paediatrics) is recommended if serum ferritin levels are below 100 ng/mL.
• For cancer patients, iron supplementation (elemental iron 200 to 300 mg/day orally) is recommended if transferrin saturation is below 20%.
• For patients in an autologous predonation programme, iron supplementation (elemental iron 200 mg/day orally) should be administered several weeks prior to initiating the autologous predeposit in order to achieve high iron stores prior to starting Silapo therapy, and throughout the course of Silapo therapy.
• For patients scheduled for major elective orthopaedic surgery, iron supplementation (elemental iron 200 mg/day orally) should be administered throughout the course of Silapo therapy. If possible, iron supplementation should be initiated prior to starting Silapo therapy to achieve adequate iron stores.

Very rarely, development of or exacerbation of porphyria has been observed in epoetin alfa-treated patients. Silapo should be used with caution in patients with porphyria.

Severe cutaneous adverse reactions (SCARs) including Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN), which can be life-threatening or fatal, have been reported in association with epoetin treatment. More severe cases have been observed with long-acting epoetins.

At the time of prescription patients should be advised of the signs and symptoms and monitored closely for skin reactions. If signs and symptoms suggestive of these reactions appear, Silapo should be withdrawn immediately and an alternative treatment considered.

If the patient has developed a severe cutaneous skin reaction such as SJS or TEN due to the use of Silapo, treatment with Silapo must not be restarted in this patient at any time.

In order to improve the traceability of ESAs, the trade name and the batch number of the administered ESA should be clearly recorded (or stated) in the patient file.

Patients should only be switched from one ESA to another under appropriate supervision.

Pure Red Cell Aplasia (PRCA)

Antibody-mediated pure red cell aplasia (PRCA) has been reported after months to years of treatment with epoetins. Cases have also been reported in patients with hepatitis C treated with interferon and ribavirin, when ESAs are used concomitantly. Silapo is not approved in the management of anaemia associated with hepatitis C.

In patients developing sudden lack of efficacy defined by a decrease in haemoglobin (1 to 2 g/dL per month) with increased need for transfusions, a reticulocyte count should be obtained and typical causes of non-response (e.g. iron, folate or Vitamin B12 deficiency, aluminium intoxication, infection or inflammation, blood loss, haemolysis and bone marrow fibrosis of any origin) should be investigated.

A paradoxical decrease in haemoglobin and development of severe anaemia associated with low reticulocyte counts should prompt to discontinue treatment with Silapo and perform anti-erythropoietin antibody testing. A bone marrow examination should also be considered for diagnosis of PRCA.

No other ESA therapy should be commenced because of the risk of cross-reaction.

Treatment of symptomatic anaemia in adult and paediatric chronic renal failure patients

Chronic renal failure patients being treated with Silapo should have haemoglobin levels measured on a regular basis until a stable level is achieved, and periodically thereafter.

In chronic renal failure patients the rate of increase in haemoglobin should be approximately 1 g/dL (0.62 mmol/L) per month and should not exceed 2 g/dL (1.25 mmol/L) per month to minimise risks of an increase in hypertension.

In patients with chronic renal failure, maintenance haemoglobin concentration should not exceed the upper limit of the haemoglobin concentration range as recommended in section 4.2. In clinical trials, an increased risk of death and serious cardiovascular events was observed when ESAs were administered to achieve a haemoglobin concentration level of greater than 12 g/dL (7.5 mmol/L).

Controlled clinical trials have not shown significant benefits attributable to the administration of epoetins when haemoglobin concentration is increased beyond the level necessary to control symptoms of anaemia and to avoid blood transfusion.

Caution should be exercised with escalation of Silapo doses in patients with chronic renal failure since high cumulative epoetin doses may be associated with an increased risk of mortality, serious cardiovascular and cerebrovascular events. In patients with a poor haemoglobin response to epoetins, alternative explanations for the poor response should be considered (see sections 4.2 and 5.1).

Chronic renal failure patients treated with Silapo by the subcutaneous route should be monitored regularly for loss of efficacy, defined as absent or decreased response to Silapo treatment in patients who previously responded to such therapy. This is characterised by a sustained decrease in haemoglobin despite an increase in Silapo dosage (see section 4.8).

Some patients with more extended dosing intervals (greater than once weekly) of Silapo may not maintain adequate haemoglobin levels (see section 5.1) and may require an increase in Silapo dose. Haemoglobin levels should be monitored regularly.

Shunt thrombosis has occurred in haemodialysis patients, especially in those who have a tendency to hypotension or whose arteriovenous fistulae exhibit complications (e.g. stenoses, aneurysms, etc.). Early shunt revision and thrombosis prophylaxis by administration of acetylsalicylic acid, for example, is recommended in these patients.

Hyperkalaemia has been observed in isolated cases though causality has not been established. Serum electrolytes should be monitored in chronic renal failure patients. If an elevated or rising serum potassium level is detected, then in addition to appropriate treatment of the hyperkalaemia, consideration should be given to ceasing Silapo administration until the serum potassium level has been corrected.

An increase in heparin dose during haemodialysis is frequently required during the course of therapy with Silapo as a result of the increased packed cell volume. Occlusion of the dialysis system is possible if heparinisation is not optimum.

Based on information available to date, correction of anaemia with Silapo in adult patients with renal insufficiency not yet undergoing dialysis does not accelerate the rate of progression of renal insufficiency.

Treatment of patients with chemotherapy-induced anaemia

Cancer patients being treated with Silapo should have haemoglobin levels measured on a regular basis until a stable level is achieved, and periodically thereafter.

Epoetins are growth factors that primarily stimulate red blood cell (RBC) production. Erythropoietin receptors may be expressed on the surface of a variety of tumour cells. As with all growth factors, there is a concern that epoetins could stimulate the growth of tumours.

The role of ESAs on tumour progression or reduced progression-free survival cannot be excluded. In controlled clinical studies, use of epoetin alfa and other ESAs have been associated with decreased locoregional tumour control or decreased overall survival:

• decreased locoregional control in patients with advanced head and neck cancer receiving radiation therapy when administered to achieve a haemoglobin concentration level of greater than 14 g/dL (8.7 mmol/L),
• shortened overall survival and increased deaths attributed to disease progression at 4 months in patients with metastatic breast cancer receiving chemotherapy when administered to achieve a haemoglobin concentration range of 12 to 14 g/dL (7.5 to 8.7 mmol/L),
• increased risk of death when administered to achieve a haemoglobin concentration level of 12 g/dL (7.5 mmol/L) in patients with active malignant disease receiving neither chemotherapy nor radiation therapy. ESAs are not indicated for use in this patient population,
• an observed 9% increase in risk for PD or death in the epoetin alfa plus SOC group from a primary analysis and a 15% increased risk that cannot be statistically ruled out in patients with metastatic breast cancer receiving chemotherapy when administered to achieve a haemoglobin concentration range of 10 to 12 g/dL (6.2 to 7.5 mmol/L).

In view of the above, in some clinical situations blood transfusion should be the preferred treatment for the management of anaemia in patients with cancer. The decision to administer recombinant erythropoietin treatment should be based on a benefit-risk assessment with the participation of the individual patient, which should take into account the specific clinical context. Factors that should be considered in this assessment should include the type of tumour and its stage; the degree of anaemia; life-expectancy; the environment in which the patient is being treated; and patient preference (see section 5.1).

In cancer patients receiving chemotherapy, the 2 to 3 week delay between ESA administration and the appearance of erythropoietin-induced red cells should be taken into account when assessing if Silapo therapy is appropriate (patient at risk of being transfused).

Surgery patients in autologous predonation programmes

All special warnings and special precautions associated with autologous predonation programmes, especially routine volume replacement, should be respected.

Patients scheduled for major elective orthopaedic surgery

Good blood management practices should always be used in the perisurgical setting.

Patients scheduled for major elective orthopaedic surgery should receive adequate antithrombotic prophylaxis, as thrombotic and vascular events may occur in surgical patients, especially in those with underlying cardiovascular disease. In addition, special precaution should be taken in patients with predisposition for development of DVTs. Moreover, in patients with a baseline haemoglobin of >13 g/dL (>8.1 mmol/L), the possibility that Silapo treatment may be associated with an increased risk of postoperative thrombotic/vascular events cannot be excluded. Therefore, Silapo should not be used in patients with baseline haemoglobin >13 g/dL (>8.1 mmol/L).

This medicinal product contains up to 0.5 mg phenylalanine in each dosage unit. Phenylalanine may be harmful for patients with phenylketonuria (PKU), a rare genetic disorder in which phenylalanine builds up because the body cannot remove it properly.

This medicinal product contains less than 1 mmol sodium (23 mg) per dosage unit, that is to say essentially ‘sodium-free’.

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.

Pregnancy

There are no or limited amount of data from the use of epoetin in pregnant women. Studies in animals have shown reproductive toxicity (see section 5.3). Consequently, Silapo should be used in pregnancy only if the potential benefit outweighs the potential risk to the foetus. The use of Silapo is not recommended in pregnant surgical patients participating in an autologous blood predonation.

Breast-feeding

It is unknown whether exogenous epoetin zeta is excreted in human milk. Silapo should be used with caution in nursing women. A decision must be made whether to discontinue breast-feeding or to discontinue/abstain from Silapo therapy taking into account the benefit of breast-feeding for the child and the benefit of therapy for the woman.

The use of Silapo is not recommended in lactating surgical patients participating in an autologous blood predonation programme.

Fertility

There are no studies assessing the potential effect of Silapo on male or female fertility.

No studies on the effects on the ability to drive and use machines have been performed.

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).

¹ Common in dialysis
² Includes arterial and venous, fatal and non fatal events, such as deep venous thrombosis, pulmonary emboli, retinal thrombosis, arterial thrombosis (including myocardial infarction), cerebrovascular accidents (including cerebral infarction and cerebral haemorrhage) transient ischaemic attacks, and shunt thrombosis (including dialysis equipment) and thrombosis within arteriovenous shunt aneurisms
³ Addressed in the subsection below and/or in section 4.4

Description of selected adverse reactions

Hypersensitivity reactions, including cases of rash (including urticaria), anaphylactic reactions, and angioneurotic oedema have been reported (see section 4.4).

Severe cutaneous adverse reactions (SCARs) including Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN), which can be life-threatening or fatal, have been reported in association with epoetin treatment (see section 4.4).

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 4.4).

Antibody-mediated pure red cell aplasia has been very rarely reported in <1/10 000 cases per patient year after months to years of treatment with epoetins (see section 4.4). More cases have been reported with subcutaneous (SC) route of administration, compared with the IV route.

Adult patients with low- or intermediate-1-risk MDS

In the randomised, double-blind, placebo-controlled, multicentre study 4 (4.7%) subjects experienced TVEs (sudden death, ischaemic stroke, embolism, and phlebitis). All TVEs occurred in the epoetin alfa group and in the first 24 weeks of the study. Three were confirmed TVE and in the remaining case (sudden death), the thromboembolic event was not confirmed. Two subjects had significant risk factors (atrial fibrillation, heart failure and thrombophlebitis).

Paediatric population with chronic renal failure on haemodialysis

The exposure of paediatric patients with chronic renal failure on haemodialysis in clinical trials and post-marketing experience is limited. No paediatric-specific adverse reactions not mentioned previously in the table above, or any that were not consistent with the underlying disease were reported in this population.

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.

In the absence of compatibility studies, this medicinal product must not be mixed with other medicinal products.