RETACRIT 6000UI / 0.6ml injection solution in pre-filled syringe medication leaflet

Retacrit 1 000 IU/0.3 mL solution for injection in pre-filled syringe

Retacrit 2 000 IU/0.6 mL solution for injection in pre-filled syringe

Retacrit 3 000 IU/0.9 mL solution for injection in pre-filled syringe

Retacrit 4 000 IU/0.4 mL solution for injection in pre-filled syringe

Retacrit 5 000 IU/0.5 mL solution for injection in pre-filled syringe

Retacrit 6 000 IU/0.6 mL solution for injection in pre-filled syringe

Retacrit 8 000 IU/0.8 mL solution for injection in pre-filled syringe

Retacrit 10 000 IU/1 mL solution for injection in pre-filled syringe

Retacrit 20 000 IU/0.5 mL solution for injection in pre-filled syringe

Retacrit 30 000 IU/0.75 mL solution for injection in pre-filled syringe

Retacrit 40 000 IU/1 mL solution for injection in pre-filled syringe

Retacrit 1 000 IU/0.3 mL solution for injection in pre-filled syringe1 pre-filled syringe with 0.3 mL solution for injection contains 1 000 international units (IU) epoetinzeta* (recombinant human erythropoietin). The solution contains 3 333 IU epoetin zeta per mL.

Retacrit 2 000 IU/0.6 mL solution for injection in pre-filled syringe1 pre-filled syringe with 0.6 mL solution for injection contains 2 000 international units (IU) epoetinzeta* (recombinant human erythropoietin). The solution contains 3 333 IU epoetin zeta per mL.

Retacrit 3 000 IU/0.9 mL solution for injection in pre-filled syringe1 pre-filled syringe with 0.9 mL solution for injection contains 3 000 international units (IU) epoetinzeta* (recombinant human erythropoietin). The solution contains 3 333 IU epoetin zeta per mL.

Retacrit 4 000 IU/0.4 mL solution for injection in pre-filled syringe1 pre-filled syringe with 0.4 mL solution for injection contains 4 000 international units (IU) epoetinzeta* (recombinant human erythropoietin). The solution contains 10 000 IU epoetin zeta per mL.

Retacrit 5 000 IU/0.5 mL solution for injection in pre-filled syringe1 pre-filled syringe with 0.5 mL solution for injection contains 5 000 international units (IU) epoetinzeta* (recombinant human erythropoietin). The solution contains 10 000 IU epoetin zeta per mL.

Retacrit 6 000 IU/0.6 mL solution for injection in pre-filled syringe1 pre-filled syringe with 0.6 mL solution for injection contains 6 000 international units (IU) epoetinzeta* (recombinant human erythropoietin). The solution contains 10 000 IU epoetin zeta per mL.

Retacrit 8 000 IU/0.8 mL solution for injection in pre-filled syringe1 pre-filled syringe with 0.8 mL solution for injection contains 8 000 international units (IU) epoetinzeta* (recombinant human erythropoietin). The solution contains 10 000 IU epoetin zeta per mL.

Retacrit 10 000 IU/1 mL solution for injection in pre-filled syringe1 pre-filled syringe with 1.0 mL solution for injection contains 10 000 international units (IU) epoetinzeta* (recombinant human erythropoietin). The solution contains 10 000 IU epoetin zeta per mL.

Retacrit 20 000 IU/0.5 mL solution for injection in pre-filled syringe1 pre-filled syringe with 0.5 mL solution for injection contains 20 000 international units (IU) epoetinzeta* (recombinant human erythropoietin). The solution contains 40 000 IU epoetin zeta per mL.

Retacrit 30 000 IU/0.75 mL solution for injection in pre-filled syringe1 pre-filled syringe with 0.75 mL solution for injection contains 30 000 international units (IU) epoetinzeta* (recombinant human erythropoietin). The solution contains 40 000 IU epoetin zeta per mL.

Retacrit 40 000 IU/1 mL solution for injection in pre-filled syringe1 pre-filled syringe with 1 mL solution for injection contains 40 000 international units (IU) epoetinzeta* (recombinant human erythropoietin). The solution contains 40 000 IU epoetin zeta per mL.

Retacrit contains 0.5 mg/mL of phenylalanine.

*Produced by recombinant DNA technology in Chinese Hamster Ovary (CHO) cell line.

For the full list of excipients, see section 6.1.

Solution for injection in pre-filled syringe (injection).

Clear, colourless solution.

Retacrit is indicated for the treatment of symptomatic anaemia associated with chronic renal failure(CRF):

o in adults and paediatrics aged 1 to 18 years on haemodialysis and adult patients on peritonealdialysis (see section 4.4).

o in adults with renal insufficiency not yet undergoing dialysis for the treatment of severe anaemiaof renal origin accompanied by clinical symptoms in patients (see section 4.4).

Retacrit is indicated in adults receiving chemotherapy for solid tumours, malignant lymphoma ormultiple 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 anaemiaand reduction of transfusion requirements.

Retacrit 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] concentrationrange between 10 to 13 g/dL [6.2 to 8.1 mmol/L], no iron deficiency) if blood saving procedures arenot available or insufficient when the scheduled major elective surgery requires a large volume ofblood (4 or more units of blood for females or 5 or more units for males).

Retacrit is indicated for non-iron deficient adults prior to major elective orthopaedic surgery having ahigh 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 rangebetween 10 to 13 g/dL or 6.2 to 8.1 mmol/L) who do not have an autologous predonation programmeavailable and with expected moderate blood loss (900 to 1 800 mL).

Retacrit is indicated for the treatment of symptomatic anaemia (haemoglobin concentration of ≤10g/dL) in adults with low- or intermediate-1-risk primary myelodysplastic syndromes (MDS) who havelow serum erythropoietin (<200 mU/mL).

Treatment with Retacrit has to be initiated under the supervision of physicians experienced in themanagement of patients with above indications.

All other causes of anaemia (iron, folate or Vitamin B12 deficiency, aluminium intoxication, infectionor inflammation, blood loss, haemolysis and bone marrow fibrosis of any origin) should be evaluatedand treated prior to initiating therapy with epoetin zeta, and when deciding to increase the dose. Inorder to ensure optimum response to epoetin zeta, adequate iron stores should be assured and ironsupplementation should be administered if necessary (see section 4.4).

Treatment of symptomatic anaemia in adult chronic renal failure patients

Anaemia symptoms and sequelae may vary with age, gender and co-morbid medical conditions; aphysician’s evaluation of the individual patient’s clinical course and condition is necessary.

The recommended desired haemoglobin concentration range is between 10 g/dL to 12 g/dL (6.2 to7.5 mmol/L). Retacrit should be administered in order to increase haemoglobin to not greater than12 g/dL (7.5 mmol/L). A rise in haemoglobin of greater than 2 g/dL (1.25 mmol/L) over a four weekperiod should be avoided. If it occurs, appropriate dose adjustment should be made as provided.

Due to intra-patient variability, occasional individual haemoglobin values for a patient above andbelow the desired haemoglobin concentration range may be observed. Haemoglobin variability shouldbe addressed through dose management, with consideration for the haemoglobin concentration rangeof 10 g/dL (6.2 mmol/L) to 12 g/dL (7.5 mmol/L).

A sustained haemoglobin level of greater than 12 g/dL (7.5 mmol/L) should be avoided. If thehaemoglobin is rising by more than 2 g/dL (1.25 mmol/L) per month, or if the sustained haemoglobinexceeds 12 g/dL (7.5 mmol/L) reduce the Retacrit dose by 25%. If the haemoglobin exceeds 13 g/dL(8.1 mmol/L), discontinue therapy until it falls below 12 g/dL (7.5 mmol/L) and then reinstitute

Retacrit therapy at a dose 25% below the previous dose.

Patients should be monitored closely to ensure that the lowest approved effective dose of Retacrit isused to provide adequate control of anaemia and of the symptoms of anaemia whilst maintaining ahaemoglobin concentration below or at 12 g/dL (7.5 mmol/L).

Caution should be exercised with escalation of erythropoiesis-stimulating agent (ESA) doses inpatients with chronic renal failure. In patients with a poor haemoglobin response to ESA, alternativeexplanations for the poor response should be considered (see sections 4.4 and 5.1).

Treatment with Retacrit is divided into two stages - correction and maintenance phase.

Adult haemodialysis patients

In patients on haemodialysis where intravenous access is readily available, administration by theintravenous route is preferable.

Correction phase

The starting dose is 50 IU/kg, 3 times per week.

If necessary, increase or decrease the dose by 25 IU/kg (3 times per week) until the desiredhaemoglobin concentration range between 10 g/dL to 12 g/dL (6.2 to 7.5 mmol/L) is achieved (thisshould be done in steps of at least four weeks).

Maintenance phase

The recommended total weekly dose is between 75 IU/kg and 300 IU/kg.

Appropriate adjustment of the dose should be made in order to maintain haemoglobin values withinthe desired concentration range between 10 g/dL to 12 g/dL (6.2 to 7.5 mmol/L).

Patients with very low initial haemoglobin (<6 g/dL or <3.75 mmol/L) may require highermaintenance doses than patients whose initial anaemia is less severe (>8 g/dL or >5 mmol/L).

Adult patients with renal insufficiency not yet undergoing dialysis

Where intravenous access is not readily available Retacrit may be administered subcutaneously.

Correction phase

Starting dose of 50 IU/kg, 3 times per week, followed if necessary by a dosage increase with 25 IU/kgincrements (3 times per week) until the desired goal is achieved (this should be done in steps of atleast four weeks).

Maintenance phase

During the maintenance phase, Retacrit can be administered either 3 times per week, and in the case ofsubcutaneous administration, once weekly or once every 2 weeks.

Appropriate adjustment of dose and dose intervals should be made in order to maintain haemoglobinvalues at the desired level: haemoglobin between 10 g/dL to 12 g/dL (6.2 to 7.5 mmol/L). Extendingdose intervals may require an increase in dose.

The maximum dosage should not exceed 150 IU/kg 3 times per week, 240 IU/kg (up to a maximum of20 000 IU) once weekly, or 480 IU/kg (up to a maximum of 40 000 IU) once every 2 weeks.

Adult peritoneal dialysis patients

Where intravenous access is not readily available Retacrit may be administered subcutaneously.

Correction phase

The starting dose is 50 IU/kg, 2 times per week.

Maintenance phase

The recommended maintenance dose is between 25 IU/kg and 50 IU/kg, 2 times per week in 2 equalinjections.

Appropriate adjustment of the dose should be made in order to maintain haemoglobin values at thedesired level between 10 g/dL to 12 g/dL (6.2 to 7.5 mmol/L).

Treatment of adult patients with chemotherapy-induced anaemia

Anaemia symptoms and sequelae may vary with age, gender, and overall burden of disease; aphysician´s evaluation of the individual patient´s clinical course and condition is necessary.

Retacrit should be administered to patients with anaemia (e.g. haemoglobin concentration ≤ 10 g/dL[6.2 mmol/L]).

The initial dose is 150 IU/kg subcutaneously, 3 times per week.

Alternatively, Retacrit can be administered at an initial dose of 450 IU/kg subcutaneously onceweekly.

Appropriate adjustment of the dose should be made in order to maintain haemoglobin concentrationswithin the desired concentration range between 10 g/dL to 12 g/dL (6.2 to 7.5 mmol/L).

Due to intra-patient variability, occasional individual haemoglobin concentrations for a patient aboveand below the desired haemoglobin concentration range may be observed. Haemoglobin variabilityshould be addressed through dose management, with consideration for the desired haemoglobinconcentration range between 10 g/dL (6.2 mmol/L) to 12 g/dL (7.5 mmol/L). A sustainedhaemoglobin concentration of greater than 12 g/dL (7.5 mmol/L) should be avoided; guidance forappropriate dose adjustment for when haemoglobin concentrations exceed 12 g/dL (7.5 mmol/L) aredescribed below.

− If the haemoglobin concentration has increased by at least 1 g/dL (0.62 mmol/L) or thereticulocyte count has increased ≥ 40 000 cells/µL above baseline after 4 weeks of treatment,the dose should remain at 150 IU/kg 3 times per week or 450 IU/kg once weekly.

− If the haemoglobin concentration increase is <1 g/dL (<0.62 mmol/L) and the reticulocyte counthas increased <40 000 cells/µl above baseline, increase the dose to 300 IU/kg 3 times per week.

If after an additional 4 weeks of therapy at 300 IU/kg 3 times per week, the haemoglobinconcentration has increased ≥ 1 g/dL (≥0.62 mmol/L) or the reticulocyte count has increased≥40 000 cells/µl, the dose should remain at 300 IU/kg 3 times per week.

− If the haemoglobin concentration has increased <1 g/dL (<0.62 mmol/L) and the reticulocytecount has increased <40 000 cells/µL above baseline, response is unlikely and treatment shouldbe discontinued.

Dose adjustment to maintain haemoglobin concentrations between 10 g/dL to 12 g/dL (6.2 to7.5 mmol/L)

If the haemoglobin concentration is increasing by more than 2 g/dL (1.25 mmol/L) per month, or if thehaemoglobin concentration level exceeds 12 g/dL (7.5 mmol/L), reduce the Retacrit dose by about25 to 50%.

If the haemoglobin concentration level exceeds 13 g/dL (8.1 mmol/L), discontinue therapy until it fallsbelow 12 g/dL (7.5 mmol/L) and then reinitiate Retacrit therapy at a dose 25% below the previousdose.

The recommended dosing regimen is described in the following diagram*:

*1 g/dL = 0.62 mmol/L; 12 g/dL = 7.5 mmol/L

Patients should be monitored closely to ensure that the lowest approved dose of ESA is used toprovide adequate control of the symptoms of anaemia.

Retacrit therapy should continue until one month after the end of chemotherapy.

Treatment of adult surgery patients in an autologous predonation programme

Mildly anaemic patients (haematocrit of 33 to 39%) requiring predeposit of ≥ 4 units of blood shouldbe treated with Retacrit 600 IU/kg intravenously, 2 times per week for 3 weeks prior to surgery.

Retacrit should be administered after the completion of the blood donation procedure.

Treatment of adult patients scheduled for major elective orthopaedic surgery

The recommended dose is Retacrit 600 IU/kg administered subcutaneously weekly for three weeks(days -21, -14 and -7) prior to surgery and on the day of surgery.

In cases where there is a medical need to shorten the lead time before surgery to less than three weeks,

Retacrit 300 IU/kg should be administered subcutaneously daily for 10 consecutive days prior tosurgery, on the day of surgery and for four days immediately thereafter.

If the haemoglobin level reaches 15 g/dL (9.38 mmol/L), or higher, during the preoperative period,administration of Retacrit should be stopped and further dosages should not be administered.

Treatment of adult patients with low- or intermediate-1-risk MDS

Retacrit should be administered to patients with symptomatic anaemia (e.g. haemoglobinconcentration ≤10 g/dL (6.2 mmol/L)).

The recommended starting dose is Retacrit 450 IU/kg (maximum total dose is 40 000 IU) administeredsubcutaneously once every week, with not less than 5 days between doses.

Appropriate dose adjustments should be made to maintain haemoglobin concentrations within thetarget range of 10 g/dL to 12 g/dL (6.2 to 7.5 mmol/L). It is recommended that initial erythroidresponse be assessed 8 to 12 weeks following initiation of treatment. Dose increases and decreasesshould be done one dosing step at a time (see diagram below). A haemoglobin concentration of greaterthan 12 g/dL (7.5 mmol/L) should be avoided.

Dose increase

Dose should not be increased over the maximum of 1 050 IU/kg (total dose 80 000 IU) per week. Ifthe patient loses response or haemoglobin concentration drops by ≥1 g/dL upon dose reduction thedose should be increased by one dosing step. A minimum of 4 weeks should elapse between doseincreases.

Dose hold and decrease

Epoetin zeta should be withheld when the haemoglobin concentration exceeds 12 g/dL (7.5 mmol/L).

Once the haemoglobin level is <11 g/dL the dose can be restarted on the same dosing step or onedosing step down based on physician judgement. Decreasing the dose by one dosing step should beconsidered if there is a rapid increase in haemoglobin (>2 g/dL over 4 weeks).

Anaemia symptoms and sequelae may vary with age, gender, and co-morbid medical conditions; aphysician's evaluation of the individual patient's clinical course and condition is necessary.

Treatment of symptomatic anaemia in chronic renal failure patients on haemodialysis

Anaemia symptoms and sequelae may vary with age, gender, and co-morbid medical conditions; aphysician's evaluation of the individual patient's clinical course and condition is necessary.

In paediatric patients the recommended haemoglobin concentration range is between 9.5 g/dL to11 g/dL (5.9 to 6.8 mmol/L). Retacrit should be administered in order to increase haemoglobin to notgreater than 11 g/dL (6.8 mmol/L). A rise in haemoglobin of greater than 2 g/dL (1.25 mmol/L) over afour week period should be avoided. If it occurs, appropriate dose adjustment should be made asprovided.

Patients should be monitored closely to ensure that the lowest approved dose of Retacrit is used toprovide adequate control of anaemia and of the symptoms of anaemia.

Treatment with Retacrit is divided into two stages - correction and maintenance phase.

In paediatric patients on haemodialysis where intravenous access is readily available, administrationby the intravenous route is preferable.

Correction phase

The starting dose is 50 IU/kg intravenously, 3 times per week.

If necessary, increase or decrease the dose by 25 IU/kg (3 times per week) until the desiredhaemoglobin concentration range of between 9.5 g/dL to 11 g/dL (5.9 to 6.8 mmol/L) is achieved (thisshould be done in steps of at least four weeks).

Maintenance phase

Appropriate adjustment of the dose should be made in order to maintain haemoglobin levels within thedesired concentration range between 9.5 g/dL to 11 g/dL (5.9 to 6.8 mmol/L).

Generally, children under 30 kg require higher maintenance doses than children over 30 kg and adults.

The following maintenance doses were observed in clinical trials after 6 months of treatment.

Dose (IU/kg given 3 times per week)

Weight (kg) Median Usual maintenance dose<10 100 75-15010-30 75 60-150>30 33 30-100

Paediatric patients with very low initial haemoglobin (<6.8 g/dL or <4.25 mmol/L) may require highermaintenance doses than patients whose initial haemoglobin is higher (>6.8 g/dL or >4.25 mmol/L).

Anaemia in chronic renal failure patients before initiation of dialysis or on peritoneal dialysis

The safety and efficacy of Retacrit in chronic renal failure patients with anaemia before initiation ofdialysis or on peritoneal dialysis have not been established. Currently available data for subcutaneoususe of epoetin alfa in these populations are described in section 5.1 but no recommendation onposology can be made.

Treatment of paediatric patients with chemotherapy-induced anaemia

The safety and efficacy of epoetin alfa in paediatric patients receiving chemotherapy have not beenestablished (see section 5.1).

Treatment of paediatric surgery patients in an autologous predonation programme

The safety and efficacy of epoetin alfa in paediatrics have not been established. No data are available.

Treatment of paediatric patients scheduled for major elective orthopaedic surgery

The safety and efficacy of epoetin alfa in paediatrics have not been established. No data are available.

Before use, leave the Retacrit syringe to stand until it reaches room temperature. This usually takesbetween 15 and 30 minutes.

Treatment of symptomatic anaemia in adult chronic renal failure patients

In patients with chronic renal failure where intravenous access is routinely available (haemodialysispatients) administration of Retacrit by the intravenous route is preferable.

Where intravenous access is not readily available (patients not yet undergoing dialysis and peritonealdialysis patients) Retacrit may be administered as a subcutaneous injection.

Treatment of adult patients with chemotherapy-induced anaemia

Retacrit should be administered as a subcutaneous injection.

Treatment of adult surgery patients in an autologous predonation programme

Retacrit should be administered by the intravenous route.

Treatment of adult patients scheduled for major elective orthopaedic surgery

Retacrit should be administered as a subcutaneous injection.

Treatment of adult patients with low- or intermediate-1-risk MDS

Retacrit should be administered as a subcutaneous injection.

Treatment of symptomatic anaemia in paediatric chronic renal failure patients on haemodialysis

In paediatric patients with chronic renal failure where intravenous access is routinely available(haemodialysis patients) administration of Retacrit by the intravenous route is preferable.

Administer over at least one to five minutes, depending on the total dose. In haemodialysed patients, abolus injection may be given during the dialysis session through a suitable venous port in the dialysisline. Alternatively, the injection can be given at the end of the dialysis session via the fistula needletubing, followed by 10 mL of isotonic saline to rinse the tubing and ensure satisfactory injection of theproduct into the circulation (see Posology, Adult haemodialysis patients).

A slower administration is preferable in patients who react to the treatment with “flu-like” symptoms(see section 4.8).

Do not administer Retacrit by intravenous infusion or in conjunction with other medicinal productsolutions (please refer to section 6.6 for further information).

A maximum volume of 1 mL at one injection site should generally not be exceeded. In case of largervolumes, more than one site should be chosen for the injection.

The injections should be given in the limbs or the anterior abdominal wall.

In those situations in which the physician determines that a patient or caregiver can safely andeffectively administer Retacrit subcutaneously themselves, instruction as to the proper dosage andadministration should be provided.

As with any other injectable product, check that there are no particles in the solution or change incolour.

“Instructions on how to inject Retacrit yourself” can be found at the end of the package leaflet.

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 shouldnot receive Retacrit or any other erythropoietin (see section 4.4).

Uncontrolled hypertension.

All contraindications associated with autologous blood predonation programmes should be respectedin patients being supplemented with Retacrit.

The use of Retacrit in patients scheduled for major elective orthopaedic surgery and not participatingin an autologous blood predonation programme is contraindicated in patients with severe coronary,peripheral arterial, carotid or cerebral vascular disease, including patients with recent myocardialinfarction or cerebral vascular accident.

Surgery patients who for any reason cannot receive adequate antithrombotic prophylaxis.

In order to improve the traceability of biological medicinal products, the name and the batch numberof the administered product should be clearly recorded.

In all patients receiving epoetin zeta, blood pressure should be closely monitored and controlled asnecessary. Epoetin zeta should be used with caution in the presence of untreated, inadequately treatedor poorly controllable hypertension. It may be necessary to add or increase anti-hypertensivetreatment. If blood pressure cannot be controlled, epoetin zeta treatment should be discontinued.

Hypertensive crisis with encephalopathy and seizures, requiring the immediate attention of a physicianand intensive medical care, have occurred also during epoetin zeta treatment in patients withpreviously normal or low blood pressure. Particular attention should be paid to sudden stabbingmigraine-like headaches as a possible warning signal (see section 4.8).

Epoetin zeta should be used with caution in patients with epilepsy, history of seizures, or medicalconditions associated with a predisposition to seizure activity such as CNS infections and brainmetastases.

Epoetin zeta should be used with caution in patients with chronic liver failure. The safety of epoetinzeta 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 somewith fatal outcomes), such as deep venous thrombosis, pulmonary emboli, retinal thrombosis, andmyocardial infarction. Additionally, cerebrovascular accidents (including cerebral infarction, cerebralhaemorrhage and transient ischaemic attacks) have been reported.

The reported risk of these TVEs should be carefully weighed against the benefits to be derived fromtreatment with epoetin zeta particularly in patients with pre-existing risk factors for TVE, includingobesity and prior history of TVEs (e.g., deep venous thrombosis, pulmonary embolism, and cerebralvascular accident).

In all patients, haemoglobin levels should be closely monitored due to a potential increased risk ofthromboembolic events and fatal outcomes when patients are treated at haemoglobin levels above theconcentration range for the indication of use.

There may be a moderate dose-dependent rise in the platelet count within the normal range duringtreatment with epoetin zeta. This regresses during the course of continued therapy. In addition,thrombocythaemia above the normal range has been reported. It is recommended that the plateletcount is regularly monitored during the first 8 weeks of therapy.

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

− For chronic renal failure patients, iron supplementation (elemental iron 200 to 300 mg/dayorally for adults and 100 to 200 mg/day orally for paediatrics) is recommended if serum ferritinlevels are below 100 ng/mL.

− For cancer patients, iron supplementation (elemental iron 200 to 300 mg/day orally) isrecommended if transferrin saturation is below 20%.

− For patients in an autologous predonation programme, iron supplementation (elemental iron200 mg/day orally) should be administered several weeks prior to initiating the autologouspredeposit in order to achieve high iron stores prior to starting epoetin zeta therapy, andthroughout the course of epoetin zeta therapy.

− For patients scheduled for major elective orthopaedic surgery, iron supplementation (elementaliron 200 mg/day orally) should be administered throughout the course of epoetin zeta therapy. Ifpossible, iron supplementation should be initiated prior to starting epoetin zeta therapy toachieve adequate iron stores.

Very rarely, development of or exacerbation of porphyria has been observed in epoetin zeta-treatedpatients. Epoetin zeta should be used with caution in patients with porphyria.

Severe cutaneous adverse reactions (SCARs) including Stevens-Johnson syndrome (SJS) and toxicepidermal necrolysis (TEN), which can be life-threatening or fatal, have been reported in associationwith 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 monitoredclosely for skin reactions. If signs and symptoms suggestive of these reactions appear, Retacrit shouldbe 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

Retacrit, treatment with Retacrit must not be restarted in this patient at any time.

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 treatmentwith epoetins. Cases have also been reported in patients with hepatitis C treated with interferon andribavirin, when ESAs are used concomitantly. Epoetin zeta is not approved in the management ofanaemia associated with hepatitis C.

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

A paradoxical decrease in haemoglobin and development of severe anaemia associated with lowreticulocyte counts should prompt to discontinue treatment with epoetin zeta and performanti-erythropoietin antibody testing. A bone marrow examination should also be considered fordiagnosis 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 epoetin zeta should have haemoglobin levelsmeasured 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 ofan increase in hypertension.

In patients with chronic renal failure, maintenance haemoglobin concentration should not exceed theupper 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 wereadministered 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 ofepoetins when haemoglobin concentration is increased beyond the level necessary to controlsymptoms of anaemia and to avoid blood transfusion.

Caution should be exercised with escalation of Retacrit doses in patients with chronic renal failuresince high cumulative epoetin doses may be associated with an increased risk of mortality, seriouscardiovascular 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 epoetin zeta by the subcutaneous route should be monitoredregularly for loss of efficacy, defined as absent or decreased response to epoetin zeta treatment inpatients who previously responded to such therapy. This is characterised by a sustained decrease inhaemoglobin despite an increase in epoetin zeta dosage (see section 4.8).

Some patients with more extended dosing intervals (greater than once weekly) of epoetin zeta may notmaintain adequate haemoglobin levels (see section 5.1) and may require an increase in epoetin zetadose. Haemoglobin levels should be monitored regularly.

Shunt thrombosis have occurred in haemodialysis patients, especially in those who have a tendency tohypotension 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. Serumelectrolytes should be monitored in chronic renal failure patients. If an elevated or rising serumpotassium level is detected, then in addition to appropriate treatment of the hyperkalaemia,consideration should be given to ceasing epoetin zeta administration until the serum potassium levelhas been corrected.

An increase in heparin dose during haemodialysis is frequently required during the course of therapywith epoetin zeta as a result of the increased packed cell volume. Occlusion of the dialysis system ispossible if heparinisation is not optimum.

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

Treatment of patients with chemotherapy-induced anaemia

Cancer patients being treated with epoetin zeta should have haemoglobin levels measured on a regularbasis until a stable level is achieved, and periodically thereafter.

Epoetins are growth factors that primarily stimulate red blood cell (RBC) production. Erythropoietinreceptors 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. Incontrolled clinical studies, use of epoetin zeta and other ESAs have been associated with decreasedlocoregional tumour control or decreased overall survival:

* decreased locoregional control in patients with advanced head and neck cancer receivingradiation therapy when administered to achieve a haemoglobin concentration level of greater than 14g/dL (8.7 mmol/L),

* shortened overall survival and increased deaths attributed to disease progression at 4 months inpatients with metastatic breast cancer receiving chemotherapy when administered to achieve ahaemoglobin 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 12g/dL (7.5 mmol/L) in patients with active malignant disease receiving neither chemotherapy norradiation therapy. ESAs are not indicated for use in this patient population,

* an observed 9% increase in risk for PD or death in the epoetin zeta plus SOC group from aprimary analysis and a 15% increased risk that cannot be statistically ruled out in patients withmetastatic breast cancer receiving chemotherapy when administered to achieve a haemoglobinconcentration 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 treatmentfor the management of anaemia in patients with cancer. The decision to administer recombinanterythropoietin treatment should be based on a benefit-risk assessment with the participation of theindividual patient, which should take into account the specific clinical context. Factors that should beconsidered 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 (seesection 5.1).

In cancer patients receiving chemotherapy, the 2 to 3 week delay between ESA administration and theappearance of erythropoietin-induced red cells should be taken into account when assessing if epoetinzeta 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 antithromboticprophylaxis, as thrombotic and vascular events may occur in surgical patients, especially in those withunderlying cardiovascular disease. In addition, special precaution should be taken in patients withpredisposition for development of DVTs. Moreover, in patients with a baseline haemoglobin of>13 g/dL (>8.1 mmol/L), the possibility that epoetin zeta treatment may be associated with anincreased risk of postoperative thrombotic/vascular events cannot be excluded. Therefore, epoetin zetashould not be used in patients with baseline haemoglobin >13 g/dL (>8.1 mmol/L).

This medicinal product contains phenylalanine which may be harmful for people withphenylketonuria.

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

No evidence exists that indicates that treatment with epoetin zeta alters the metabolism of othermedicinal products.

Medicinal products that decrease erythropoiesis may decrease the response to epoetin zeta.

Since cyclosporin is bound by RBCs there is potential for a drug interaction. If epoetin zeta is givenconcomitantly with cyclosporin, blood levels of cyclosporin should be monitored and the dose ofcyclosporin adjusted as the haematocrit rises.

No evidence exists that indicates an interaction between epoetin zeta and G-CSF or GM-CSF withregard to haematological differentiation or proliferation of tumour biopsy specimens in vitro.

In female adult patients with metastatic breast cancer, subcutaneous co-administration of40 000 IU/mL epoetin alfa with trastuzumab 6 mg/kg had no effect on the pharmacokinetics oftrastuzumab.

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

It is unknown whether exogenous epoetin zeta is excreted in human milk. Epoetin zeta should be usedwith caution in nursing women. A decision must be made whether to discontinue breast-feeding or todiscontinue/abstain from Retacrit therapy taking into account the benefit of breast-feeding for the childand the benefit of therapy for the woman.

The use of epoetin zeta is not recommended in lactating surgical patients participating in anautologous blood predonation programme.

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

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

Retacrit has no or negligible influence on the ability to drive and use machines.

The most frequent adverse drug reaction during treatment with epoetin alfa is a dose-dependentincrease in blood pressure or aggravation of existing hypertension. Monitoring of the blood pressureshould 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 arediarrhoea, nausea, vomiting, pyrexia and headache. Influenza-like illness may occur especially at thestart of treatment.

Respiratory tract congestion, which includes events of upper respiratory tract congestion, nasalcongestion and nasopharyngitis, have been reported in studies with extended interval dosing in adultpatients 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).

Of a total 3 417 subjects in 25 randomised, double-blinded, placebo or standard of care controlledstudies, the overall safety profile of epoetin alfa was evaluated in 2 094 anaemic subjects. Includedwere 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 exposedcancer subjects in 16 studies of anaemia due to chemotherapy; 147 exposed subjects in 2 studies forautologous blood donation; 213 exposed subjects in 1 study in the perisurgical period, and102 exposed subjects in 2 MDS studies. Adverse drug reactions reported by ≥1% of subjects treatedwith 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 theavailable data).

MedDRA System Organ Adverse Reaction (Preferred Frequency

Classification (SOC) Term Level)

Blood and lymphatic system Pure red cell aplasia3, Raredisorders Thrombocythemia

Metabolism and nutrition Hyperkalaemia1 Uncommondisorders

Immune system disorders Hypersensitivity3 Uncommon

Anaphylactic reaction3 Rare

Nervous system disorders Headache Common

Convulsion Uncommon

Vascular disorders Hypertension, Venous and Commonarterial thrombosis2

Hypertensive crisis3 Not known

Respiratory, thoracic and Cough Commonmediastinal disorders Respiratory tract congestion Uncommon

Gastrointestinal disorders Diarrhoea, Nausea, Vomiting Very common

Skin and subcutaneous tissue Rash Commondisorders Urticaria3 Uncommon

Angioneurotic oedema3 Not known

Musculoskeletal and Arthralgia, Bone pain, Commonconnective tissue disorders Myalgia, Pain in extremity

Congenital, familial and Porphyria acute3 Raregenetic disorders

General disorders and Pyrexia Very commonadministration site conditions Chills, Influenza like illness, Common

Injection site reaction, Oedemaperipheral

Drug ineffective3 Not known

Investigations Anti-erythropoietin antibody Rarepositive1 Common in dialysis2 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 (includingcerebral infarction and cerebral haemorrhage) transient ischaemic attacks, and shunt thrombosis (includingdialysis equipment) and thrombosis within arteriovenous shunt aneurisms3 Addressed in the subsection below and/or in section 4.4

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

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

Hypertensive crisis with encephalopathy and seizures, requiring the immediate attention of a physicianand intensive medical care, have occurred also during epoetin zeta treatment in patients withpreviously normal or low blood pressure. Particular attention should be paid to sudden stabbingmigraine-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 patientyear after months to years of treatment with epoetins (see section 4.4). More cases have been reportedwith 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 epoetinalfa 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 riskfactors (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 andpost-marketing experience is limited. No paediatric-specific adverse reactions not mentionedpreviously in the table above, or any that were not consistent with the underlying disease werereported in this population.

Reporting suspected adverse reactions after authorisation of the medicinal product is important. Itallows continued monitoring of the benefit/risk balance of the medicinal product. Healthcareprofessionals are asked to report any suspected adverse reactions via the national reporting systemlisted in Appendix V.

The therapeutic margin of erythropoietin is very wide. Overdosage of erythropoietin may produceeffects that are extensions of the pharmacological effects of the hormone. Phlebotomy may beperformed if excessively high haemoglobin levels occur. Additional supportive care should beprovided as necessary.

Pharmacotherapeutic group: Other antianaemic preparations, erythropoietin ATC code: B03XA01

Retacrit is a biosimilar medicinal product. Detailed information is available on the website of the

European Medicines Agency https://www.ema.europa.eu.

Erythropoietin (EPO) is a glycoprotein hormone produced primarily by the kidney in response tohypoxia and is the key regulator of red blood cell (RBC) production. EPO is involved in all phases oferythroid development, and has its principal effect at the level of erythroid precursors. After EPObinds to its cell surface receptor, it activates signal transduction pathways that interfere with apoptosisand stimulates erythroid cell proliferation. Recombinant human EPO (epoetin zeta), expressed in

Chinese hamster ovary cells, has a 165 amino acid sequence identical to that of human urinary EPO;the 2 are indistinguishable on the basis of functional assays. The apparent molecular weight oferythropoietin is 32 000 to 40 000 dalton.

Erythropoietin is a growth factor that primarily stimulates red cell production. Erythropoietin receptorsmay be expressed on the surface of a variety of tumour cells.

Healthy volunteers

After single doses (20 000 to 160 000 IU subcutaneously) of epoetin alfa, a dose-dependent responsewas observed for the pharmacodynamic markers investigated including: reticulocytes, RBCs, andhaemoglobin. A defined concentration-time profile with peak and return to baseline was observed forchanges in percent reticulocytes. A less defined profile was observed for RBCs and haemoglobin. Ingeneral, all pharmacodynamic markers increased in a linear manner with dose reaching a maximumresponse at the highest dose levels.

Further pharmacodynamic studies explored 40 000 IU once weekly versus 150 IU/kg 3 times perweek. Despite differences in concentration-time profiles the pharmacodynamic response (as measuredby changes in percent reticulocytes, haemoglobin, and total RBCs) was similar between theseregimens. Additional studies compared the 40 000 IU once-weekly regimen of epoetin alfa withbiweekly doses ranging from 80 000 to 120 000 IU subcutaneously. Overall, based on the results ofthese pharmacodynamic studies in healthy subjects, the 40 000 IU once-weekly dosing regimen seemsto be more efficient in producing RBCs than the biweekly regimens despite an observed similarity inreticulocyte production in the once-weekly and biweekly regimens.

Chronic renal failure

Epoetin alfa has been shown to stimulate erythropoiesis in anaemic patients with CRF, includingdialysis and pre-dialysis patients. The first evidence of a response to epoetin alfa is an increase in thereticulocyte count within 10 days, followed by increases in the red cell count, haemoglobin andhaematocrit, usually within 2 to 6 weeks. The haemoglobin response varies between patients and maybe impacted by iron stores and the presence of concurrent medical problems.

Chemotherapy-induced anaemia

Epoetin alfa administered 3 times per week or once weekly has been shown to increase haemoglobinand decrease transfusion requirements after the first month of therapy in anaemic cancer patientsreceiving chemotherapy.

In a study comparing the 150 IU/kg, 3 times-per-week and 40 000 IU, once-weekly dosing regimens inhealthy subjects and in anaemic cancer subjects the time profiles of changes in percent reticulocytes,haemoglobin, and total red blood cells were similar between the two dosing regimens in both healthyand anaemic cancer subjects. The AUCs of the respective pharmacodynamic parameters were similarbetween the 150 IU/kg, 3 times-per-week and 40 000 IU, once-weekly dosing regimens in healthysubjects and also in anaemic cancer subjects.

Adult surgery patients in an autologous predonation programme

Epoetin alfa has been shown to stimulate red blood cell production in order to augment autologousblood collection, and to limit the decline in haemoglobin in adult patients scheduled for major electivesurgery who are not expected to predeposit their complete perioperative blood needs. The greatesteffects are observed in patients with low haemoglobin (≤ 13 g/dL; 8.1 mmol/L).

Treatment of adult patients scheduled for major elective orthopaedic surgery

In patients scheduled for major elective orthopaedic surgery with a pretreatment haemoglobin of>10 to ≤ 13 g/dL, epoetin alfa has been shown to decrease the risk of receiving allogeneic transfusionsand hasten erythroid recovery (increased haemoglobin levels, haematocrit levels, and reticulocytecounts).

Chronic renal failure

Epoetin alfa has been studied in clinical trials in adult anaemic CRF patients, including haemodialysisand pre-dialysis patients, to treat anaemia and maintain haematocrit within a target concentration rangeof 30 to 36%.

In clinical trials at starting doses of 50 to 150 IU/kg, three times per week, approximately 95% of allpatients responded with a clinically significant increase in haematocrit. After approximately twomonths of therapy, virtually all patients were transfusion-independent. Once the target haematocritwas achieved, the maintenance dose was individualised for each patient.

In the three largest clinical trials conducted in adult patients on dialysis, the median maintenance dosenecessary to maintain the haematocrit between 30 to 36% was approximately 75 IU/kg given 3 timesper week.

In a double-blind, placebo-controlled, multicentre, quality of life study in CRF patients onhaemodialysis, clinically and statistically significant improvement was shown in the patients treatedwith epoetin alfa compared to the placebo group when measuring fatigue, physical symptoms,relationships and depression (Kidney Disease Questionnaire) after six months of therapy. Patientsfrom the group treated with epoetin alfa were also enrolled in an open-label extension study whichdemonstrated improvements in their quality of life that were maintained for an additional 12 months.

Adult patients with renal insufficiency not yet undergoing dialysis

In clinical trials conducted in patients with CRF not on dialysis treated with epoetin alfa, the averageduration of therapy was nearly five months. These patients responded to epoetin alfa therapy in amanner similar to that observed in patients on dialysis. Patients with CRF not on dialysis demonstrateda dose-dependent and sustained increase in haematocrit when epoetin alfa was administered by eitheran intravenous or subcutaneous route. Similar rates of rise of haematocrit were noted when epoetinalfa was administered by either route. Moreover, epoetin alfa doses of 75 to 150 IU/kg per week havebeen shown to maintain haematocrits of 36 to 38% for up to six months.

In 2 studies with extended interval dosing of epoetin alfa (3 times per week, once weekly, once every2 weeks, and once every 4 weeks) some patients with longer dosing intervals did not maintainadequate haemoglobin levels and reached protocol-defined haemoglobin withdrawal criteria (0% inonce weekly, 3.7% in once-every-2-weeks, and 3.3% in the once-every-4-weeks groups).

A randomized prospective trial (CHOIR) evaluated 1,432 anaemic chronic renal failure patients whowere not undergoing dialysis. Patients were assigned to epoetin alfa treatment targeting a maintenancehaemoglobin level of 13.5 g/dL (higher than the recommended haemoglobin concentration level) or11.3 g/dL. A major cardiovascular event (death, myocardial infarction, stroke or hospitalization forcongestive heart failure) occurred among 125 (18%) of the 715 patients in the higher haemoglobingroup compared to 97 (14%) among the 717 patients in the lower haemoglobin group (hazard ratio[HR] 1.3, 95% CI: 1.0, 1.7, p = 0.03).

Pooled post-hoc analyses of clinical studies of ESAs have been performed in chronic renal failurepatients (on dialysis, not on dialysis, in diabetic and non-diabetic patients). A tendency towardsincreased risk estimates for all-cause mortality, cardiovascular and cerebrovascular events associatedwith higher cumulative ESA doses independent of the diabetes or dialysis status was observed (seesections 4.2 and 4.4).

Treatment of patients with chemotherapy-induced anaemia

Epoetin alfa has been studied in clinical trials in adult anaemic cancer patients with lymphoid andsolid tumours, and patients on various chemotherapy regimens, including platinum andnon-platinum-containing regimens. In these trials, epoetin alfa administered 3 times per week andonce weekly has been shown to increase haemoglobin and decrease transfusion requirements after thefirst month of therapy in anaemic cancer patients. In some studies, the double-blind phase wasfollowed by an open-label phase during which all patients received epoetin alfa and a maintenance ofeffect was observed.

Available evidence suggests patients with haematological malignancies and solid tumours respondequivalently to epoetin alfa therapy, and that patients with or without tumour infiltration of the bonemarrow respond equivalently to epoetin alfa therapy. Comparable intensity of chemotherapy in theepoetin alfa and placebo groups in the chemotherapy trials was demonstrated by a similar area underthe neutrophil time curve in patients treated with epoetin alfa and placebo-treated patients, as well asby a similar proportion of patients in groups treated with epoetin alfa and placebo-treated groupswhose absolute neutrophil counts fell below 1 000 and 500 cells/μL.

In a prospective, randomised, double-blind, placebo-controlled trial conducted in 375 anaemic patientswith various non-myeloid malignancies receiving non-platinum chemotherapy, there was a significantreduction of anaemia-related sequelae (e.g. fatigue, decreased energy, and activity reduction), asmeasured by the following instruments and scales: Functional Assessment of Cancer Therapy-

Anaemia (FACT-An) general scale, FACT-An fatigue scale, and Cancer Linear Analogue Scale(CLAS). Two other smaller, randomised, placebo-controlled trials failed to show a significantimprovement in quality of life parameters on the EORTC-QLQ-C30 scale or CLAS, respectively.

Survival and tumour progression have been examined in five large controlled studies involving a totalof 2 833 patients, of which four were double-blind placebo-controlled studies and one was anopen-label study. The studies either recruited patients who were being treated with chemotherapy (twostudies) or used patient populations in which ESAs are not indicated: anaemia in patients with cancernot receiving chemotherapy, and head and neck cancer patients receiving radiotherapy. The desiredhaemoglobin concentration level in two studies was >13 g/dL (8.1 mmol/L); in the remaining threestudies it was 12 to 14 g/dL (7.5 to 8.7 mmol/L). In the open-label study there was no difference inoverall survival between patients treated with recombinant human erythropoietin and controls. In thefour placebo-controlled studies the hazard ratios for overall survival ranged between 1.25 and 2.47 infavour of controls. These studies have shown a consistent unexplained statistically significant excessmortality in patients who have anaemia associated with various common cancers who receivedrecombinant human erythropoietin compared to controls. Overall survival outcome in the trials couldnot be satisfactorily explained by differences in the incidence of thrombosis and related complicationsbetween those given recombinant human erythropoietin and those in the control group.

A patient-level data analysis has also been performed on more than 13 900 cancer patients (chemo-,radio-, chemoradio-, or no therapy) participating in 53 controlled clinical trials involving severalepoetins. Meta-analysis of overall survival data produced a hazard ratio point estimate of 1.06 infavour of controls (95% CI: 1.00, 1.12; 53 trials and 13 933 patients) and for the cancer patientsreceiving chemotherapy, the overall survival hazard ratio was 1.04 (95% CI: 0.97, 1.11; 38 trials and10 441 patients). Meta-analyses also indicate consistently a significantly increased relative risk ofthromboembolic events in cancer patients receiving recombinant human erythropoietin (see section4.4).

A randomised, open-label, multicentre study was conducted in 2 098 anaemic women with metastaticbreast cancer, who received first line or second line chemotherapy. This was a non inferiority studydesigned to rule out a 15% risk increase in tumour progression or death of epoetin alfa plus standard ofcare (SOC) as compared with SOC alone. At the time of clinical data cutoff, the median progressionfree survival (PFS) per investigator assessment of disease progression was 7.4 months in each arm(HR 1.09, 95% CI: 0.99, 1.20), indicating the study objective was not met. Significantly fewer patientsreceived RBC transfusions in the epoetin alfa plus SOC arm (5.8% versus 11.4%); however,significantly more patients had thrombotic vascular events in the epoetin alfa plus SOC arm (2.8%versus 1.4%). At the final analysis, 1 653 deaths were reported. Median overall survival in the epoetinalfa plus SOC group was 17.8 months compared with 18.0 months in the SOC alone group (HR 1.07,95% CI: 0.97, 1.18). The median time to progression (TTP) based on investigator-determinedprogressive disease (PD) was 7.5 months in the epoetin alfa plus SOC group and 7.5 months in the

SOC group (HR 1.099, 95% CI: 0.998, 1.210). The median TTP based on IRC-determined PD was8.0 months in the epoetin alfa plus SOC group and 8.3 months in the SOC group (HR 1.033, 95% CI:0.924, 1.156).

Autologous predonation programme

The effect of epoetin alfa in facilitating autologous blood donation in patients with low haematocrits(≤ 39% and no underlying anaemia due to iron deficiency) scheduled for major orthopaedic surgerywas evaluated in a double-blind, placebo-controlled study conducted in 204 patients, and asingle-blind placebo controlled study in 55 patients.

In the double-blind study, patients were treated with epoetin alfa 600 IU/kg or placebo intravenouslyonce daily every 3 to 4 days over 3 weeks (total 6 doses). On average, patients treated with epoetinalfa were able to predeposit significantly more units of blood (4.5 units) than placebo-treated patients(3.0 units).

In the single-blind study, patients were treated with epoetin alfa 300 IU/kg or 600 IU/kg or placebointravenously once daily every 3 to 4 days over 3 weeks (total 6 doses). Patients treated with epoetinalfa were also able to predeposit significantly more units of blood (epoetin alfa 300 IU/kg = 4.4 units;epoetin alfa 600 IU/kg = 4.7 units) than placebo-treated patients (2.9 units).

Epoetin alfa therapy reduced the risk of exposure to allogeneic blood by 50% compared to patients notreceiving epoetin alfa.

Major elective orthopaedic surgery

The effect of epoetin alfa (300 IU/kg or 100 IU/kg) on the exposure to allogeneic blood transfusionhas been evaluated in a placebo-controlled, double-blind clinical trial in non-iron deficient adultpatients scheduled for major elective orthopaedic hip or knee surgery. Epoetin alfa was administeredsubcutaneously for 10 days prior to surgery, on the day of surgery, and for four days after surgery.

Patients were stratified according to their baseline haemoglobin (≤ 10 g/dL, >10 to ≤ 13 g/dL and>13 g/dL).

Epoetin alfa 300 IU/kg significantly reduced the risk of allogeneic transfusion in patients with apretreatment haemoglobin of >10 to ≤13 g/dL. Sixteen percent of epoetin alfa 300 IU/kg, 23% ofepoetin alfa 100 IU/kg and 45% of placebo-treated patients required transfusion.

An open-label, parallel-group trial in non-iron deficient adult subjects with a pretreatmenthaemoglobin of ≥ 10 to ≤ 13 g/dL who were scheduled for major orthopaedic hip or knee surgerycompared epoetin alfa 300 IU/kg subcutaneously daily for 10 days prior to surgery, on the day ofsurgery and for four days after surgery to epoetin alfa 600 IU/kg subcutaneously once weekly for3 weeks prior to surgery and on the day of surgery.

From pretreatment to presurgery, the mean increase in haemoglobin in the 600 IU/kg weekly group(1.44 g/dL) was twice than that observed in the 300 IU/kg daily group (0.73 g/dL). Mean haemoglobinlevels were similar for the two treatment groups throughout the postsurgical period.

The erythropoietic response observed in both treatment groups resulted in similar transfusion rates(16% in the 600 IU/kg weekly group and 20% in the 300 IU/kg daily group).

Treatment of adult patients with low- or intermediate-1-risk MDS

A randomised, double-blind, placebo-controlled, multicentre study evaluated the efficacy and safety ofepoetin alfa in adult anaemic subjects with low- or intermediate-1-risk MDS.

Subjects were stratified by serum erythropoietin (sEPO) level and prior transfusion status at screening.

Key baseline characteristics for the <200 mU/mL stratum are shown in the table below.

Baseline Characteristics for Subjects with sEPO <200mU/mL at Screening

Randomised

Epoetin alfa Placebo

Total (N)b 85a 45

Screening sEPO <200 mU/mL 71 39(N)

Haemoglobin (g/L)

N 71 39

Mean 92.1 (8.57) 92.1 (8.51)

Median 94.0 96.0

Range (71, 109) (69, 105)95% CI for Mean (90.1, 94.1) (89.3, 94.9)

Prior Transfusions

N 71 39

Yes 31 (43.7%) 17 (43.6%)≤2 RBC Units 16 (51.6%) 9 (52.9%)˃2 and ≤4 RBC Units 14 (45.2%) 8 (47.1%)˃4 RBC Units 1 (3.2%) 0

No 40 (56.3%) 22 (56.4%)a one subject did not have sEPO datab in the ≥200 mU/mL stratum there were 13 subjects in the epoetin alfa group and 6 subjects in the placebogroup

Erythroid response was defined according to International Working Group (IWG) 2006 criteria as ahaemoglobin increase ≥1.5 g/dl from baseline or a reduction of RBC units transfused by an absolutenumber of at least 4 units every 8 weeks compared to the 8 weeks prior to baseline, and a responseduration of at least 8 weeks.

Erythroid response during the first 24 weeks of the study was demonstrated by 27/85 (31.8%) of thesubjects in the epoetin alfa group compared to 2/45 (4.4%) of the subjects in the placebo group(p<0.001). All of the responding subjects were in the stratum with sEPO <200 mU/mL duringscreening. In that stratum, 20/40 (50%) subjects without prior transfusions demonstrated erythroidresponse during the first 24 weeks, compared with 7/31 (22.6%) subjects with prior transfusions (twosubjects with prior transfusion reached primary endpoint based on reduction of RBC units transfusedby an absolute number of at least 4 units every 8 weeks compared to the 8 weeks prior to baseline).

Median time from baseline to first transfusion was statistically significantly longer in the epoetin alfagroup compared to placebo (49 vs. 37 days; p=0.046). After 4 weeks of treatment the time to firsttransfusion was further increased in the epoetin alfa group (142 vs. 50 days, p=0.007). The percentageof subjects who were transfused in the epoetin alfa group decreased from 51.8% in the 8 weeks priorto baseline to 24.7% between weeks 16 and 24, compared to the placebo group which had an increasein transfusion rate from 48.9% to 54.1% over the same time periods.

Chronic renal failure

Epoetin alfa was evaluated in an open-label, non-randomised, open dose-range, 52-week clinical studyin paediatric CRF patients undergoing haemodialysis. The median age of patients enrolled in the studywas 11.6 years (range 0.5 to 20.1 years).

Epoetin alfa was administered at 75 IU/kg/week intravenously in 2 or 3 divided doses post-dialysis,titrated by 75 IU/kg/week at intervals of 4 weeks (up to a maximum of 300 IU/kg/week), to achieve a1 g/dL/month increase in haemoglobin. The desired haemoglobin concentration range was 9.6 to11.2 g/dL. Eighty-one percent of patients achieved the haemoglobin concentration level. The mediantime to target was 11 weeks and the median dose at target was 150 IU/kg/week. Of the patients whoachieved the target, 90% did so on a 3 times-per-week dosing regimen.

After 52 weeks, 57% of patients remained in the study, receiving a median dose of 200 IU/kg/week.

Clinical data with subcutaneous administration in children are limited. In 5 small, open label,uncontrolled studies (number of patients ranged from 9-22, total N=72), Epoetin alfa has beenadministered subcutaneously in children at starting doses of 100 IU/kg/week to 150 IU/kg/week withthe possibility to increase up to 300 IU/kg/week. In these studies, most were predialysis patients(N=44), 27 patients were on peritoneal dialysis and 2 were on haemodialysis with age ranging from4 months to 17 years. Overall, these studies have methodological limitations but treatment wasassociated with positive trends towards higher haemoglobin levels. No unexpected adverse eventswere reported (see section 4.2).

Chemotherapy-induced anaemia

Epoetin alfa 600 IU/kg (administered intravenously or subcutaneously once weekly) has beenevaluated in a randomised, double-blind, placebo-controlled, 16-week study and in a randomised,controlled, open-label, 20-week study in anaemic paediatric patients receiving myelosuppressivechemotherapy for the treatment of various childhood non-myeloid malignancies.

In the 16-week study (n=222), in the epoetin alfa-treated patients there was no statistically significanteffect on patient-reported or parent-reported Paediatric Quality of Life Inventory or Cancer Modulescores compared with placebo (primary efficacy endpoint). In addition, there was no statisticaldifference between the proportion of patients requiring pRBC transfusions between the Epoetin alfagroup and placebo.

In the 20-week study (n=225), no significant difference was observed in the primary efficacy endpoint,i.e. the proportion of patients who required a RBC transfusion after Day 28 (62% of epoetin alfapatients versus 69% of standard therapy patients).

Following subcutaneous injection, serum levels of erythropoietin reach a peak between 12 and18 hours post-dose. There was no accumulation after multiple dose administration of 600 IU/kgadministered subcutaneously weekly.

The absolute bioavailability of subcutaneous injectable erythropoietin is approximately 20% in healthysubjects.

The mean volume of distribution was 49.3 mL/kg after intravenous doses of 50 and 100 IU/kg inhealthy subjects. Following intravenous administration of erythropoietin in subjects with chronic renalfailure, the volume of distribution ranged from 57-107 mL/kg after single dosing (12 IU/kg) to42-64 mL/kg after multiple dosing (48-192 IU/kg), respectively. Thus, the volume of distribution isslightly greater than the plasma space.

The half-life of erythropoietin following multiple dose intravenous administration is approximately4 hours in healthy subjects. The half-life for the subcutaneous route is estimated to be approximately24 hours in healthy subjects.

The mean CL/F for the 150 IU/kg 3 times-per-week and 40 000 IU once-weekly regimens in healthysubjects were 31.2 and 12.6 mL/h/kg, respectively. The mean CL/F for the 150 IU/kg,3-times-per-week and 40 000 IU, once-weekly regimens in the anaemic cancer subjects were 45.8 and11.3 mL/h/kg, respectively. In most anaemic subjects with cancer receiving cyclic chemotherapy CL/Fwas lower after subcutaneous doses of 40 000 IU once weekly and 150 IU/kg, 3 times per weekcompared with the values for healthy subjects.

In healthy subjects, a dose-proportional increase in serum erythropoietin concentrations was observedafter intravenous administration of 150 and 300 IU/kg, 3 times per week. Administration of singledoses of 300 to 2 400 IU/kg subcutaneous erythropoietin resulted in a linear relationship betweenmean Cmax and dose and between mean AUC and dose. An inverse relationship between apparentclearance and dose was noted in healthy subjects.

In studies to explore extending the dosing interval (40 000 IU once weekly and 80 000, 100 000, and120 000 IU biweekly), a linear but non-dose-proportional relationship was observed between mean

Cmax and dose, and between mean AUC and dose at steady state.

Erythropoietins exhibit a dose-related effect on haematological parameters which is independent ofroute of administration.

A half-life of approximately 6.2 to 8.7 hours has been reported in paediatric subjects with chronicrenal failure following multiple dose intravenous administration of erythropoietin. Thepharmacokinetic profile of erythropoietins in children and adolescents appears to be similar to that ofadults.

Pharmacokinetic data in neonates is limited.

A study of 7 preterm very low birth weight neonates and 10 healthy adults given i.v. erythropoietinsuggested that distribution volume was approximately 1.5 to 2 times higher in the preterm neonatesthan in the healthy adults, and clearance was approximately 3 times higher in the preterm neonatesthan in healthy adults.

In chronic renal failure patients, the half-life of intravenously administered erythropoietin is slightlyprolonged, approximately 5 hours, compared to healthy subjects.

In repeated dose toxicological studies in dogs and rats, but not in monkeys, epoetin alfa therapy wasassociated with subclinical bone marrow fibrosis. Bone marrow fibrosis is a known complication ofchronic renal failure in humans and may be related to secondary hyperparathyroidism or unknownfactors. The incidence of bone marrow fibrosis was not increased in a study of haemodialysis patientswho were treated with epoetin alfa for 3 years compared to a matched control group of dialysispatients who had not been treated with epoetin alfa.

Epoetin alfa does not induce bacterial gene mutation (Ames Test), chromosomal aberrations inmammalian cells, micronuclei in mice, or gene mutation at the HGPRT locus.

Long-term carcinogenicity studies have not been carried out. Conflicting reports in the literature,based on in vitro findings from human tumour samples, suggest erythropoietins may play a role astumour proliferators. This is of uncertain significance in the clinical situation.

In cell cultures of human bone marrow cells, epoetin alfa stimulates erythropoiesis specifically anddoes not affect leucopoiesis. Cytotoxic actions of epoetin alfa on bone marrow cells could not bedetected.

In animal studies, epoetin alfa has been shown to decrease foetal body weight, delay ossification andincrease foetal mortality when given in weekly doses of approximately 20 times the recommendedhuman weekly dose. These changes are interpreted as being secondary to decreased maternal bodyweight gain, and the significance to humans is unknown given therapeutic dose levels.

Disodium phosphate dihydrate

Sodium dihydrogen phosphate dihydrate

Sodium chloride

Calcium chloride dihydrate

Polysorbate 20

Glycine

Leucine

Isoleucine

Threonine

Glutamic acid

Phenylalanine

Water for injections

Sodium hydroxide (pH adjuster)

Hydrochloric acid (pH adjuster)

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

30 months

Store in a refrigerator (2°C to 8°C). This temperature range should be closely maintained untiladministration to the patient.

For the purpose of ambulatory use, the medicinal product may be taken out of the refrigerator, withoutbeing replaced, for a maximum period of 3 days at a temperature not above 25°C. If the medicinalproduct has not been used at the end of this period, it should be disposed of.

Do not freeze or shake.

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

Retacrit 1 000 IU/0.3 mL solution for injection in pre-filled syringe

Pre-filled syringe Type I glass with a fixed steel injection needle and a plunger stopper with PTFEcoating with or without a needle guard or needle-trap device.

Each pre-filled syringe contains 0.3 mL solution.

Each pack contains 1 or 6 pre-filled syringes.

Retacrit 2 000 IU/0.6 mL solution for injection in pre-filled syringe

Pre-filled syringe Type I glass with a fixed steel injection needle and a plunger stopper with PTFEcoating with or without a needle guard or needle-trap device.

Each pre-filled syringe contains 0.6 mL solution.

Each pack contains 1 or 6 pre-filled syringes.

Retacrit 3 000 IU/0.9 mL solution for injection in pre-filled syringe

Pre-filled syringe Type I glass with a fixed steel injection needle and a plunger stopper with PTFEcoating with or without a needle guard or needle-trap device.

Each pre-filled syringe contains 0.9 mL solution.

Each pack contains 1 or 6 pre-filled syringes.

Retacrit 4 000 IU/0.4 mL solution for injection in pre-filled syringe

Pre-filled syringe Type I glass with a fixed steel injection needle and a plunger stopper with PTFEcoating with or without a needle guard or needle-trap device.

Each pre-filled syringe contains 0.4 mL solution.

Each pack contains 1 or 6 pre-filled syringes.

Retacrit 5 000 IU/0.5 mL solution for injection in pre-filled syringe

Pre-filled syringe Type I glass with a fixed steel injection needle and a plunger stopper with PTFEcoating with or without a needle guard or needle-trap device.

Each pre-filled syringe contains 0.5 mL solution.

Each pack contains 1 or 6 pre-filled syringes.

Retacrit 6 000 IU/0.6 mL solution for injection in pre-filled syringe

Pre-filled syringe Type I glass with a fixed steel injection needle and a plunger stopper with PTFEcoating with or without a needle guard or needle-trap device.

Each pre-filled syringe contains 0.6 mL solution.

Each pack contains 1 or 6 pre-filled syringes.

Retacrit 8 000 IU/0.8 mL solution for injection in pre-filled syringe

Pre-filled syringe Type I glass with a fixed steel injection needle and a plunger stopper with PTFEcoating with or without a needle guard or needle-trap device.

Each pre-filled syringe contains 0.8 mL solution.

Each pack contains 1 or 6 pre-filled syringes.

Retacrit 10 000 IU/1 mL solution for injection in pre-filled syringe

Pre-filled syringe Type I glass with a fixed steel injection needle and a plunger stopper with PTFEcoating with or without a needle guard or needle-trap device.

Each pre-filled syringe contains 1 mL solution.

Each pack contains 1 or 6 pre-filled syringes.

Retacrit 20 000 IU/0.5 mL solution for injection in pre-filled syringe

Pre-filled syringe Type I glass with a fixed steel injection needle and a plunger stopper with PTFEcoating with or without a needle guard or needle-trap device.

Each pre-filled syringe contains 0.5 mL solution.

Each pack contains 1, 4 or 6 pre-filled syringes.

Multipacks contain 6 (6 x 1) pre-filled syringes.

Retacrit 30 000 IU/0.75 mL solution for injection in pre-filled syringe

Pre-filled syringe Type I glass with a fixed steel injection needle and a plunger stopper with PTFEcoating with or without a needle guard or needle-trap device.

Each pre-filled syringe contains 0.75 mL solution.

Each pack contains 1, 4 or 6 pre-filled syringes.

Multipacks contain 4 (4 x 1) pre-filled syringes.

Retacrit 40 000 IU/1 mL solution for injection in pre-filled syringe

Pre-filled syringe Type I glass with a fixed steel injection needle and a plunger stopper with PTFEcoating with or without a needle guard or needle-trap device.

Each pre-filled syringe contains 1 mL solution.

Each pack contains 1, 4 or 6 pre-filled syringes.

Multipacks contain 4 (4 x 1) pre-filled syringes.

Not all pack sizes may be marketed.

Retacrit should not be used and discarded

* if the seal is broken,

* if the liquid is coloured or you can see particles floating in it,

* if any liquid has leaked out of the pre-filled syringe or condensation is visible within the sealedblister,

* if you know, or think that it may have been accidentally frozen, or

* if there has been a refrigerator failure.

The product is for single use only. Only take one dose of Retacrit from each syringe.

Do not shake.

Any unused medicinal product or waste material should be disposed of in accordance with localrequirements.

Pfizer Europe MA EEIG

Boulevard de la Plaine 171050 Bruxelles

Belgium

Retacrit 1 000 IU/0.3 mL solution for injection in pre-filled syringe

EU/1/07/431/001 1 pre-filled syringe

EU/1/07/431/002 6 pre-filled syringes

EU/1/07/431/026 1 pre-filled syringe with needle guard

EU/1/07/431/027 6 pre-filled syringes with needle guard

EU/1/07/431/054 1 pre-filled syringe with needle-trap

EU/1/07/431/055 6 pre-filled syringes with needle-trap

Retacrit 2 000 IU/0.6 mL solution for injection in pre-filled syringe

EU/1/07/431/003 1 pre-filled syringe

EU/1/07/431/004 6 pre-filled syringes

EU/1/07/431/028 1 pre-filled syringe with needle guard

EU/1/07/431/029 6 pre-filled syringes with needle guard

EU/1/07/431/056 1 pre-filled syringe with needle-trap

EU/1/07/431/057 6 pre-filled syringes with needle-trap

Retacrit 3 000 IU/0.9 mL solution for injection in pre-filled syringe

EU/1/07/431/005 1 pre-filled syringe

EU/1/07/431/006 6 pre-filled syringes

EU/1/07/431/030 1 pre-filled syringe with needle guard

EU/1/07/431/031 6 pre-filled syringes with needle guard

EU/1/07/431/058 1 pre-filled syringe with needle-trap

EU/1/07/431/059 6 pre-filled syringes with needle-trap

Retacrit 4 000 IU/0.4 mL solution for injection in pre-filled syringe

EU/1/07/431/007 1 pre-filled syringe

EU/1/07/431/008 6 pre-filled syringes

EU/1/07/431/032 1 pre-filled syringe with needle guard

EU/1/07/431/033 6 pre-filled syringes with needle guard

EU/1/07/431/060 1 pre-filled syringe with needle-trap

EU/1/07/431/061 6 pre-filled syringes with needle-trap

Retacrit 5 000 IU/0.5 mL solution for injection in pre-filled syringe

EU/1/07/431/009 1 pre-filled syringe

EU/1/07/431/010 6 pre-filled syringes

EU/1/07/431/034 1 pre-filled syringe with needle guard

EU/1/07/431/035 6 pre-filled syringes with needle guard

EU/1/07/431/062 1 pre-filled syringe with needle-trap

EU/1/07/431/063 6 pre-filled syringes with needle-trap

Retacrit 6 000 IU/0.6 mL solution for injection in pre-filled syringe

EU/1/07/431/011 1 pre-filled syringe

EU/1/07/431/012 6 pre-filled syringes

EU/1/07/431/036 1 pre-filled syringe with needle guard

EU/1/07/431/037 6 pre-filled syringes with needle guard

EU/1/07/431/064 1 pre-filled syringe with needle-trap

EU/1/07/431/065 6 pre-filled syringes with needle-trap

Retacrit 8 000 IU/0.8 mL solution for injection in pre-filled syringe

EU/1/07/431/013 1 pre-filled syringe

EU/1/07/431/014 6 pre-filled syringes

EU/1/07/431/038 1 pre-filled syringe with needle guard

EU/1/07/431/039 6 pre-filled syringes with needle guard

EU/1/07/431/066 1 pre-filled syringe with needle-trap

EU/1/07/431/067 6 pre-filled syringes with needle-trap

Retacrit 10 000 IU/1 mL solution for injection in pre-filled syringe

EU/1/07/431/015 1 pre-filled syringe

EU/1/07/431/016 6 pre-filled syringes

EU/1/07/431/040 1 pre-filled syringe with needle guard

EU/1/07/431/041 6 pre-filled syringes with needle guard

EU/1/07/431/068 1 pre-filled syringe with needle-trap

EU/1/07/431/069 6 pre-filled syringes with needle-trap

Retacrit 20 000 IU/0.5 mL solution for injection in pre-filled syringe

EU/1/07/431/017 1 pre-filled syringe

EU/1/07/431/020 4 pre-filled syringes

EU/1/07/431/021 6 pre-filled syringes

EU/1/07/431/042 1 pre-filled syringe with needle guard

EU/1/07/431/045 4 pre-filled syringes with needle guard

EU/1/07/431/046 6 pre-filled syringes with needle guard

EU/1/07/431/051 6 (6 x 1) pre-filled syringes (multipack)

EU/1/07/431/070 1 pre-filled syringe with needle-trap

EU/1/07/431/071 4 pre-filled syringes with needle-trap

EU/1/07/431/072 6 pre-filled syringes with needle-trap

Retacrit 30 000 IU/0.75 mL solution for injection in pre-filled syringe

EU/1/07/431/018 1 pre-filled syringe

EU/1/07/431/022 4 pre-filled syringes

EU/1/07/431/023 6 pre-filled syringes

EU/1/07/431/043 1 pre-filled syringe with needle guard

EU/1/07/431/047 4 pre-filled syringes with needle guard

EU/1/07/431/048 6 pre-filled syringes with needle guard

EU/1/07/431/052 4 (4 x 1) pre-filled syringes (multipack)

EU/1/07/431/073 1 pre-filled syringe with needle-trap

EU/1/07/431/074 4 pre-filled syringes with needle-trap

EU/1/07/431/075 6 pre-filled syringes with needle-trap

Retacrit 40 000 IU/1 mL solution for injection in pre-filled syringe

EU/1/07/431/019 1 pre-filled syringe

EU/1/07/431/024 4 pre-filled syringes

EU/1/07/431/025 6 pre-filled syringes

EU/1/07/431/044 1 pre-filled syringe with needle guard

EU/1/07/431/049 4 pre-filled syringes with needle guard

EU/1/07/431/050 6 pre-filled syringes with needle guard

EU/1/07/431/053 4 (4 x 1) pre-filled syringes (multipack)

EU/1/07/431/076 1 pre-filled syringe with needle-trap

EU/1/07/431/077 4 pre-filled syringes with needle-trap

EU/1/07/431/078 6 pre-filled syringes with needle-trap

Date of first authorisation: 18 December 2007

Date of latest renewal: 15 November 2012

Detailed information on this medicinal product is available on the website of the European Medicines

Agency https://www.ema.europa.eu.