BINOCRIT 40000UI / 1ml injection solution in pre-filled syringe medication leaflet

Binocrit 1 000 IU/0.5 mL solution for injection in a pre-filled syringe

Binocrit 2 000 IU/1 mL solution for injection in a pre-filled syringe

Binocrit 3 000 IU/0.3 mL solution for injection in a pre-filled syringe

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

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

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

Binocrit 7 000 IU/0.7 mL solution for injection in a pre-filled syringe

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

Binocrit 9 000 IU/0.9 mL solution for injection in a pre-filled syringe

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

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

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

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

Binocrit 1 000 IU/0.5 mL solution for injection in a pre-filled syringe

Each mL of solution contains 2 000 IU of epoetin alfa* corresponding to 16.8 micrograms per mL

A pre-filled syringe of 0.5 mL contains 1 000 international units (IU) corresponding to 8.4 microgramsepoetin alfa. *

Binocrit 2 000 IU/1 mL solution for injection in a pre-filled syringe

Each mL of solution contains 2 000 IU of epoetin alfa* corresponding to 16.8 micrograms per mL

A pre-filled syringe of 1 mL contains 2 000 international units (IU) corresponding to 16.8 microgramsepoetin alfa. *

Binocrit 3 000 IU/0.3 mL solution for injection in a pre-filled syringe

Each mL of solution contains 10 000 IU of epoetin alfa* corresponding to 84.0 micrograms per mL

A pre-filled syringe of 0.3 mL contains 3 000 international units (IU) correspondingto 25.2 micrograms epoetin alfa. *

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

Each mL of solution contains 10 000 IU of epoetin alfa* corresponding to 84.0 micrograms per mL

A pre-filled syringe of 0.4 mL contains 4 000 international units (IU) correspondingto 33.6 micrograms epoetin alfa. *

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

Each mL of solution contains 10 000 IU of epoetin alfa* corresponding to 84.0 micrograms per mL

A pre-filled syringe of 0.5 mL contains 5 000 international units (IU) correspondingto 42.0 micrograms epoetin alfa. *

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

Each mL of solution contains 10 000 IU of epoetin alfa* corresponding to 84.0 micrograms per mL

A pre-filled syringe of 0.6 mL contains 6 000 international units (IU) correspondingto 50.4 micrograms epoetin alfa. *

Binocrit 7 000 IU/0.7 mL solution for injection in a pre-filled syringe

Each mL of solution contains 10 000 IU of epoetin alfa* corresponding to 84.0 micrograms per mL

A pre-filled syringe of 0.7 mL contains 7 000 international units (IU) correspondingto 58.8 micrograms epoetin alfa. *

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

Each mL of solution contains 10 000 IU of epoetin alfa* corresponding to 84.0 micrograms per mL

A pre-filled syringe of 0.8 mL contains 8 000 international units (IU) correspondingto 67.2 micrograms epoetin alfa. *

Binocrit 9 000 IU/0.9 mL solution for injection in a pre-filled syringe

Each mL of solution contains 10 000 IU of epoetin alfa* corresponding to 84.0 micrograms per mL

A pre-filled syringe of 0.9 mL contains 9 000 international units (IU) correspondingto 75.6 micrograms epoetin alfa. *

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

Each mL of solution contains 10 000 IU of epoetin alfa* corresponding to 84.0 micrograms per mL

A pre-filled syringe of 1 mL contains 10 000 international units (IU) correspondingto 84.0 micrograms epoetin alfa. *

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

Each mL of solution contains 40 000 IU of epoetin alfa* corresponding to 336.0 micrograms per mL

A pre-filled syringe of 0.5 mL contains 20 000 international units (IU) correspondingto 168.0 micrograms epoetin alfa. *

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

Each mL of solution contains 40 000 IU of epoetin alfa* corresponding to 336.0 micrograms per mL

A pre-filled syringe of 0.75 mL contains 30 000 international units (IU) correspondingto 252.0 micrograms epoetin alfa. *

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

Each mL of solution contains 40 000 IU of epoetin alfa* corresponding to 336.0 micrograms per mL

A pre-filled syringe of 1 mL contains 40 000 international units (IU) correspondingto 336.0 micrograms epoetin alfa. *

* Produced in Chinese Hamster Ovary (CHO) cells by recombinant DNA technology

For the full list of excipients, see section 6.1.

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

Clear, colourless solution

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

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

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

Binocrit 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.

Binocrit 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).

Binocrit 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).

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

Treatment with Binocrit has to be initiated under the supervision of physicians experienced in themanagement of patients with the 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 alfa, and when deciding to increase the dose. Inorder to ensure optimum response to epoetin alfa, 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 to 7.5 mmol/L). Binocrit should be administered in order to increase haemoglobin to not greaterthan 12 g/dL (7.5 mmol/L). A rise in haemoglobin of greater than 2 g/dL (1.25 mmol/L) over a fourweek period 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 Binocrit 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

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

Patients should be monitored closely to ensure that the lowest approved effective dose of Binocrit 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 CRF. In patients with a poor haemoglobin response to ESA, alternative explanations forthe poor response should be considered (see section 4.4 and 5.1).

Treatment with Binocrit 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 Binocrit 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, Binocrit can be administered either 3 times per week, and in the caseof subcutaneous 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 and 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 maximumof 20 000 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 Binocrit 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.

Binocrit 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, Binocrit 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) isdescribed 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 reticulocytecount has increased < 40 000 cells/µL above baseline, increase the dose to 300 IU/kg 3 timesper week. If after an additional 4 weeks of therapy at 300 IU/kg 3 times per week, thehaemoglobin concentration has increased  1 g/dL ( 0.62 mmol/L) or the reticulocyte counthas 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 to 7.5 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 Binocrit dose byabout 25 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 Binocrit therapy at a dose 25% below the previousdose.

The recommended dosing regimen is described in the following diagram:

150 IU/kg 3x/weekor 450 IU/kg once weeklyfor 4 weeks

Reticulocyte count increase  40 000/µL Reticulocyte count increase< 40 000/µLor Hb increase  1 g/dL and Hb increase < 1 g/dL

Target Hb 300 IU/kg(≤ 12 g/dL) 3x/weekfor 4 weeks

Reticulocyte count increase  40 000/µLor Hb increase  1 g/dL

Reticulocyte count increase< 40 000/µLand Hb increase < 1 g/dL

Discontinue therapy

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

Epoetin alfa 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 Binocrit 600 IU/kg intravenously, 2 times per week for 3 weeks prior to surgery.

Binocrit 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 Binocrit 600 IU/kg, administered subcutaneously weekly for three weeks(days -21, -14 and -7) prior to surgery and on the day of surgery (day 0).

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

Binocrit 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 Binocrit should be stopped and further dosages should not be administered.

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

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

The recommended starting dose is Binocrit 450 IU/kg (maximum total dose is 40 000 IU)administered subcutaneously 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. If the patient loses response or haemoglobin concentration drops by ≥ 1 g/dL upon dosereduction the dose should be increased by one dosing step. A minimum of 4 weeks should elapsebetween dose increases.

Dose hold and decrease: Epoetin alfa should be withheld when the haemoglobin concentrationexceeds 12 g/dL (7.5 mmol/L). Once the haemoglobin level is < 11 g/dL the dose can be restarted onthe same dosing step or one dosing step down based on physician judgement. Decreasing the dose byone dosing step should be considered if there is a rapid increase in haemoglobin (> 2 g/dLover 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/dLto 11 g/dL (5.9 to 6.8 mmol/L). Binocrit should be administered in order to increase haemoglobin tonot greater than 11 g/dL (6.8 mmol/L). A rise in haemoglobin of greater than 2 g/dL (1.25 mmol/L)over a four week period should be avoided. If it occurs, appropriate dose adjustment should be madeas provided.

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

Treatment with Binocrit 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.

Paediatric patients with very low initial haemoglobin (< 6.8 g/dL or < 4.25 mmol/L) may requirehigher maintenance 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 epoetin alfa in chronic renal failure patients with anaemia before initiationof dialysis or on peritoneal dialysis have not been established. Currently available data forsubcutaneous use of epoetin alfa in these populations are described in section 5.1 but norecommendation on posology 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 Binocrit syringe to stand until it reaches room temperature. This usually takesbetween 15 and 30 minutes.

As with any other injectable product, check that there are no particles in the solution or change incolour. Binocrit is a sterile but unpreserved product and is for single use only. Administer the amountrequired.

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 Binocrit by the intravenous route is preferable.

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

Treatment of adult patients with chemotherapy-induced anaemia

Binocrit should be administered as a subcutaneous injection.

Treatment of adult surgery patients in an autologous predonation programme

Binocrit should be administered by the intravenous route.

Treatment of adult patients scheduled for major elective orthopaedic surgery

Binocrit should be administered as a subcutaneous injection.

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

Binocrit 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 Binocrit 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 Binocrit 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 Binocrit subcutaneously themselves, instruction as to the proper dosage andadministration should be provided.

Graduation rings

The syringe contains graduation rings to provide for the administration of a part of the dose (seesection 6.6). However the product is for single use only. Only one dose of Binocrit from each syringeshould be taken.

“Instructions on how to inject Binocrit 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 erythropoietinshould not receive Binocrit or any other erythropoietin (see section 4.4).

- Uncontrolled hypertension.

- All contraindications associated with autologous blood predonation programmes should berespected in patients being supplemented with Binocrit.

The use of Binocrit 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.

Traceablility

In order to improve the traceability of erythropoiesis-stimulating agents (ESAs), the trade name andthe 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.

In all patients receiving epoetin alfa, blood pressure should be closely monitored and controlled asnecessary. Epoetin alfa 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 alfa 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 alfa 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 alfa 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 alfa should be used with caution in patients with chronic liver failure. The safety of epoetinalfa 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 thromboses 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 alfa 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 alfa. 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 alfa, 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 alfa, adequate iron stores should be assured and ironsupplementation should be administered if necessary (see section 4.2). For the selection of the besttreatment option according to the patient’s needs, current treatment guidelines on iron supplementationin combination with dose instructions approved and outlined in the SmPC of the iron medicationshould be followed:

- For chronic renal failure patients, iron supplementation is recommended if serum ferritin levelsare below 100 ng/mL.

- For cancer patients, iron supplementation is recommended if transferrin saturation isbelow 20%.

- For patients in an autologous predonation programme, iron supplementation should beadministered several weeks prior to initiating the autologous predeposit in order to achieve highiron stores prior to starting epoetin alfa therapy, and throughout the course of epoetin alfatherapy.

- For patients scheduled for major elective orthopaedic surgery, iron supplementation should beadministered throughout the course of epoetin alfa therapy. If possible, iron supplementationshould be initiated prior to starting epoetin alfa therapy to achieve adequate iron stores.

Very rarely, development of or exacerbation of porphyria has been observed in epoetin alfa-treatedpatients. Epoetin alfa 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, Binocrit 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

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

Pure Red Cell Aplasia (PRCA)

Antibody-mediated PRCA has been reported after months to years of epoetin alfa treatment. Caseshave also been reported in patients with hepatitis C treated with interferon and ribavirin, when ESAsare used concomitantly. Epoetin alfa is not approved in the management of anaemia associated withhepatitis C.

In patients developing sudden lack of efficacy defined by a decrease in haemoglobin (1 to 2 g/dLor 0.62 to 1.25 mmol/L per month) with increased need for transfusions, a reticulocyte count should beobtained and typical causes of non-response (e.g. iron, folate or vitamin B12 deficiency, aluminiumintoxication, infection or inflammation, blood loss, haemolysis and bone marrow fibrosis of anyorigin) should be investigated.

A paradoxical decrease in haemoglobin and development of severe anaemia associated with lowreticulocyte counts should prompt to discontinue treatment with epoetin alfa 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 alfa 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 studies,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 studies 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 Binocrit 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 section 4.2 and 5.1).

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

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

Shunt thromboses 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 alfa administration until the serum potassium levelhas been corrected.

An increase in heparin dose during haemodialysis is frequently required during the course of therapywith epoetin alfa 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 alfa 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 alfa 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 tumourprogression or reduced progression-free survival cannot be excluded. In controlled clinical studies, useof epoetin alfa and other ESAs have been associated with decreased locoregional tumour control ordecreased overall survival:

- decreased locoregional control in patients with advanced head and neck cancer receivingradiation therapy when administered to achieve a haemoglobin concentration level of greaterthan 14 g/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 levelof 12 g/dL (7.5 mmol/L) in patients with active malignant disease receiving neitherchemotherapy nor radiation therapy. ESAs are not indicated for use in this patient population,

- an observed 9% increase in risk for progress of disease (PD) or death in the epoetin alfa plusstandard of care group from a primary analysis and a 15% increased risk that cannot bestatistically ruled out in patients with metastatic breast cancer receiving chemotherapy whenadministered 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 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 epoetinalfa 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 deep venous thrombosis (DVTs). Moreover, in patients with abaseline haemoglobin of > 13 g/dL (> 8.1 mmol/L), the possibility that epoetin alfa treatment may beassociated with an increased risk of postoperative thrombotic/vascular events cannot be excluded.

Therefore, epoetin alfa should not be used in patients with baseline haemoglobin > 13 g/dL(> 8.1 mmol/L).

This medicine 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 alfa alters the metabolism of othermedicinal products.

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

Since cyclosporin is bound by RBCs there is potential for a medicinal product interaction. If epoetinalfa is given concomitantly with cyclosporin, blood levels of cyclosporin should be monitored and thedose of cyclosporin adjusted as the haematocrit rises.

No evidence exists that indicates an interaction between epoetin alfa and granulocytecolony-stimulating factor (G-CSF) or granulocyte macrophage colony-stimulating factor (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-administrationof 40 000 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 alfa in pregnant women. Studies inanimals have shown reproductive toxicity (see section 5.3). Consequently, epoetin alfa should be usedin pregnancy only if the potential benefit outweighs the potential risk to the foetus. The use of epoetinalfa is not recommended in pregnant surgical patients participating in an autologous blood predonationprogramme.

It is unknown whether exogenous epoetin alfa is excreted in human milk. A risk to thenewborns/infants cannot be excluded.

Epoetin alfa should be used with caution in nursing women. A decision must be made whether todiscontinue breast-feeding or to discontinue/abstain from therapy with epoetin alfa taking into accountthe benefit of breast-feeding for the child and the benefit of epoetin alfa therapy for the woman.

The use of epoetin alfa is not recommended in lactating surgical patients participating in an autologousblood predonation programme.

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

No studies on the effects on the ability to drive and use machines have been performed. Binocrit hasno 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 studies 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 CRF studies (2 studies in pre-dialysis[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,and 102 exposed subjects in 2 MDS studies. Adverse drug reactions reported by ≥ 1% of subjectstreated with epoetin alfa in these studies 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 fromthe available data).

MedDRA System Organ Adverse Reaction (Preferred Frequency

Classification (SOC) Term Level)

Blood and lymphatic system Pure red cell aplasia3,disorders Thrombocythaemia Rare

Metabolism and nutrition 1disorders Hyperkalaemia Uncommon

Immune system disorders Hypersensitivity3 Uncommon

Anaphylactic reaction3 Rare

Nervous system disorders Headache Common

Convulsion Uncommon

Hypertension, Venous and

Vascular disorders arterial thromboses2 Common

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 Urticaria Uncommon

Angioneurotic oedema3 Not known

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

Congenital, familial and geneticdisorders Porphyria acute3 Rare

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

Injection site reaction, Oedema Common

MedDRA System Organ Adverse Reaction (Preferred Frequency

Classification (SOC) Term Level)peripheral

Medicinal product ineffective3 Not known

Investigations Anti-erythropoietin antibodypositive Rare1 Common in dialysis2 Includes arterial and venous, fatal and non fatal events, such as deep venous thrombosis, pulmonaryemboli, retinal thrombosis, arterial thrombosis (including myocardial infarction), cerebrovascularaccidents (including cerebral infarction and cerebral haemorrhage) transient ischaemic attacks, andshunt thrombosis (including dialysis 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).

SCARs including SJS and TEN, which can be life-threatening or fatal, have been reported inassociation with 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 alfa 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 epoetin alfa (see section 4.4). More cases have beenreported with subcutaneous route of administration, compared with the intravenous 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 studies 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 epoetin alfa is very wide. Overdosage of epoetin alfa may produce effectsthat are extensions of the pharmacological effects of the hormone. Phlebotomy may be performed ifexcessively high haemoglobin levels occur. Additional supportive care should be provided asnecessary.

Pharmacotherapeutic group: other antianaemic preparations, erythropoietin, ATC code: B03XA01.

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

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

Erythropoietin (EPO) is a glycoprotein hormone produced primarily by the kidney in response tohypoxia and is the key regulator of RBC production. EPO is involved in all phases of erythroiddevelopment, and has its principal effect at the level of erythroid precursors. After EPO binds to itscell surface receptor, it activates signal transduction pathways that interfere with apoptosis andstimulates erythroid cell proliferation.

Recombinant human EPO (epoetin alfa), expressed in Chinese hamster ovary cells, has a 165 aminoacid sequence identical to that of human urinary EPO; the 2 are indistinguishable on the basis offunctional assays. The apparent molecular weight of erythropoietin 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).

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 allogeneictransfusions and hasten erythroid recovery (increased haemoglobin levels, haematocrit levels, andreticulocyte counts).

Chronic renal failure

Epoetin alfa has been studied in clinical studies in adult anaemic CRF patients, includinghaemodialysis and pre-dialysis patients, to treat anaemia and maintain haematocrit within a targetconcentration range of 30 to 36%.

In clinical studies 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 studies conducted in adult patients on dialysis, the median maintenancedose necessary to maintain the haematocrit between 30 to 36% was approximately 75 IU/kggiven 3 times per 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 studies 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, onceevery 2 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 randomised prospective study evaluated 1 432 anaemic chronic renal failure patients who were notundergoing dialysis. Patients were assigned to epoetin alfa treatment targeting a maintenancehaemoglobin level of 13.5 g/dL (higher than the recommended haemoglobin concentration level)or 11.3 g/dL. A major cardiovascular event (death, myocardial infarction, stroke or hospitalisation 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 (seesection 4.2 and section 4.4).

Treatment of patients with chemotherapy-induced anaemia

Epoetin alfa has been studied in clinical studies in adult anaemic cancer patients with lymphoid andsolid tumors, and patients on various chemotherapy regimens, including platinum andnon-platinum-containing regimens. In these studies, 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 studies 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 study conducted in 375 anaemicpatients with various non-myeloid malignancies receiving non-platinum chemotherapy, there was asignificant reduction of anaemia-related sequelae (e.g. fatigue, decreased energy, and activityreduction), as measured 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 studies 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 studiescould not be satisfactorily explained by differences in the incidence of thrombosis and relatedcomplications between 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 studies 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 studies 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 studiesand 10 441 patients). Meta-analyses also indicate consistently a significantly increased relative risk ofthromboembolic events in cancer patients receiving recombinant human erythropoietin (seesection 4.4).

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 as compared with standard of care alone. At the time of clinical data cutoff, the medianprogression free survival (PFS) per investigator assessment of disease progression was 7.4 months ineach arm (HR 1.09, 95% CI: 0.99, 1.20), indicating the study objective was not met. Significantlyfewer patients received RBC transfusions in the epoetin alfa plus standard of care arm (5.8% versus11.4%); however, significantly more patients had thrombotic vascular events in the epoetin alfa plusstandard of care arm (2.8% versus 1.4%). At the final analysis, 1 653 deaths were reported. Medianoverall survival in the epoetin alfa plus standard of care group was 17.8 months comparedwith 18.0 months in the standard of care alone group (HR 1.07, 95% CI: 0.97, 1.18). The median timeto progression (TTP) based on investigator-determined progressive disease (PD) was 7.5 months in theepoetin alfa plus standard of care group and 7.5 months in the standard of care group (HR 1.099, 95%

CI: 0.998, 1.210). The median TTP based on IRC-determined PD was 8.0 months in the epoetin alfaplus standard of care group and 8.3 months in the standard of care 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 study 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 study 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 weeklyfor 3 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 erythropoetin (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 < 200 mU/mL at Screening

Randomised

Total (N)b Epoetin alfa Placebo85a 45

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

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 theplacebo group

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). Thepercentage of subjects who were transfused in the epoetin alfa group decreased from 51.8% inthe 8 weeks prior to baseline to 24.7% between weeks 16 and 24, compared to the placebo groupwhich had an increase in 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 achievea 1 g/dL/month increase in haemoglobin. The desired haemoglobin concentration rangewas 9.6 to 11.2 g/dL. Eighty-one percent of patients achieved the haemoglobin concentration level.

The median time to target was 11 weeks and the median dose at target was 150 IU/kg/week. Of thepatients who achieved 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 rangingfrom 4 months to 17 years. Overall, these studies have methodological limitations but treatment wasassociated with positive trends towards higher haemoglobin levels. No unexpected adverse reactionswere 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 efficacyendpoint, i.e. the proportion of patients who required a RBC transfusion after Day 28 (62% of epoetinalfa patients versus 69% of standard therapy patients).

Following subcutaneous injection, serum levels of epoetin alfa reach a peak between 12 and 18 hourspost-dose. There was no accumulation after multiple dose administration of 600 IU/kg administeredsubcutaneously weekly.

The absolute bioavailability of subcutaneous injectable epoetin alfa 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 epoetin alfa in subjects with chronic renalfailure, the volume of distribution ranged from 57-107 mL/kg after single dosing (12 IU/kg) to 42-64 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 epoetin alfa following multiple dose intravenous administration isapproximately 4 hours in healthy subjects.

The half-life for the subcutaneous route is estimated to be approximately 24 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 forthe 150 IU/kg, 3 times-per-week and 40 000 IU, once-weekly regimens in the anaemic cancer subjectswere 45.8 and 11.3 mL/h/kg, respectively. In most anaemic subjects with cancer receiving cyclicchemotherapy, CL/F was lower after subcutaneous doses of 40 000 IU once weeklyand 150 IU/kg, 3 times-per-week compared with the values for healthy subjects.

Linearity/Non-linearity

In healthy subjects, a dose-proportional increase in serum epoetin alfa 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 epoetin alfa resulted in a linear relationship between mean

Cmax and dose and between mean AUC and dose. An inverse relationship between apparent clearanceand dose was noted in healthy subjects.

In studies to explore extending the dosing interval (40 000 IU once weekly and 80 000, 100 000,and 120 000 IU biweekly), a linear but non-dose-proportional relationship was observed betweenmean Cmax and dose, and between mean AUC and dose at steady state.

Epoetin alfa exhibits a dose-related effect on haematological parameters which is independent of routeof 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 epoetin alfa. The pharmacokineticprofile of epoetin alfa in children and adolescents appears to be similar to that of adults.

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 epoetin alfa 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.

Sodium dihydrogen phosphate dihydrate

Disodium phosphate dihydrate

Sodium chloride

Glycine

Polysorbate 80

Water for injections

Hydrochloric acid (for pH-adjustment)

Sodium hydroxide (for pH-adjustment)

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

2 years

Store and transport refrigerated (2 °C to 8 °C). This temperature range should be closely maintaineduntil administration 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.

Pre-filled syringes (glass type I), with or without a needle safety guard, with plunger stopper(Teflon-faced rubber) sealed in a blister.

Binocrit 1 000 IU/0.5 mL solution for injection in a pre-filled syringe

Each syringe contains 0.5 mL of solution for injection.

Pack of 1 or 6 syringes.

Binocrit 2 000 IU/1 mL solution for injection in a pre-filled syringe

Each syringe contains 1 mL of solution for injection.

Pack of 1 or 6 syringes.

Binocrit 3 000 IU/0.3 mL solution for injection in a pre-filled syringe

Each syringe contains 0.3 mL of solution for injection.

Pack of 1 or 6 syringes.

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

Each syringe contains 0.4 mL of solution for injection.

Pack of 1 or 6 syringes.

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

Each syringe contains 0.5 mL of solution for injection.

Pack of 1 or 6 syringes.

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

Each syringe contains 0.6 mL of solution for injection.

Pack of 1 or 6 syringes.

Binocrit 7 000 IU/0.7 mL solution for injection in a pre-filled syringe

Each syringe contains 0.7 mL of solution for injection.

Pack of 1 or 6 syringes.

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

Each syringe contains 0.8 mL of solution for injection.

Pack of 1 or 6 syringes.

Binocrit 9 000 IU/0.9 mL solution for injection in a pre-filled syringe

Each syringe contains 0.9 mL of solution for injection.

Pack of 1 or 6 syringes.

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

Each syringe contains 1 mL of solution for injection.

Pack of 1 or 6 syringes.

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

Each syringe contains 0.5 mL of solution for injection.

Pack of 1, 4 or 6 syringes.

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

Each syringe contains 0.75 mL of solution for injection.

Pack of 1, 4 or 6 syringes.

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

Each syringe contains 1 mL of solution for injection.

Pack of 1, 4 or 6 syringes.

Not all pack sizes may be marketed.

Binocrit should not be used and discarded

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

- if the seal is broken,

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

- if there has been a refrigerator failure.

The pre-filled syringes are ready to use (see section 4.2). The pre-filled syringe should not be shaken.

Syringes are embossed with graduation rings in order to enable partial use if required. Each graduationring corresponds to a volume of 0.1 mL. The product is for single use only. Only take one dose of

Binocrit from each syringe discarding unwanted solution before injection.

Using the pre-filled syringe with a needle safety guard

The needle safety guard covers the needle after injection to prevent needle stick injury. This does notaffect normal operation of the syringe. Depress the plunger slowly and evenly until the entire dose hasbeen given and the plunger cannot be depressed any further. While maintaining pressure on theplunger, remove the syringe from the patient. The needle safety guard will cover the needle whenreleasing the plunger.

Using the pre-filled syringe without a needle safety guard

Administer the dose as per standard protocol.

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

Sandoz GmbH

Biochemiestr. 106250 Kundl

Austria

Binocrit 1 000 IU/0.5 mL solution for injection in a pre-filled syringe

EU/1/07/410/001

EU/1/07/410/002

EU/1/07/410/027

EU/1/07/410/028

Binocrit 2 000 IU/1 mL solution for injection in a pre-filled syringe

EU/1/07/410/003

EU/1/07/410/004

EU/1/07/410/029

EU/1/07/410/030

Binocrit 3 000 IU/0.3 mL solution for injection in a pre-filled syringe

EU/1/07/410/005

EU/1/07/410/006

EU/1/07/410/031

EU/1/07/410/032

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

EU/1/07/410/007

EU/1/07/410/008

EU/1/07/410/033

EU/1/07/410/034

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

EU/1/07/410/009

EU/1/07/410/010

EU/1/07/410/035

EU/1/07/410/036

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

EU/1/07/410/011

EU/1/07/410/012

EU/1/07/410/037

EU/1/07/410/038

Binocrit 7 000 IU/0.7 mL solution for injection in a pre-filled syringe

EU/1/07/410/017

EU/1/07/410/018

EU/1/07/410/039

EU/1/07/410/040

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

EU/1/07/410/013

EU/1/07/410/014

EU/1/07/410/041

EU/1/07/410/042

Binocrit 9 000 IU/0.9 mL solution for injection in a pre-filled syringe

EU/1/07/410/019

EU/1/07/410/020

EU/1/07/410/043

EU/1/07/410/044

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

EU/1/07/410/015

EU/1/07/410/016

EU/1/07/410/045

EU/1/07/410/046

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

EU/1/07/410/021

EU/1/07/410/022

EU/1/07/410/047

EU/1/07/410/053

EU/1/07/410/048

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

EU/1/07/410/023

EU/1/07/410/024

EU/1/07/410/049

EU/1/07/410/054

EU/1/07/410/050

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

EU/1/07/410/025

EU/1/07/410/026

EU/1/07/410/051

EU/1/07/410/055

EU/1/07/410/052

Date of first authorisation: 28 August 2007

Date of latest renewal: 18 June 2012

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

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