NeoRecormon solution for injection Pre-Filled Syringe

No change of content. 

4.4     Special warnings and precautions for use

[ … ]

Blood pressure monitoring

An increase in blood pressure or aggravation of existing hypertension, especially in cases of rapid PCV increase can occur. These increases in blood pressure can be treated with medicinal products. If blood pressure rises cannot be controlled by drug therapy, a transient interruption of NeoRecormon therapy is recommended. Particularly at beginning of therapy, regular monitoring of the blood pressure is recommended, including between dialyses. Hypertensive crisis with encephalopathy-like symptoms may occur and require the immediate attention of a physician and intensive medical care. Particular attention should be paid to sudden stabbing migraine like headaches as a possible warning sign.

Severe cutaneous adverse reactions (SCARs) including Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN), which can be life-threatening or fatal, have been reported in association with epoetin treatment (see section 4.8). More severe cases have been observed with long-acting epoetins.At the time of prescription patients should be advised of the signs and symptoms and monitored closely for skin reactions. If signs and symptoms suggestive of these reactions appear, NeoRecormon should be withdrawn immediately and an alternative treatement considered.If the patient has developed a severe cutaneous skin reaction such as SJS or TEN due to the use of NeoRecormon, treatment with ESA must not be restarted in this patient at any time.

[ … ]

4.8     Undesirable effects

[ … ]

Patients in an autologous blood predonation programme

Patients in an autologous blood predonation programme have been reported to show a slightly higher frequency of thromboembolic events. However, a causal relationship with treatment with NeoRecormon could not be established.

In placebo controlled trials temporary iron deficiency was more pronounced in patients treated with NeoRecormon than in controls (see section 4.4).

Adverse reactions are listed in Table 3 below.

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

10.     DATE OF REVISION OF THE TEXT

24 November 2017

SUMMARY OF PRODUCT CHARACTERISTICS

1.       NAME OF THE MEDICINAL PRODUCT

NeoRecormon 500 IU  solution for injection in pre-filled syringe.

NeoRecormon 2000 IU solution for injection in pre-filled syringe

NeoRecormon 3000 IU solution for injection in pre-filled syringe

NeoRecormon 4000 IU solution for injection in pre-filled syringe

NeoRecormon 5000 IU solution for injection in pre-filled syringe

NeoRecormon 6000 IU solution for injection in pre-filled syringe

NeoRecormon 10,000 IU solution for injection in pre-filled syringe

NeoRecormon 20,000 IU solution for injection in pre-filled syringe

NeoRecormon 30,000 IU solution for injection in pre-filled syringe

2.       QUALITATIVE AND QUANTITATIVE COMPOSITION

NeoRecormon 500 IU  solution for injection in pre-filled syringe

One pre-filled syringe with 0.3 ml solution for injection contains 500 international units (IU) corresponding to 4.15 micrograms epoetin beta* (recombinant human erythropoietin).

One ml solution for injection contains 1667 IU epoetin beta.

NeoRecormon 2000 IU solution for injection in pre-filled syringe

One pre-filled syringe with 0.3 ml solution for injection contains 2000 international units (IU) corresponding to 16.6 micrograms epoetin beta* (recombinant human erythropoietin).

One ml solution for injection contains 6667 IU epoetin beta.

NeoRecormon 3000 IU solution for injection in pre-filled syringe

One pre-filled syringe with 0.3 ml solution for injection contains 3000 international units (IU) corresponding to 24.9 micrograms epoetin beta* (recombinant human erythropoietin).

One ml solution for injection contains 10,000 IU epoetin beta.

NeoRecormon 4000 IU solution for injection in pre-filled syringe

One pre-filled syringe with 0.3 ml solution for injection contains 4000 international units (IU) corresponding to 33.2 micrograms epoetin beta* (recombinant human erythropoietin).

One ml solution for injection contains 13,333 IU epoetin beta.

NeoRecormon 5000 IU solution for injection in pre-filled syringe

One pre-filled syringe with 0.3 ml solution for injection contains 5000 international units (IU) corresponding to 41.5 micrograms epoetin beta* (recombinant human erythropoietin).

One ml solution for injection contains 16,667 IU epoetin beta.

NeoRecormon 6000 IU solution for injection in pre-filled syringe

One pre-filled syringe with 0.3 ml solution for injection contains 6000 international units (IU) corresponding to 49.8 micrograms epoetin beta* (recombinant human erythropoietin).

One ml solution for injection contains 20,000 IU epoetin beta.

NeoRecormon 10,000 IU solution for injection in pre-filled syringe

One pre-filled syringe with 0.6 ml solution for injection contains 10,000 international units (IU) corresponding to 83 micrograms epoetin beta* (recombinant human erythropoietin).

One ml solution for injection contains 16,667 IU epoetin beta.

NeoRecormon 20,000 IU solution for injection in pre-filled syringe

One pre-filled syringe with 0.6 ml solution for injection contains 20,000 international units (IU) corresponding to 166 micrograms epoetin beta* (recombinant human erythropoietin).

One ml solution for injection contains 33,333 IU epoetin beta.

NeoRecormon 30,000 IU solution for injection in pre-filled syringe

One pre-filled syringe with 0.6 ml solution for injection contains 30,000 international units (IU) corresponding to 250 micrograms epoetin beta* (recombinant human erythropoietin).

One ml solution for injection contains 50,000 IU epoetin beta.

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

[….]

4.8     Undesirable effects

[….]

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions (see details below).

Ireland

HPRA Pharmacovigilance

Earlsfort Terrace

IRL - Dublin 2

Tel: +353 1 6764971

Fax: +353 1 6762517

Website: www.hpra.ie

e-mail: medsafety@hpra.ie

Malta

ADR Reporting

Website: www.medicinesauthority.gov.mt/adrportal

United Kingdom

Yellow Card Scheme

Website: www.mhra.gov.uk/yellowcard  or search for MHRA Yellow Card in the Google Play or Apple App Store

6.4     Special precautions for storage

Store in a refrigerator (2°C – 8°C).

Keep the pre-filled syringe in the outer carton, in order to protect from light.

For the purpose of ambulatory use, the patient may remove the medicinal product from the refrigerator and store it at room temperature (not above 25°C) for one single period of up to 3 days.

6.5     Nature and contents of container

Pre-filled syringe (Type I glass) with a tip cap and a plunger stopper (teflonised rubber). with an injection needle (30G1/2). Each syringe contains 0.3 ml solution.

Pack sizes of 1 pre‑filled syringe and 1 needle or 6 pre‑filled syringes and 6 needles.

NeoRecormon 500 IU, 2000 IU, 3000 IU, 4000 IU, 5000 IU and 6000 IU:

Each pre‑filled syringe contains 0.3 ml solution.

NeoRecormon 10,000 IU, 20,000 IU and 30,000 IU: Each pre‑filled syringe contains 0.6 ml solution.

NeoRecormon is provided in the following pack‑sizes:

NeoRecormon 500 IU

1 prefilled syringe with one needle (30G1/2) or

6 pre-filled syringes with 6 needles (30G1/2).

NeoRecormon 2000 IU, 3000 IU, 4000 IU,5000 IU, 6000 IU, 10,000 IU and 20,000IU

1 prefilled syringe with one needle (27G1/2) or

6 pre-filled syringes with 6 needles (27G1/2).

NeoRecormon 30,000 IU

1 prefilled syringe with one needle (27G1/2) or

4 pre-filled syringes with 4 needles (27G1/2).

NeoRecormon 500 IU, NeoRecormon 2000 IU, NeoRecormon 3000 IU, NeoRecormon 4000 IU, NeoRecormon 5000 IU and NeoRecormon 6000 IU solution for injection in pre-filled syringe

Each pre‑filled syringe contains 0.3 ml solution.

NeoRecormon 10,000 IU, NeoRecormon 20,000 IU and NeoRecormon 30,000 IU solution for injection in pre-filled syringe

Each pre‑filled syringe contains 0.6 ml solution.

NeoRecormon is provided in the following pack‑sizes:

NeoRecormon 500 IU solution for injection in pre-filled syringe

1 prefilled syringe with one needle (30G1/2) or 6 pre-filled syringes with 6 needles (30G1/2).

NeoRecormon 2000 IU, NeoRecormon 3000 IU, NeoRecormon 4000 IU, NeoRecormon 5000 IU, NeoRecormon 6000 IU, NeoRecormon 10,000 IU and NeoRecormon 20,000 IU solution for injection in pre-filled syringe

1 prefilled syringe with one needle (27G1/2) or 6 pre-filled syringes with 6 needles (27G1/2).

NeoRecormon 30,000 IU solution for injection in pre-filled syringe

1 prefilled syringe with one needle (27G1/2) or 4 pre-filled syringes with 4 needles (27G1/2).

Not all pack sizes may be marketed.

8.       MARKETING AUTHORISATION NUMBERS

EU/1/97/031/025 ‑– 026

EU/1/97/031/029 ‑– 030

EU/1/97/031/031 – 032

EU/1/97/031/033 ‑– 034

EU/1/97/031/035 ‑– 036

EU/1/97/031/037 – 038

EU/1/97/031/041 -– 042  

EU/1/97/031/043 -– 044  

EU/1/97/031/045 -– 046

10.     DATE OF REVISION OF THE TEXT

06 November 2017

Underlined text has been added, text with strike-through deleted:

2.         QUALITATIVE AND QUANTITATIVE COMPOSITION

[…]

Excipient(s) with known effect:Excipients:

Phenylalanine (up to 0.3 mg/syringe)

Sodium (less than 1 mmol/syringe)

For a the full list of excipients, see section 6.1.

4.1       Therapeutic indications

NeoRecormon is indicated for:

-           Treatment of symptomatic anaemia associated with chronic renal failure (CRF) in adult and paediatric patients.

-           Prevention of anaemia of prematurity in infants with a birth weight of 750 to 1500 g and a gestational age of less than 34 weeks.

-           Treatment of symptomatic anaemia in adult patients with non-myeloid malignancies receiving chemotherapy.

-           Increasing the yield of autologous blood from patients in a pre-donation programme.

             Its use in this indication must be balanced against the reported increased risk of thromboembolic events. Treatment should only be given to patients with moderate anaemia (Hb 10 ‑ 13 g/dl [6.21 ‑ 8.07 mmol/l], no iron deficiency) if blood conserving procedures are not available or insufficient when the scheduled major elective surgery requires a large volume of blood (4 or more units of blood for females or 5 or more units for males). See section 5.1

4.2       Posology and method of administration

Therapy with NeoRecormon should be initiated by physicians experienced in the above mentioned indications. As anaphylactoid reactions were observed in isolated cases, it is recommended that the first dose be administered under medical supervision.

The  pre-filled syringe is ready for use. Only solutions which are clear or slightly opalescent, colourless and practically free of visible particles may be injected.

 in pre-filled syringe is a sterile but unpreserved product. Under no circumstances should more than one dose be administered per syringe; the medicinal product is for single use only.

Posology

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

Anaemia symptoms and sequelae may vary with age, gender, and overall burden of disease; a physician’s evaluation of the individual patient’s clinical course and condition is necessary. NeoRecormon should be administered either subcutaneously or intravenously in order to increase haemoglobin to not greater than 12 g/dl (7.5 mmol/l). Subcutaneous use is preferable in patients who are not receiving haemodialysis to avoid puncture of peripheral veins. In case of intravenous administration, the solution should be injected over approx. 2 minutes, e.g. in haemodialysis patients via the arterio-venous fistula at the end of dialysis.

[…]

Prevention of anaemia of prematurity:

The solution is administered subcutaneously at a dose of 3 x 250 IU/kg b.w. per week. Treatment with NeoRecormon should start as early as possible, preferably by day 3 of life. Premature infants who have already been transfused by the start of treatment with NeoRecormonNeoRecormon are not likely to benefit as much as untransfused infants. The treatment should last for 6 weeks The recommended treatment duration is 6 weeks.

[…]

Method of administration

The NeoRecormon pre-filled syringe is ready for use. Only solutions which are clear or slightly opalescent, colourless and practically free of visible particles may be injected.

NeoRecormon in pre-filled syringe is a sterile but unpreserved product. Under no circumstances should more than one dose be administered per syringe; the medicinal product is for single use only.

4.3       Contraindications

Hypersensitivity to the active substance or any of the excipients listed in section 6.1.

[…]

4.4       Special warnings and precautions for use

NeoRecormon should be used with caution in the presence of refractory anaemia with excess blasts in transformation, epilepsy, thrombocytosis, and chronic liver failure. Folic acid and vitamin B₁₂ deficiencies should be ruled out as they reduce the effectiveness of NeoRecormon.

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

In order to ensure effective erythropoiesis, iron status should be evaluated for all patients prior to and during treatment and supplementary iron therapy may be necessary and conducted in accordance with therapeutic guidelines.

Severe aluminium overload due to treatment of renal failure may compromise the effectiveness of NeoRecormon.

The indication for treatment with NeoRecormon of nephrosclerotic patients not yet undergoing dialysis should be defined individually, as a possible acceleration of progression of renal failure cannot be ruled out with certainty.

Pure red cell aplasia (PRCA)

PRCA caused by neutralising anti-erythropoietin antibodies has been reported in association with erythropoietin therapy, including NeoRecormon. These antibodies have been shown to cross-react with all erythropoietic proteins, and patients suspected or confirmed to have neutralising antibodies to erythropoietin should not be switched to NeoRecormon (see section 4.8).

PRCA in patients with Hepatitis C

A paradoxical decrease in haemoglobin and development of severe anaemia associated with low reticulocyte counts should prompt to discontinue treatment with epoetin and perform anti-erythropoietin antibody testing. Cases have been reported in patients with hepatitis C treated with interferon and ribavirin, when epoetins are used concomitantly. Epoetins are not approved in the management of anaemia associated with hepatitis C.

In chronic renal failure patients Blood pressure monitoring

aAn increase in blood pressure or aggravation of existing hypertension, especially in cases of rapid PCV increase can occur. These increases in blood pressure can be treated with medicinal products. If blood pressure rises cannot be controlled by drug therapy, a transient interruption of NeoRecormon therapy is recommended. Particularly at beginning of therapy, regular monitoring of the blood pressure is recommended, including between dialyses. Hypertensive crisis with encephalopathy-like symptoms may occur and require the immediate attention of a physician and intensive medical care. Particular attention should be paid to sudden stabbing migraine like headaches as a possible warning sign.

Chronic renal failure

In chronic renal failure patients there may be a moderate dose‑dependent rise in the platelet count within the normal range during treatment with NeoRecormonNeoRecormon, especially after intravenous administration. This regresses during the course of continued therapy. It is recommended that the platelet count be monitored regularly during the first 8 weeks of therapy.

Haemoglobin concentration

In patients with chronic renal failure, maintenance haemoglobin concentration should not exceed the upper limit of the target haemoglobin concentration recommended in section 4.2. In clinical trials, an increased risk of death and serious cardiovascular events or cerebrovascular events including stroke was observed when erythropoiesis stimulating agents (ESAs) were administered to target a haemoglobin of greater than 12 g/dl (7.5 mmol/l).

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

In premature infants there may be a slight rise in platelet counts, particularly up to day 12 ‑ 14 of life, therefore platelets should be monitored regularly.

Effect on tumour growth

Epoetins are growth factors that primarily stimulate red blood cell production. Erythropoietin receptors may be expressed on the surface of a variety of tumour cells. As with all growth factors, there is a concern that epoetins could stimulate the growth of tumours. In several controlled studies, epoetins have not been shown to improve overall survival or decrease the risk of tumour progression in patients with anaemia associated with cancer.

In controlled clinical studies, use of NeoRecormon and other erythropoiesis-stimulating agents (ESAs) have shown:

-           shortened time to tumour progression in patients with advanced head and neck cancer receiving radiation therapy when administered to target a haemoglobin of greater than 14 g/dl (8.7 mmol/l),

-           shortened overall survival and increased deaths attributed to disease progression at 4 months in patients with metastatic breast cancer receiving chemotherapy when administered to target a haemoglobin of 12-14 g/dl (7.5-8.7 mmol/l),

-           increased risk of death when administered to target a haemoglobin of 12 g/dl (7.5 mmol/l) in patients with active malignant disease receiving neither chemotherapy nor radiation therapy. ESAs are not indicated for use in this patient population.

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

There may be an increase in blood pressure which can be treated with drugs. It is therefore recommended to monitor blood pressure, in particular in the initial treatment phase in cancer patients.

Platelet counts and haemoglobin level should also be monitored at regular intervals in cancer patients.

In patients in an autologous blood predonation programme there may be an increase in platelet count, mostly within the normal range. Therefore, it is recommended that the platelet count be determined at least once a week in these patients. If there is an increase in platelets of more than 150 x 10⁹/l or if platelets rise above the normal range, treatment with NeoRecormon should be discontinued.

In preterm infants a potential risk of erythropoietin to cause retinopathy could not be excluded, therefore caution should be exercised and the decision to treat a preterm infant should be balanced against the potential benefit and risk of this treatment and available alternative options.

In chronic renal failure patients an increase in heparin dose during haemodialysis is frequently required during the course of therapy with NeoRecormon as a result of the increased packed cell volume. Occlusion of the dialysis system is possible if heparinisation is not optimum.

Early shunt revision and thrombosis prophylaxis by administration of acetylsalicylic acid, for example, should be considered in chronic renal failure patients at risk of shunt thrombosis.

Serum potassium and phosphate levels should be monitored regularly during therapy with NeoRecormon. Potassium elevation has been reported in a few uraemic patients receiving NeoRecormon, though causality has not been established. If an elevated or rising potassium level is observed then consideration should be given to ceasing administration of NeoRecormon until the level has been corrected.

For use of NeoRecormon in an autologous predonation programme, the official guidelines on principles of blood donation must be considered, in particular:

-           only patients with a PCV ³ 33 % (haemoglobin ³ 11 g/dl [6.83 mmol/l]) should donate;

-           special care should be taken with patients below 50 kg weight;

-           the single volume drawn should not exceed approx. 12 % of the patient's estimated blood volume.

Treatment should be reserved for patients in whom it is considered of particular importance to avoid homologous blood transfusion taking into consideration the risk/benefit assessment for homologous transfusions.

Misuse

Misuse by healthy persons may lead to an excessive increase in packed cell volume. This may be associated with life‑threatening complications of the cardiovascular system.

Excipients

NeoRecormon in pre-filled syringe contains up to 0.3 mg phenylalanine/syringe as an excipient. Therefore this should be taken into consideration in patients affected with severe forms of phenylketonuria.

This medicinal product contains less than 1 mmol sodium (23 mg) per syringe, i.e. essentially “sodium-free”.

Traceability of NeoRecormon

In order to improve the traceability of erythropoiesis-stimulating agents (ESAs), the trade name of the administered ESA should be clearly recorded (or stated) in the patient file.In order to improve the traceability of ESAs, the name of the prescribed ESA should be clearly recorded (or: stated) in the patient file.

4.5       Interaction with other medicinal products and other forms of interaction

The clinical results obtained so far do not indicate any interaction of NeoRecormon with other medicinal products.

Animal experiments revealed that epoetin beta does not increase the myelotoxicity of cytostatic medicinal products like etoposide, cisplatin, cyclophosphamide, and fluorouracil.

4.6       Fertility, Ppregnancy and lactation

Fertility

Animal studies do not indicate direct or indirect harmful effects with respect to pregnancy, embryonal/foetal development, parturition or postnatal development (see section 5.3).

Pregnancy

.For epoetin beta no clinical data on exposed pregnancies are available.

Caution should be exercised when prescribing to pregnant women.

Breast-feeding

It is unknown whether epoetin beta is excreted in human milk. A decision on whether to continue/discontinue breast-feeding or to continue/discontinue therapy with epoetin beta should be made taking into account the benefit of breast-feeding to the child and the benefit of epoetin beta therapy to the woman.

4.7       Effects on ability to drive and use machines

NeoRecormonNeoRecormon has no influence on the ability to drive and use machines.

4.8       Undesirable effects

Summary of the safety profile

Based on results from clinical trials including 1725 patients approximately 8 % of patients treated with NeoRecormonNeoRecormon are expected to experience adverse reactions.

-           Anaemic patients with chronic renal failure

The most frequent adverse reaction during treatment with NeoRecormonNeoRecormon is an increase in blood pressure or aggravation of existing hypertension, especially in cases of rapid PCV increase (see section 4.4). Hypertensive crisis with encephalopathy-like symptoms (e.g. headaches and confused state, sensorimotor disorders ‑ such as speech disturbance or impaired gait ‑ up to tonoclonic seizures) may also occur in individual patients with otherwise normal or low blood pressure (see section 4.4).

Shunt thromboses may occur, especially in patients who have a tendency to hypotension or whose arteriovenous fistulae exhibit complications (e.g. stenoses, aneurisms), see section 4.4. In most cases, a fall in serum ferritin values simultaneous with a rise in packed cell volume is observed (see section 4.4). In addition, transient increases in serum potassium and phosphate levels have been observed in isolated cases (see section 4.4).

In isolated cases, neutralising anti erythropoietin antibody-mediated pure red cell aplasia (PRCA) associated with NeoRecormonNeoRecormon therapy has been reported. In case anti-erythropoietin

antibody-mediated PRCA is diagnosed, therapy with NeoRecormonNeoRecormon must be discontinued and patients should not be switched to another erythropoietic protein (see section 4.4).

Adverse reactions are listed in Table 1 below.

The incidences of undesirable effects in clinical trials, considered related to treatment with NeoRecoromon are shown in the table below. Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness.

-           Patients with cancer

Epoetin beta treatment-related headache and hypertension which can be treated with drugs are common (>1%, <10%) (see section 4.4).

In some patients, a fall in serum iron parameters is observed (see section 4.4).

Clinical studies have shown a higher frequency of thromboembolic events in cancer patients treated with NeoRecormonNeoRecormon compared to untreated controls or placebo. In patients treated with NeoRecormonNeoRecormon, this incidence is 7 % compared to 4 % in controls; this is not associated with any increase in thromboembolic mortality compared with controls.

Adverse reactions are listed in Table 2 below.

The incidences of undesirable effects in clinical trials, considered related to treatment with NeoRecoromon are shown in the table below. Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness.

-           Patients in an autologous blood predonation programme

Patients in an autologous blood predonation programme have been reported to show a slightly higher frequency of thromboembolic events. However, a causal relationship with treatment with NeoRecormonNeoRecormon could not be established.

In placebo controlled trials temporary iron deficiency was more pronounced in patients treated with NeoRecormonNeoRecormon than in controls (see section 4.4).

Adverse reactions are listed in Table 3 below.

Tabulated list of adverse reactions

Adverse reactions are listed according to MedDRA system organ class and frequency category. Frequency categories are defined using the following convention:

very common (≥1/10); common (≥1/100 to <1/10); uncommon (≥1/1,000 to <1/100); rare (≥1/10,000 to <1/1,000); very rare (<1/10,000); not known (cannot be estimated from the available data).

Table 1:                Adverse reactions attributed to the treatment with NeoRecormon in controlled clinical trials in CKD patients

Table 2:                Adverse reactions attributed to the treatment with NeoRecormon in controlled clinical trials in cancer patients

Table 3 :               Adverse reactions attributed to the treatment with NeoRecormon  in controlled clinical trials in patients in an autologous blood predonation programme

-           Premature infants

A fall in serum ferritin values is very common (>10%) (see section 4.4).

-           Description of selected adverse reactionsAll indications

Rarely Rarely(≥1/10.000 to ≤1/1.000), epoetin beta treatment-related skin reactions such as rash, pruritus, urticaria or injection site reactions may occur. In very rare cases cases(≤1/10.000), epoetin beta treatment-related anaphylactoid reactions have been reported. However, in controlled clinical studies no increased incidence of hypersensitivity reactions was found.

In very rare cases cases(≤1/10.000), particularly when starting treatment, epoetin beta treatment-related flu-like symptoms such as fever, chills, headaches, pain in the limbs, malaise and/or bone pain have been reported. These reactions were mild or moderate in nature and subsided after a couple of hours or days.

Data from a controlled clinical trial with epoetin alfa or darbepoetin alfa, reported an incidence of stroke as common (≥1/100 to <1/10).

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the national reporting system listed in Appendix V.(see details below).

Ireland

HPRA Pharmacovigilance

Earlsfort Terrace

IRL - Dublin 2

Tel: +353 1 6764971

Fax: +353 1 6762517

Website: www.hpra.ie

e-mail:medsafety@hpra.ie

Malta

ADR Reporting

Website: www.medicinesauthority.gov.mt/adrportal

United Kingdom

Yellow Card Scheme

Website: www.mhra.gov.uk/yellowcard

5.1       Pharmacodynamic properties

Pharmacotherapeutic group: antianaemic, ATC code: B03XA01

Mechanism of action

ErythropoietinNeorecormon is a glycoprotein that stimulates the formation of erythrocytes from its committed progenitors. It acts as a mitosis stimulating factor and differentiation hormone

Epoetin beta, the active substance of NeoRecormon, is identical in its amino acid and carbohydrate composition to erythropoietin that has been isolated from the urine of anaemic patients.

The biological efficacy of epoetin beta has been demonstrated after intravenous and subcutaneous administration in various animal models in vivo (normal and uraemic rats, polycythaemic mice, dogs). After administration of epoetin beta, the number of erythrocytes, the Hb values and reticulocyte counts increase as well as the ⁵⁹Fe‑incorporation rate.

An increased ³H‑thymidine incorporation in the erythroid nucleated spleen cells has been found in vitro (mouse spleen cell culture) after incubation with epoetin beta.

Investigations in cell cultures of human bone marrow cells showed that epoetin beta stimulates erythropoiesis specifically and does not affect leucopoiesis. Cytotoxic actions of epoetin beta on bone marrow or on human skin cells were not detected.

After single dose administration of epoetin beta no effects on behaviour or locomotor activity of mice and circulatory or respiratory function of dogs were observed.

Clinical efficacy and safety

In a randomised, double-blind, placebo-controlled study of 4,038 CRFchronic renal failure patients not on dialysis with type 2 diabetes and haemoglobin levels ≤ 11 g/dL, patients received either treatment with darbepoetin alfa to target haemoglobin levels of 13 g/dL or placebo (see section 4.4). The study did not meet either primary objective of demonstrating a reduction in risk for all-cause mortality, cardiovascular morbidity, or end stage renal disease (ESRD). Analysis of the individual components of the composite endpoints showed the following HR (95% CI): death 1.05 (0.92, 1.21), stroke 1.92 (1.38, 2.68), congestive heart failure (CHF) 0.89 (0.74, 1.08), myocardial infarction (MI) 0.96 (0.75, 1.23), hospitalisation for myocardial ischaemia 0.84 (0.55, 1.27), ESRD 1.02 (0.87, 1.18).

[…]

6.5       Nature and contents of container

500 IU:

Pre-filled syringe (Type I glass) with a tip cap and a plunger stopper (teflonised rubber) with an injection needle (30G1/2). Each syringe contains 0.3 ml solution.

Pack sizes of 1 pre‑filled syringe and 1 needle or 6 pre‑filled syringes and 6 needles.

0.3 ml of solution in pre-filled syringe (Type I glass) with a tip cap and a plunger stopper (teflonised rubber) with a needle 30G1/2.

Pack sizes of 1 or 6

2000 IU, 3000 IU, 4000 IU, 5000 IU, 6000 IU:

Pre-filled syringe (Type I glass) with a tip cap and a plunger stopper (teflonised rubber) with an injection needle (27G1/2). Each syringe contains 0.3 ml solution.

Pack sizes of 1 pre‑filled syringe and 1 needle or 6 pre‑filled syringes and 6 needles.

0.3 ml of solution in pre-filled syringe (Type I glass) with a tip cap and a plunger stopper (teflonised rubber) with a needle 27G1/2.

Pack sizes of 1 or 6

10,000 IU, 20,000IU:

Pre-filled syringe (Type I glass) with a tip cap and a plunger stopper (teflonised rubber) with an injection needle (27G1/2). Each syringe contains 0.6 ml solution.

Pack sizes of 1 pre‑filled syringe and 1 needle or 6 pre‑filled syringes and 6 needles.

0.6 ml of solution in pre-filled syringe (Type I glass) with a tip cap and a plunger stopper (teflonised rubber) with a needle 27G1/2.

Pack sizes of 1 or 6

30,000IU:

Pre-filled syringe (Type I glass) with a tip cap and a plunger stopper (teflonised rubber) with an injection needle (27G1/2). Each syringe contains 0.6 ml solution.

Pack sizes of 1 pre‑filled syringe and 1 needle or 4 pre‑filled syringes and 4 needles.

0.6 ml of solution in pre-filled syringe (Type I glass) with a tip cap and a plunger stopper (teflonised rubber) with a needle 27G1/2.

Pack sizes of 1 or 4

10.       DATE OF REVISION OF THE TEXT

23 July 2015

2.       QUALITATIVE AND QUANTITATIVE COMPOSITION

One pre-filled syringe with 0.3 ml solution for injection contains 2000 international units (IU) corresponding to 16.6 micrograms epoetin beta* (recombinant human erythropoietin).

One ml solution for injection contains 6667 IU epoetin beta.

4.4     Special warnings and precautions for use

Haemoglobin concentration

In patients with chronic renal failure, maintenance haemoglobin concentration should not exceed the upper limit of the target haemoglobin concentration recommended in section 4.2. In clinical trials, an increased risk of death and serious cardiovascular events or cerebrovascular events including stroke was observed when erythropoiesis stimulating agents (ESAs) were administered to target a haemoglobin of greater than 12 g/dl (7.5 mmol/l).

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

In order to improve the traceability of ESAs, the name of the prescribed ESA should be clearly recorded (or: stated) in the patient file.

4.8     Undesirable effects

Data from a controlled clinical trial with epoetin alfa or darbepoetin alfa, reported an incidence of stroke as common (≥1/100 to <1/10).

5.1     Pharmacodynamic properties

In a randomised, double-blind, placebo-controlled study of 4,038 CRF patients not on dialysis with type 2 diabetes and haemoglobin levels ≤ 11 g/dL, patients received either treatment with darbepoetin alfa to target haemoglobin levels of 13 g/dL or placebo (see section 4.4). The study did not meet either primary objective of demonstrating a reduction in risk for all-cause mortality, cardiovascular morbidity, or end stage renal disease (ESRD). Analysis of the individual components of the composite endpoints showed the following HR (95% CI): death 1.05 (0.92, 1.21), stroke 1.92 (1.38, 2.68), congestive heart failure (CHF) 0.89 (0.74, 1.08), myocardial infarction (MI) 0.96 (0.75, 1.23), hospitalisation for myocardial ischaemia 0.84 (0.55, 1.27), ESRD 1.02 (0.87, 1.18).

10.     DATE OF REVISION OF THE TEXT

11^th March 20116^th October 2011

Underlined text has been deleted:

2.         QUALITATIVE AND QUANTITATIVE COMPOSITION

One pre-filled syringe with 0.3 ml solution for injection contains 500 international units (IU) corresponding to 4.15 micrograms epoetin beta* (recombinant human erythropoietin).

One ml solution for injection contains 1667 IU epoetin beta.

One pre-filled syringe with 0.3 ml solution for injection contains 1000 international units (IU) corresponding to 8.3 micrograms epoetin beta* (recombinant human erythropoietin).

One ml solution for injection contains 3333 IU epoetin beta.

One pre-filled syringe with 0.3 ml solution for injection contains 2000 international units (IU) corresponding to 16.6 micrograms epoetin beta* (recombinant human erythropoietin).

One ml solution for injection contains 6667 IU epoetin beta.

One pre-filled syringe with 0.3 ml solution for injection contains 3000 international units (IU) corresponding to 24.9 micrograms epoetin beta* (recombinant human erythropoietin).

One ml solution for injection contains 10,000 IU epoetin beta.

One pre-filled syringe with 0.3 ml solution for injection contains 4000 international units (IU) corresponding to 33.2 micrograms epoetin beta* (recombinant human erythropoietin).

One ml solution for injection contains 13,333 IU epoetin beta.

One pre-filled syringe with 0.3 ml solution for injection contains 5000 international units (IU) corresponding to 41.5 micrograms epoetin beta* (recombinant human erythropoietin).

One ml solution for injection contains 16,667 IU epoetin beta.

One pre-filled syringe with 0.3 ml solution for injection contains 6000 international units (IU) corresponding to 49.8 micrograms epoetin beta* (recombinant human erythropoietin).

One ml solution for injection contains 20,000 IU epoetin beta.

One pre-filled syringe with 0.6 ml solution for injection contains 10,000 international units (IU) corresponding to 83 micrograms epoetin beta* (recombinant human erythropoietin).

One ml solution for injection contains 16,667 IU epoetin beta.

One pre-filled syringe with 0.6 ml solution for injection contains 20,000 international units (IU) corresponding to 166 micrograms epoetin beta* (recombinant human erythropoietin).

One ml solution for injection contains 33,333 IU epoetin beta.

One pre-filled syringe with 0.6 ml solution for injection contains 30,000 international units (IU) corresponding to 250 micrograms epoetin beta* (recombinant human erythropoietin).

One ml solution for injection contains 50,000 IU epoetin beta.

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

Excipients:

Phenylalanine (up to 0.3 mg/syringe)

Sodium (less than 1 mmol/syringe)

For a full list of excipients, see section 6.1.

6.5      Nature and contents of container

500 IU, 1000 IU:

0.3 ml of solution in pre-filled syringe (Type I glass) with a tip cap and a plunger stopper (teflonised rubber) with a needle 30G1/2.

Pack sizes of 1 or 6

2000 IU, 3000 IU, 4000 IU, 5000 IU, 6000 IU:

0.3 ml of solution in pre-filled syringe (Type 1 glass) with a tip cap and a plunger stopper (teflonised rubber) with a needle of 27G1/2.

Pack sizes of 1 or 6

10,000 IU, 20,000IU:

0.6 ml of solution in pre-filled syringe (Type I glass) with a tip cap and a plunger stopper (teflonised rubber) with a needle 27G1/2. (4 pre-filled syringes and 4 needles for 30,000 IU).

Pack sizes of 1 or 6

30,000IU:

0.6 ml of solution in pre-filled syringe (Type I glass) with a tip cap and a plunger stopper (teflonised rubber) with a needle 27G1/2.

Pack sizes of 1 or 4

Not all pack sizes may be marketed.

8.         MARKETING AUTHORISATION NUMBERS

NeoRecormon 500 IU solution for injection in pre-filled syringe:

EU/1/97/031/025 - 026

NeoRecormon 1000 IU solution for injection in pre-filled syringe:

EU/1/97/031/027 - 028

NeoRecormon 2000 IU solution for injection in pre-filled syringe:

EU/1/97/031/029 - 030

NeoRecormon 3000 IU solution for injection in pre-filled syringe:

EU/1/97/031/031 - 032

NeoRecormon 4000 IU solution for injection in pre-filled syringe:

EU/1/97/031/041 - 042

NeoRecormon 5000 IU solution for injection in pre-filled syringe:

EU/1/97/031/033 - 034

NeoRecormon 6000 IU solution for injection in pre-filled syringe:

EU/1/97/031/043 - 044

NeoRecormon 10,000 IU solution for injection in pre-filled syringe:

EU/1/97/031/035 - 036

NeoRecormon 20,000 IU solution for injection in pre-filled syringe:

EU/1/97/031/037 - 038

NeoRecormon 30,000 IU solution for injection in pre-filled syringe:

EU/1/97/031/045 - 046

9.         DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

500, 1000, 2000, 3000, 5000, 10,000, 20,000 IU:

Date of the first authorisation: 2 April 1998

Date of the last renewal: 16 July 2007

4000, 6000 IU:

Date of the first authorisation: 10 February 2000

Date of the last renewal: 16 July 2007

30,000 IU:

Date of the first authorisation: 23 February 2004

Date of the last renewal: 16 July 2007

Underlined text has been added, text with strike through deleted:

4.4     Special warnings and precautions for use

[…]

Haemoglobin concentration

In patients with chronic renal failure, maintenance haemoglobin concentration should not exceed the upper limit of the target haemoglobin concentration recommended in section 4.2. In clinical trials, an increased risk of death and serious cardiovascular events or cerebrovascular events including stroke was observed when erythropoiesis stimulating agents (ESAs) were administered to target a haemoglobin of greater than 12 g/dl (7.5 mmol/l).

[…]

In order to improve the traceability of ESAs, the name of the prescribed ESA should be clearly recorded (or: stated) in the patient file.

4.8     Undesirable effects

[…]

Data from a controlled clinical trial with epoetin alfa or darbepoetin alfa, reported an incidence of stroke as common (≥1/100 to <1/10).

Underlined text has been added, text with strike through deleted:

4.4     Special warnings and precautions for use

A paradoxical decrease in haemoglobin and development of severe anaemia associated with low reticulocyte counts should prompt to discontinue treatment with epoetin and perform anti-erythropoietin antibody testing. Cases have been reported in patients with hepatitis C treated with interferon and ribavirin, when epoetins are used concomitantly. Epoetins are not approved in the management of anaemia associated with hepatitis C.

5.1     Pharmacodynamic properties

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 several epoetins. Meta-analysis of overall survival data produced a hazard ratio point estimate of 1.06 in favour of controls (95% CI: 1.00, 1.12; 53 trials and 1393313,933 patients) and for cancer patients receiving chemotherapy, the overall survival hazard ratio was 1.04 (95% CI: 0.97, 1.11; 38 trials and 10, 441 patients). Meta-analyses also indicate consistently a significantly increased relative risk of thromboembolic events in cancer patients receiving recombinant human erythropoietin (see Section 4.4).

A systematic review has also been performed involving more than 9000 cancer patients participating in 57 clinical trials. Meta-analysis of overall survival data produced a hazard ratio point estimate of 1.08 in favour of controls (95 % CI: 0.99, 1.18; 42 trials and 8167 patients). An increased relative risk of thromboembolic events (RR 1.67, 95 % CI: 1.35, 2.06, 35 trials and 6769 patients) was observed in patients treated with recombinant human erythropoietin. There is therefore consistent evidence to suggest that there may be significant harm to patients with cancer who are treated with recombinant human erythropoietin. The extent to which these outcomes might apply to the administration of recombinant human erythropoietin to patients with cancer, treated with chemotherapy to achieve haemoglobin concentrations less than 13 g/dl, is unclear because few patients with these characteristics were included in the data reviewed.

Underlined text has been added, text with strike through deleted:

4.1     Therapeutic indications

-        Treatment of symptomatic anaemia associated with chronic renal failure (CRF)(renal anaemia) in adult and paediatric patients on dialysis.

-        Treatment of symptomatic renal anaemia in patients not yet undergoing dialysis.

4.2       Posology and method of administration

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

Anaemia symptoms and sequelae may vary with age, gender, and overall burden of disease; a physician’s evaluation of the individual patient’s clinical course and condition is necessary. NeoRecormon should be administered subcutaneously in order to increase haemoglobin to not greater than 12  g/dl (7.5  mmol/l).

Due to intra-patient variability, occasional individual haemoglobin values for a patient above and below the desired haemoglobin level may be observed. Haemoglobin variability should be addressed through dose management, with consideration for the haemoglobin target range of 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; guidance for appropriate dose adjustment for when haemoglobin values exceeding 12  g/dl (7.5  mmol/l) are observed are described below.

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 made as provided. If the rate of rise in haemoglobin is greater than 2  g/dl (1.25  mmol/l) in one month or if the haemoglobin level is increasing and approaching 12  g/dl (7.45  mmol/l), the dose is to be reduced by approximately 25 %. If the haemoglobin level continues to increase, therapy should be interrupted until the hemoglobin level begins to decrease, at which point therapy should be restarted at a dose approximately 25 % below the previously administered dose.

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

The aim of treatment is to increase the packed cell volume to 30 ‑ 35 % where the weekly increase should be at least 0.5 vol %. A value of 35 % should not be exceeded.

In the presence of hypertension or existing cardiovascular, cerebrovascular or peripheral vascular diseases, the weekly increase in the PCVHb and the target PCVHb should be determined individually taking into account the clinical picture. In some patients the optimum PCV may be below 30 %.

1.       Correction phase

The initial dosage is 3 x 20 IU/kg body weight per week. The dosage may be increased every 4 weeks by 3 x 20 IU/kg per week if the increase of Hbpacked cell volume is not adequate (< 0.25 g/dl5 % per week).

The weekly dose can also be divided into daily doses.

The maximum dose should not exceed 720 IU/kg per week.

2.       Maintenance phase

To maintain an Hb packed cell volume of between 10 and 12 g/dl30 and 35 %, the dosage is initially reduced to half of the previously administered amount. Subsequently, the dose is adjusted at intervals of one or two weeks individually for the patient (maintenance dose).

Treatment of symptomatic chemotherapy-induced anaemia in cancer patients:

NeoRecormon should be administered by the subcutaneous route to patients with anaemia (e.g. haemoglobin concentration ≤ 10g/dl (6.2 mmol/l)). Anaemia symptoms and sequelae may vary with age, gender, and overall burden of disease; a physician’s evaluation of the individual patient’s clinical course and condition is necessary.

The reconstituted solution is administered subcutaneously; tThe weekly dose can be given as one injection per week or in divided doses 3 to 7 times per week.

Due to intra-patient variability, occasional individual haemoglobin values for a patient above and below the desired haemoglobin level may be observed. Haemoglobin variability should be addressed through dose management, with consideration for the haemoglobin target range of 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; guidance for appropriate dose adjustment for when haemoglobin values exceeding 12  g/dl (7.5  mmol/l) are observed are described below.

NeoRecormon treatment is indicated if the haemoglobin value is £ 11 g/dl (6.83 mmol/l). Haemoglobin levels should not exceed 13 g/dl (8.07 mmol/l) (see section 5.1).

Once the therapeutic objective for an individual patient has been achieved, the dose should be reduced by 25 to 50 % in order to maintain haemoglobin at that level. If required, further dose reduction may be instituted to ensure that haemoglobin level does not exceed 13 g/dl.

Appropriate dose titration should be considered.

If the haemoglobin exceeds 12  g/dl (7.5  mmol/l), the dose should be reduced by approximately 25 to 50 %. Treatment with NeoRecormon should be temporarily discontinued if haemoglobin levels exceed 13  g/dl (8.1  mmol/l). Therapy should be reinitiated at approximately 25 % lower than the previous dose after haemoglobin levels fall to 12  g/dl (7.5  mmol/l) or below.

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

4.4     Special warnings and precautions for use

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

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

Effect on tumour growth

Epoetins are growth factors that primarily stimulate red blood cell production. Erythropoietin receptors may be expressed on the surface of a variety of tumour cells. As with all growth factors, there is a concern that epoetins could stimulate the growth of tumoursany type of malignancy. In several controlled studies, epoetins have not been shown to improve overall survival or decrease the risk of tumour progression in patients with anaemia associated with cancer.

In controlled clinical studies, use of NeoRecormon and other erythropoiesis-stimulating agents (ESAs) have shown:

-        shortened time to tumour progression in patients with advanced head and neck cancer receiving radiation therapy when administered to target a haemoglobin of greater than 14  g/dl (8.7  mmol/l),

-        shortened overall survival and increased deaths attributed to disease progression at 4 months in patients with metastatic breast cancer receiving chemotherapy when administered to target a haemoglobin of 12-14  g/dl (7.5-8.7  mmol/l),

-        increased risk of death when administered to target a haemoglobin of 12  g/dl (7.5  mmol/l) in patients with active malignant disease receiving neither chemotherapy nor radiation therapy. ESAs are not indicated for use in this patient population.

Two controlled clinical studies in which epoetins were administered to patients with various cancers including head and neck cancer, and breast cancer, have shown an unexplained excess mortality.

There may be an increase in blood pressure which can be treated with drugs. It is therefore recommended to monitor blood pressure, in particular in the initial treatment phase in cancer patients.

5.1     Pharmacodynamic properties

Survival and tumour progression have been examined in five large controlled studies involving a total of 2833 patients, of which four were double-blind placebo-controlled studies and one was an open-label study. Two of the studies recruited patients who were being treated with chemotherapy.  The target haemoglobin concentration in two studies was >13  g/dl; in the remaining three studies it was 12-14  g/dl. In the open-label study there was no difference in overall survival between patients treated with recombinant human erythropoietin and controls. In the four placebo-controlled studies the hazard ratios for overall survival ranged between 1.25 and 2.47 in favour of controls. These studies have shown a consistent unexplained statistically significant excess mortality in patients who have anaemia associated with various common cancers who received recombinant human erythropoietin compared to controls. Overall survival outcome in the trials could not be satisfactorily explained by differences in the incidence of thrombosis and related complications between those given recombinant human erythropoietin and those in the control group.

An individual patient data based meta-analysis, which included data from all 12 controlled clinical studies in anaemic cancer patients conducted with NeoRecormon (n=2301), showed an overall hazard ratio point estimate for survival of 1.13 in favour of controls (95 % CI 0.87, 1.46). In patients with baseline haemoglobin ≤ 10  g/dl (n=899), the hazard ratio point estimate for survival was 0.98 (95 % CI 0.68 to 1.40). An increased relative risk for thromboembolic events was observed in the overall population (RR 1.62, 95 % CI: 1.13, 2.31).

A systematic review has also been performed involving more than 9000 cancer patients participating in 57 clinical trials. Meta-analysis of overall survival data produced a hazard ratio point estimate of 1.08 in favour of controls (95 % CI: 0.99, 1.18; 42 trials and 8167 patients). An increased relative risk of thromboembolic events (RR 1.67, 95 % CI: 1.35, 2.06, 35 trials and 6769 patients) was observed in patients treated with recombinant human erythropoietin. There is therefore consistent evidence to suggest that there may be significant harm to patients with cancer who are treated with recombinant human erythropoietin. The extent to which these outcomes might apply to the administration of recombinant human erythropoietin to patients with cancer, treated with chemotherapy to achieve haemoglobin concentrations less than 13  g/dl, is unclear because few patients with these characteristics were included in the data reviewed.

There is insufficient information to establish whether the use of epoetin products have an adverse effect on time to tumour progression or progression free survival.

Two studies explored the effect of epoetins on survival and/or tumour progression with higher haemoglobin targets.

In a randomised placebo-controlled study using epoetin alfa in 939 metastatic breast cancer patients, study drug was administered to attempt to maintain haemoglobin levels between 12 and 14 g/dL. At four months, death attributed to disease progression was higher (6 % vs. 3 %) in women receiving epoetin alfa. The overall mortality was significantly higher in the epoetin alfa arm.

In another placebo-controlled study using epoetin beta in 351 patients with head and neck cancer, study drug was administered to maintain the haemoglobin levels of 14 g/dL in women and 15 g/dL in men. Locoregional progression free survival was significantly shorter in patients receiving epoetin beta. The results of this study were confounded by imbalances between the treatment groups, especially with regard to tumor localisation, smoking status and the heterogeneity of the study population.

In addition, several other studies have shown a tendency to improved survival suggesting that epoetin has no negative effect on tumour progression.

UK / Ireland

SUMMARY OF PRODUCT CHARACTERISTICS

NeoRecormon®

1.       NAME OF THE MEDICINAL PRODUCT

NeoRecormon Solutionsolution for injection in pre-filled syringe.

2.       QUALITATIVE AND QUANTITATIVE COMPOSITION

1One pre-filled syringe with 0.3ml solution for injection contains 500 international units (IU) corresponding to 4.15 micrograms  epoetin beta* (recombinant human erythropoietin).

1One pre-filled syringe with 0.3 ml solution for injection contains 1000 international units (IU) corresponding to 8.3 micrograms epoetin beta* (recombinant human erythropoietin).

1One pre-filled syringe with 0.3ml solution for injection contains 2000 international units (IU) corresponding to 16.6 micrograms  epoetin beta* (recombinant human erythropoietin).

1One pre-filled syringe with 0.3ml solution for injection contains 3000 international units (IU) corresponding to 24.9 micrograms  epoetin beta* (recombinant human erythropoietin).

1One pre-filled syringe with 0.3ml solution for injection contains 4000 international units (IU) corresponding to 33.2 micrograms  epoetin beta* (recombinant human erythropoietin).

1One pre-filled syringe with 0.3ml solution for injection contains 5000 international units (IU) corresponding to 41.5 micrograms  epoetin beta* (recombinant human erythropoietin).

1One pre-filled syringe with 0.3ml solution for injection contains 6000 international units (IU) corresponding to 49.8 micrograms  epoetin beta* (recombinant human erythropoietin).

1One pre-filled syringe with 0.6ml solution for injection contains 10,000 international units (IU) corresponding to 83 micrograms  epoetin beta* (recombinant human erythropoietin).

1One pre-filled syringe with 0.6ml solution for injection contains 20,000 international units (IU) corresponding to 166 micrograms epoetin beta* (recombinant human erythropoietin).

1One pre-filled syringe with 0.6ml solution for injection contains 30,000 international units (IU) corresponding to 250 micrograms epoetin beta* (recombinant human erythropoietin).

* ProducedRecombinant human erythropoietin produced by recombinant DNA technology in CHO cell line.

Excipients:

Phenylalanine (up to 0.3 mg/syringe)

For a full list of excipients, see 6.1.

4.1     Therapeutic indications

-        Treatment of anaemia associated with chronic renal failure (renal anaemia) in patients on dialysis.

-        Treatment of symptomatic renal anaemia in patients not yet undergoing dialysis.

-        Prevention of anaemia of prematurity in infants with a birth weight of 750 to 1500 g and a gestational age of less than 34 weeks.

-        Treatment of symptomatic anaemia in adult patients with with all non-myeloid malignancies solid tumours receiving chemotherapy.

-        Treatment of symptomatic anaemia in adult patients with multiple myeloma, low grade non-Hodgkin’s lymphoma or chronic lymphocytic leukaemia, who have a relative erythropoietin deficiency and are receiving anti-tumour therapy. Deficiency is defined as an inappropriately low serum erythropoietin level in relation to the degree of anaemia.

-        Increasing the yield of autologous blood from patients in a pre-donation programme.

          Its use in this indication must be balanced against the reported increased risk of thromboembolic events. Treatment should only be given to patients with moderate anaemia (Hb 10 ‑ 13 g/dl [6.21 ‑ 8.07 mmol/l], no iron deficiency) if blood conserving procedures are not available or insufficient when the scheduled major elective surgery requires a large volume of blood (4 or more units of blood for females or 5 or more units for males).

4.2     Posology and method of administration

Treatment of symptomatic anaemia in cancer patients with solid tumours:

The reconstitutedsolution is administered subcutaneously; the weekly dose can be given as one injection per week or in divided doses 3 to 7 times per week.

The recommended initial dose is 30,000 IU per week (corresponding to approximately 450 IU/kg body weight per week, based on an average weighted patient).

NeoRecormon treatment is indicated if the haemoglobin value is £ 11  g/dl (6.83  mmol/l). Haemoglobin levels should not exceed 13  g/dl (8.07  mmol/l) (see section 5.1).

If, after 4 weeks of therapy, the haemoglobin value has increased by at least 1  g/dl (0.62  mmol/l), the current dose should be continued. If the haemoglobin value has not increased by at least 1  g/dl (0.62  mmol/l), a doubling of the weekly dose should be considered. If, after 8 weeks of therapy, the haemoglobin value has not increased by at least 1  g/dl (0.62  mmol/l), response is unlikely and treatment should be discontinued.

The therapy should be continued up to 4 weeks after the end of chemotherapy.

The maximum dose should not exceed 60,000 IU per week.

Once the therapeutic objective for an individual patient has been achieved, the dose should be reduced by 25 to 50 % in order to maintain haemoglobin at that level. If required, further dose reduction may be instituted to ensure that haemoglobin level does not exceed 13  g/dl.

If the rise in haemoglobin is greater than 2  g/dl (1.3  mmol/l) in 4 weeks, the dose should be reduced by 25 to 50 %.

The solution is administered subcutaneously; the weekly dose can be divided into 3 to 7 single doses.

NeoRecormon treatment is indicated if the haemoglobin value is £ 11 g/dl (6.83 mmol/l). The recommended initial dose is 450 IU/kg body weight per week.

Haemoglobin level should not exceed 13 g/dl (8.07 mmol/l) (see section 5.1).

If, after 4 weeks, a patient does not show a satisfactory response in terms of haemoglobin values, then the dose should be doubled. The therapy should be continued up to 3 weeks after the end of chemotherapy.

If haemoglobin falls by more than 1 g/dl (0.62 mmol/l) in the first cycle of chemotherapy despite concomitant NeoRecormon therapy, further therapy may not be effective.

Once the therapeutic objective for an individual patient has been achieved, the dose should be reduced by 25 to 50% in order to maintain haemoglobin at that level. If required, further dose reduction may be instituted to ensure that haemoglobin level does not exceed 13 g/dl.

If the rise in haemoglobin is greater than 2 g/dl (1.3 mmol/l) in 4 weeks, the dose should be reduced by 25 to 50%.

Treatment of symptomatic anaemia in patients with multiple myeloma, low-grade non-Hodgkin’s lymphoma or chronic lymphocytic leukaemia

Patients with multiple myeloma, non-Hodgkin’s lymphoma or chronic lymphocytic leukaemia should have a relative erythropoietin deficiency. Deficiency is defined as an inappropriately low serum erythropoietin level in relation to the degree of anaemia:

serum erythropoietin level of £ 100 mU/ml at a haemoglobin of > 9 to < 10 g/dl
(> 5.58 to < 6.21 mmol/l)

serum erythropoietin level of £ 180 mU/ml at a haemoglobin of > 8 to £ 9 g/dl
(> 4.96 to £ 5.58 mmol/l)

serum erythropoietin level of £ 300 mU/ml at a haemoglobin of £ 8 g/dl (£ 4.96 mmol/l)

The above values should be measured at least 7 days after the last blood transfusion and the last cycle of cytotoxic chemotherapy.

The solution is administered subcutaneously; the weekly dose can be given as one injection per week or in divided doses 3 to 7 times per week.

The recommended initial dose is 450 IU/kg body weight per week.

Haemoglobin level should not exceed 13 g/dl (8.07 mmol/l) (see section 5.1).

If, after 4 weeks of therapy, the haemoglobin value has increased by at least 1 g/dl (0.62 mmol/l), the current dose should be continued. If the haemoglobin value has not increased by at least 1 g/dl (0.62 mmol/l), a dose increase to 900 IU/kg body weight, given in divided doses 2 to 7 times per week, may be considered. If, after 8 weeks of therapy, the haemoglobin value has not increased by at least 1 g/dl (0.62 mmol/l), response is unlikely and treatment should be discontinued.

Clinical studies have shown that response to epoetin beta treatment is delayed by about 2 weeks in chronic lymphocytic leukaemia patients, as compared with patients with multiple myeloma,

non-Hodgkin’s lymphoma and solid tumours. The therapy should be continued up to 4 weeks after the end of chemotherapy.

The maximum dose should not exceed 900 IU/kg body weight per week.

Once the therapeutic objective for an individual patient has been achieved, the dose should be reduced by 25 to 50% in order to maintain haemoglobin at that level. If required, further dose reduction may be instituted to ensure that haemoglobin level does not exceed 13 g/dl.

If the rise in haemoglobin is greater than 2 g/dl (1.3 mmol/l) in 4 weeks, the dose should be reduced by 25 to 50%.

Therapy should only be reintroduced if the erythropoietin deficiency is the most likely cause of the anaemia.

4.3     Contraindications

Hypersensitivity to the active substance or any of the excipients.

Poorly controlled hypertension.

In the indication "increasing the yield of autologous blood": myocardial infarction or stroke in the month preceding treatment, unstable angina pectoris, increased risk of deep venous thrombosis such as history of venous thromboembolic disease.

NeoRecormon must not be used in the presence of poorly controlled hypertension and known hypersensitivity to the active substance or to any of the excipients.

In the indication "increasing the yield of autologous blood", NeoRecormon must not be used in patients who, in the month preceding treatment, have suffered a myocardial infarction or stroke, patients with unstable angina pectoris, or patients who are at risk of deep venous thrombosis such as those with a history of venous thromboembolic disease.

4.5     Interaction with other medicinal products and other forms of interaction

The clinical results obtained so far do not indicate any interaction of NeoRecormon with other medicinal productssubstances.

Animal experiments revealed that epoetin beta does not increase the myelotoxicity of cytostatic medicinal productsdrugs like etoposide, cisplatin, cyclophosphamide, and fluorouracil.

4.6     Pregnancy and lactation

For epoetin beta no clinical data on exposed pregnancies are available. Animal studies do not indicate direct or indirect harmful effects with respect to pregnancy, embryonal/foetal development, parturition or postnatal development (see 5.3).

Caution should be exercised when prescribing to pregnant women.

Animal experiments have yielded no indications of teratogenic effects of epoetin beta in dosing regimens that do not lead to an unphysiologically high PCV. No adequate experience in human pregnancy and lactation has been gained, but a potential risk appears to be minimal under therapeutic conditions.

4.7     Effects on ability to drive and use machines

NeoRecormon has no influence on the ability to drive and use machines.

No effects on ability to drive or use machines have been observed.

4.8     Undesirable effects

-        Patients with solid tumours, multiple myeloma, non-Hodgkin’s lymphoma or chronic lymphocytic leukaemiacancer

6.4     Special precautions for storage

Store in a refrigerator (2°C – 8°C).

Store at 2°C – 8°C (in a refrigerator).

10.     DATE OF REVISION OF THE TEXT

4 January 2007

Detailed information on this medicinal product is available on the website of the European Medicines Agency (EMEA) http://www.emea.europa.eu/