Roche Products Limited

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/