Erythropoietic agents

Darbepoetin alfa

Each pre-filled syringe contains 10 micrograms of darbepoetin alfa in 0.4 ml (25 µg/ml). Each pre-filled syringe contains 15 micrograms of darbepoetin alfa in 0.375 ml (40 µg/ml). Each pre-filled syringe contains 20 micrograms of darbepoetin alfa in 0.5 ml (40 µg/ml). Each pre-filled syringe contains 30 micrograms of darbepoetin alfa in 0.3 ml (100 µg/ml). Each pre-filled syringe contains 40 micrograms of darbepoetin alfa in 0.4 ml (100 µg/ml). Each pre-filled syringe contains 50 micrograms of darbepoetin alfa in 0.5 ml (100 µg/ml). Each pre-filled syringe contains 60 micrograms of darbepoetin alfa in 0.3 ml (200 µg/ml). Each pre-filled syringe contains 80 micrograms of darbepoetin alfa in 0.4 ml (200 µg/ml). Each pre-filled syringe contains 100 micrograms of darbepoetin alfa in 0.5 ml (200 µg/ml). Each pre-filled syringe contains 130 micrograms of darbepoetin alfa in 0.65 ml (200 µg/ml). Each pre-filled syringe contains 150 micrograms of darbepoetin alfa in 0.3 ml (500 µg/ml). Each pre-filled syringe contains 300 micrograms of darbepoetin alfa in 0.6 ml (500 µg/ml). Each pre-filled syringe contains 500 micrograms of darbepoetin alfa in 1 ml (500 µg/ml). Darbepoetin alfa is produced by gene-technology in Chinese Hamster Ovary Cells (CHO-K1). Excipients: Each pre-filled syringe contains 1.52 mg of sodium in 0.4 ml. Each pre-filled syringe contains 1.42 mg of sodium in 0.375 ml. Each pre-filled syringe contains 1.90 mg of sodium in 0.5 ml. Each pre-filled syringe contains 1.14 mg of sodium in 0.3 ml. Each pre-filled syringe contains 1.52 mg of sodium in 0.4 ml. Each pre-filled syringe contains 1.90 mg of sodium in 0.5 ml. Each pre-filled syringe contains 1.14 mg of sodiumin 0.3 ml. Each pre-filled syringe contains 1.52 mg of sodium in 0.4 ml. Each pre-filled syringe contains 1.90 mg of sodium in 0.5 ml. Each pre-filled syringe contains 2.46 mg of sodium in 0.65 ml. Each pre-filled syringe contains 1.14 mg of sodium in 0.3 ml. Each pre-filled syringe contains 2.27 mg of sodium in 0.6 ml. Each pre-filled syringe contains 3.79 mg of sodium in 1 ml

Solution for injection (injection) in a pre-filled syringe. Clear, colourless solution.

Treatment of symptomatic anaemia associated with chronic renal failure (CRF) in adults and paediatric patients. Treatment of symptomatic anaemia in adult cancer patients with non-myeloid malignancies receiving chemotherapy.

Aranesp treatment should be initiated by physicians experienced in the above mentioned indications.

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. Aranesp 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 the puncture of peripheral veins.

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.

Treatment with Aranesp is divided into two stages, correction and maintenance phase. Guidance is given separately for adult and paediatric patients.

Adult patients with chronic renal failure

Correction phase:

The initial dose by subcutaneous or intravenous administration is 0.45 µg/kg body weight, as a single injection once weekly. Alternatively, in patients not on dialysis, an initial dose of 0.75 μg/kg may be administered subcutaneously as a single injection once every two weeks. If the increase in haemoglobin is inadequate (less than 1 g/dl (0.6 mmol/l) in four weeks) increase the dose by approximately 25%. Dose increases must not be made more frequently than once every four weeks.

If the rise in haemoglobin is greater than 2 g/dl (1.25 mmol/l) in four weeks reduce the dose by approximately 25%. If the haemoglobin exceeds 12 g/dl (7.5 mmol/l), a dose reduction should be considered. If the haemoglobin continues to increase, the dose should be reduced by approximately 25%. If after a dose reduction, haemoglobin continues to increase, the dose should be temporarily withheld until the haemoglobin begins to decrease, at which point therapy should be reinitiated at approximately 25% lower than the previous dose.

The haemoglobin should be measured every one or two weeks until it is stable. Thereafter the haemoglobin can be measured at longer intervals.

Maintenance phase:

In the maintenance phase, Aranesp may continue to be administered as a single injection once weekly or once every two weeks. Dialysis patients converting from once weekly to once every other week dosing with Aranesp should initially receive a dose equivalent to twice the previous once weekly dose. In patients not on dialysis, once the target haemoglobin has been achieved with once every two week dosing, Aranesp may be administered subcutaneously once monthly using an initial dose equal to twice the previous once every two week dose.

Dosing should be titrated as necessary to maintain the haemoglobin target.

If a dose adjustment is required to maintain haemoglobin at the desired level, it is recommended that the dose is adjusted by approximately 25%.

If the rise in haemoglobin is greater than 2 g/dl (1.25 mmol/l) in four weeks reduce the dose by approximately 25%, depending on the rate of increase. If the haemoglobin exceeds 12 g/dl (7.5 mmol/l), a dose reduction should be considered. If the haemoglobin continues to increase, the dose should be reduced by approximately 25%. If after a dose reduction, haemoglobin continues to increase, the dose should be temporarily withheld until the haemoglobin begins to decrease, at which point therapy should be reinitiated at approximately 25% lower than the previous dose.

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

After any dose or schedule adjustment the haemoglobin should be monitored every one or two weeks. Dose changes in the maintenance phase of treatment should not be made more frequently than every two weeks.

When changing the route of administration the same dose must be used and the haemoglobin monitored every one or two weeks so that the appropriate dose adjustments can be made to keep the haemoglobin at the desired level.

Clinical studies have demonstrated that adult patients receiving r-HuEPO one, two or three times weekly may be converted to once weekly or once every other week Aranesp. The initial weekly dose of Aranesp (µg/week) can be determined by dividing the total weekly dose of r-HuEPO (IU/week) by 200. The initial every other week dose of Aranesp (µg/every other week) can be determined by dividing the total cumulative dose of r-HuEPO administered over a two-week period by 200. Because of individual variability, titration to optimal therapeutic doses is expected for individual patients. When substituting Aranesp for r-HuEPO the haemoglobin should be monitored every one or two weeks and the same route of administration should be used.

Paediatric population with chronic renal failure

Treatment of paediatric patients younger than 1 year of age has not been studied.

Correction phase:

For patients  11 years of age, the initial dose by subcutaneous or intravenous administration is 0.45 μg/kg body weight, as a single injection once weekly. Alternatively, in patients not on dialysis, an initial dose of 0.75 μg/kg may be administered subcutaneously as a single injection once every two weeks. If the increase in haemoglobin is inadequate (less than 1g/dl (0.6 mmol/l) in four weeks) increase the dose by approximately 25%. Dose increases must not be made more frequently than once every four weeks.

If the rise in haemoglobin is greater than 2 g/dl (1.25 mmol/l) in four weeks reduce the dose by approximately 25%, depending on the rate of increase. If the haemoglobin exceeds 12 g/dl (7.5 mmol/l), a dose reduction should be considered. If the haemoglobin continues to increase, the dose should be reduced by approximately 25%. If after a dose reduction, haemoglobin continues to increase, the dose should be temporarily withheld until the haemoglobin begins to decrease, at which point therapy should be reinitiated at approximately 25% lower than the previous dose.

The haemoglobin should be measured every one or two weeks until it is stable. Thereafter the haemoglobin can be measured at longer intervals.

No guidance regarding the correction of haemoglobin is available for paediatric patients 1 to 10 years of age.

Maintenance phase:

For paediatric patients  11 years of age, in the maintenance phase, Aranesp may continue to be administered as a single injection once weekly or once every two weeks. Dialysis patients converting from once weekly to once every other week dosing with Aranesp should initially receive a dose equivalent to twice the previous once weekly dose. In patients not on dialysis, once the target haemoglobin has been achieved with once every two week dosing, Aranesp may be administered subcutaneously once monthly using an initial dose equal to twice the previous once every two week dose.

For paediatric patients 1-18 years of age, clinical data in paediatric patients has demonstrated that patients receiving r-HuEPO two or three times weekly may be converted to once weekly Aranesp, and those receiving r-HuEPO once weekly may be converted to once every other week Aranesp. The initial weekly paediatric dose of Aranesp (µg/week) can be determined by dividing the total weekly dose of r-HuEPO (IU/week) by 240. The initial every other week dose of Aranesp (μg/every other week) can be determined by dividing the total cumulative dose of r-HuEPO administered over a two-week period by 240. Because of individual variability, titration to optimal therapeutic doses is expected for individual patients. When substituting Aranesp for r-HuEPO the haemoglobin should be monitored every one or two weeks and the same route of administration should be used.

Dosing should be titrated as necessary to maintain the haemoglobin target.

If a dose adjustment is required to maintain haemoglobin at the desired level, it is recommended that the dose is adjusted by approximately 25%.

If the rise in haemoglobin is greater than 2 g/dl (1.25 mmol/l) in four weeks reduce the dose by approximately 25%, depending on the rate of increase. If the haemoglobin exceeds 12 g/dl (7.5 mmol/l), a dose reduction should be considered. If the haemoglobin continues to increase, the dose should be reduced by approximately 25%. If after a dose reduction, haemoglobin continues to increase, the dose should be temporarily withheld until the haemoglobin begins to decrease, at which point therapy should be reinitiated at approximately 25% lower than the previous dose.

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

After any dose or schedule adjustment the haemoglobin should be monitored every one or two weeks. Dose changes in the maintenance phase of treatment should not be made more frequently than every two weeks.

When changing the route of administration the same dose must be used and the haemoglobin monitored every one or two weeks so that the appropriate dose adjustments can be made to keep the haemoglobin at the desired level.

Treatment of symptomatic chemotherapy induced anaemia in cancer patients

Aranesp should be administered by the subcutaneous route to patients with anaemia (e.g. haemoglobin concentration  10 g/dl (6.2 mmol/l)) in order to increase haemoglobin to not greater than 12 g/dl (7.5 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.

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 adjustments for when haemoglobin values exceeding 12 g/dl (7.5 mmol/l) are observed are described below.

The recommended initial dose is 500 μg (6.75 μg/kg) given once every three weeks, or once weekly dosing can be given at 2.25 μg/kg body weight. If the clinical response of the patient (fatigue, haemoglobin response) is inadequate after nine weeks, further therapy may not be effective.

Aranesp therapy should be discontinued approximately four weeks after the end of chemotherapy.

Once the therapeutic objective for an individual patient has been achieved, the dose should be reduced by 25 to 50% in order to ensure that the lowest approved dose of Aranesp is used to maintain haemoglobin at a level that controls the symptoms of anaemia. Appropriate dose titration between 500 μg, 300 μg, and 150 μg should be considered.

Patients should be monitored closely, if the haemoglobin exceeds 12 g/dl (7.5 mmol/l), the dose should be reduced by approximately 25 to 50%. Treatment with Aranesp 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.

If the rise in haemoglobin is greater than 2 g/dl (1.25 mmol/l) in 4 weeks, the dose should be reduced by 25 to 50%.

Method of administration

Aranesp is administered either subcutaneously or intravenously as described in the posology. Rotate the injection sites and inject slowly to avoid discomfort at the site of injection.

Aranesp is supplied ready for use in a pre-filled syringe. The instructions for use, handling and disposal are given in section 6.6.

Aranesp treatment should be initiated by physicians experienced in the above mentioned indications.

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. Aranesp 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 the puncture of peripheral veins.

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.

Treatment with Aranesp is divided into two stages, correction and maintenance phase. Guidance is given separately for adult and paediatric patients.

Adult patients with chronic renal failure

Correction phase:

The initial dose by subcutaneous or intravenous administration is 0.45 µg/kg body weight, as a single injection once weekly. Alternatively, in patients not on dialysis, an initial dose of 0.75 μg/kg may be administered subcutaneously as a single injection once every two weeks. If the increase in haemoglobin is inadequate (less than 1 g/dl (0.6 mmol/l) in four weeks) increase the dose by approximately 25%. Dose increases must not be made more frequently than once every four weeks.

If the rise in haemoglobin is greater than 2 g/dl (1.25 mmol/l) in four weeks reduce the dose by approximately 25%. If the haemoglobin exceeds 12 g/dl (7.5 mmol/l), a dose reduction should be considered. If the haemoglobin continues to increase, the dose should be reduced by approximately 25%. If after a dose reduction, haemoglobin continues to increase, the dose should be temporarily withheld until the haemoglobin begins to decrease, at which point therapy should be reinitiated at approximately 25% lower than the previous dose.

The haemoglobin should be measured every one or two weeks until it is stable. Thereafter the haemoglobin can be measured at longer intervals.

Maintenance phase:

In the maintenance phase, Aranesp may continue to be administered as a single injection once weekly or once every two weeks. Dialysis patients converting from once weekly to once every other week dosing with Aranesp should initially receive a dose equivalent to twice the previous once weekly dose. In patients not on dialysis, once the target haemoglobin has been achieved with once every two week dosing, Aranesp may be administered subcutaneously once monthly using an initial dose equal to twice the previous once every two week dose.

Dosing should be titrated as necessary to maintain the haemoglobin target.

If a dose adjustment is required to maintain haemoglobin at the desired level, it is recommended that the dose is adjusted by approximately 25%.

If the rise in haemoglobin is greater than 2 g/dl (1.25 mmol/l) in four weeks reduce the dose by approximately 25%, depending on the rate of increase. If the haemoglobin exceeds 12 g/dl (7.5 mmol/l), a dose reduction should be considered. If the haemoglobin continues to increase, the dose should be reduced by approximately 25%. If after a dose reduction, haemoglobin continues to increase, the dose should be temporarily withheld until the haemoglobin begins to decrease, at which point therapy should be reinitiated at approximately 25% lower than the previous dose.

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

After any dose or schedule adjustment the haemoglobin should be monitored every one or two weeks. Dose changes in the maintenance phase of treatment should not be made more frequently than every two weeks.

When changing the route of administration the same dose must be used and the haemoglobin monitored every one or two weeks so that the appropriate dose adjustments can be made to keep the haemoglobin at the desired level.

Clinical studies have demonstrated that adult patients receiving r-HuEPO one, two or three times weekly may be converted to once weekly or once every other week Aranesp. The initial weekly dose of Aranesp (µg/week) can be determined by dividing the total weekly dose of r-HuEPO (IU/week) by 200. The initial every other week dose of Aranesp (µg/every other week) can be determined by dividing the total cumulative dose of r-HuEPO administered over a two-week period by 200. Because of individual variability, titration to optimal therapeutic doses is expected for individual patients. When substituting Aranesp for r-HuEPO the haemoglobin should be monitored every one or two weeks and the same route of administration should be used.

Paediatric population with chronic renal failure

Treatment of paediatric patients younger than 1 year of age has not been studied.

Correction phase:

For patients  11 years of age, the initial dose by subcutaneous or intravenous administration is 0.45 μg/kg body weight, as a single injection once weekly. Alternatively, in patients not on dialysis, an initial dose of 0.75 μg/kg may be administered subcutaneously as a single injection once every two weeks. If the increase in haemoglobin is inadequate (less than 1g/dl (0.6 mmol/l) in four weeks) increase the dose by approximately 25%. Dose increases must not be made more frequently than once every four weeks.

If the rise in haemoglobin is greater than 2 g/dl (1.25 mmol/l) in four weeks reduce the dose by approximately 25%, depending on the rate of increase. If the haemoglobin exceeds 12 g/dl (7.5 mmol/l), a dose reduction should be considered. If the haemoglobin continues to increase, the dose should be reduced by approximately 25%. If after a dose reduction, haemoglobin continues to increase, the dose should be temporarily withheld until the haemoglobin begins to decrease, at which point therapy should be reinitiated at approximately 25% lower than the previous dose.

The haemoglobin should be measured every one or two weeks until it is stable. Thereafter the haemoglobin can be measured at longer intervals.

No guidance regarding the correction of haemoglobin is available for paediatric patients 1 to 10 years of age.

Maintenance phase:

For paediatric patients  11 years of age, in the maintenance phase, Aranesp may continue to be administered as a single injection once weekly or once every two weeks. Dialysis patients converting from once weekly to once every other week dosing with Aranesp should initially receive a dose equivalent to twice the previous once weekly dose. In patients not on dialysis, once the target haemoglobin has been achieved with once every two week dosing, Aranesp may be administered subcutaneously once monthly using an initial dose equal to twice the previous once every two week dose.

For paediatric patients 1-18 years of age, clinical data in paediatric patients has demonstrated that patients receiving r-HuEPO two or three times weekly may be converted to once weekly Aranesp, and those receiving r-HuEPO once weekly may be converted to once every other week Aranesp. The initial weekly paediatric dose of Aranesp (µg/week) can be determined by dividing the total weekly dose of r-HuEPO (IU/week) by 240. The initial every other week dose of Aranesp (μg/every other week) can be determined by dividing the total cumulative dose of r-HuEPO administered over a two-week period by 240. Because of individual variability, titration to optimal therapeutic doses is expected for individual patients. When substituting Aranesp for r-HuEPO the haemoglobin should be monitored every one or two weeks and the same route of administration should be used.

Dosing should be titrated as necessary to maintain the haemoglobin target.

If a dose adjustment is required to maintain haemoglobin at the desired level, it is recommended that the dose is adjusted by approximately 25%.

If the rise in haemoglobin is greater than 2 g/dl (1.25 mmol/l) in four weeks reduce the dose by approximately 25%, depending on the rate of increase. If the haemoglobin exceeds 12 g/dl (7.5 mmol/l), a dose reduction should be considered. If the haemoglobin continues to increase, the dose should be reduced by approximately 25%. If after a dose reduction, haemoglobin continues to increase, the dose should be temporarily withheld until the haemoglobin begins to decrease, at which point therapy should be reinitiated at approximately 25% lower than the previous dose.

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

After any dose or schedule adjustment the haemoglobin should be monitored every one or two weeks. Dose changes in the maintenance phase of treatment should not be made more frequently than every two weeks.

When changing the route of administration the same dose must be used and the haemoglobin monitored every one or two weeks so that the appropriate dose adjustments can be made to keep the haemoglobin at the desired level.

Treatment of symptomatic chemotherapy induced anaemia in cancer patients

Aranesp should be administered by the subcutaneous route to patients with anaemia (e.g. haemoglobin concentration  10 g/dl (6.2 mmol/l)) in order to increase haemoglobin to not greater than 12 g/dl (7.5 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.

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 adjustments for when haemoglobin values exceeding 12 g/dl (7.5 mmol/l) are observed are described below.

The recommended initial dose is 500 μg (6.75 μg/kg) given once every three weeks, or once weekly dosing can be given at 2.25 μg/kg body weight. If the clinical response of the patient (fatigue, haemoglobin response) is inadequate after nine weeks, further therapy may not be effective.

Aranesp therapy should be discontinued approximately four weeks after the end of chemotherapy.

Once the therapeutic objective for an individual patient has been achieved, the dose should be reduced by 25 to 50% in order to ensure that the lowest approved dose of Aranesp is used to maintain haemoglobin at a level that controls the symptoms of anaemia. Appropriate dose titration between 500 μg, 300 μg, and 150 μg should be considered.

Patients should be monitored closely, if the haemoglobin exceeds 12 g/dl (7.5 mmol/l), the dose should be reduced by approximately 25 to 50%. Treatment with Aranesp 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.

If the rise in haemoglobin is greater than 2 g/dl (1.25 mmol/l) in 4 weeks, the dose should be reduced by 25 to 50%.

Method of administration

Aranesp is administered either subcutaneously or intravenously as described in the posology. Rotate the injection sites and inject slowly to avoid discomfort at the site of injection.

Aranesp is supplied ready for use in a pre-filled syringe. The instructions for use, handling and disposal are given in section 6.6.

Aranesp treatment should be initiated by physicians experienced in the above mentioned indications.

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. Aranesp 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 the puncture of peripheral veins.

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.

Treatment with Aranesp is divided into two stages, correction and maintenance phase. Guidance is given separately for adult and paediatric patients.

Adult patients with chronic renal failure

Correction phase:

The initial dose by subcutaneous or intravenous administration is 0.45 µg/kg body weight, as a single injection once weekly. Alternatively, in patients not on dialysis, an initial dose of 0.75 μg/kg may be administered subcutaneously as a single injection once every two weeks. If the increase in haemoglobin is inadequate (less than 1 g/dl (0.6 mmol/l) in four weeks) increase the dose by approximately 25%. Dose increases must not be made more frequently than once every four weeks.

If the rise in haemoglobin is greater than 2 g/dl (1.25 mmol/l) in four weeks reduce the dose by approximately 25%. If the haemoglobin exceeds 12 g/dl (7.5 mmol/l), a dose reduction should be considered. If the haemoglobin continues to increase, the dose should be reduced by approximately 25%. If after a dose reduction, haemoglobin continues to increase, the dose should be temporarily withheld until the haemoglobin begins to decrease, at which point therapy should be reinitiated at approximately 25% lower than the previous dose.

The haemoglobin should be measured every one or two weeks until it is stable. Thereafter the haemoglobin can be measured at longer intervals.

Maintenance phase:

In the maintenance phase, Aranesp may continue to be administered as a single injection once weekly or once every two weeks. Dialysis patients converting from once weekly to once every other week dosing with Aranesp should initially receive a dose equivalent to twice the previous once weekly dose. In patients not on dialysis, once the target haemoglobin has been achieved with once every two week dosing, Aranesp may be administered subcutaneously once monthly using an initial dose equal to twice the previous once every two week dose.

Dosing should be titrated as necessary to maintain the haemoglobin target.

If a dose adjustment is required to maintain haemoglobin at the desired level, it is recommended that the dose is adjusted by approximately 25%.

If the rise in haemoglobin is greater than 2 g/dl (1.25 mmol/l) in four weeks reduce the dose by approximately 25%, depending on the rate of increase. If the haemoglobin exceeds 12 g/dl (7.5 mmol/l), a dose reduction should be considered. If the haemoglobin continues to increase, the dose should be reduced by approximately 25%. If after a dose reduction, haemoglobin continues to increase, the dose should be temporarily withheld until the haemoglobin begins to decrease, at which point therapy should be reinitiated at approximately 25% lower than the previous dose.

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

After any dose or schedule adjustment the haemoglobin should be monitored every one or two weeks. Dose changes in the maintenance phase of treatment should not be made more frequently than every two weeks.

When changing the route of administration the same dose must be used and the haemoglobin monitored every one or two weeks so that the appropriate dose adjustments can be made to keep the haemoglobin at the desired level.

Clinical studies have demonstrated that adult patients receiving r-HuEPO one, two or three times weekly may be converted to once weekly or once every other week Aranesp. The initial weekly dose of Aranesp (µg/week) can be determined by dividing the total weekly dose of r-HuEPO (IU/week) by 200. The initial every other week dose of Aranesp (µg/every other week) can be determined by dividing the total cumulative dose of r-HuEPO administered over a two-week period by 200. Because of individual variability, titration to optimal therapeutic doses is expected for individual patients. When substituting Aranesp for r-HuEPO the haemoglobin should be monitored every one or two weeks and the same route of administration should be used.

Paediatric population with chronic renal failure

Treatment of paediatric patients younger than 1 year of age has not been studied.

Correction phase:

For patients  11 years of age, the initial dose by subcutaneous or intravenous administration is 0.45 μg/kg body weight, as a single injection once weekly. Alternatively, in patients not on dialysis, an initial dose of 0.75 μg/kg may be administered subcutaneously as a single injection once every two weeks. If the increase in haemoglobin is inadequate (less than 1g/dl (0.6 mmol/l) in four weeks) increase the dose by approximately 25%. Dose increases must not be made more frequently than once every four weeks.

If the rise in haemoglobin is greater than 2 g/dl (1.25 mmol/l) in four weeks reduce the dose by approximately 25%, depending on the rate of increase. If the haemoglobin exceeds 12 g/dl (7.5 mmol/l), a dose reduction should be considered. If the haemoglobin continues to increase, the dose should be reduced by approximately 25%. If after a dose reduction, haemoglobin continues to increase, the dose should be temporarily withheld until the haemoglobin begins to decrease, at which point therapy should be reinitiated at approximately 25% lower than the previous dose.

The haemoglobin should be measured every one or two weeks until it is stable. Thereafter the haemoglobin can be measured at longer intervals.

No guidance regarding the correction of haemoglobin is available for paediatric patients 1 to 10 years of age.

Maintenance phase:

For paediatric patients  11 years of age, in the maintenance phase, Aranesp may continue to be administered as a single injection once weekly or once every two weeks. Dialysis patients converting from once weekly to once every other week dosing with Aranesp should initially receive a dose equivalent to twice the previous once weekly dose. In patients not on dialysis, once the target haemoglobin has been achieved with once every two week dosing, Aranesp may be administered subcutaneously once monthly using an initial dose equal to twice the previous once every two week dose.

For paediatric patients 1-18 years of age, clinical data in paediatric patients has demonstrated that patients receiving r-HuEPO two or three times weekly may be converted to once weekly Aranesp, and those receiving r-HuEPO once weekly may be converted to once every other week Aranesp. The initial weekly paediatric dose of Aranesp (µg/week) can be determined by dividing the total weekly dose of r-HuEPO (IU/week) by 240. The initial every other week dose of Aranesp (μg/every other week) can be determined by dividing the total cumulative dose of r-HuEPO administered over a two-week period by 240. Because of individual variability, titration to optimal therapeutic doses is expected for individual patients. When substituting Aranesp for r-HuEPO the haemoglobin should be monitored every one or two weeks and the same route of administration should be used.

Dosing should be titrated as necessary to maintain the haemoglobin target.

If a dose adjustment is required to maintain haemoglobin at the desired level, it is recommended that the dose is adjusted by approximately 25%.

If the rise in haemoglobin is greater than 2 g/dl (1.25 mmol/l) in four weeks reduce the dose by approximately 25%, depending on the rate of increase. If the haemoglobin exceeds 12 g/dl (7.5 mmol/l), a dose reduction should be considered. If the haemoglobin continues to increase, the dose should be reduced by approximately 25%. If after a dose reduction, haemoglobin continues to increase, the dose should be temporarily withheld until the haemoglobin begins to decrease, at which point therapy should be reinitiated at approximately 25% lower than the previous dose.

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

After any dose or schedule adjustment the haemoglobin should be monitored every one or two weeks. Dose changes in the maintenance phase of treatment should not be made more frequently than every two weeks.

When changing the route of administration the same dose must be used and the haemoglobin monitored every one or two weeks so that the appropriate dose adjustments can be made to keep the haemoglobin at the desired level.

Treatment of symptomatic chemotherapy induced anaemia in cancer patients

Aranesp should be administered by the subcutaneous route to patients with anaemia (e.g. haemoglobin concentration  10 g/dl (6.2 mmol/l)) in order to increase haemoglobin to not greater than 12 g/dl (7.5 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.

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 adjustments for when haemoglobin values exceeding 12 g/dl (7.5 mmol/l) are observed are described below.

The recommended initial dose is 500 μg (6.75 μg/kg) given once every three weeks, or once weekly dosing can be given at 2.25 μg/kg body weight. If the clinical response of the patient (fatigue, haemoglobin response) is inadequate after nine weeks, further therapy may not be effective.

Aranesp therapy should be discontinued approximately four weeks after the end of chemotherapy.

Once the therapeutic objective for an individual patient has been achieved, the dose should be reduced by 25 to 50% in order to ensure that the lowest approved dose of Aranesp is used to maintain haemoglobin at a level that controls the symptoms of anaemia. Appropriate dose titration between 500 μg, 300 μg, and 150 μg should be considered.

Patients should be monitored closely, if the haemoglobin exceeds 12 g/dl (7.5 mmol/l), the dose should be reduced by approximately 25 to 50%. Treatment with Aranesp 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.

If the rise in haemoglobin is greater than 2 g/dl (1.25 mmol/l) in 4 weeks, the dose should be reduced by 25 to 50%.

Method of administration

Aranesp is administered either subcutaneously or intravenously as described in the posology. Rotate the injection sites and inject slowly to avoid discomfort at the site of injection.

Aranesp is supplied ready for use in a pre-filled syringe. The instructions for use, handling and disposal are given in section 6.6.

Hypersensitivity to darbepoetin alfa, r-HuEPO or any of the excipients.

Poorly controlled hypertension.

General

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.

Blood pressure should be monitored in all patients, particularly during initiation of Aranesp therapy. If blood pressure is difficult to control by initiation of appropriate measures, the haemoglobin may be reduced by decreasing or withholding the dose of Aranesp. Cases of severe hypertension, including hypertensive crisis, hypertensive encephalopathy, and seizures, have been observed in CRF patients treated with Aranesp.

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.

Non-response to therapy with Aranesp should prompt a search for causative factors. Deficiencies of iron, folic acid or vitamin B12 reduce the effectiveness of ESAs and should therefore be corrected. Intercurrent infections, inflammatory or traumatic episodes, occult blood loss, haemolysis, severe aluminium toxicity, underlying haematologic diseases, or bone marrow fibrosis may also compromise the erythropoietic response. A reticulocyte count should be considered as part of the evaluation. If typical causes of non-response are excluded, and the patient has reticulocytopenia, an examination of the bone marrow should be considered. If the bone marrow is consistent with PRCA, testing for anti-erythropoietin antibodies should be performed.

Pure red cell aplasia caused by neutralising anti-erythropoietin antibodies has been reported in association with ESAs, including Aranesp. This has been predominantly reported in patients with CRF treated subcutaneously. 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 Aranesp.

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.

Active liver disease was an exclusion criteria in all studies of Aranesp, therefore no data are available from patients with impaired liver function. Since the liver is thought to be the principal route of elimination of darbepoetin alfa and r-HuEPO, Aranesp should be used with caution in patients with liver disease.

Aranesp should also be used with caution in those patients with sickle cell anaemia.

Misuse of Aranesp 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.

The needle cover of the pre-filled syringe contains dry natural rubber (a derivative of latex), which may cause allergic reactions.

In patients with chronic renal failure, maintenance haemoglobin concentration should not exceed the upper limit of the target haemoglobin concentration recommended. In clinical studies, an increased risk of death, serious cardiovascular or cerebrovascular events including stroke, and vascular access thrombosis was observed when 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.

Aranesp should be used with caution in patients with epilepsy. Convulsions have been reported in patients receiving Aranesp.

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

Chronic renal failure patients

In patients with chronic renal failure, maintenance haemoglobin concentration should not exceed the upper limit of the target haemoglobin concentration recommended. In clinical studies, an increased risk of death, serious cardiovascular or cerebrovascular events including stroke, and vascular access thrombosis was observed when 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.

Supplementary iron therapy is recommended for all patients with serum ferritin values below 100 µg/l or whose transferrin saturation is below 20%.

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

Cancer patients

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 Aranesp and other 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), ESAs are not indicated for use in this patient population

• 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.

In patients with solid tumours or lymphoproliferative malignancies, if the haemoglobin value exceeds 12 g/dl (7.5 mmol/l), the dosage adaptation should be closely respected, in order to minimise the potential risk of thromboembolic events. Platelet counts and haemoglobin level should also be monitored at regular intervals.

The clinical results obtained so far do not indicate any interaction of darbepoetin alfa with other substances. However, there is potential for an interaction with substances that are highly bound to red blood cells e.g. cyclosporin, tacrolimus. If Aranesp is given concomitantly with any of these treatments, blood levels of these substances should be monitored and the dosage adjusted as the haemoglobin rises.

General

There have been reports of serious allergic reactions including anaphylactic reaction, angioedema, allergic bronchospasm, skin rash and urticaria associated with darbepoetin alfa.

Clinical trial experience

Chronic renal failure patients

Data presented from controlled studies included 1357 patients, 766 who received Aranesp and 591 patients who received r-HuEPO. In the Aranesp group, 83% were receiving dialysis and 17% were not receiving dialysis.

Injection site pain was reported as attributable to treatment in studies where Aranesp was administered via subcutaneous injection. This was seen more frequently than with r-HuEPO. The injection site discomfort was generally mild and transient in nature and occurred predominantly after the first injection.

Incidence of adverse reactions from controlled clinical studies are:

Cancer patients

Adverse reactions were determined based on pooled data from seven randomised, double-blind placebo-controlled studies of Aranesp with a total of 2112 patients (Aranesp 1200, placebo 912). Patients with solid tumours (e.g., lung, breast, colon, ovarian cancers) and lymphoid malignancies (e.g., lymphoma, multiple myeloma) were enrolled in the clinical studies.

Incidence of adverse reactions from controlled clinical studies are:

Postmarketing experience

The following adverse reactions have been identified during postmarketing use of Aranesp:

• Pure Red Cell Aplasia. In isolated cases, neutralising anti-erythropoietin antibody mediated pure red cell aplasia (PRCA) associated with Aranesp therapy have been reported predominantly in patients with CRF treated subcutaneously. In case PRCA is diagnosed, therapy with Aranesp must be discontinued and patients should not be switched to another recombinant erythropoietic protein.

• Allergic reactions, including anaphylactic reaction, angioedema, skin rash and urticaria. Frequency is not known (cannot be estimated from the available data).

• Convulsions. Frequency is not known (cannot be estimated from the available data).

• Hypertension. Frequency is not known (cannot be estimated from the available data).

Amgen

POM

21 November 2011