Epoetin Beta

Epoetin beta is a recombinant human erythropoietin. Erythropoietin is a glycoprotein that stimulates the formation of red blood cells from committed progenitor cells, acting as a mitosis-stimulating factor and a differentiation hormone. The active substance of NeoRecormon is identical in amino acid and carbohydrate composition to erythropoietin isolated from the urine of anaemic patients.

Mechanism of Action

• Erythropoietic action: epoetin beta stimulates the formation of erythrocytes from committed progenitors, as a mitosis-stimulating factor and differentiation hormone.
• Effect on blood counts: in animal models (normal and uraemic rats, polycythaemic mice, dogs), intravenous and subcutaneous epoetin beta raised the number of erythrocytes, haemoglobin values, reticulocyte counts and the iron incorporation rate.
• Selectivity: in human bone marrow cell cultures, epoetin beta stimulated erythropoiesis specifically and did not affect leucopoiesis. No cytotoxic action on bone marrow or human skin cells was detected.
• Tumour cells: erythropoietin receptors may be expressed on the surface of a variety of tumour cells (see Special Instructions).

Pharmacokinetics

• Absorption: after subcutaneous injection in uraemic patients, slow absorption produces a serum concentration plateau, with the maximum reached after 12 to 28 hours on average. Bioavailability by this route is 23 to 42% of that after intravenous administration.
• Distribution: the volume of distribution is one to two times the plasma volume.
• Elimination: after intravenous injection in healthy volunteers and uraemic patients, the half-life is 4 to 12 hours. After subcutaneous injection the terminal half-life is longer, 13 to 28 hours on average.

• Chronic renal failure: treatment of symptomatic anaemia associated with chronic renal failure in adult and paediatric patients.
• Anaemia of prematurity: prevention of anaemia of prematurity in infants with a birth weight of 750 to 1,500 g and a gestational age of less than 34 weeks.
• Chemotherapy-induced anaemia: treatment of symptomatic anaemia in adult patients with non-myeloid malignancies receiving chemotherapy.
• Autologous blood pre-donation: increasing the yield of autologous blood from patients in a pre-donation programme. Its use must be balanced against the reported increased risk of thromboembolic events. Treatment is only for patients with moderate anaemia (haemoglobin 10 to 13 g/dL, no iron deficiency) if blood-conserving procedures are unavailable or insufficient and the planned major elective surgery needs a large volume of blood (4 or more units for women, 5 or more for men).

• Hypersensitivity to the active substance or to any excipient.
• Poorly controlled hypertension.
• In the autologous blood indication: myocardial infarction or stroke in the month before treatment, unstable angina pectoris, and an increased risk of deep vein thrombosis such as a history of venous thromboembolic disease.

Based on clinical trials in 1,725 patients, about 8% of patients treated are expected to have adverse reactions.

• Chronic renal failure: the most frequent reaction is a rise in blood pressure or worsening of existing hypertension, especially with a rapid rise in packed cell volume. Hypertensive crisis with encephalopathy-like symptoms (headache and confusion, speech disturbance or impaired gait, up to tonic-clonic seizures) can occur even with normal or low blood pressure. Shunt thrombosis may occur, especially with a tendency to hypotension or complications of the arteriovenous fistula. Serum ferritin usually falls as the packed cell volume rises, and transient rises in potassium and phosphate have been seen in isolated cases. In isolated cases, PRCA caused by neutralising anti-erythropoietin antibodies has been reported.
• Cancer: headache and hypertension are common and can be treated. Serum iron parameters fall in some patients. Thromboembolic events were more frequent than in untreated or placebo controls (7% against 4%), without any increase in thromboembolic mortality.
• Autologous blood pre-donation: a slightly higher frequency of thromboembolic events was reported, without an established causal link. Temporary iron deficiency was more pronounced than in controls.

Very common (≥1/10): fall in serum ferritin in premature infants.

Common (≥1/100 to <1/10): hypertension; headache; thromboembolic events (cancer patients).

Uncommon (≥1/1,000 to <1/100): hypertensive crisis (renal failure).

Rare (≥1/10,000 to <1/1,000): shunt thrombosis (renal failure).

Very rare (<1/10,000): thrombocytosis (renal failure).

The SmPC also describes, without a table entry: rarely, skin reactions such as rash, pruritus, urticaria or injection site reactions; in very rare cases, anaphylactoid reactions, and flu-like symptoms (fever, chills, headache, limb pain, malaise, bone pain) especially at the start of treatment, which were mild or moderate and eased within hours or days. A controlled trial of other erythropoiesis-stimulating agents reported stroke as common. Severe cutaneous adverse reactions, including Stevens-Johnson syndrome and toxic epidermal necrolysis, can be life-threatening or fatal and have been reported with epoetins.

• Clinical results so far do not indicate any interaction of epoetin beta with other medicinal products.
• Animal experiments showed that epoetin beta does not increase the myelotoxicity of cytostatic medicines such as etoposide, cisplatin, cyclophosphamide and fluorouracil.
• Folic acid and vitamin B12 deficiencies reduce the effectiveness of epoetin beta and must be ruled out; supplementary iron may be needed (see Special Instructions).

Therapy must be started by a physician experienced in the indications above. Because anaphylactoid reactions were seen in isolated cases, the first dose should be given under medical supervision. The pre-filled syringe is ready for use; only solutions that are clear or slightly opalescent, colourless and practically free of visible particles may be injected. The syringe is sterile but unpreserved and for single use only, so never give more than one dose from one syringe.

Chronic Renal Failure (Adults and Children)

• Route: subcutaneously or intravenously, to raise haemoglobin to not more than 12 g/dL. Subcutaneous use is preferable in patients not on haemodialysis, to avoid puncturing peripheral veins. For intravenous use, inject over about 2 minutes, in haemodialysis patients via the arteriovenous fistula at the end of dialysis.
• Target: haemoglobin 10 to 12 g/dL; avoid a sustained level above 12 g/dL and a rise of more than 2 g/dL over four weeks. In hypertension or existing cardiovascular, cerebrovascular or peripheral vascular disease, the weekly rise and the target are set individually.
• Correction phase, subcutaneous: 3 × 20 IU/kg per week, raised every 4 weeks by 3 × 20 IU/kg per week if the haemoglobin rise is inadequate (below 0.25 g/dL per week). The weekly dose can be divided into daily doses.
• Correction phase, intravenous: 3 × 40 IU/kg per week, raised after 4 weeks to 80 IU/kg three times a week and then by 20 IU/kg increments at monthly intervals if needed. By either route the maximum is 720 IU/kg per week.
• Maintenance phase: the dose is first cut to half the previous amount, then adjusted individually every one or two weeks. Subcutaneously, the weekly dose can be one injection a week or divided doses three or seven times a week; patients stable on once-weekly dosing may move to once every two weeks, which may need a higher dose.
• Dose changes: if haemoglobin rises by more than 2 g/dL in a month or approaches 12 g/dL, reduce the dose by about 25%; if it keeps rising, interrupt until it begins to fall, then restart about 25% below the previous dose.
• Children: on average, the younger the child, the higher the dose needed. Follow the recommended schedule, since the individual response cannot be predicted.
• Duration: treatment is normally long term and can be interrupted at any time. Data on once-weekly dosing come from studies lasting 24 weeks.

Prevention of Anaemia of Prematurity

3 × 250 IU/kg per week, given subcutaneously, for 6 weeks. Premature infants already transfused before treatment starts are less likely to benefit than untransfused infants.

Chemotherapy-Induced Anaemia (Adults)

• Start: subcutaneously, in patients with anaemia (for example haemoglobin 10 g/dL or less), 30,000 IU per week (about 450 IU/kg per week for an average patient), as one injection a week or divided into doses 3 to 7 times a week.
• After 4 weeks: if haemoglobin has risen by at least 1 g/dL, continue the dose. If not, consider doubling the weekly dose. If it has not risen by at least 1 g/dL after 8 weeks, a response is unlikely and treatment should stop. The maximum is 60,000 IU per week.
• Dose changes: once the goal is reached, reduce the dose by 25 to 50% to hold haemoglobin there. If haemoglobin exceeds 12 g/dL, or rises by more than 2 g/dL in 4 weeks, reduce by about 25 to 50%. Interrupt if it exceeds 13 g/dL, and restart about 25% lower once it is 12 g/dL or less.
• Duration: continue up to 4 weeks after chemotherapy ends.

Increasing the Yield of Autologous Blood

Given intravenously over about 2 minutes, or subcutaneously, twice weekly for 4 weeks. When the packed cell volume allows donation (33% or more), give it at the end of the donation, and keep the packed cell volume at or below 48% throughout. The surgical team sets the dose for each patient from the amount of blood to be pre-donated and the endogenous red cell reserve, using the SmPC graphs. The maximum is 1,600 IU/kg per week intravenously or 1,200 IU/kg per week subcutaneously.

Traceability

The name and batch number of the product given must be clearly recorded.

Haemoglobin Targets in Renal Failure

Maintenance haemoglobin must not exceed the upper limit of the recommended target (12 g/dL). In clinical trials, an increased risk of death and of serious cardiovascular or cerebrovascular events, including stroke, was observed when ESAs were given to target a haemoglobin above 12 g/dL (7.45 mmol/L). Controlled trials have not shown significant benefit from raising haemoglobin beyond the level needed to control symptoms and avoid transfusion. Caution is needed when escalating doses, since high cumulative doses may be associated with a higher risk of death and of serious cardiovascular and cerebrovascular events; if the response is poor, other explanations should be considered.

Effect on Tumour Growth

Epoetins are growth factors that mainly stimulate red blood cell production, and erythropoietin receptors may be present on a variety of tumour cells. As with all growth factors, there is a concern that epoetins could stimulate tumour growth. In several controlled studies, epoetins have not been shown to improve overall survival or to lower the risk of tumour progression in patients with cancer-related anaemia. In controlled clinical studies, NeoRecormon and other ESAs showed:

• shortened time to tumour progression in advanced head and neck cancer treated with radiation therapy, when targeting haemoglobin above 14 g/dL;
• shortened overall survival and more deaths attributed to disease progression at 4 months in metastatic breast cancer treated with chemotherapy, when targeting haemoglobin of 12 to 14 g/dL;
• increased risk of death at a target haemoglobin of 12 g/dL in patients with active malignant disease receiving neither chemotherapy nor radiation therapy (ESAs are not indicated for this population).

Because of this, blood transfusion should in some clinical situations be the preferred treatment of anaemia in cancer patients. The decision to give a recombinant erythropoietin should rest on a benefit-risk assessment made with the patient, taking account of tumour type and stage, degree of anaemia, life expectancy, the setting in which the patient is treated and patient preference. Blood pressure, platelet counts and haemoglobin should be monitored at regular intervals in cancer patients.

Pure Red Cell Aplasia (PRCA)

PRCA caused by neutralising anti-erythropoietin antibodies has been reported with erythropoietin therapy, including NeoRecormon. These antibodies cross-react with all erythropoietic proteins, so patients suspected or confirmed to have them should not be switched to NeoRecormon. A paradoxical fall in haemoglobin with severe anaemia and low reticulocyte counts should prompt stopping epoetin and testing for anti-erythropoietin antibodies. Such cases have been reported in hepatitis C patients treated with interferon and ribavirin when epoetins were used at the same time; epoetins are not approved for anaemia associated with hepatitis C.

Blood Pressure

Blood pressure may rise or existing hypertension worsen, especially with a rapid rise in packed cell volume. It can be treated with medicines; if it cannot be controlled, a temporary interruption of NeoRecormon is recommended. Monitor blood pressure regularly, particularly at the start and between dialyses. Hypertensive crisis with encephalopathy-like symptoms may occur and needs immediate medical attention and intensive care; sudden stabbing, migraine-like headache is a possible warning sign.

Severe Cutaneous Reactions

Severe cutaneous adverse reactions, including Stevens-Johnson syndrome and toxic epidermal necrolysis, can be life-threatening or fatal and have been reported with epoetins; more severe cases were seen with long-acting epoetins. Patients should be told the signs and symptoms at the time of prescription and be monitored closely for skin reactions. If such signs appear, NeoRecormon should be withdrawn immediately and an alternative considered. After a severe cutaneous reaction attributed to NeoRecormon, no ESA may ever be restarted.

Other Precautions

• Use with caution in refractory anaemia with excess blasts in transformation, epilepsy, thrombocytosis and chronic liver failure. Folic acid and vitamin B12 deficiencies must be ruled out, as they reduce effectiveness.
• Iron and aluminium: iron status should be checked before and during treatment, with supplementary iron where needed. Severe aluminium overload may reduce effectiveness.
• Nephrosclerosis: in patients not yet on dialysis, the indication is decided individually, as a possible acceleration of renal failure cannot be ruled out.
• Platelets: in renal failure a moderate dose-dependent rise within the normal range may occur, especially after intravenous use; monitor regularly during the first 8 weeks. In pre-donation patients, check platelets at least weekly and stop treatment if they rise by more than 150 × 10⁹/L or above the normal range.
• Dialysis: the heparin dose often needs to be increased, as the dialysis system can clot if heparinisation is not optimal. Consider early shunt revision and thrombosis prophylaxis (for example acetylsalicylic acid) in patients at risk of shunt thrombosis. Monitor potassium and phosphate regularly; if potassium is high or rising, consider stopping until it is corrected.
• Premature infants: platelets may rise slightly up to day 12 to 14 of life and should be monitored. A risk of retinopathy could not be excluded, so the decision to treat must balance benefit, risk and the available alternatives.
• Autologous pre-donation: official blood donation guidelines apply: only patients with a packed cell volume of 33% or more (haemoglobin 11 g/dL or more) should donate, take special care below 50 kg, and do not draw more than about 12% of the estimated blood volume at once. Reserve treatment for patients in whom avoiding donor blood transfusion is particularly important.
• Misuse: misuse by healthy people may raise the packed cell volume excessively, with life-threatening cardiovascular complications.

Pregnancy, Breastfeeding and Fertility

• Pregnancy: there are no clinical data on exposed pregnancies; take caution when prescribing to pregnant women.
• Breastfeeding: it is unknown whether epoetin beta passes into human milk. Decide whether to continue or stop breastfeeding, or to continue or stop treatment, weighing the benefit of breastfeeding to the child against the benefit of treatment to the woman.
• Fertility: animal studies do not indicate direct or indirect harmful effects on pregnancy, embryonal or foetal development, birth or postnatal development.

Excipients

Each pre-filled syringe contains up to 0.3 mg phenylalanine, which matters in severe phenylketonuria. It contains less than 1 mmol (23 mg) sodium, that is, it is essentially sodium-free. It also contains polysorbate 20 (0.034 mg per 0.3 mL syringe, 0.063 mg per 0.6 mL syringe), which may cause allergic reactions.

Effect on Driving

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

Store in a refrigerator at 2 °C to 8 °C, and keep the pre-filled syringe in the outer carton to protect it from light. Keep the cold chain unbroken during transport and delivery. For ambulatory use, the patient may take the product out of the refrigerator and keep it at room temperature (not above 25 °C) for one single period of up to 3 days.

2 years.

Prescription only (Rx), under restricted medical prescription (Annex II B of the marketing authorisation). Therapy is started by a physician experienced in the indications. It is supplied as pre-filled syringes on prescription to the hospital, dialysis unit or clinic that administers it, or to the patient for ambulatory use as the SmPC allows, with cold-chain delivery at 2–8 °C. See the SmPC for pack sizes.