Epoetin Zeta

Epoetin zeta is a recombinant human erythropoietin (EPO), a glycoprotein hormone produced in Chinese hamster ovary cells. Natural EPO is made mainly by the kidney in response to low tissue oxygen and is the key regulator of red blood cell production. Silapo is a biosimilar medicinal product, as is Retacrit.

Mechanism of Action

• Natural role of EPO: it acts in all phases of erythroid development, with its main effect on erythroid precursors.
• Receptor signalling: once EPO binds its cell-surface receptor, signalling pathways are activated that interfere with apoptosis and stimulate erythroid cell proliferation. DrugBank describes activation of JAK2 and then STAT5, which moves to the nucleus and switches on genes for cell division and differentiation, including the anti-apoptotic protein Bcl-x.
• Recombinant product: its 165-amino-acid sequence is identical to that of human urinary EPO, and the two cannot be told apart in functional assays. The apparent molecular weight is 32,000 to 40,000 dalton.
• Effect on blood counts: in healthy volunteers, single subcutaneous doses of 20,000 to 160,000 IU of epoetin gave a dose-dependent rise in reticulocytes, red blood cells and haemoglobin.
• Tumour cells: erythropoietin receptors may be expressed on the surface of a variety of tumour cells (see Special Instructions).

Pharmacokinetics

• Absorption: after subcutaneous injection, serum levels peak 12 to 18 hours after the dose. Absolute bioavailability by this route is about 20% in healthy subjects, and weekly subcutaneous doses of 600 IU/kg did not accumulate.
• Distribution: mean volume of distribution was 49.3 mL/kg after intravenous doses of 50 and 100 IU/kg in healthy subjects, and 42 to 107 mL/kg in chronic renal failure, slightly more than the plasma space.
• Metabolism and elimination: after binding its receptor the hormone is internalised and degraded (DrugBank). The half-life is about 4 hours after repeated intravenous doses in healthy subjects and is estimated at about 24 hours by the subcutaneous route. Apparent clearance (CL/F) in healthy subjects was 31.2 mL/h/kg on 150 IU/kg three times weekly and 12.6 mL/h/kg on 40,000 IU once weekly; the SmPC gives the values in cancer patients.
• Dose relationship: exposure rose in proportion to dose after intravenous doses of 150 and 300 IU/kg, and linearly with single subcutaneous doses of 300 to 2,400 IU/kg. With extended dosing intervals the relationship was linear but not dose-proportional at steady state. The effect on haematological parameters is dose-related and independent of the route of administration.

• Symptomatic anaemia in chronic renal failure (CRF): in adults and children aged 1 to 18 years on haemodialysis and adults on peritoneal dialysis; and in adults with renal insufficiency not yet on dialysis, for severe anaemia of renal origin accompanied by clinical symptoms.
• Chemotherapy-induced anaemia: adults receiving chemotherapy for solid tumours, malignant lymphoma or multiple myeloma who are at risk of transfusion as assessed by the patient’s general status (for example cardiovascular status, pre-existing anaemia at the start of chemotherapy), to treat anaemia and reduce transfusion requirements.
• Autologous blood predonation: adults in a predonation programme, to increase the yield of autologous blood. Only for patients with moderate anaemia (haemoglobin 10 to 13 g/dL, no iron deficiency) when blood-saving 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).
• Major elective orthopaedic surgery: non-iron-deficient adults at high perceived risk of transfusion complications, to reduce exposure to donor (allogeneic) blood. Restricted to moderate anaemia (for example haemoglobin 10 to 13 g/dL) with no autologous predonation programme available and an expected moderate blood loss (900 to 1,800 mL).
• Myelodysplastic syndromes (MDS): symptomatic anaemia (haemoglobin 10 g/dL or less) in adults with low- or intermediate-1-risk primary MDS who have low serum erythropoietin (under 200 mU/mL).

• Hypersensitivity to the active substance or to any excipient.
• Pure red cell aplasia (PRCA) after treatment with any erythropoietin: such patients must not receive epoetin zeta or any other erythropoietin.
• Uncontrolled hypertension.
• Autologous predonation programmes: all contraindications of the programme apply to patients given epoetin zeta.
• Patients scheduled for major elective orthopaedic surgery who are not in a predonation programme: severe coronary, peripheral arterial, carotid or cerebral vascular disease, including recent myocardial infarction or cerebral vascular accident.
• Surgery patients who for any reason cannot receive adequate antithrombotic prophylaxis.

The most frequent adverse reaction is a dose-dependent rise in blood pressure or worsening of existing hypertension, so blood pressure should be monitored, particularly at the start of treatment. In clinical trials of epoetin the most frequent reactions were diarrhoea, nausea, vomiting, pyrexia and headache, and influenza-like illness may occur, especially at the start. Respiratory tract congestion (upper respiratory tract or nasal congestion, nasopharyngitis) was reported in studies with extended dosing intervals in adults with renal insufficiency not yet on dialysis. The frequencies below come from 25 controlled studies in which 2,094 anaemic subjects received epoetin.

Very common (≥1/10): diarrhoea, nausea and vomiting; pyrexia.

Common (≥1/100 to <1/10): headache; hypertension; venous and arterial thromboses, fatal and non-fatal (deep vein thrombosis, pulmonary embolism, retinal thrombosis, arterial thrombosis including myocardial infarction, cerebrovascular accidents including cerebral infarction and haemorrhage, transient ischaemic attacks, shunt thrombosis including in dialysis equipment); cough; rash; arthralgia, bone pain, myalgia and pain in the extremities; chills, influenza-like illness, injection site reaction and peripheral oedema.

Uncommon (≥1/1,000 to <1/100): hyperkalaemia (common in dialysis patients); hypersensitivity; convulsion; respiratory tract congestion; urticaria.

Rare (≥1/10,000 to <1/1,000): pure red cell aplasia; thrombocythaemia; anaphylactic reaction; acute porphyria; positive anti-erythropoietin antibodies.

Not known: hypertensive crisis; angioneurotic oedema; loss of efficacy (drug ineffective).

Serious reactions to watch for are antibody-mediated PRCA, thrombotic vascular events, hypertensive crisis with encephalopathy and seizures, anaphylaxis, and severe cutaneous reactions (Stevens-Johnson syndrome, toxic epidermal necrolysis), which can be life-threatening or fatal.

• Metabolism of other medicines: there is no evidence that erythropoietin alters it.
• Medicines that reduce erythropoiesis may reduce the response to epoetin zeta.
• Ciclosporin: it is bound by red blood cells, so an interaction is possible. Ciclosporin blood levels should be monitored and the dose adjusted as the haematocrit rises.
• G-CSF and GM-CSF: no evidence of an interaction with regard to haematological differentiation or proliferation of tumour biopsy specimens in vitro.
• Trastuzumab: in women with metastatic breast cancer, subcutaneous co-administration of an epoetin (40,000 IU/mL) with trastuzumab 6 mg/kg did not change the pharmacokinetics of trastuzumab.
• Interferon and ribavirin: PRCA has been reported in hepatitis C patients when ESAs were used together with interferon and ribavirin. Epoetin zeta is not approved for anaemia associated with hepatitis C.
• Iron: iron stores should be assessed before starting and iron supplementation given if indicated; most patients with chronic kidney disease need iron while taking an ESA (DrugBank).

Treatment must be started under the supervision of a physician experienced in managing the conditions above. Before starting, and before any dose increase, other causes of anaemia (iron, folate or vitamin B12 deficiency, aluminium intoxication, infection or inflammation, blood loss, haemolysis, bone marrow fibrosis of any origin) are evaluated and treated, and adequate iron stores are assured, with iron supplementation if necessary. The syringe is left to reach room temperature before use (usually 15 to 30 minutes) and the solution is checked for particles or a change in colour.

Route of Administration

• Intravenous: preferred in haemodialysis patients, where intravenous access is routinely available, and used for autologous predonation. Inject over at least 1 to 5 minutes, depending on the total dose. In haemodialysis, a bolus may be given through a venous port in the dialysis line during the session, or at the end of the session via the fistula needle tubing followed by 10 mL of isotonic saline. Give more slowly in patients who react with flu-like symptoms. Do not give as an intravenous infusion or mixed with other solutions.
• Subcutaneous: used where intravenous access is not readily available (patients not yet on dialysis, peritoneal dialysis) and for chemotherapy-induced anaemia, major elective orthopaedic surgery and MDS. Generally no more than 1 mL per injection site (use more than one site for larger volumes); inject into the limbs or the anterior abdominal wall.
• Self-injection: where the physician determines that a patient or caregiver can safely and effectively inject subcutaneously themselves, they must be instructed in the correct dose and technique. Instructions on how to inject Silapo yourself are in section 3 of the package leaflet.

Chronic Renal Failure (Adults)

• Target: haemoglobin 10 to 12 g/dL, never above 12 g/dL. Avoid a rise of more than 2 g/dL over four weeks. Treatment has a correction phase and a maintenance phase.
• Haemodialysis: start at 50 IU/kg three times a week, preferably intravenously; change by 25 IU/kg (three times a week) in steps of at least four weeks until the target is reached. Maintenance is a total of 75 to 300 IU/kg per week. Patients with a very low starting haemoglobin (below 6 g/dL) may need higher maintenance doses than those with milder anaemia (above 8 g/dL).
• Not yet on dialysis: start at 50 IU/kg three times a week, with 25 IU/kg increments at intervals of at least four weeks; subcutaneous injection is used where intravenous access is not readily available. Maintenance can be three times a week or, subcutaneously, once weekly or once every 2 weeks (longer intervals may need a higher dose). Maximum: 150 IU/kg three times a week, 240 IU/kg (up to 20,000 IU) once weekly, or 480 IU/kg (up to 40,000 IU) once every 2 weeks.
• Peritoneal dialysis: start at 50 IU/kg twice a week; maintenance 25 to 50 IU/kg twice a week in two equal injections. Subcutaneous injection is used where intravenous access is not readily available.
• Dose changes: if haemoglobin rises by more than 2 g/dL per month, or stays above 12 g/dL, reduce the dose by 25%. If it exceeds 13 g/dL, stop until it falls below 12 g/dL, then restart at a dose 25% below the previous one. Use the lowest dose that controls the anaemia and its symptoms.

Chemotherapy-Induced Anaemia (Adults)

• Start: in patients with anaemia (for example haemoglobin 10 g/dL or less), 150 IU/kg subcutaneously three times a week, or 450 IU/kg subcutaneously once weekly. Target haemoglobin 10 to 12 g/dL.
• After 4 weeks: if haemoglobin has risen by at least 1 g/dL, or reticulocytes by 40,000 cells/µL or more, keep the dose. If the haemoglobin rise is under 1 g/dL and the reticulocyte rise under 40,000 cells/µL, increase to 300 IU/kg three times a week. If neither threshold is reached after a further 4 weeks, a response is unlikely and treatment should stop.
• Dose changes: if haemoglobin rises by more than 2 g/dL per month or exceeds 12 g/dL, reduce the dose by about 25 to 50%. If it exceeds 13 g/dL, stop until it falls below 12 g/dL and restart at a dose 25% lower.
• Duration: continue until one month after chemotherapy ends.

Autologous Predonation and Major Orthopaedic Surgery (Adults)

• Autologous predonation: mildly anaemic patients (haematocrit 33 to 39%) who need to predeposit 4 or more units of blood receive 600 IU/kg intravenously twice a week for 3 weeks before surgery, after the blood donation is completed.
• Major elective orthopaedic surgery: 600 IU/kg subcutaneously once weekly for three weeks (21, 14 and 7 days before surgery) and on the day of surgery. If the lead time must be under three weeks, 300 IU/kg subcutaneously daily for 10 consecutive days before surgery, on the day of surgery and for four days afterwards. Stop if haemoglobin reaches 15 g/dL or more before the operation.

Myelodysplastic Syndromes (Adults)

• Start: for symptomatic anaemia (for example haemoglobin 10 g/dL or less), 450 IU/kg (maximum total dose 40,000 IU) subcutaneously once a week, with at least 5 days between doses. Target haemoglobin 10 to 12 g/dL; avoid levels above 12 g/dL.
• Review and steps: the first erythroid response is assessed 8 to 12 weeks after starting. Doses are raised or lowered one dosing step at a time (see the SmPC diagram).
• Increase: not above 1,050 IU/kg (80,000 IU in total) per week, at least 4 weeks apart. Increase by one step if response is lost or haemoglobin falls by 1 g/dL or more after a dose reduction.
• Hold or reduce: withhold the dose when haemoglobin exceeds 12 g/dL, and restart on the same step or one step lower once it is below 11 g/dL. Consider one step lower if haemoglobin rises quickly (more than 2 g/dL over 4 weeks).

Children and Adolescents

• Chronic renal failure on haemodialysis (ages 1 to 18): target haemoglobin 9.5 to 11 g/dL, not above 11 g/dL. Start at 50 IU/kg intravenously three times a week; change by 25 IU/kg in steps of at least four weeks. Children under 30 kg generally need higher maintenance doses than children over 30 kg and adults. In clinical trials the usual maintenance doses after 6 months (IU/kg three times a week) were 75 to 150 (median 100) below 10 kg, 60 to 150 (median 75) at 10 to 30 kg, and 30 to 100 (median 33) above 30 kg. Children with a very low starting haemoglobin (below 6.8 g/dL) may need higher maintenance doses than children whose haemoglobin is higher.
• Not established: safety and efficacy have not been established in children with renal anaemia before dialysis or on peritoneal dialysis (no dose recommendation can be made), in chemotherapy-induced anaemia, or before surgery (no data).

Traceability and Switching

The trade name and batch number of the ESA given must be recorded in the patient file. Patients should be switched from one ESA to another only under appropriate supervision.

Haemoglobin Targets

• Renal failure: maintenance haemoglobin must not exceed the upper limit of the recommended range (12 g/dL in adults, 11 g/dL in children). In clinical trials, an increased risk of death and serious cardiovascular events was observed when ESAs were given to reach a haemoglobin above 12 g/dL (7.5 mmol/L). Controlled trials have not shown significant benefit from raising haemoglobin beyond the level needed to control symptoms and avoid transfusion. Haemoglobin should rise by about 1 g/dL per month and not more than 2 g/dL per month, to limit the risk of hypertension.
• Dose escalation: caution is needed when raising doses in renal failure, 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. Some patients on dosing intervals longer than once weekly may not keep adequate haemoglobin levels and may need a higher dose. Patients on subcutaneous treatment should be checked regularly for loss of efficacy (a sustained fall in haemoglobin despite a higher dose).
• All patients: haemoglobin should be monitored closely, because treatment at levels above the range for the indication may increase the risk of thromboembolic events and fatal outcomes.

Tumour Progression and Survival

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, and a role for ESAs in tumour progression or reduced progression-free survival cannot be excluded. In controlled clinical studies, ESAs were associated with decreased locoregional tumour control or decreased overall survival:

• decreased locoregional control in advanced head and neck cancer treated with radiation therapy, when haemoglobin was taken above 14 g/dL (8.7 mmol/L);
• shortened overall survival and more deaths attributed to disease progression at 4 months in metastatic breast cancer treated with chemotherapy, when haemoglobin was taken to 12 to 14 g/dL;
• increased risk of death at a haemoglobin of 12 g/dL in patients with active malignant disease receiving neither chemotherapy nor radiation therapy (ESAs are not indicated for this population);
• a 9% increase in the risk of disease progression or death, and a 15% increase that cannot be statistically ruled out, in metastatic breast cancer patients on chemotherapy when haemoglobin was taken to 10 to 12 g/dL.

Because of this, blood transfusion should in some clinical situations be the preferred treatment of anaemia in cancer patients. The decision to give an 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. Red cells appear 2 to 3 weeks after an ESA dose, and this delay should be considered when judging whether the patient is at risk of transfusion. Haemoglobin should be measured regularly until stable and periodically afterwards.

Pure Red Cell Aplasia (PRCA)

Antibody-mediated PRCA has been reported after months to years of treatment with epoetins, and in hepatitis C patients treated with interferon and ribavirin when ESAs are used at the same time (epoetin zeta is not approved for anaemia associated with hepatitis C). If efficacy is suddenly lost, defined as a fall in haemoglobin of 1 to 2 g/dL per month with a greater need for transfusions, a reticulocyte count should be obtained and typical causes of non-response investigated (iron, folate or vitamin B12 deficiency, aluminium intoxication, infection or inflammation, blood loss, haemolysis, bone marrow fibrosis). A paradoxical fall in haemoglobin with severe anaemia and a low reticulocyte count should prompt stopping epoetin zeta and testing for anti-erythropoietin antibodies; a bone marrow examination should also be considered. No other ESA should be started because of the risk of cross-reaction.

Blood Pressure and Seizures

Blood pressure must be closely monitored and controlled in every patient. Use caution if hypertension is untreated, inadequately treated or hard to control; antihypertensive treatment may need to be added or increased, and treatment should be stopped if blood pressure cannot be controlled. Hypertensive crisis with encephalopathy and seizures, needing immediate medical attention and intensive care, has also occurred in patients with previously normal or low blood pressure; sudden stabbing, migraine-like headache is a possible warning signal. Use caution in epilepsy, a history of seizures, or conditions that predispose to seizures such as CNS infections and brain metastases.

Thrombotic Vascular Events

An increased incidence of thrombotic vascular events has been observed with ESAs: venous and arterial thromboses and embolism (some fatal), including deep vein thrombosis, pulmonary embolism, retinal thrombosis and myocardial infarction, as well as cerebrovascular accidents (cerebral infarction, cerebral haemorrhage, transient ischaemic attacks). The risk must be weighed against the expected benefit, particularly in patients with risk factors such as obesity or a history of thromboembolic events.

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, treatment must be withdrawn immediately and an alternative considered. After a severe cutaneous reaction attributed to the product, it must never be restarted.

Iron, Platelets and Other Precautions

• Iron: ferritin usually falls as the packed cell volume rises. Iron supplementation is recommended if serum ferritin is below 100 ng/mL in renal failure (elemental iron 200 to 300 mg/day orally in adults, 100 to 200 mg/day in children) and if transferrin saturation is below 20% in cancer patients (200 to 300 mg/day). In predonation programmes and before major orthopaedic surgery, 200 mg/day is given: before the first predeposit and throughout for predonation, and throughout treatment for surgery, starting beforehand if possible.
• Platelets: a moderate dose-dependent rise within the normal range may occur and regresses with continued treatment; thrombocythaemia above the normal range has been reported. Platelet counts should be monitored regularly in the first 8 weeks.
• Liver and porphyria: use caution in chronic liver failure (safety not established in hepatic dysfunction) and in porphyria, which has very rarely developed or worsened during treatment.

Renal Failure and Dialysis

Shunt thrombosis has occurred in haemodialysis patients, especially with a tendency to hypotension or fistula complications; early shunt revision and thrombosis prophylaxis (for example acetylsalicylic acid) is recommended. Hyperkalaemia has been seen in isolated cases; serum electrolytes should be monitored and, if potassium is high or rising, stopping treatment until it is corrected should be considered. The heparin dose often needs to be increased during haemodialysis as the packed cell volume rises, and the dialysis system can clot if heparinisation is not optimal. On current information, correcting anaemia in adults not yet on dialysis does not speed up the progression of renal insufficiency.

Surgery Patients

In autologous predonation programmes, all the programme’s special warnings, especially routine volume replacement, must be respected. Before major elective orthopaedic surgery, good blood management practice should always be used and adequate antithrombotic prophylaxis given, since thrombotic and vascular events may occur in surgical patients, especially those with underlying cardiovascular disease; take special care in patients prone to deep vein thrombosis. Epoetin zeta should not be used if baseline haemoglobin is above 13 g/dL, as an increased risk of postoperative thrombotic or vascular events cannot be excluded.

Pregnancy, Breastfeeding and Fertility

• Pregnancy: there are no or limited data in pregnant women, and animal studies showed reproductive toxicity. Use only if the potential benefit outweighs the potential risk to the foetus. It is not recommended in pregnant surgical patients in an autologous predonation programme.
• Breastfeeding: it is unknown whether epoetin zeta passes into human milk. Use with caution; a decision must be made whether to stop breastfeeding or to stop or withhold treatment, weighing the benefit of breastfeeding for the child against the benefit of therapy for the woman. It is not recommended in breastfeeding surgical patients in an autologous predonation programme.
• Fertility: no studies have assessed any effect on male or female fertility.

Excipients

Each dosage unit contains up to 0.5 mg phenylalanine, which may be harmful in phenylketonuria (PKU), a rare genetic disorder in which phenylalanine builds up because the body cannot remove it properly. It also contains less than 1 mmol (23 mg) sodium per dosage unit, that is, it is essentially sodium-free.

Effect on Driving

No studies on the effects on the ability to drive and use machines have been performed.

Store in a refrigerator at 2 °C to 8 °C, and keep this range closely maintained until the dose is given to the patient, so the cold chain must be unbroken from dispatch to administration. Do not freeze or shake. Keep the pre-filled syringe in the outer carton to protect it from light.

For ambulatory use, the product may be taken out of the refrigerator, without being put back, for a maximum of 3 days at a temperature not above 25 °C. If it has not been used by the end of that period, it must be disposed of.

30 months when stored refrigerated as above. Do not use after the expiry date.

Prescription only (Rx), under restricted medical prescription (Annex II B of the marketing authorisation). Treatment is started under the supervision of a physician experienced in managing the conditions listed under Indications. Epoetin zeta is given in hospitals and dialysis units, and by subcutaneous self-injection where the physician judges that the patient or a caregiver can do so safely. It is therefore supplied as pre-filled syringes on prescription to the hospital, dialysis unit or clinic that administers it, or to the patient or treating clinic, with cold-chain delivery at 2–8 °C. See the SmPC for pack sizes.