EPREX®
REGISTRATION NUMBERS
|
Pre-filled syringes |
Single-dose vials |
29/30.4/0769
29/30.4/0770
W/30.4/221 |
W/30.4/219
W/30.4/220
W/30.4/221 |
PROPRIETARY NAME
(and dosage form)
EPREX®
|
Pre-filled syringes |
Single-dose vials |
EPREX 2 000/0,5 mL
EPREX 4 000/0,4 mL
EPREX 10 000 |
EPREX 2 000
EPREX 4 000
EPREX 10 000 |
DESCRIPTIVE NAME OF THE MEDICINE
Recombinant human erythropoietin, most common abbreviation: r-HuEPO.
PHARMACOLOGICAL CLASSIFICATION
A.30.4 Biologicals - Other.
SCHEDULING STATUS
Schedule 4.
COMPOSITION
r-HuEPO is a sterile phosphate-buffered solution for parenteral administration available in vials and pre-filled syringes.
PRE-FILLED
SYRINGE
COMPONENTS |
CONCENTRATION PER PRE-FILLEDSYRINGE |
|
Active ingredient |
2000 IU/0,5 mL |
4000 IU/0,4 mL |
10 000 IU/1 mL |
|
r-HuEPO |
16,8 micrograms/0,5 mL |
33,6 micrograms/0,4 mL |
84 micrograms/1,0 mL |
|
Inactives: Sodium chloride, sodium phosphate (monobasic dihydrate and dibasic dehydrate), polysorbate 80, glycine (stabiliser) and water for injection. Contains no preservatives |
SINGLE-DOSE
VIAL
COMPONENTS |
CONCENTRATION PER SINGLE-DOSE VIAL |
|
Active ingredient |
2 000 IU/1,0 mL |
4 000 IU/1,0 mL |
10 000 IU/1,0 mL |
|
r-HuEPO |
16,8 micrograms /1,0 mL |
33,6 micrograms /1,0 mL |
84 micrograms./1,0 mL |
|
Inactives: Sodium chloride, sodium phosphate (monobasic dihydrate and dibasic dehydrate), polysorbate 80, glycine (stabiliser) and water for injection. Contains no preservatives |
IDENTIFICATION
A clear, colourless solution, free from visible foreign material.
PHARMACOLOGICAL ACTION OF THE MEDICINE
Erythropoietin (EPO) is a sialylglycoprotein hormone which is the primary regulator of red blood cell formation in mammals. Recombinant human erythropoietin (r-HuEPO) is a purified glycoprotein which stimulates erythropoiesis. It is produced from mammalian cells into which the gene coding for human erythropoietin has been inserted. r-HuEPO is indistinguishable from human urinary erythropoietin by biological activity and immunological reactivity. r-HuEPO has a molecular mass of about 30 000 daltons. The protein moiety, a single chain polypeptide with 165 amino acids, has a sequence molecular mass of 18 244 daltons. The carbohydrate moiety with three N-linked and one 0-linked carbohydrate groups corresponds to a mass fraction of approximately 40%.
Pharmacokinetics:
Intravenous route
Measurement of the r-HuEPO following multiple dose intravenous administration revealed a half-life of approximately 4 hours in normal healthy volunteers and a more prolonged half-life in renal failure patients, approximately 5 hours.
Subcutaneous route
Following subcutaneous injection, serum levels are much lower than those achieved following intravenous injection, the levels increase slowly and reach a peak between 12 and 18 hours post-dose. The peak is always well below that achieved using the intravenous route.
There is no accumulation. The half-life is difficult to eva luate for the subcutaneous route and is estimated to be about 24 hours. The bioavailability of subcutaneous injectable erythropoietin is much lower than that of the intravenously administered EPREX i.e. approximately 20%.
INDICATIONS
EPREX is indicated for the following:
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• |
Symptomatic or transfusion requiring anaemia associated with chronic renal failure. |
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Anaemia in patients with cancer (non-myeloid malignancies) where anaemia is due to the effect of concomitantly administered chemotherapy. EPREX is indicated to decrease the need for transfusions in patients who will be receiving concomitant chemotherapy for a minimum of two months. EPREX is not indicated for the treatment of anaemia in cancer patients due to other factors such as iron folate deficiencies, haemolysis or gastro-intestinal bleeding which should be managed appropriately. |
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To increase the yield of autologous blood from patients in a predonation programme initiated to reduce the risk of exposure to homologous blood transfusions. Treatment is indicated in patients with moderate anaemia (PCV approximately 33 to 39%, and no iron deficiency) if blood conserving procedures are not available or insufficient either:
a) When the scheduled major elective surgery requires a large volume of blood (4 or more units blood for females or 5 or more units for males) or
b) When the period necessary to obtain the required volume of autologous blood is too short. |
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• |
To increase red cell production and hasten erythroid recovery in adult patients with a haemoglobin (Hb) >10 g/dL to <13 g/dL scheduled for elective surgery and not participating in an autologous predonation programme. |
CONTRA-INDICATIONS
Safety in pregnancy and lactation has not been established. Safety and efficacy in children have not been established.
r-HuEPO is contra-indicated in patients with:
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uncontrolled hypertension. |
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known hypersensitivity to mammalian-cell derived products. |
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known hypersensitivity to any of the components of this product. |
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myeloid malignancies. |
The use of EPREX in patients scheduled for elective surgery and not participating in an autologous blood pre-donation program is contra-indicated in patients with severe coronary, peripheral arterial, carotid, or cerebral vascular disease, including patients with recent myocardial infarction or cerebral vascular accident.
DOSAGE AND DIRECTIONS FOR USE
• Chronic renal failure patients:
In patients with chronic renal failure, EPREX should only be administered by the intravenous route - with subcutaneous use there is a significant risk of Pure Red Cell Aplasia. (see Side-effects and Special Precautions - Pure Red Cell Aplasia (PRCA).
Intravenous
The recommended starting dose of r-HuEPO is 50 IU/kg, three times per week, administered as an intravenous injection over 1-2 minutes. Further dose increments should depend upon the initial haemoglobin response (proposed rate <2 g/dL per month). If required, dose increments in steps of 25 IU/kg in intervals of four weeks are recommended.
If the rate of haemoglobin rise exceeds 2 g/dL per month at 50 IU/kg, three times per week, downward dosage adjustments should be made by omitting one of the weekly doses. When an Hb level of 10-12 g/dL (HCT 30-35%) has been achieved, the dose should be titrated to maintain the haemoglobin within the target range. Clinical experience suggests that the maintenance dose is from one-half to two thirds of the dose that was administered at the time of attainment of the target haemoglobin. The optimal level of Hb is left to the discretion of the physician, however 10-12 g/dL has been shown to be well tolerated. Available data indicate that patients starting treatment at very low Hb levels (<6 g/dL) may require higher maintenance dosages than those starting; therapy with Hb above 8 g/dL; the latter group of patients may need weekly doses as low as 100 IU/kg.
In patients with chronic renal failure and clinically evident ischaemic heart disease or congestive cardiac failure, the maintenance haemoglobin concentration should not exceed 10-12 g/dL as higher mortality and an increase in vascular access shunt thrombosis were noted in the higher haematocrit (42 +3%) target population in a clinical study comparing the effects of two haematocrit target levels (42 +3%) and (30 +3%) on morbidity and mortality. The mechanism accounting for the observed higher mortality in association with the higher haematocrit level appears to be unrelated to the higher haematocrit per se.
Iron status should be eva luated for all patients prior to and during treatment. Iron supplementation should be administered if necessary. A reduced response may be observed in patients with aluminium intoxication or infection.
Correction phase
The initial dosage is 50 IU/kg three times per week. If haemoglobin does not increase by 1 g/dL after 1 month of treatment, the dosage may be raised after 1 month to 75 IU/kg body weight - three times per week - and if further increments are needed they should be at 25 IU/kg body weight, three times per week, at monthly intervals, to achieve a packed cell volume between 30 and 35 vol. %. The maximum dosage should not exceed 240 IU/kg body weight three times per week.
Maintenance phase
The dose has to be adjusted individually to maintain a packed cell volume of between 30-35 vol. %.
The maintenance dose is approximately half the dose administered in the correction phase.
When changing from one route of administration to the other the same dose should be used, and the haemoglobin should be monitored carefully (e.g. weekly) so that appropriate changes in EPREX dose can be made to keep the haemoglobin within the target range.
• Cancer patients:
The recommended starting dose of r-HuEPO is 150 IU/kg subcutaneously three times per week.
Treatment may be administered for up to 3 months, beyond which no current data is available.
Dose adjustment
The haematocrit should be monitored on a weekly basis during the dose adjustment phase of r-HuEPO therapy. If the haematocrit exceeds 40%, the dose of r-HuEPO should be withheld until the haematocrit falls to 36%. The dose of r-HuEPO should be reduced by 25% when treatment is resumed and titrated to maintain the desired haematocrit. If the initial dose of r-HuEPO includes a very rapid haematocrit response (e.g. an increase of more than 4 percentage points in any 2 week period), the dose of r-HuEPO should be reduced.
There is no reported data on the use of EPREX in doses in excess of 150 IU/kg three times per week which would allow recommendations for dose escalation in non-responding patients.
• Adult surgery patients in an autologous pre-donation programme:
The intravenous route of administration should be used.
Mildly anaemic patients (haematocrit of 33-39%) requiring predeposit of >4 units of blood should be treated with EPREX at 150 to 600 IU/kg two times weekly for three weeks prior to surgery.
All patients being treated with EPREX should receive adequate iron supplementation (e.g. 200 mg oral elemental iron daily) throughout the course of EPREX treatment.
Iron supplementation should be started as soon as possible, even several weeks prior to initiating the autologous predeposit, in order to achieve high iron stores prior to starting therapy with EPREX.
• Adult elective surgery patients not participating in an autologous predonation programme:
The subcutaneous route of administration should be used.
The recommended dosage regimen is 600 IU/kg EPREX given weekly for three weeks (Days -21, -14, and -7) prior to surgery and on the day of surgery. In cases where there is a medical need to shorten the lead time before surgery to less than three weeks, 300 IU/kg EPREX should be given for 10 consecutive days prior to surgery, on the day of surgery, and for four days immediately thereafter.
The administration of EPREX should be stopped as soon as the haemoglobin level reaches 15 g/dL in the preoperative period, even if not all the planned EPREX doses have been given.
All patients being treated with EPREX should receive adequate iron supplementation (e.g. 200 mg oral elemental iron daily) throughout the course of EPREX treatment. If possible, iron supplementation should start prior to EPREX therapy, to achieve adequate iron stores.
Administration Instructions:
General:
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Parenteral drug products should be visually inspected for particulate matter and discolouration prior to administration. |
For vial presentations:
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Prepare r-HuEPO for intravenous/subcutaneous injection by drawing solution into a syringe from the vial. Attach needle for intravenous/subcutaneous injection. |
For vial and pre-filled syringe presentations:
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Administer as intravenous injection over 1-2 minutes. In patients on dialysis, the injection should follow the dialysis procedure. Slow injection over 5 minutes may be beneficial to those who experience flu-like symptoms. |
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Do not administer by intravenous infusion or in conjunction with other drug solutions. |
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For the subcutaneous route a maximum of 1 mL at one injection site should generally not be exceeded. In the case of larger volumes, more than one site should be chosen for the injection. |
SIDE-EFFECTS AND SPECIAL PRECAUTIONS
Side-effects:
Particular care should be taken during the initial months of therapy. The following adverse events have been observed:
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Increased blood pressure and hypertensive encephalopathy. |
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Thrombosis of vascular access sites, e.g. fistula. |
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Flu-like symptoms, bone pain and chills following injections. |
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Seizures. |
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Allergic skin reactions, including palpebral oedema, possibly allergic in nature. |
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Headache. |
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Pain or discomfort at the subcutaneous injection site may occur. |
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As a growth factor, the possibility that r-HuEPO may potentiate growth of some tumours, particularly myeloid tumours, cannot be excluded. |
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Pure Red Cell Aplasia (erythroblastopenia) has been reported in chronic renal failure patients especially with subcutaneous administration (Refer to section " Special Precautions for Use"). |
Cancer Patients:
Thrombotic vascular events can occur in cancer patients as a consequence of their disease, comorbidities, and treatment thereof. An increased incidence of such events has been observed in patients receiving erythropoietic agents, including patients receiving EPREX.
Surgery patients in autologous pre-donation programs:
Independent of EPREX treatment, routine volume replacements should be performed in surgical patients with underlying cardiovascular disease following phlebotomy, as thrombotic and vascular events may occur.
Elective surgery patients not participating in an autologous predonation programme:
Patients scheduled for elective surgery should receive adequate antithrombotic prophylaxis as appropriate for the surgical procedure.
Special precautions for use:
|
r-HuEPO should be used with caution in those patients with controlled hypertension, ischaemic vascular disease, history of seizures, or suspected allergy to the product. |
In patients with chronic renal failure and clinically evident ischaemic heart disease or congestive cardiac failure, the maintenance haemoglobin concentration should not exceed 10-12 g/dL. Refer to "Dosage and Directions for Use."
Iron eva luation: Prior to and during EPREX therapy, the patient's iron stores, including transferrin saturation (serum iron divided by iron binding capacity) and serum ferritin, should be eva luated. Transferrin saturation should be at least 20%, and ferritin should be at least 100 ng/mL. Supplemental iron may be required to increase and maintain transferrin saturation to levels that will adequately support EPREX-stimulated erythropoiesis.
Delayed or diminished response: If the patient fails to respond or to maintain a response, the following aetiologies should be considered and eva luated:
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1) |
Iron deficiency: functional iron deficiency may develop with normal ferritin levels but low transferrin saturation (less than 20%), presumably due to the inability to mobilize iron stores rapidly enough to support increased erythropoiesis. Virtually all patients will eventually require supplemental iron therapy. |
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2) |
Underlying infectious or inflammatory processes. |
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3) |
Occult blood loss. |
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4) |
Underlying haematologic diseases (i.e. thalassaemia, refractory anaemia, or other myelodysplastic disorders). |
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5) |
Vitamin deficiencies: folic acid or vitamin B12. |
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6) |
Haemolysis. |
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7) |
Aluminium intoxication. |
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8) |
Osteitis fibrosa cystica. |
The parenteral administration of any biologic product should be attended by appropriate precautions in case allergic or other untoward reactions occur (see "Contra-indications"). While transient rashes have occasionally been observed concurrently with EPREX therapy, no serious allergic or anaphylactic reactions have been reported.
The safety and efficacy of EPREX therapy have not been established in patients with a known history of a seizure disorder or underlying haematologic disease (e.g. sickle cell anaemia, myelodysplastic syndromes, or hypercoagulable disorders).
In some female patients, menses have resumed following EPREX therapy; the possibility of potential pregnancy should be discussed and the need for contraception eva luated.
EPREX should be used with caution in patients with known porphyria.
Pure Red Cell Aplasia (erythroblastopenia) has been reported in chronic renal failure patients with EPREX. In most of these patients, antibodies to erythropoietins have been observed. As the PRCA cases are mainly associated with the subcutaneous route of administration, EPREX should only be administered to chronic renal failure patients by the intravenous route. In patients developing sudden lack of efficacy, typical causes of non-response (e.g. iron, folate or Vitamin B12 deficiency, aluminium intoxication, infection or inflammation, blood loss, and haemolysis) should be investigated. If no cause is identified, a bone marrow examination should be considered. If PRCA is diagnosed, therapy with EPREX must be immediately discontinued and testing for erythropoietin antibodies should be considered. Patients should not be switched to another product as anti-erythropoietin antibodies cross-react with other erythropoietins. Other causes of PRCA should be excluded and appropriate therapy instituted.
Patients should be closely monitored for changes in haemoglobin, blood pressure and serum electrolytes, because preliminary evidence suggests that hypertensive episodes (in some cases associated with hypertensive encephalopathy and seizures) are most likely to occur in patients experiencing a rapid Hb response. An increase of Hb of less than 2 g/dL per month is recommended.
If blood pressure begins to increase, or is accompanied by headache, more aggressive antihypertensive treatment should be used. In cases where the rise in blood pressure is difficult to control, the patients should be admitted to the hospital or clinic for observation until their BP is adequately controlled.
In chronic renal failure patients, correction of anaemia may lead to increased appetite and increased potassium intake. If hyperkalaemia occurs in patients on dialysis, diet and dialysis prescription should be appropriately modified. Increase in pre-dialysis urea and creatinine may occur in individual patients as a result of increased protein intake, in which case dialysis regimen modification may be necessary. The haemodialysis patients should be monitored for evidence of increased clotting, and if present, an increase in dialysis heparin may be required.
Special warnings:
If hypertension develops, fluid overload should be appropriately treated if present. In the absence of fluid overload, therapy with peripheral dilators is preferred. In extreme situations, phlebotomy may be considered in individual patients, especially if the Hb is above 12g/dL or has risen in excess of 2 g/dL/month. If an episode of acute hypertension occurs with or without encephalopathy, r-HuEPO should be stopped (Hb concentration will subsequently decrease by approximately 0,5 g/dL weekly).
In seizures EEG and CT-scan are considered useful to rule out other causes of seizures and may be performed and repeated as necessary. r-HuEPO should be reintroduced only with close monitoring of Hb and blood pressure until the Hb is stabilised in the range of 10-12 g/dL.
Interactions:
There are no known clinically significant interactions, but the effect of r-HuEPO may be potentiated by the simultaneous therapeutic administration of a haematinic agent such as ferrous sulphate when a deficiency state exists.
KNOWN SYMPTOMS OF OVERDOSAGE AND PARTICULARS OF TREATMENT
Response to r-HuEPO is dose related and individualised. Therapeutic response to excessive doses may lead to hypertension. Phlebotomy may be performed if excessively high haemoglobin levels occur, see "Special Warnings".
Treatment is symptomatic and supportive.
PRESENTATION:
Packs of one or six 1 mL single dose vials.
Packs of six 0,4; 0,5 or 1 mL pre-filled syringes.
STORAGE INSTRUCTIONS:
STORE AT 2 TO 8°C. DO NOT FREEZE OR SHAKE. PROTECT FROM LIGHT.
KEEP OUT OF REACH OF CHILDREN. |
