Data Sheet
EPREX®
Epoetin alfa (rch) intravenous and subcutaneous injection
Most common abbreviation: r-HuEPO. Its CAS Registry Number is 113427-24-0.
Presentation
EPREX® is a sterile, preservative-free buffered protein solution of epoetin alfa (rch) in pre-filled syringes of 1,000 IU in 0.5 mL, 2,000 IU in 0.5 mL, 3,000 IU in 0.3 mL, 4,000 IU in 0.4 mL, 5,000 IU in 0.5 mL, 6,000 IU in 0.6 mL, and 10,000 IU in 1.0 mL. The formulation is stabilised with glycine (5 mg/mL) and polysorbate 80 (0.30 mg/mL). The pre-filled syringes are fitted with the PROTECS™ needle guard device. All formulations also contain sodium chloride at 1.7 - 5.8 mg, sodium phosphate - monobasic dihydrate at 0.35 - 1.16 mg, sodium phosphate - dibasic dihydrate at 0.67 - 2.22 mg and sodium citrate at less than 5 mmol.
Uses
Actions
Erythropoietin is an endogenous glycoprotein that stimulates red blood cell production. Epoetin alfa (rch) is purified from a Chinese hamster ovary cell line into which the gene coding for human erythropoietin has been inserted. The molecular weight is about 30,400 daltons and the protein moiety, a single chain polypeptide of 165 amino acids, has a molecular weight of 18,244 daltons. The carbohydrate moiety with three N-linked and one 0-linked carbohydrate groups corresponds to a weight fraction of approximately 40%. Epoetin alfa (rch) is indistinguishable from human erythropoietin in biological activity and immunological reactivity.
Pharmacokinetics
Erythropoietin stimulates erythropoiesis in anaemic patients with chronic renal failure in whom the endogenous production of erythropoietin is impaired. Because of the length of time required for erythropoiesis - several days for erythroid progenitors to mature and be released into the circulation - a clinically significant increase in haemoglobin is usually not observed in less than two weeks and may require up to ten weeks in some patients.
Measurement of Epoetin alfa (rch) following intravenous administration showed 10% excretion by the kidneys with the major routes of elimination not determined. After intravenous administration the mean half lives in normal volunteers ranged from 4.0 to 6.1 hours and in patients with chronic renal failure from 6.5 to 9.3 hours. Following subcutaneous injection, serum levels are much lower than the levels achieved following IV injection; the levels increase slowly and reach a peak between 12 and 18 hours post-dose. The peak is always well below the peak achieved using the IV route (approximately 1/20th of the value). Following subcutaneous injection, erythropoietin serum levels remain elevated above baseline for about 72 hours. There is no accumulation when thrice weekly dosing is used: the levels remain the same, whether they are determined 24 hours after the first injection or 24 hours after the last injection. The half-life is difficult to evaluate for the subcutaneous route and is estimated about 24 hours. The bioavailability of subcutaneous injectable erythropoietin is much lower than that of the intravenous drug: approximately 20-30%. No information is available in the young and in the elderly. Due to decreased metabolism patients with hepatic dysfunction may have increased erythropoiesis with EPREX.
Indications
EPREX is indicated for:
- The treatment of severe anaemia of renal origin accompanied by clinical symptoms in patients with renal insufficiency not yet undergoing dialysis.
- Anaemia associated with chronic renal failure in paediatric and adult patients on dialysis.
- Anaemia in patients with non-myeloid malignancies where anaemia is due to the effect of concomitantly administered chemotherapy.
- Adult patients with mild-to-moderate anaemia (haemoglobin > 100 to < 130g/L) scheduled for elective surgery with an expected moderate blood loss (2-4 units or 900 to 1800mL) to reduce exposure to allogeneic blood transfusion and to facilitate erythropoietic recovery.
- To augment autologous blood collection and to limit the decline in haemoglobin in anaemic adult patients undergoing major surgery who are not expected to pre-deposit their complete peri-operative blood needs.
Dosage and Administration
During therapy, haematological parameters should be monitored regularly. Doses must be individualised to ensure that haemoglobin is maintained at an appropriate level for each patient.
As a single anaphylactic reaction was observed in one patient during the course of clinical testing, it is recommended that the first dose be administered under medical supervision.
For treatment of anaemia associated with renal insufficiency or chronic renal failure:
In patients with chronic renal failure, where intravenous access is routinely available (haemodialysis patients) administration of EPREX by the intravenous route is preferable. Where intravenous access is not readily available (patient not yet on dialysis and peritoneal dialysis patients) EPREX may be administered subcutaneously.
In patients maintained on haemodialysis, EPREX should always be administered after completion of dialysis.
Adults:
The recommended starting dose of epoetin alfa (rch) is 50 IU/kg, three times per week, administered as i.v. or s.c. injection over 1-2 minutes. Further dose increments should depend upon the initial response (proposed rate <20 g/L per month). Because of the length of time required for erythropoiesis - several days for erythroid progenitors to mature and be released into the circulation - a clinically significant increase in hematocrit is usually not observed in less than 2 weeks and may require up to 6 weeks in some patients.
If required, dose increments in steps of 25 IU/kg in intervals of four weeks are recommended. If the rate of haemoglobin rise exceeds 20 g/L per month at 50 IU/kg, three times per week, downward dosage adjustments should be made in the amount administered in each dose and by omitting one of the weekly doses. Similar downward dose adjustments should be made if the Hb level exceeds 120 g/L. Maximum dose should generally not exceed 200 IU/kg three times per week.
When a target haemoglobin concentration of 100-120 g/L (95 to 110g/L in paediatric patients) has been achieved, the total maintenance weekly dose (average 100-300 IU/kg) can be apportioned in two or three injections.
In patients with chronic renal failure, maintenance haemoglobin concentration should not exceed the upper limit of the target haemoglobin concentration.
Available data indicate that patients starting treatment at very low Hb levels (<60g/L) may require higher maintenance dosages than those starting therapy with Hb above 80 g/L; the latter group of patients may need weekly doses as low as 100 IU/kg.
Iron status should be evaluated for all patients prior to and during treatment and iron supplementation administered if necessary. Other causes of anaemia (such as Vitamin B12 or folate deficiency) should be excluded before starting therapy with epoetin alfa. Non-response to epoetin alfa should prompt a search for causative factors. These include: iron, folate, or vitamin B12 deficiency; aluminium intoxication; intercurrent infections, inflammatory or traumatic episodes; occult blood loss; haemolysis; and bone marrow fibrosis of any origin.
Children:
For paediatric haemodialysis patients:
The treatment is divided into 2 stages:
Correction phase
50 IU/kg/3 times per week by the intravenous route. When a dose adjustment is necessary, this should be done in steps of 25 IU/kg/3 times per week at intervals of at least 4 weeks until the desired goal is achieved.
Maintenance phase:
Generally, children under 30 kg require higher maintenance doses than children over 30 kg and adults. For example, the following maintenance doses were observed in clinical trials after 6 months of treatment.
| Weight (kg) | Median | Dose (IU/kg given 3 x / week) Usual maintenance dose |
|---|---|---|
| <10 | 100 | 75 - 150 |
| 10 - 30 | 75 | 60 - 150 |
| > 30 | 33 | 30 - 100 |
The clinical data available suggest that those patients whose initial haemoglobin is very low (<6.8 g/dL) may require higher maintenance doses than those whose initial anaemia is less severe (>6.8 g/dL).
Method of Administration
- Parenteral medicine products should be visually inspected for particulate matter and discoloration prior to administration. Product exhibiting particulate matter or discolouration must not be used. Do not shake, shaking may denature the glycoprotein, rendering it inactive.
- Epoetin alfa in single use syringes contains no preservatives. Do not re-use syringe. Discard unused portion.
- Prepare EPREX for injection from the prefilled syringe.
- Administer as i.v. or s.c. 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. For subcutaneous dosing a maximum volume of 1mL at any one injection site should not be exceeded. In the case of larger volumes the injection should be divided between more than one site.
Do not dilute or transfer to any other container. Do not administer by intravenous infusion or in conjunction with other medicine solutions.
The pre-filled syringes are fitted with the PROTECS™ needle guard device to help prevent needle stick injuries after use. The EPREX Consumer Medicine Information includes full instructions for the use and handling of pre-filled syringes.
For treatment of anaemia associated with non-myeloid malignancies:
Adults
The target haemoglobin concentration should be up to 120 g/L in men and women and it should not be exceeded.
Starting dose:
The recommended starting dose of EPREX is 150 IU/kg as a subcutaneous injection three times per week for 4 weeks.
Increase dose:
If the haemoglobin has increased by at least 10 g/L (0.62 mmol/L) or the reticulocyte count has increased ≥ 40,000 cells/microlitre above baseline after 4 weeks of treatment, the dose should remain at 150 IU/kg. If the haemoglobin increase is < 10 g/L (< 0.62 mmol/L) and the reticulocyte count has increased < 40,000 cells/microlitre above baseline, increase the dose to 300 IU/kg.
If after an additional 4 weeks of therapy at 300 IU/kg, the haemoglobin has increased ≥ 10 g/L (≥ 0.62 mmol/L) or the reticulocyte count has increased ≥ 40,000 cells/microlitre the dose should remain at 300 IU/kg. However, if the haemoglobin has increased < 10 g/L (< 0.62 mmol/L) and the reticulocyte count has increased < 40,000 cells/microlitre above baseline, response is unlikely and treatment should be discontinued.
A rate of rise in haemoglobin of greater than 10g/L per 2 week or 20g/L per month, or haemoglobin levels of >120g/L should be avoided. If the haemoglobin is rising by more than 10 g/L per two week or 20g/L per month, or haemoglobin is approaching 120g/L, reduce the Epoetin Alfa dose by about 25-50% depending on the rate of rise of haemoglobin. If the haemoglobin exceeds 120g/L, withhold therapy until it falls below 120g/L and then reinitiate Epoetin Alfa at a dose 25% below the previous dose.
Adult patients scheduled for elective surgery:
The subcutaneous route of administration should be used.
The recommended dose 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 daily 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 150 g/L in the pre-operative period, even if not all the planned EPREX doses have been given.
All patients being treated with EPREX should receive adequate iron supplementation (eg 200mg oral elemental iron daily) throughout the course of EPREX treatment. If possible, iron supplementation should be started prior to EPREX therapy, to achieve adequate iron stores.
Anaemic adult surgery patients in an Autologous Pre-donation Programme (ABD)
The intravenous route should be used. The recommended dose is 300 - 600 IU/kg twice weekly for three weeks, together with at least 200 mg oral elemental iron daily.
Contraindications
EPREX is contraindicated in patients with uncontrolled hypertension, known sensitivity to mammalian cell derived products, and/or hypersensitivity to any component of the product. Patients who develop Pure Red Cell Aplasia (PRCA) following treatment with any erythropoietin product should not receive EPREX or any other erythropoietin.
The use of EPREX in patients scheduled for elective surgery (and who are not participating in an autologous blood pre deposit programme), is contraindicated in patients with severe coronary, peripheral arterial, carotid, or cerebral vascular disease, including patients with recent myocardial infarction or cerebral vascular accident.
Surgery patients who for any reason cannot receive adequate antithrombotic prophylaxis or treatment.
Precautions
Cardiovascular and Thrombotic Events / Increased Mortality
Cardiovascular and thrombotic events such as myocardial ischaemia and infarction, cerebrovascular haemorrhage and infarction, transient ischaemic attacks, deep venous thrombosis, arterial thrombosis, pulmonary emboli, retinal thrombosis and haemodialysis graft occlusion have been reported in patients receiving erythropoiesis stimulating agents such as EPREX.
EPREX and other erythropoiesis-stimulating agents increased the risk for death and for serious cardiovascular events in controlled clinical trials when administered to target a haemoglobin of greater than 120 g/L. There was an increased risk of serious arterial and venous thromboembolic events, including myocardial infarction, stroke, congestive heart failure and haemodialysis graft occlusion. A rate of haemoglobin rise of greater than 10 g/L over 2 weeks may also contribute to these risks.
In all patients, haemoglobin levels should be closely monitored due to a potential increased risk of thromboembolic events and fatal outcomes when patients are treated at haemoglobin levels above the target for the indication of use.
Growth Factor Potential / Increased Tumour Progression
Epoetin alfa is a growth factor that primarily stimulates red blood cell production. Like all growth factors there is a theoretical concern that epoetin alfa could act as a growth factor for any tumour type, particularly myeloid malignancies. Erythropoiesis-stimulating agents (ESAs), when administered to target a haemoglobin of greater than 120 g/L, shortened the time to tumour progression in patients with advanced head and neck cancer receiving radiation therapy. ESAs also shortened survival in patients with metastatic breast cancer receiving chemotherapy when administered to a target haemoglobin greater than 120 g/L.
Use in Cancer Patients
A study comparing another erythropoiesis-stimulating agent with placebo in patients with anaemia of cancer who were not being treated with chemotherapy demonstrated no benefit in terms of reduced transfusion requirements. In addition, there were an increased number of deaths in the active group (26% vs 20%). EPREX should only be used to treat cancer patients with anaemia where the anaemia has arisen as a result of concomitantly administered chemotherapy. The target haemoglobin should be up to 120 g/L in men and women and it should not be exceeded.
An investigational study in women with metastatic breast cancer intended to determine whether erythropoietin treatment that extended beyond the correction of anaemia could improve treatment outcomes. However, in that study overall mortality, mortality attributed to disease progression, and incidence of fatal thromboembolic events were all higher in patients receiving Epoetin alfa than in those receiving placebo.
Hypertension
Patients with uncontrolled hypertension should not be treated with EPREX; blood pressure should be controlled adequately before initiation of therapy. Blood pressure may rise during treatment of anaemia with EPREX. Hypertensive encephalopathy and seizures have been observed.
Special care should be taken to closely monitor and control blood pressure in patients treated with EPREX. During EPREX therapy, patients should be advised of the importance of compliance with antihypertensive therapy and dietary restrictions. If blood pressure is difficult to control after initiation of appropriate measures, the dose of EPREX should be reduced or temporarily withheld until haemoglobin begins to decrease (see DOSAGE AND ADMINISTRATION).
Pure Red Cell Aplasia
In chronic renal failure patients, antibody-mediated pure red cell aplasia (PRCA) (erythroblastopaenia) has been rarely reported after months to years of treatment with erythropoietins. Cases also have been rarely reported in patients with hepatitis C treated with interferon and ribavirin, when ESAs are used concomitantly. ESAs are not approved in the management of anaemia associated with hepatitis C.
In most of these PRCA patients antibodies to erythropoietins have been reported. In patients developing sudden lack of efficacy typical causes of non-response should be investigated. If no cause is identified, a bone marrow examination should be considered.
If pure red cell aplasia (PRCA) is diagnosed, EPREX must be immediately discontinued and testing for erythropoietin antibodies should be considered. If antibodies to erythropoietin are detected patients should not be switched to another ESA product as anti-erythropoietin antibodies cross-react with other ESAs. Other causes of pure red cell aplasia should be excluded, and appropriate therapy instituted.
Seizures
Seizures have occurred in patients with CRF receiving EPREX with a frequency of from 3 to 7%, usually during the first 90 days of treatment. Blood pressure and premonitory neurological symptoms should be closely monitored. Patients should be cautioned to avoid potentially hazardous activities such as driving or operating heavy machinery during this period.
General
EPREX should be used with caution in those patients with pre-existing hypertension, ischaemic vascular disease, history of seizures, in the presence of epilepsy and chronic liver failure, or suspected allergy to any components of the product, porphyria or gout.
The safety and effectiveness of epoetin alfa has not been established in patients with underlying haematologic diseases (e.g. haemolytic anaemia, sickle cell disease, thalassemia, porphyria).
Erythropoiesis-stimulating agents (ESAs) are not necessarily equivalent. Therefore, it should be emphasised that patients should only be switched from one ESA (such as EPREX) to another ESA with the authorisation of the treating physician.
There may be a moderate dose-dependent rise in the platelet count, within the normal range, during treatment with Epoetin alfa. This regresses during the course of continued therapy. In addition, thrombocythaemia above the normal range has been reported. It is recommended that the platelet count should be regularly monitored during the first 8 weeks of therapy.
Rarely, exacerbation of porphyria has been observed in Epoetin alfa-treated patients with chronic renal failure. EPREX has not caused increased urinary excretion of porphyrin metabolites in normal volunteers, even in the presence of a rapid erythropoietic response. Nevertheless, EPREX should be used with caution in patients with known porphyria.
Increased serum uric acid may occur in patients whose haemoglobin is rising more than approximately 20 g/L per month. Consequently EPREX should be used with caution in patients with a history of gout.
The safety and dosage regime of EPREX has not been established in the presence of hepatic dysfunction. Due to decreased metabolism, patients with hepatic dysfunction may have increased erythropoiesis with EPREX.
Renal dialysis
Correction of anaemia with EPREX does not appear to affect dialysis efficiency. However, anincrease in appetite could lead to increased potassium intake and hyperkalaemia in both dialysis and pre-dialysis patients. This and other alterations in serum chemistry should be managed by dietary alterations and modifications of the dialysis prescription, if appropriate.
Serum electrolytes should be monitored in chronic renal failure patients. If an elevated (or rising) serum potassium level is detected consideration should be given to ceasing epoetin alfa treatment until hyperkalaemia has been corrected.
In some pre-clinical toxicological studies in dogs and rats, but not in monkeys, epoetin alfa (rch) therapy was associated with subclinical bone marrow fibrosis. Bone marrow fibrosis is a known complication of chronic renal failure in humans and may be related to secondary hyperparathyroidism or unknown factors. The incidence of bone marrow fibrosis was not increased in a study of dialysis patients who were treated with EPREX for 12-19 months compared with the incidence of bone marrow fibrosis in a matched control group of dialysis patients who had not been treated with EPREX. In a 13-week study, dogs were treated subcutaneously or intravenously with 80, 240, or 520 IU/kg/day. The majority of dogs treated subcutaneously and 50% of dogs treated intravenously developed anaemia with or without bone marrow hypoplasia. The cause of these observations is unknown, however, no cases of paradoxical anaemia have been reported in haematologically normal humans treated with EPREX, making the significance of the findings in dogs unclear.
Use in Surgery
Potentially correctable anaemia should be investigated and appropriately treated before considering therapy with EPREX prior to elective surgery.
In patients with a baseline haemoglobin of >130 g/L (8.1 mmol/L), the possibility that EPREX treatment may be associated with an increased risk of postoperative thrombotic vascular events cannot be excluded. Therefore, it should not be used in patients with a baseline haemoglobin >130 g/L (8.1 mmol/L).
All special precautions associated with autologous pre-donation programmes, especially routine volume replacement, should be respected.
Use in Pregnancy
The drug is classed as Category B3. EPREX should be administered during pregnancy only if clearly needed. It is not known whether Epoetin alfa (rch) crosses the placenta or whether it can cause fetal harm when administered to a pregnant woman. Animal studies have shown no evidence of teratogenic activity in rats or rabbits at Epoetin alfa (rch) dosages up to 55 IU/kg/day administered intravenously. However, intravenous administration of Epoetin alfa (rch) at dose levels of 20-500 IU/kg/day in rats causes decreased fertility, increased pre-and post-implantation loss, decreased fetal weight and retardation of ossification.
In pregnant or lactating surgical patients participating in an autologous blood predonation programme, the use of EPREX is not recommended.
Use in Lactation
EPREX should be administered during lactation only if clearly needed. It is not known whether Epoetin alfa (rch) is excreted in breast milk or whether it can cause harm to the infant when administered to a lactating woman. Intravenous administration of the drug to lactating rats at 500 IU/kg/day causes retardation of growth and development of the offspring.
Use in Children
Efficacy: Clinical trials of EPREX in children supported the following effects - correction of anaemia; reduction or elimination of transfusion-requirements; improvement of the bleeding tendency in uraemia; increased weight and appetite; and the reduction of cytotoxic antibodies. Possible but not conclusive effects were an improvement in exercise capacity and short-term cardiovascular effects. Long-term cardiovascular effects, effects on growth rate, improved prospects for renal transplantation, and improved quality of life were unproved.
Safety: Incomplete information is available, particularly on the rate of change of haemoglobin and blood pressure.
Dose: Available data supports a dose of 25 IU/kg three times a week rather than 50 IU/kg three times a week.
Carcinogenesis, mutagenesis
Long-term carcinogenicity studies have not been carried out. There are conflicting reports in the literature regarding whether erythropoietins may play a role as tumour proliferators. These reports, based on in vitro findings from human tumour samples, are of uncertain significance in the clinical situation. In a standard series of assays for genotoxic potential, Epoetin alfa (rch) did not induce gene mutations or cause chromosomal damage.
Effect on Ability to Drive and Operate Machinery
Due to the increased risk of hypertension during the initial phase of EPREX treatment, patients with chronic renal failure should use caution when performing potentially hazardous activities, such as driving or operating machinery, until the optimal maintenance dose of EPREX has been established.
Adverse Effects
Clinical Trial Data
The most frequent adverse drug reaction during treatment with Epoetin alfa is a dose-dependent increase in blood pressure or aggravation of existing hypertension. Monitoring of the blood pressure should be performed, particularly at the start of therapy. Other common adverse drug reactions observed in clinical trials of Epoetin alfa are diarrhoea, nausea, headache, influenza-like illness, pyrexia, rash, and vomiting. Influenza-like illness including headaches, joint pains, myalgia, and pyrexia may occur especially at the start of treatment.
Serious adverse drug reactions include venous and arterial thromboses and embolism (including some with fatal outcomes), such as deep venous thrombosis, pulmonary emboli, arterial thrombosis, retinal thrombosis, and shunt thrombosis (including dialysis equipment). In a cumulative analysis of 10 double-blind, randomized, placebo-controlled trials in subjects with cancer receiving chemotherapy, deep venous thrombosis was reported in 2.1% and pulmonary embolism in 1.2% of the 1564 subjects exposed to Epoetin alfa, compared to 1.2% and 1.2%, respectively, of the 1207 subjects exposed to placebo. Additionally, cerebrovascular accidents (including cerebral infarction and cerebral haemorrhage) and transient ischaemic attacks have been reported in clinical trials of Epoetin alfa.
Hypersensitivity reactions, including cases of rash, urticaria, anaphylactic reaction, and angioneurotic oedema have been reported.
Hypertensive crisis with encephalopathy and seizures, requiring the immediate attention of a physician and intensive medical care, have occurred also during Epoetin alfa treatment in patients with previously normal or low blood pressure. Particular attention should be paid to sudden stabbing migraine-like headaches as a possible warning signal.
The overall safety profile of EPREX was evaluated in 142 subjects with chronic renal failure and in 765 subjects with cancer who participated in placebo-controlled, double-blind clinical registration trials. Adverse drug reactions reported by ≥ 0.2% of EPREX-treated subjects in these trials are shown in Table 1.
Table 1. Adverse Drug Reactions Reported by ≥ 0.2% of Subjects in Clinical Registration Trials with EPREX.
| System/Organ Class Adverse Drug Reaction |
EPREX Clinical Trial Data | |||
|---|---|---|---|---|
| CRF | Cancer | |||
| EPREX | Placebo | EPREX | Placebo | |
| N=96 | N=46 | N=488 | N=277 | |
| (%) | (%) | (%) | (%) | |
| Blood & Lymphatic System Disorders | ||||
| Thrombocythaemia | NR | NR | 0.2 | NR |
| Nervous System Disorders | ||||
| Cerebral Haemorrhage* | NR | NR | 0.41 | NR |
| Seizures | 2.1 | 2.2 | 0.2 | NR |
| Headache | 33 | 46 | 3.7 | 3.6 |
| Vascular Disorders | ||||
| Deep Vein Thrombosis* | NR | NR | 1.6 | 0.36 |
| Hypertension | 4.1 | NR | 2.5 | 1.1 |
| Gastrointestinal Disorders | ||||
| Nausea | 10.7 | 7.6 | 17 | 32 |
| Diarrhoea | 1 | NR | 5.7 | 4.4 |
| Vomiting | 2.1 | NR | 4.9 | 5.4 |
| Skin and Subcutaneous Tissue Disorders | ||||
| Rash | 1 | NR | 1.2 | 1.1 |
| Musculoskeletal, Connective Tissue, and Bone Disorders | ||||
| Arthralgia | 23 | 20 | 1.4 | 1.8 |
| Myalgia | NR | NR | 1 | 1.4 |
| General Disorders and Administration Site Conditions | ||||
| Influenza-Like Illness | 19 | 26 | 4.9 | 3.3 |
| Pyrexia | NR | NR | 12 | 11 |
| Injury, Poisoning, and Procedural Complications | ||||
| Shunt Thromboses (including dialysis equipment) | 1.1 | 2.2 | NA | NA |
KEY: NR=not reported; NA=not applicable.
*Including cases with a fatal outcome.
Additional adverse drug reactions with unknown incidence rates identified through other controlled and non-controlled clinical trials with Epoetin alfa are shown in Table 2.
Table 2. Additional Adverse Drug Reactions With Unknown Incidence Rate Identified in Other Clinical Trials of Epoetin alfa
| System/Organ Class Adverse Drug Reactionb |
|---|
| Immune System Disorders |
| Anaphylactic Reaction |
| Hypersensitivity |
| Nervous System Disorders |
| Cerebrovascular Accidenta |
| Hypertensive Encephalopathy |
| Transient Ischaemic Attacks |
| Eye Disorders |
| Retinal Thrombosis |
| Vascular Disorders |
| Hypertensive Crisis |
| Arterial Thrombosis |
| Respiratory, Thoracic, and Mediastinal Disorders |
| Pulmonary embolisma, |
| Skin and Subcutaneous Tissue Disorders |
| Urticaria |
| Angioneurotic Oedema |
| Congenital and Familial/Genetic Disorders |
| Porphyria |
| General Disorders and Administration Site Conditions |
| Drug Ineffective |
| Peripheral Oedema |
| Injection Site Reaction |
a Including cases with fatal outcomes.
b Venous and arterial thromboembolic events have been reported in patients receiving EPREX (See Section 4.8.1, Clinical Trial Data).Renal Failure Patients
In chronic renal failure patients, haemoglobin levels greater than 120 g/L may be associated with a higher risk of cardiovascular events, including death. (See Precautions).
Shunt thromboses have occurred in haemodialysis patients, especially in those who have a tendency to hypotension or whose arteriovenous fistulae exhibit complications.
Cancer Patients
An increased incidence of thromboembolic events has been reported in cancer patients receiving erythropoiesis-stimulating agents (ESAs), including Epoetin alfa (see Precautions).
Post-marketing data
Adverse drug reactions identified during the postmarketing experience with Epoetinum alfa are included in Table 3. In the table, the frequencies are provided according to the following convention:
Very common ≥1/10
Common ≥1/100 and < 1/10
Uncommon ≥1/1,000 and <1/100
Rare ≥1/10,000, <1/1,000
Very rare <1/10,000, including isolated reports
Antibody-mediated pure red cell aplasia has been very rarely reported (<1/10,000 cases per patient-year) after months to years of treatment with EPREX.
Table 3. Adverse Drug Reactions Identified During Postmarketing Experience with EPREX by Frequency Category Estimated from Spontaneous Reporting Rates
| Table 3. Adverse Drug Reactions Identified During Postmarketing Experience with EPREX by Frequency Category Estimated from Spontaneous Reporting Rates | |
| System/Organ Class | |
|---|---|
| Frequency | Adverse Drug Reaction |
| Blood & Lymphatic System Disorders | |
| Very rare | Erythropoietin Antibody-Mediated Pure Red Cell Aplasia |
| Investigations | |
| Very rare | Anti-erythropoietin Antibody Positive |
Interactions
There are no known clinically significant medicine interactions, but the effect of epoetin alfa (rch) may be potentiated by the simultaneous therapeutic administration of a haematinic agent such as ferrous sulfate when a deficiency state exists.
No evidence exists that indicates that treatment with Epoetin alfa (rch) alters the metabolism of other drugs. However, since cyclosporin is bound by RBC's there is potential for a drug interaction. If Epoetin alfa (rch) is given concomitantly with cyclosporin, blood levels of cyclosporin should be monitored and the dose of cyclosporin adjusted as the haematocrit rises.
No evidence exists that indicates an interaction between Epoetin alfa (rch) and G-CSF or GM-CSF with regard to haematological differentiation or proliferation of tumor biopsy specimens in vitro.
In patients with metastatic breast cancer, subcutaneous co-administration of 40,000 IU/mL Epoetin alfa with trastuzumab (6 mg/kg) had no effect on the pharmacokinetics of trastuzumab.
Overdose
Response to EPREX is dose-related and individualised. In case of excessive erythropoietic response from an overdose of EPREX, dosing should be stopped and phlebotomy can be considered. Supportive care should be provided for hypertensive or convulsive events that may be related to overdosing with epoetin alfa (rch).
Pharmaceutical Precautions
Store at 2°C to 8°C. Do not freeze or shake. This temperature range should be closely maintained until administration to the patient. Store in original package in order to protect from light.
When the product is about to be used, it may be removed from the refrigerator and stored at room temperature (below 25°C) for a maximum single period of seven days.
The product should not be used, and discarded
- if the seal is broken,
- if the liquid is coloured or you can see particles floating in it,
- if you know, or think that it may have been accidentally frozen, or
- if there has been a refrigeration failure.
Any waste material should be disposed of in accordance with local requirements. Prefilled syringes shelf life - 18 months.
Medicine Classification
Prescription Medicine.
Package Quantities
1,000 IU/0.5mL; 2,000 IU/0.5mL; 3,000 IU/0.3mL; 4,000 IU/0.4mL; 5,000 IU/0.5mL; 6,000 IU/0.6mL; 10,000 IU/1.0mL: in boxes of 6 pre-filled syringes.
Name and Address of the Sponsor
Janssen-Cilag (New Zealand) Ltd,
Ground Floor
105 Carlton Gore Road, Newmarket
Auckland, NEW ZEALAND
Tel: (09) 523 8700
Fax: (09) 523 1646
Date of Preparation
23 April 2009