ERYSAA PREFILLED SYRINGE 2,000 IU / 0.5 ml: Each pre-filled syringe contains Epoetin alfa 2,000 international units (IU) corresponding to 16.8 micrograms Epoetin alfa.
ERYSAA PREFILLED SYRINGE 4,000 IU / 0.4 ml: Each pre-filled syringe contains Epoetin alfa 4,000 international units (IU) corresponding to 33.6 micrograms Epoetin alfa.
Epoetin alfa is a glycoprotein that is produced by recombinant DNA technology.
ERYSAA PREFILLED SYRINGE 2,000 IU / 0.5 ml is a sterile, clear, colorless liquid in phosphate-buffered solution for intravenous administration that is available in single-use, graduated pre-filled syringes containing 2,000 IU / 0.5 ml.
ERYSAA PREFILLED SYRINGE 4,000 IU / 0.4 ml is a sterile, clear, colorless liquid in phosphate-buffered solution for intravenous administration that is available in single-use, graduated pre-filled syringes containing 4,000 IU / 0.4ml.
Pharmacology: Pharmacodynamics: ERYSAA stimulates erythropoiesis by the same mechanism as endogenous erythropoietin.
ERYSAA (Epoetin alfa) obtained by gene technology is glycosylated and is identical in its amino acid and carbohydrate composition to endogenous human erythropoietin that has been isolated from the urine of anaemic patients.
ERYSAA has the highest possible purity according to the latest state of the art technology. In particular, no residues of the cell line used for the production are detectable at the concentrations of the active ingredient that are used in humans.
Healthy volunteers: After single I.V. bolus (100 IU/kg) of ERYSAA, the pharmacodynamic marker reticulocyte was investigated. ERYSAA increases the reticulocyte count within 7 days of initiation as similar to the pharmacodynamic profile of reference medicinal product Eprex.
Phase I study (PG-EPO-Ph1) in healthy subjects provided comparative pharmacodynamic data on ERYSAA versus Eprex. For 27 subjects who completed the study per protocol, the blood levels of RBC, haemoglobin, haematocrit and reticulocyte were determined up to 28 days following single-dose intravenous administration of Eprex or ERYSAA at an IV bolus dose of 100 IU/kg. The key PD parameters of absolute reticulocyte count were calculated as follows: median Tmax was 7 days for both Eprex and ERYSAA. Emax was 95.4(±21.7)*103/μL and 93.4(±24.2) *103/μL for Eprex and ERYSAA, respectively and AUEClast was 1773.6(±404.0) *103/μL*day and 1832.6(±414.4) *103/μL*day for Eprex and ERYSAA, respectively. The point-estimates and 90% CIs for both Emax GMR (test/reference) and AUEClast GMR (test/reference) lie within the equivalence margin of 0.8~1.25 and thus fulfill the criteria for PD comparability between ERYSAA and Eprex.
Clinical Trials: The multi-center, multi-national, double-blind, randomized, active controlled, parallel-group Phase III study (PG-EPO-Ph3) was conducted in a total of 298 Malaysian and Korean subjects where both populations were exposed to treatment of the product. The 2000 IU/0.5ml strength was tested during the study and showed therapeutic equivalence with the reference product Eprex so similar clinical effect can be expected on the hemoglobin levels of patients. The study design also includes exposure to the ERYSAA of up to 12-months during the open label phase to assess the long-term immunogenicity safety (see Adverse Reactions).
Pharmacokinetics: Healthy volunteers: After single I.V. bolus (100 IU/kg) of ERYSAA was observed for their plasma erythropoietin concentrations determined up to 24 hours. Measurement of epoetin alfa following single dose intravenous administration revealed a half-life of approximately 7 hours in normal volunteers.
A Phase I study (PG-EPO-Ph1) in healthy subjects provided pharmacokinetic (PK) data on ERYSAA in comparison to Eprex. In that study, 27 individual subjects completed the study per protocol and had their plasma erythropoietin concentrations determined up to 24 hours following single-dose intravenous administration of Eprex or ERYSAA at an IV bolus dose of 100 IU/kg. The key PK parameters of plasma erythropoietin concentration were calculated as follows: Tmax was 0.083 hours for both Eprex and ERYSAA treatment groups. Cmax was 2518.50(±269.30) mIU/mL and 2531.21(±272.50) mIU/mL for Eprex and ERYSAA, respectively, and AUClast was 17094.51(±2141.31) hr*mIU/mL, and 16464.51(±1872.40) hr*mIU/mL for Eprex and ERYSAA, respectively. In addition, respective CL values for Eprex and ERYSAA were 0.41(±0.06) L/hr and 0.42(±0.04) L/hr. The point-estimates and 90% CIs for both Cmax geometric mean ratio (GMR) (test/reference) and AUClast GMR (test/reference) lie within the equivalence margin of 0.8~1.25 and thus fulfill the criteria for PK comparability between ERYSAA and Eprex.
Toxicology: Preclinical Safety Data: Single Dose Toxicity: No single dose toxicity studies were performed. According to literature data, the highest epoetin alfa dose tested was > 40 times the highest human dose administered clinical today (600 IU/kg).
Repeated Dose Toxicity: In accordance with the guidelines on the evaluation of biosimilar products, a repeat-dose toxicity study with 2-week recovery was conducted in one animal species with 2 different dosages (100 IU/kg and 500 IU/kg) administered daily for 28 days to examine and compare the safety of study drug ERYSAA and comparator drug Eprex. The results demonstrated that two drugs were not different in terms of toxicity. And during the test period, no death occurred in either males or females.
ERYSAA is an erythropoiesis-stimulating agent (ESA) indicated for: Treatment of anaemia associated with chronic renal failure in adult haemodialysis and predialysis patients and paediatric patients on haemodialysis.
To facilitate autologous blood collection within a predeposit program and decrease the risk of receiving allogeneic blood transfusions in patients with hematocrits of 33 - 39%, who are scheduled for major elective surgery and are expected to require more blood than that which can be obtained through autologous blood collection techniques in the absence of Epoetin alfa.
Adult haemodialysis patients:
In patients on haemodialysis, where intravenous access is readily available, the intravenous route of administration should be used for ERYSAA.
The treatment is divided into two stages: Correction phase: 50 IU/kg three times per week. When necessary, dose adjustments should be made in increments of 25 IU/kg three times per week at intervals of at least 4 weeks until the target haemoglobin concentration (10-12 g/dL) is achieved.
Maintenance phase: Adjust dosage in order to maintain haemoglobin values at the desired level: Hb between 10 and 12 g/dL. The maintenance dose should be individualised for each chronic renal failure patient. The recommended total weekly dose is between 75 and 300 IU/kg. Available data suggests that patients with a baseline haemoglobin (<6 g/L) may require higher maintenance doses than patients with a baseline haemoglobin (>8 g/L).
Paediatric Haemodialysis Patients:
The treatment is divided into two stages: Correction phase: 50 IU/kg three times per week by the intravenous route. When necessary, dose adjustments should be made in increments of 25 IU/kg three times per week at intervals of at least 4 weeks until the target haemoglobin concentration (9.5-11 g/dL) is achieved.
Maintenance phase: Adjust dosage in order to maintain haemoglobin values at the desired level: Hb between 9.5 - 11 g/dl. Generally, children less than 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. (See Table 1.)
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Available data suggest that patients whose initial haemoglobin is very low (haemoglobin <6.8 g/dL) may require higher maintenance doses than patients whose initial haemoglobin is higher (haemoglobin 6.8 g/dL).
Adult surgery patients in an autologous predonation programme:
The intravenous route of administration should be used for ERYSAA. Epoetin alfa should be administered after the completion of each blood donation procedure. Iron status should be evaluated for all patients prior to treatment with Epoetin alfa. Iron deficiency, if present, should be corrected before allowing a patient to enroll in an autologous blood donation programme. In anemic patients, the cause of anaemia should be explored before starting therapy with Epoetin alfa. All patients being treated with Epoetin alfa should receive adequate iron supplementation (e.g. 200 mg oral elemental iron daily) throughout the course of Epoetin alfa treatment. In order to achieve high iron stores prior to starting Epoetin alfa therapy, iron supplementation should be started as soon as possible, even several weeks prior to initiating the autologous pre-deposit. Mildly anaemic patients (haematocrit of 33 to 39% and/or haemoglobin 10 to 13 g/dL), requiring predeposit of ≥ 4 units of blood, should be treated with Epoetin alfa at 600 IU/kg 2 times weekly for 3 weeks prior to surgery. For those patients who require a lesser degree of erythropoietin stimulation, a dose regimen of 150-300 IU/kg administered twice weekly has been shown to augment autologous pre-donation and to decrease the subsequent decline in haematocrit.
ROUTE OF ADMINISTRATION:
ERYSAA is preservative free sterile solution for single use only.
This medicinal product must not be administered by intravenous infusion, or mixed with other medicinal products.
This medicinal product is not approved for subcutaneous use.
Epoetin alfa should be administered over at least one to five minutes, depending on the total dose. A slower injection may be preferable in patients who react to the treatment with flu-like symptoms. In haemodialysis patients, a bolus injection may be given during dialysis via a suitable venous port in the dialysis line. Alternatively, at the completion of a haemodialysis session, the injection can be given via the fistula needle tubing, followed by 10 ml of isotonic saline to rinse the tubing and to ensure satisfactory injection of the product into the circulation. Epoetin alfa should not be administered by intravenous infusion or mixed with other drugs.
Special instruction for use:
The pre-filled syringe is ready for use. Each syringe should be used for a single injection only. Do not re-use syringe. Discard unused portion. ERYSAA must not be shaken or mixed with any other liquid. Shaking may denature the glycoprotein, rendering it inactive.
Do not use ERYSAA if: the blister sealing is broken or the blister is damaged in any way; the liquid is coloured or floating particles can be seen in it; any liquid has leaked out of the pre-filled syringe or condensation visible within the sealed blister; you know or think it may have been accidentally frozen.
OVERDOSE AND TREATMENT: The therapeutic margin of Epoetin alfa is very wide. Overdose of epoetin alfa may produce effects that are extensions of the pharmacological effects of the hormone. Phlebotomy may be performed if excessively high haemoglobin levels occur. Additional supportive care should be provided as necessary.
Hypersensitivity to the active substance or to any of the excipients.
Hypersensitivity to mammalian cell- derived products.
Patients who develop antibody-mediated Pure Red Cell Aplasia (PRCA) following treatment with any erythropoietin should not receive Epoetin alfa or any other erythropoietin.
All contraindications associated with autologous blood predonation programs should be respected in patients being supplemented with ESA.
Patients scheduled for elective surgery, who are not participating in an autologous blood pre-deposit programme and who have 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.
Cardiovascular and Thrombotic Events/ Increased Mortality: An increased incidence of thrombotic vascular events (TVEs) has been observed in patients receiving epoetin alfa. These include venous and arterial thromboses and embolism (including some with fatal outcomes), such as deep venous thrombosis, pulmonary emboli, retinal thrombosis and myocardial infarction. Additionally, cerebrovascular accidents (including cerebral infarction, cerebral haemorrhage and transient ischaemic attacks) have been reported.
The reported risk of TVEs should be carefully weighed against the benefits to be derived from treatment with epoetin alfa particularly in patients with pre-existing risk factors. 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.
Use in Chronic Renal Failure Patients: Chronic renal failure patients being treated with epoetin alfa should have haemoglobin levels measured on a regular basis until a stable level is achieved, and periodically thereafter. In chronic renal failure patients the rate of increase in haemoglobin should be approximately 10 g/L per month and should not exceed 20 g/L per month to minimise risks of an increase in hypertension.
In patients with chronic renal failure, maintenance haemoglobin concentration should not exceed the upper limit of the target haemoglobin concentration range as recommended under Recommended Dosage. In controlled trials, haemoglobin levels targeted to 130 g/L were associated with a higher risk of cardiovascular events, including death.
Patients with chronic renal failure and insufficient haemoglobin response to ESA therapy may be at even greater risk for cardiovascular events and mortality than other patients. Shunt thromboses have occurred in haemodialysis patients, especially in those who have a tendency to hypotension or whose arteriovenous fistulae exhibit complications (e.g., stenoses, aneurysms, etc.) Early shunt revision and thrombosis prophylaxis by administration of acetylsalicylic acid, for example, is recommended in these patients.
Hyperkalaemia has been observed in isolated cases. Serum electrolytes should be monitored in chronic renal failure patients. If an elevated or rising serum potassium level is detected, then in addition to the appropriate treatment of the hyperkalaemia, consideration should be given to ceasing ESA administration until the serum potassium level has been corrected.
Hypertension: In all patients receiving epoetin alfa, blood pressure should be closely monitored and controlled as necessary. Epoetin alfa should be used with caution in the presence of untreated, inadequately treated or poorly controllable hypertension. It may be necessary to add or increase antihypertensive treatment. If blood pressure cannot be controlled, epoetin alfa treatment should be discontinued.
Hypertensive crisis with encephalopathy and seizures, requiring the immediate attention of a physician and intensive medical care, have also occurred during ESA 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.
Pure Red Cell Aplasia: Cases of pure red cell aplasia (PRCA) have been reported after months to years of treatment with erythropoietins. Most cases of PRCA associated with ESA occurred in patients receiving subcutaneous (SC) administration. Cases also have been 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 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 antibodies to erythropoietin are detected, patients should not be switched to another ESA product as antierythropoietin antibodies cross-react with other ESAs.
Use in Surgery Patients in an Autologous Pre-Donation Programme (ABD): All special precautions associated with autologous pre-donation programmes, especially routine volume replacement, should be respected.
Seizures: Seizures have occurred in patients receiving ESA. Therefore, ESA should be used with caution in patients with epilepsy, history of seizures, or medical conditions associated with a predisposition to seizure activity such as CNS infections and brain metastases.
Sensitivity/ Resistance: The parenteral administration of any biologic product should be attended by appropriate precautions in case allergic or other untoward reactions occur. Hypersensitivity reactions, including cases of rash, urticaria, anaphylactic reaction, and angioneurotic edema have been reported.
Severe Cutaneous Adverse Reactions: Blistering and skin exfoliation reactions including erythema multiforme and Stevens-Johnson syndrome (SJS)/toxic epidermal necrolysis (TEN), have been reported in association with ESA treatment. Discontinue ESA therapy immediately if a severe cutaneous adverse reaction, such as SJS/TEN, is suspected.
Iron Supplementation: Other causes of anaemia (iron, folate or Vitamin B12 deficiency, aluminium intoxication, infection or inflammation, blood loss, haemolysis and bone marrow fibrosis of any origin) should be evaluated and treated prior to initiating therapy with ESA, and when deciding to increase the dose. In most cases, the ferritin values in the serum fall simultaneously with the rise in packed cell volume. In order to ensure optimum response to ESA, adequate iron stores should be assured and iron supplementation should be administered if necessary: For chronic renal failure patients, iron supplementation (elemental iron 200-300 mg/day orally for adults and 100-200 mg/day orally for paediatrics) is recommended if serum ferritin levels are below 100 ng/mL.
For cancer patients, iron supplementation (elemental iron 200-300 mg/day orally) is recommended if transferring saturation is below 20%.
For patients in an autologous predonation programme, iron supplementation (elemental iron 200 mg/day orally) should be administered several weeks prior to initiating the autologous predeposit in order to achieve high iron stores prior to starting ESA therapy, and throughout the course of ESA therapy.
General: There may be a moderate dose-dependent rise in the platelet count within the normal range during treatment with ESA. 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 is regularly monitored during the first 8 weeks of therapy.
Very rarely, exacerbation of porphyria has been observed in ESA-treated patients. ESAs should be used with caution in patients with known porphyria.
ESA should also be used with caution in patients with chronic liver failure. The safety and dosage regime of ESA has not been established in the presence of hepatic dysfunction.
Patients should only be switched from one ESA to another under appropriate supervision.
Effect on Ability to Drive and Operate Machinery: No studies on the effects of epoetin alfa on the ability to drive and use machines have been performed.
Epoetin alfa has no or negligible influence on the ability to drive or use machines. But due to the increased risk of hypertension during the initial phase of Epoetin alfa treatment, patients with chronic renal failure should use caution when performing hazardous activities, such as driving or operating machinery, until the optimal maintenance dose of Epoetin alfa has been established.
There are no adequate and well-controlled studies with epoetin alfa in pregnant women. ESA should be administered during pregnancy only if clearly needed and if the potential benefit justifies the potential risk to the foetus. In pregnant or lactating surgical patients participating in an autologous blood predonation programme, the use of ESA is not recommended. It is not known whether epoetin alfa (rch) is excreted in breast milk.
To determine long term safety, the TEAEs that had occurred in 274 subjects administered at least one dose of PDA10 in the entire study period including the OLE phase were evaluated and the numbers of TEAEs per patient year were analyzed. In addition to this, the numbers of TEAEs per patient year for 146 subjects in the Eprex group during the maintenance phase was also presented as a reference.
The adverse events (AEs) that had occurred in the entire study period were summarized by System Organ Class (SOC) and Preferred Term (PT) and their tabulated summary (≥ 2% of incidence rate by PT) is provided in Table 2 as follows.
The incidence of TEAEs per exposure year was similar between the groups treated with PDA10 and Eprex. Among 274 subjects in the PDA10 group who had received at least one dose of PDA10 in the entire study period including the OLE phase, 169 subjects (61.68% [613 events; 3.22 events per patient year]) had at least one TEAE during the entire study period.
By system organ class (SOC), the most common TEAE in the PDA10 group was 'Infections and infestations' with 119 events reported by 74 subjects (27.01% [0.63 events per patient year]), followed by 'Injury, poisoning and procedural complications' with 68 events reported by 46 subjects (16.79% [0.36 events per patient year]). By PT, the most common TEAE was 'Hypertension' with 71 events reported by 21 subjects (7.66% [0.37 events per patient year]), followed by 'Nasopharyngitis' with 32 events reported by 20 subjects (7.30% [0.17 events per patient year]). Adverse events (AEs) were summarized by System Organ Class (SOC) and Preferred Term (PT) and their tabulated summary is provided in Table 2. (See Table 2.)
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The adverse drug reactions (ADRs), were 10 events reported by 5 subjects (1.69%) including 6 events by 3 subjects (2.00%) in the ERYSAA group and 4 events by 2 subjects (1.37%) in the Eprex group.
By SOC, the most common ADR in the PDA10 group was 'Vascular disorders' with 39 events reported by 3 subjects (1.09% [0.21 events per patient year]), followed by 'Nervous system disorders' with 2 events reported by 2 subjects (0.73% [0.01 events per patient year]) and 'Skin and subcutaneous tissue disorders' with 1 event reported by 1 subject (0.36% [0.01 event per patient year]). By PT, the most common ADR was 'Hypertension' with 37 events reported by 2 subjects (0.73% [0.19 events per patient year]), followed by 'Blood pressure inadequately controlled', 'Hypertensive crisis', 'Cerebral infarction', 'Haemorrhage intracranial' and 'Rash' with 1 event reported by 1 subject each (0.36% [0.01 event per patient year]). The ADRs reported during the entire study are presented by SOC and PT in Table 3. (See Table 3.)
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No evidence of interaction of epoetin with other drugs was observed in the course of clinical trials. However, since cyclosporine is bound by RBCs there is potential for a drug interaction. If epoetin alfa is given concomitantly with cyclosporine, blood levels of cyclosporine should be monitored and the dose of cyclosporine adjusted as the haematocrit rises.
Incompatibilities: Do not dilute or transfer to any other container. Do not administer byintravenous infusion or in conjunction with other drug solutions.
Store at (2°C ~ 8°C).
Do not freeze or shake. Shaking may denature the glycoprotein, rendering it inactive.
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.
Shelf-Life: 24 months.
B03XA01 - erythropoietin ; Belongs to the class of other antianemic preparations. Used in the treatment of anemia.
Soln for inj (sterile, clear, colorless liquid in pre-filled syringe) 2,000 IU/0.5 mL x 6's. 4,000 IU/0.4 mL x 6's.