Espogen

Recombinant human erythropoietin alpha.

1.0 ml of Espogen Injection contains Recombinant Human Erythropoietin alpha (INN: epoetin alfa) 4,000 or 10,000 IU.
Stabilizer: Human serum albumin 2.5 mg.
Erythropoietin is a 165 amino acid glycoprotein which is produced in the kidney and stimulates the division and differentiation of committed erythroid progenitors in the bone marrow. Espogen Injection is human erythropoietin preparation manufactured by recombinant DNA technology. Espogen is produced by mammalian cells into which the human erythropoietin gene has been introduced and contains the identical amino acid sequence of isolated natural erythropoietin.

Treatment of anemia of chronic renal failure (CRF) patients with symptomatic anemia and requiring blood transfusion.
Treatment of reduction of transfusion requirements in patients: receiving chemotherapy for solid tumours; malignant lymphoma or multiple myeloma; at risk of transfusion as assessed by the patients general status.
Treatment of HIV-infected patients dependent upon the endogeneous serum erythropoietin level.

Chronic renal failure (CRF) patients: Starting dose of Espogen therapy is 50U/kg, 3 times per week by slow s.c or i.v. injection over 1-2 minutes. Further dose increase should be determined according to initial response. Dose may be increased by 25U/kg every four weeks, if needed. Also, when the increasing rate of hemoglobin is more than 2g/dl after 50U/kg is administered, dose should be adjusted by omitting one of the three doses per week. The target range of the treatment is about 10g/dl as hemoglobin concentration (30% as hematocrit). If therapeutic effect of Espogen in anemia is achieved, 25-50U/kg as a maintenance dose is generally administered 2-3 times per week. It is known that the target range of hemoglobin is 10-12g/dl. The patients who started the therapy at a low level of hemoglobin (6g/dl) need higher maintenance dose than those who didn't start the therapy at less than 8g/dl of hemoglobin and dose should be adjusted depending on age. In any case, maximum dose should not exceed 200U/kg in a single day 3 times per week. Iron stores should be evaluated prior to or during the therapy and iron should be administered, if necessary. In case of aluminum poisoning or infectious disease patients, response may be diminished. Even in case of patients not requiring dialysis, maintenance dose should be determined depending on the severity of anemic symptoms or age, however, it has been reported that 36-38% of hematocrit was sustained for more than 6 months.
Cancer patients on chemotherapy:The recommended initial dose of Espogen is 150 U/kg as a subcutaneous injection three times a week. The dose of Espogen can be increased up to 300 U/kg three times a week. If the hematocrit exceeds 40%, the dose of Espogen should be withheld until it falls to 36%. The dose of Espogen should be reduced by 25% when treatment is resumed or the dose is titrated to maintain the desire hematocrit. If the initial dose of Espogen includes a very rapid hematocrit response, the dose should be reduced. The hematocrit should be monitored on a weekly basis until hematocrit becomes stable.
HIV-Infected patients: The recommended starting dose of Espogen is 100U/kg as an intravenous or subcutaneous injection three times a week for 8 weeks. The dose can be increased by 50 to 100U/kg three times a week. If patients have not responded satisfactorily to a 300U/kg three times a week, it is unlikely that they will respond to higher doses. If the hematocrit exceeds 40%, the dose of Espogen should be withheld until it falls to 36%. The dose of Espogen should be reduced by 25% when treatment is resumed or the dose is titrated to maintain to desire hematocrit.

Treatment: Responses to Espogen are individualized according to dose. In case of overdosage, hypertensive symptoms may occur. If hemoglobin increases excessively, phlebotomy can be indicated.

Espogen should not be administered to following patients: This product or other erythropoietin preparations should not be administered to patients with history of Pure Red Cell Aplasia (PRCA) after treatment of erythropoietin preparations; Patients with hypersensitivity to this product or other erythropoietin preparations; Patients with uncontrolled hypertension; Patients with hypersensitivity to mammalian cell-derived product or human albumin.
Espogen should be cautiously administered to following patients: Patients with hypertension (Rise in blood pressure caused by erythropoietin administration has been recognized and hypertensive encephalopathy may arise; Patients with history of hypersensitivity to drug; Patients with predisposition to allergy; Patients with myocardial infarction, pulmonary infarction, cerebral infarction and so on, or patients with a chance of thromboembolism by the history of these (It has been reported that the blood viscosity increases with erythropoietin and thromboembolism may be exacerbated or induced. Also since there is a chance of acceleration in blood coagulation, especially in case erythropoietin is administered in order to store autologous blood and after operation, sufficient monitoring is required); Premature with ventricular hemorrhage and intracerebral hemorrhage (Cerebral hemorrhage may be exacerbated by erythropoietin administration).
General Precautions: Administration of Espogen should be limited to patients with renal anemia and cancer who are causing inconvenience in daily lives by being accompanied during anemia. Moreover, Espogen should be intended for patients with less than 10g/dl of hemoglobin (30% as hematocrit) in case of renal anemia and with not less than 200mU/ml of erythropoietin in case of cancers.
Espogen should not be administered to the other anemias such as dehematizing anemia, panhematopenia, aluminum storage disease, etc.
Sufficient examination by asking should be made to estimate responses like shock, etc. Moreover, in case administration is initiated or the first dose after discontinuation is administered, it is desirable that total volume be administered after confirming that abnormal response would not occur, by injecting little amount into vein.
During therapy, hemoglobin and hematocrit should be regularly monitored (about once a week in the early phase of administration, once per every other week in the maintenance phase) with sufficient care to avoid exceeding target range of hematopoiesis (≥12g/dl as hemoglobin or ≥36% as hematocrit). If it is recognized hematopoiesis required is exceeded, appropriate treatments including discontinuance of administration should be exceeded, appropriate treatments including discontinuance of administration should be made.
Since rise in blood pressure and hypertensive encephalopathy may occur, blood pressure and hematocrit should be increased slowly. Also, hematocrit may increase even after administration is discontinued, and sufficient monitoring should be made. Therefore, blood pressure in patients treated with Espogen, particularly patients with cardiovascular disease or patients with chance of hypertension should be carefully monitored. As in case of patients with rapid increase in hematocrit (increases by more than 4% in a 2-week period), excessive rise in hematocrit may exacerbate hypertension, dose should be adjusted.
Among patients with chronic renal failure (CRF) involved in clinical trials of Espogen, seizures have been observed, Higher rate of seizures (about 2.5% of patients) appeared in patients on dialysis during the first 90 days of therapy than later time period. In double-blind, placebo-controlled trials involving cancer patients on chemotherapy, seizures were reported in 3.2% (N = 2/63) of patients treated with Espogen and 2.9% (N = 2/68) of patients related with placebo. Seizures occurred in 1.6% (N = 1/63) of patients treated with Espogen, associated with significant increase in blood pressure hematocrit. However, both patients treated with Espogen had underlying CNS disease which might have been related to seizures. Therefore, blood pressure and previously known neurologic symptoms should be closely monitored in patients with Espogen.
Since the thrombotic events such as myocardial infarction, pulmonary embolism, cerebrovascular accident, or transient ischemic attack were observed during Espogen therapy, the patients with vascular disease should be carefully monitored.
Since hyperkalemia may be caused by Espogen administration, proper dietary management should be carried out.
Because shunt occlusion and residual blood within the hemodialysis kits may occur, hemokinetic volume in shunt or hemodialysis kits should be sufficiently monitored. In such case, appropriate measures such as reestablishment of shunt or increase of anticoagulant and so on should be taken.
Since iron is important to Espogen therapy, in case of iron deficiency, iron should be supplemented.
Espogen is primarily a growth factor of erythropoiesis. However, the possibility that Espogen may act as a growth factor of tumor type, particularly such as myeloid malignancies cannot be excluded.
Incidence of Pure Red Cell Aplasia (PRCA) has been rarely reported among CRF patients with administration of erythropoietin preparation from months to years. Since most cases of PRCA were found after administration of erythropoietin preparation via s.c. injection, the i.v. route is recommended for the injection of this product. Anti-erythropoietin antibody was found in most cases of PRCA patients. In cases of unexpected diminish of effect, the patients should be checked for the typical causes of non-response to this preparation such as iron, folic acid, or vitamin B12 deficiency, aluminum storage disease, infection or inflammation, exsanguinations, and hematolysis. For the case of PRCA with unknown causes, inspection of marrow should be considered. Diagnosis of PRCA should be followed by checking the presence of anti-erythropoietin antibody and discontinue of administration of this preparation. Since antibodies against an erythropoietin preparation show cross-reactivity to other erythropoietin preparations, any erythropoietin preparations should not be used. Other causes of PRCA should be checked for adequate treatments.
Precautions on application: Espogen should not be injected in conjunction with other drugs.
In case of patients on hemodialysis, it is recommendable Espogen be injected after hemodialysis. And it is desirable Espogen be injected slowly over more than 5 minutes to the patients with flu-like symptoms.
Espogen should not be administered by intravenous infusion.
Use in Pregnancy: Since the safety of Espogen in pregnant patients has not been established, it is desirable not to administer Espogen to women who are pregnant or have possibility to be pregnant. However, Espogen may be administered only if benefit for the treatment exceeds potential risk.
Use in Children: The safety of Espogen in children has not been established.
Use in the Elderly: Since physiological function is generally lowered and cardiovascular complications such as hypertension increase in geriatric patients, dosage and frequency should be appropriate adjusted by measuring blood pressure, hemoglobin, or hematocrit and so on.

Pregnancy: Since the safety of Espogen in pregnant patients has not been established, it is desirable not to administer Espogen to women who are pregnant or have possibility to be pregnant. However, Espogen may be administered only if benefit for the treatment exceeds potential risk.

The Erythropoiesis-stimulation agents (ESAs) may increase the risk of Serious Adverse Events, for example Hypertension, Lack of effect/efficacy (LOE), and Pure Red Blood Cell Aplasia (PRCA)
An incidence of Thrombotic vascular events (TVEs) should be carefully weighed against the benefits to be derived from treatment with Epoetin alfa particularly in patients with pre-existing risk factors for TVEs, including obesity and prior history of TVEs (Eg., deep venous thrombosis, pulmonary embolism and also the cancer patients
Pure Red Blood Cell Aplasia (PRCA): In Thailand have high report of Antibody-mediated pure red blood cell aplasia (PRCA) after administering Epoetin subcutaneous route in long term use of chronic renal failure patients. And also have an incidence of Pure Red Blood Cell Aplasia (PRCA) in patients with hepatitis C with interferon and ribavirin, when the erythropoiesis-stimulating agents (ESAs) are used concomitantly.
In chronic renal failure patients developing sudden lack of efficacy with decrease of hemoglobin and need for transfusion, a reticulocyte count should be obtained, and typical causes of non-response should be investigated. In case reticulocyte index less than 20,000/microliter or less than 0.5% with normal platelets and white blood cells the anti-erythropoietin antibodies and bone marrow testing should be performed to investigate the PRCA.
In case of PRCA patients should prompt to discontinue treatment with Epoetin and other ESA therapy because of the risk of cross-reaction.
Shock: Because shock may occur in rare case, sufficient monitoring should be made and if abnormality is recognized, the administration should be discontinued and proper treatments should be made.
Circulatory System: Rise in blood pressure, thrombosis of blood vessel contact region such as lachrymal duct and so on, and sometimes tachycardia may occur.
Hypertensive encephalopathy: Since hypertensive encephalopathy showing headache, consciousness disorder, seizure etc caused by sudden rise in the blood pressure is observed and cerebral hemorrhage may occur, administer with sufficient care monitoring the trend of blood pressure, hematocrit and so on.
Encephalopathy: as encephalopathy may occur, observe sufficiently and administration should be discontinued and appropriate treatment should be made in case abnormality is recognized.
Skin: Itch, rash, acne and so on may sometimes occur.
Liver: Hepatosis including AST, ALT, LDH, ALP, Total bilirubin, etc may sometimes occur. Abdominal pain can also occur.
Digestive system: Nausea, vomiting, anorexia, and diarrhea may sometimes occur. Abdominal pain can also occur.
Blood: Increase in leukocyte and eosinophil may sometimes occur. Decrease in granulocyte may sometimes occur in prematures. Serum potassium, BUN, creatinine and uric acid may sometimes increase. Rickets may sometimes occur in prematures. Incidence of Pure Red Cell Aplasia (PRCA) has been rarely reported among CRF patients with administration of erythropoietin preparation from months to years.
The others: Eyeground hemorrhage, splenomegaly, nasal hemorrhage, sometimes headache, dizziness, pyrexia, slight fever, feeling of flush, malaise, arthralgia, myalgia, bitter taste of mouth, convulsion and blepharedema may occur.
Espogen is generally well-tolerated. The adverse effects reported are frequent sequelae of CRF and may not necessarily attributable to erythropoietin therapy.
Chronic renal failure (CRF) patients: In double-blind, placebo-controlled studies involving over 300 patients with CRF, the events reported in greater than 5% of patients are as following table. (See Table 1).

Click on icon to see table/diagram/image

In the clinical trials involving 567 patients on dialysis, the adverse effect reported most frequently were hypertension (0.75%), headache (0.40%), tachycardia (0.31%), nausea and vomiting (0.26%), clotted vascular access (0.25%), shortness of breath (0.14%), hyperkalemia (0.11%) and diarrhea. Other reported events occurred at a rate of less than 0.10% per patient per year. Events reported to have occurred within several hours of administration of rhEPO were rare, mild, and transient, and included flu-like symptoms such as arthralgias and myalgias. In all studies analyzed to date, rhEPO administration was generally well-tolerated irrespective of the route of administration.
Cancer patients: In double-blind, placebo-controlled studies of up to 3 months duration involving 131 cancer patients, adverse effects with an incidence of greater than 10% are as following table. (See Table 2.)

Click on icon to see table/diagram/image

Although some statistically significant difference between patients treated with rhEPO and placebo were noted, the overall adverse effects reported were consistent with the disease process of cancer. Even in a clinical trial in which patients (N = 72) were treated for up to 32 weeks with doses as high as 927U/kg, the adverse effects reported were consistent with progression of cancer. Based on comparable survival data, and on the percentage of patients treated with rhEPO and placebo who discontinued therapy due to death, disease progression or adverse effects (22% and 13%, respectively), the clinical results between two groups appeared to be similar. Available data from animal tumor models and measurement of proliferation of solid tumor cells from clinical biopsy specimens in response to rhEPO suggests rhEPO doesn't accelerate tumor growth. Nevertheless, the possibility the rhEPO may promote growth of some tumors, particularly myeloid tumors, cannot be excluded. A randomized comparative phase IV clinical trial is currently ongoing for further evaluation of this issue. The mean peripheral white blood cell count was unchanged following rhEPO therapy compared to placebo-treated group.

Store in hermetic container at 2-8°C in the refrigerator.
Shelf-life: 24 Months.

Haematopoietic Agents

B03XA01 - erythropoietin ; Belongs to the class of other antianemic preparations. Used in the treatment of anemia.

S