EPIAO

Each vial also contains human albumin, sodium chloride, sodium citrate, citric acid and water for injection as excipients.
Epoetin α, a generic name for human recombinant erythropoietin, is produced by recombinant DNA technology in Chinese Hamster Cells (CHO).

Pharmacology: Male SD rats with induced chronic renal failure (CRF) were treated either with Epiao or Epogen (Amgen) at the same dosage. The anemic state associated with these animals was significantly (p<0.01) corrected, irrespective of the source of the erythropoietin (p>0.05). However, Epiao therapy could not improve renal function, nor histological changes were corrected, except glomerulus capillary blood vessel cluster proliferated, and the number of red blood cells in the vessels increased.
Epiao can stimulate erythropoiesis in anemic patients with CRF, including both patients on dialysis and those who do not require dialysis. The first evidence of a response to the 2 or 3 times weekly administration of Epiao is an increase in the reticulocyte count within 10 days, followed by increases in the red cell count, hemoglobin and hematocrit, usually within 2-6 weeks. 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 <2 weeks and may require up to 6 weeks in some patients. Once the hematocrit reaches the target range (30-36%), that level can be sustained by Epiao therapy in the absence of iron deficiency and concurrent illnesses.
The rate of hematocrit increase varies among patients and is dependent upon the dose of Epiao, within a therapeutic range of approximately 50-300 u/kg 3 times weekly.
A greater biologic response is not observed at doses exceeding 300 u/kg 3 times weekly. There are other factors affecting the rate and extent of response eg, availability of iron stage, baseline hematocrit and the presence of concurrent medical problems.
Pharmacokinetics: Serum rh EPO Concentration: Healthy Men: After IV administration of epoetin alfa 300 iu to 7 healthy male adults, 2 half-life times of serum Epiao are achieved at 0.4 and 7 hrs separately after its peak level.
Hemodialysis (HD) Patients with Renal Failure: After IV administration of epoetin α 300 iu to 11 HD patients with renal failure, the serum epoetin α concentration showed the same variation tendency as that of healthy men with the half-life of 6 hrs.
The half-life of serum epoetin α is 5.9 hrs when 8 people received epoetin α 1500 iu IV, and 7.5 hrs for 3000 iu IV (12 people). The elimination time of epoetin α prolongs a little when the dose is increased.
Urine Excretion: 24 hrs later after IV administration of epoetin α 300 iu to 7 healthy volunteers, 0.88% of the dose was excreted in the urine.
Toxicology: Preclinical Safety Data: The LD₅₀ of epoetin α in mice when administered either IV or SC are >1 x 10⁶ u/kg, which is >6700 times of the regular clinical dose and 3,330 times of the maximum clinical effective dose.
There were no irreversible changes observed in systemic examination during long-term (4-5 weeks) toxicity studies in rats and dogs treated with up to 1000 u/kg daily of Epiao. No effect of recombinant erythropoietin on reproduction system, mutagenic potential and oncogenic/carcinogenic potential have been documented, nor observed with Epiao.

Treatment of anemia associated with CRF. Treatment of anemia in cancer patients treated with chemotherapy.

CRF Patients: Epoetin α should be administrated under direct medical supervision. Epoetin α may be given either as an IV or SC injection, 2-3 times weekly. The dose should be adjusted according to anemia degree, age and other related factors.
Treatment with Epiao is divided into 2 stages, correction and maintenance phase.
Correction Phase: The recommended starting dose is 100-150 iu/kg for hemodialysis (HD) and continuous ambulatory peritoneal dialysis (CAPD) patients, and 75-100 iu/kg for patients not on dialysis (ND). The dose may be increased by 15-30 iu/kg 4 weeks after administration as the increment of hematocrit is <0.5 vol%/week. But the maximum dose increase should not exceed 30 iu/kg weekly and hematocrit should not exceed 36 vol%, usually at 30-33%.
Maintenance Phase: The dose of Epiao should be reduced to ²/₃ of the correction phase as hematocrit approaches 30-33% or hemoglobin approaches 100-110 g/L. Hematocrit should be monitored every 2-4 weeks to prevent excessive erythropoiesis and keep hematocrit and hemoglobin at proper level.
For HD patients, IV injection is recommended while SC injection is suggested for CAPD and ND patients.
Cancer Patients on Chemotherapy: Epiao treatment is not recommended for patients with baseline serum endogenous erythropoietin level >200 MIU/mL, for patients with lower baseline serum endogenous erythropoietin level respond more vigorously to Epiao than patients with higher erythropoietin levels. The recommended starting dose is 150 iu/kg SC, 3 times weekly for 4-8 weeks. If the response is not satisfactory in terms of reducing transfusion requirements or increasing hematocrit after 8 weeks of therapy, the dose of Epiao can be increased up to 200 iu/kg 3 times weekly. If the hematocrit exceeds 40%, the dose of Epiao should be withheld until the hematocrit falls to 36%. The dose of Epiao should be reduced by 25% when treatment is resumed and titrated to maintain the desired hematocrit. The dose of Epiao should be withheld as hematocrit exceeds 40% or its increase exceeds 4% in any 2-week period.
Administration: Using aseptic techniques, attach a sterile needle to a sterile syringe, and withdraw into the syringe an appropriate volume of solution as an IV or SC injection.

The maximum amount of Epiao that can be safely administered in single or multiple doses has not been determined.

Uncontrolled hypertension. Known hypersensitivity to mammalian cell-derived products and human albumin.

Hematocrit should be monitored regularly (once a week in correction phase and every other weeks in maintenance phase), to avoid excessive erythropoiesis (hematocrit should be no more than 36 vol%). Epiao should be discontinued if excessive erythropoiesis occurs.
Diet habits should be modified to prevent hyperkalemia and dose should be adjusted according to the physician's instructions when hyperkalemia occurs.
Attention should be brought up to patients with symptoms eg, cardiac infarction, pulmonary infarction, cerebral infarction or with manifestation of allergy.
If serum ferritin is <100 ng/mL or transferrin saturation <20%, supplemental iron is required.
If a patient fails to respond or maintain a response to Epiao therapy, the following etiologies should be considered: Folic acid or vitamin B12 deficiency and aluminum intoxication.
Be cautious in administering the erythropoietin preparation to patients with history of pure red cell aplasia (PRCA).
Effects on the Ability to Drive or Operate Machinery: Patients should be cautious to avoid potentially hazardous activities eg, driving or operating heavy machinery during therapy, since there is higher tendency of seizures and hypertension in patients treated with Epiao.
Use in pregnancy & lactation: The safety of epoetin α in pregnant women has not been established. Epoetin α should be used during pregnancy only if potential benefit justifies the potential risk to the fetus.
It is not known whether epoetin α is excreted in human milk. Caution should be taken when epoetin α is administered to a nursing mother.
Use in children: The safety and effectiveness of epoetin α have not been established in infants and children, but generally it is considered safe.
Use in the elderly: Monitor blood pressure, hemoglobin or hematocrit frequently and adjust the doses and administration frequency properly, in consideration of hypertension and circulatory system diseases.

Use in pregnancy & lactation: The safety of epoetin α in pregnant women has not been established. Epoetin α should be used during pregnancy only if potential benefit justifies the potential risk to the fetus.
It is not known whether epoetin α is excreted in human milk. Caution should be taken when epoetin α is administered to a nursing mother.

For CRF Patients: Epiao is generally well tolerated. The adverse events reported are frequent sequelae of CRF and are not necessarily attributable to Epiao therapy. In a combined clinical trial involving 151 CRF patients, the events reported were listed in the following table.

Click on icon to see table/diagram/image

In all studies analyzed to date (P.R. China), Epiao administration was generally well tolerated, irrespective of the route of administration.
Hypertension: Increases in blood pressure have been reported as the main side effect in clinical trials.
Thrombotic Events: In patients treated with Epiao in P.R. China, there have been rare reports of serious or unusual thromboembolic events eg, migratory thrombophlebitis, microvascular thrombosis, pulmonary embolus, and thrombosis of the retinal artery, and temporal and renal veins. Collectively, these events have been reported in <0.0001 events per patient-year; in no case has a causal relationship been established.
Allergic Reactions: There have been no reports of serious allergic reactions or anaphylaxis associated with erythropoietin administration during clinical trials. Skin rashes and urticaria have been observed rarely and when reported have generally been mild and transient in nature.
There have been rare cases for development of antibodies to erythropoietin in patients treated to date. In fact, a report of 13 anemic patients with CRF who developed neutralizing antibodies and PRCA after taking recombinant human erythropoietin products has been published in the New England Journal of Medicine. Nevertheless, if PRCA occurs, epoetin α should be immediately discontinued and appropriate therapy initiated.
For Cancer Patients on Chemotherapy: Adverse reactions reported in phase III clinical trials with Epiao in cancer patients were consistent with the underlying disease state. The clinical trial is designed for 3 months duration involving 121 patients. There are only 3 cases with skin reaction, 1 with hypertension and 2 with asthma and dizziness.

No evidence of interaction of Epiao with other drugs was observed in the course of clinical trials and clinical application to date.
Incompatibilities: In the absence of incompatibility studies, Epiao should not be mixed or administered as an infusion with other medicinal products.

Instructions for Use, Handling and Disposal: Epiao vial is a sterile but unpreserved product. Each vial is for single use only, and any medicinal product remaining in the vial should be discarded.
Before administration, the Epiao solution should be inspected for visible particles.
Only solutions that are colorless, clear or slightly opalescent should be injected. Do not shake. Allow the vial to reach room temperature before injecting.
Rotate the injection sites and inject slowly to avoid discomfort at the site of injection.
Any disposal of unused product or waste material should be in accordance with local requirements.

Store at 2-8°C. Do not freeze. Protect from light.
For ambulatory use, Epiao may be removed from storage once for a maximum single period of 7 days at room temperature (up to 25°C).
Shelf-Life: 24 months.

Haematopoietic Agents / Supportive Care Therapy

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

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