2009.05.27 – Recombinant Human Erythropoietin Injection


2009.05.27 – Recombinant Human Erythropoietin Injection

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Rat: after continually intravenous or intraperitoneal administration of 80IU/kg/day for 4 weeks, 20IU/kg/day for 13 weeks or 10IU/kg/day continually for 52 weeks, polycythemia can be observed for overdosage and long-term therapy with

[Drug Names]
Generic Name: Recombinant Human Erythropoietin Injection
Trade Name: EPIAO
Chinese Phonetic Alphabet: Chongzu Ren Hongxibao Shengchengsu Zhusheye
Ingredients: Recombinant Human Erythropoietin, Human Serum Albumin

Colorless and transparent liquid, pH 6.9±0.5

[Pharmacology and Toxicology]

1. Pharmacology
Erythropoietin is a glycoprotein which is excreted in the kidney and stimulates the division and differentiation of committed erythroid progenitors in the bone marrow. It can increase the production of CFU-E and BFU-E.

2. Toxicology

2.1 Acute toxicity:the LD50 of EPIAO in mice, rats and dogs by intravenous injection and the LD50 of EPIAO in 4-day-old rats are more than 20,000IU /kg.

2.2 Sub-acute and Chronic toxicity:

Rat: after continually intravenous or intraperitoneal administration of 80IU/kg/day for 4 weeks, 20IU/kg/day for 13 weeks or 10IU/kg/day continually for 52 weeks, polycythemia can be observed for overdosage and long-term therapy with EPIAO may result in fibrosis.

Dog: after intravenous administration of 200IU/kg/day continually for 4 weeks, 100IU/kg/day continually for 13 weeks and 20IU/kg/day continually for 52 weeks, polycythemia can be observed for overdosage and long-term therapy with EPIAO may result in fibrosis and construction change of kidney.

After subcutaneous administration, absorption of erythropoietin is slow from the injection site.   Increase of serum concentration of EPO can be observed 2 hours after administration and the peak concentration is achieved 18 hours post dosing. Bone marrow is the specific absorption organ and EPO is absorbed mainly in liver and kidney. It has been demonstrated that metabolism of EPO occurs mainly in liver, and by other pathways such as degradation in kidney, bone marrow and spleen.  EPO is not mainly excreted in kidney and less than 10% non-degraded EPO is excreted in kidney of anemia patients treated with EPO.

Anemia associated with renal failure: including patients on hemodialysis (HD) and non-dialysis (ND).
Peri-operative red blood cell mobilization
Anemia associated with chemotherapy in cancer patients with non-myeloid malignancies. rhEPO is not indicated for the treatment of anemia due to other factors such as iron or folate deficiencies, hemolysis or gastrointestinal bleeding.

[Dosage and Administration]
Anemia of renal failure: rhEPO should be administrated under direct medical supervision. rhEPO may be administrated subcutaneously or intravenously, 2~3 times weekly. The dose should be adjusted according to anemia degree, age and other related factors. The following administration is suggested:
Therapy period: The recommended starting dose is 100~150IU/kg bodyweight weekly for HD patients, and 75~100IU/kg for ND patients. The dose may be increased by 15~30IU/kg 4 weeks after administration the increment of hematocrit (Hct) is less than 0.5vol% per week. The maximum increase dose should not exceed 30IU/kg/week and Hct should not exceed 36vol%, usually at 30~33%vol%.
Maintenance period: when Hct reaches 30~33volor hemoglobin (Hb) reaches 100-110g/L, the dose should be adjusted to two thirds of the therapeutic dose. Hct should be monitored every 2~4 weeks to prevent excessive erythropoiesis and keep Hct and Hb at proper level.
Peri-operative red blood cell mobilization: Elective surgery patients with Hb between 100~130g/L receive rhEPO 150IU/kg subcutaneously, 3 times weekly, starting 10 days prior to, and for 4 days after surgery. rhEPO can relieve anemia in and after surgery, reduce peri-operative transfusion requirements and correct anemia after surgery. Oral iron should be given at the same time in case of iron deficiency.
Anemia in cancer patients on chemotherapy: rhEPO treatment is not recommended for patients with serum endogenous EPO level more than 200mu/ml. It is demonstrated that for patients with lower baseline serum EPO level respond more vigorously to rhEPO than patients with higher baseline EPO levels. The recommended starting dose is 150IU/kg bodyweight, 3 times weekly by SC administration. The dose may be increased to 200IU/kg if transfusion requirements are not decreased or Hct is still lower after 8 weeks therapy. 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. If the starting dose of EPIAO includes a very rapid hematocrit response (e.g., an increase of more than 4 percentage points in any 2-week period), the dose of EPIAO should be reduced.
Directions for use: Using aseptic techniques, attach a sterile needle to a sterile syringe, and withdraw into the syringe an appropriate volume of solution as an intravenous or subcutaneous injection.

[Adverse reactions]
Common reactions: headache, fever and fatigue occurred occasionally at the beginning of rhEPO therapy. Myalgia and arthralgia have been observed rarely. Most of these symptoms can be corrected by expectant treatments and the therapy can be continued. For those failed to be relieved, the therapy should be discontinued.
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. A low dose administration prior to the full dose treatment is recommended for the patients administered with EPIAO initially or those resume the treatment of EPIAO. Any abnormality should be treated appropriately and the EPIAO administration should be discontinued.
Cardio-cerebral vascular system: Increases in blood pressure, deterioration of hypertension, headache induced by hypertensive encephalopathy and spasm have been reported in clinical trials. Therefore, Blood pressure should be monitored carefully and if necessary, the dose of rhEPO should be adjusted/ terminated and hypotensive agents may be used.
Blood system: with the increase of Hct due to administration of rhEPO, the blood viscosity can be observed increasing. So measures should be taken to prevent from thrombosis.
Liver: enhancement of GOT and GPT are rarely observed.
Gastrointestinal: anorexia, nausea, vomiting and diarrhea occur rarely.

EPIAO is contraindicated in patients with:
–Uncontrolled hypertension
–Known hypersensitivity to mammalian cell-derived products, e.g. human albumin
–Uncontrolled combined infection

Hematocrit should be monitored regularly (once a week in correction phase and twice a week in maintenance phase) to avoid excessive erythropoiesis (hematocrit should be no more than 36vol%). EPIAO should be discontinued if excessive erythropoiesis occurs.
Diet habits should be modified to prevent hyperkalemia and dose should be adjusted according to the doctor’s instructions when hyperkalemia occurs.
Attention should be paid to patients with symptoms as cardiac infarction, pulmonary infarction, cerebral infarction or those with allergic history of drugs and manifestation of allergy.
If serum ferritin is less than 100ng/ml or transferrin saturation less than 20%, supplemental iron is required.
If a patient fails to respond or maintain a response to rhEPO therapy, the following etiologies should be considered: Folic acid or vitamin B12 deficiency; Aluminum intoxication.
The product should be disused when fissure or damage is observed on the vial or turbidity or precipitate is observed in the solution. Do not administer more than one dose per vial. Any medicinal product remaining in the vial should be discarded.

[Pregnancy and nursing mothers]
The safety of EPO therapy in pregnant women has not been established.
It is not known whether EPO is excreted in human milk. Cautions should be taken when EPO is administered to a nursing mother.

[Pediatric Use]
The safety and effectiveness of EPO in children have not been established in infants and children (no clinical experience).

[Geriatrics Use]
For the elders, blood pressure and hematocrit should be monitored frequently and the dose and frequency of administration should be adjusted accordingly.

[Drug interactions]
No evidence of interaction of rhEPO with other drugs was observed in the course of clinical trials.

The maximum amount of rhEPO that can be safely administered in single or multiple doses has not been determined. Therapy with overdose of EPIAO can result in polycythemia and deadly complication of cardiovascular system.

[How Supplied]
1.0 ml solution for each vial, containing rhEPO 2000IU/ 3000IU/ 4000IU/ 10000IU

Store at 2-8. Avoid direct sunshine.

[Shelf life]
Two years.

[Approval No.]
2000IU/vial: GUOYAOZHUNZIS19980073
3000IU/vial: GUOYAOZHUNZIS19980074
4000IU/vial: GUOYAOZHUNZIS19980072
10000IU/vial: GUOYAOZHUNZIS20010001

Shenyang Sunshine Pharmaceutical Co., Ltd.

No.3 A1, 10th Road, Shenyang Economy& Technology Development Zone, Shenyang 110027, P.R. China



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