What Is Erythropoietin Beta?

Main components: recombinant human erythropoietin-
Excipients include: urea, sodium chloride, polysorbate-20, sodium dihydrogen phosphate dihydrate, disodium hydrogen phosphate dodecahydrate, calcium chloride dihydrate, glycine, L-leucine, L-isoleucine, L-threonine, L-glutamic acid, L-phenylalanine, water for injection.

Recombinant human erythropoietin beta injection, the indication is suitable for patients with anemia caused by chronic renal failure, including those undergoing hemodialysis, peritoneal dialysis and non-dialysis treatment. Treatment of symptomatic anemia in adult patients with non-myeloid malignancy undergoing chemotherapy. This product is used in the treatment of anemia, and can only be used when anemia symptoms appear.

Drug Name

Recombinant human erythropoietin beta injection

Drug type

prescription

Recombinant human erythropoietin beta injection ingredients

Main components: recombinant human erythropoietin-
Excipients include: urea, sodium chloride, polysorbate-20, sodium dihydrogen phosphate dihydrate, disodium hydrogen phosphate dodecahydrate, calcium chloride dihydrate, glycine, L-leucine, L-isoleucine, L-threonine, L-glutamic acid, L-phenylalanine, water for injection.

Characteristics of recombinant human erythropoietin beta injection

This product is a colorless, clear or slightly milky injection.

Indications of recombinant human erythropoietin beta injection

This product is suitable for anemia caused by chronic renal failure, including those undergoing hemodialysis, peritoneal dialysis and non-dialysis treatment.
Treatment of symptomatic anemia in adult patients with non-myeloid malignancy undergoing chemotherapy.
This product is used in the treatment of anemia, and can only be used when anemia symptoms appear.

Recombinant human erythropoietin beta injection specifications

2000IU / 0.3ml / branch: Each prefilled syringe contains 2000IU of recombinant human erythropoietin-ß in a volume of 0.3ml.
4000IU / 0.3ml / branch: Each prefilled syringe contains 4000IU of recombinant human erythropoietin-ß in a volume of 0.3ml.
5000IU / 0.3ml / branch: Each prefilled syringe contains 5000IU of recombinant human erythropoietin-ß in a volume of 0.3ml.
6000IU / 0.3ml / piece: Each prefilled syringe contains 6000IU of recombinant human erythropoietin-ß in a volume of 0.3ml.
10000IU / 0.6ml / piece: Each pre-filled syringe contains 10,000IU of recombinant human erythropoietin-ß in a volume of 0.6ml.

Usage and dosage of recombinant human erythropoietin beta injection

Rocoman treatment should be performed under the guidance of a doctor with extensive experience in the above indications. Since allergic-like reactions are observed in individual cases, it is recommended that the first dose be administered under medical supervision.
It should be noted that this product can only be used for injection when the solution is clear or slightly milky, colorless and almost no visible particles.
The medicine in the pre-filled syringe is sterile, but not preservative-treated. Under no circumstances should each syringe be injected multiple times.
Treatment of symptomatic anemia in adults and children with chronic renal failure.
The symptoms and sequelae of anemia in a patient vary with age, gender, and total disease burden; doctors need to evaluate the clinical course and status of individual patients. Hemoglobin levels can be raised subcutaneously or intravenously to a level not exceeding 12 g / dl (7.5 mmol / l). For patients without hemodialysis, subcutaneous injection is preferred to avoid puncturing the peripheral vein.
If administered intravenously, it should be done in about 2 minutes, for example, for hemodialysis patients who are injected via an arteriovenous fistula at the end of dialysis.
Because of individual patient differences, it can be clinically observed that individual patients' hemoglobin values occasionally exceed or fall below expected hemoglobin levels. Considering that the target hemoglobin concentration is between 10 g / dl (6.2 mmol / l) and 12 g / dl (7.5 mmol / l), different hemoglobin levels can be achieved through dose management. Continuous hemoglobin levels in excess of 12 g / dl (7.5 mmol / l) should be avoided; when hemoglobin values exceed 12 g / dl (7.5 mmol / l), the dosage can be adjusted according to the following guidelines:
Increases in hemoglobin levels over 2 g / dl (1.25 mmol / l) after 4 weeks of administration should be avoided. If this occurs, the dose should be adjusted according to the following principles. If hemoglobin rises by more than 2 g / dl (1.25 mmol / l) or hemoglobin levels are approaching 12 g / dl (7.45 mmol / l) after one month, the dose should be reduced by 25%. If the hemoglobin level continues to increase, treatment should be stopped until the hemoglobin level begins to decrease, and then treatment should be restarted at a dose 25% lower than the previous dose.
Patients should be closely monitored to ensure that the lowest dose of Rocoman is sufficient to control the patient's symptoms of anemia.
When hypertension or cardiovascular, cerebrovascular or peripheral vascular disease occurs, the weekly increase in hemoglobin and the target concentration of treatment should be determined according to the individual condition of the patient.
Rokman's treatment is divided into two phases:
1. Correction period-subcutaneous injection:
The starting dose is 20 IU / kg body weight 3 times a week. If the hemoglobin rise is not ideal ([0.25 g / dl per week), the dose can be increased every 4 weeks, 3 times a week, 20 IU / kg body weight each time.
The weekly dose can be divided into daily doses.
Intravenous administration:
The starting dose is 20 IU / kg body weight 3 times a week. After 4 weeks the dose can be increased to 80 IU / kg each time, 3 times a week. If necessary, an additional 20 IU / kg can be added each month thereafter, 3 times a week.
For the above two routes of administration, the maximum dose does not exceed 720 IU / kg per week.
2. In the maintenance period, in order to maintain the hemoglobin level at 10-12g / dl, the dosage should be reduced to half of the dosage during the treatment period. Subsequently, the patient's dose (maintenance dose) is adjusted every week or two.
If subcutaneous injection is used, the weekly dose can be administered once a week, or divided into three or seven times a week. Patients who are stable once a week can be switched to dosing once every two weeks. Increased dose may be required in this case.
Results from clinical trials in children indicate that younger patients typically require higher doses of rocoman. However, since the response of each patient cannot be predicted, the recommended dosing regimen should be followed.
Rocoman is generally used for long-term treatment, but can be discontinued at any time if needed. Data on once-a-week dosing are from clinical trials over a 24-week course.
Treatment of patients with cancer-induced symptomatic anemia due to chemotherapy (for example, hemoglobin concentration 10g / dl (6.2mmol / l)) should be given by subcutaneous injection of rocoman. The symptoms and sequelae of anemia in a patient vary with age, gender, and total disease burden; physicians need to evaluate the clinical course and status of individual patients.
The weekly dose can be given as a single injection or divided into 3 to 7 single doses.
The recommended initial dose is 30,000 IU / week (equivalent to a dose of approximately 450 IU / kg body weight per week for a medium-weight patient).
Because of individual patient differences, it can be clinically observed that individual patients' hemoglobin values occasionally exceed or fall below expected hemoglobin levels. Considering that the target hemoglobin concentration is between 10 g / dl (6.2 mmol / l) and 12 g / dl (7.5 mmol / l), different hemoglobin levels can be produced through dose management. Continuous hemoglobin levels in excess of 12 g / dl (7.5 mmol / l) should be avoided; when hemoglobin values exceed 12 g / dl (7.5 mmol / l), guidelines for dose adjustment are set out below:
If hemoglobin has increased by at least 1 g / dl (0.62 mmol / l) after 4 weeks of treatment, the current dose should be continued. If hemoglobin levels have not increased by at least 1 g / dl (0.62 mmol / l), then doubling the weekly dose may be considered. If the hemoglobin level does not increase by at least 1 g / dl (0.62 mmol / l) after 8 weeks of treatment, a treatment response is unlikely to occur and treatment should be discontinued.
Treatment should continue until 4 weeks after the end of chemotherapy.
The maximum dose should not exceed 60,000 IU per week.
Once the individual patient's treatment goal is reached, the dose should be reduced by 25-50%, and hemoglobin should be maintained at that level. Consideration should be given to appropriate dose adjustments.
If the hemoglobin level exceeds 12 g / dl (7.5 mmol / l), the dose should be reduced by 25-50%. If the hemoglobin level exceeds 13 g / dl (8.1 mmol / l), Rocoman treatment should be temporarily stopped. When the hemoglobin level is reduced to 12 g / dl (7.5 mmol / l) or lower, the rocoman treatment can be restarted at a dose 25% lower than the previous dose.
If after 4 weeks of treatment, the hemoglobin level rises above 2 g / dl (1.3 mmol / l) or reaches 12 g / dl (7.5 mmol / l), the dose should be reduced by 25% to 50%.
Patients should be closely monitored to ensure that the lowest dose of Rocoman can adequately control the patient's symptoms of anemia.

Adverse reactions of recombinant human erythropoietin beta injection

Based on the results of clinical trials including 1,725 patients, it is estimated that approximately 8% of patients treated with Rocoman will experience adverse reactions.
The most common adverse reactions during Rocoman treatment in patients with anemia in chronic renal failure are elevated blood pressure or exacerbation of existing hypertension, especially when PCV (hematocrit) increases rapidly (see Precautions). In addition, individuals with normal or low blood pressure may develop hypertension crisis with encephalopathy-like symptoms (such as headaches and confusion, sensory dyskinesias-such as speech disorders or impaired gait-until tonic spasticity) .
Bypass thrombosis may occur, especially in patients with a tendency to hypotension or complications of arteriovenous fistulas (such as stenosis, aneurysms) (see Precautions). In most cases, a decrease in serum ferritin levels and an increase in hematocrit can be observed. In addition, transient increases in serum potassium and phosphate levels have been observed in individual cases.
In some cases, Rocoman treatment can cause anti-erythrocyte neutralizing antibody-mediated simple red blood cell regeneration disorder (PRCA). If PRCA is diagnosed, rocoman treatment must be discontinued and the patient must not switch to another erythropoietin for treatment (see note).
The following table lists the incidence of adverse reactions in clinical trials that are believed to be related to rocoman treatment. The adverse reactions that occur are listed in order of decreasing severity.

Common adverse reactions (can be treated with drugs) associated with erythropoietin-beta treatment in cancer patients include headache and hypertension (1%, [10%). (See note)
A decrease in serum iron ion parameters was observed in some patients (see Precautions).
Clinical trials have shown that thromboembolic events occur more frequently in patients treated with rocoman than in untreated or placebo-treated patients. The incidence of thromboembolism in patients treated with rocoman was 7%, compared with 4% in patients in the control group. Compared with patients in the control group, the incidence of thromboembolism was higher in the rocoman group without accompanying thromboembolic events. Increased mortality.
The following table lists the incidence of adverse reactions that occurred in clinical trials and were considered to be related to rocoman treatment. The adverse reactions that occur are listed in order of decreasing severity.

All indications may show rare skin reactions (1 / 10.000 to 1 / 1.000) during erythro-beta treatment, such as rash, pruritus, urticaria, or injection site reactions. Allergic-like reactions have been reported in extremely rare cases (1 / 10.000). However, no increase in the incidence of allergic reactions has been found in controlled clinical trials.
In extremely rare cases (1 / 10.000), especially at the beginning of treatment, flu-like symptoms such as fever, chills, headache, limb pain, discomfort and / or bone pain have been reported. Most of the above reactions are mild or moderate, and subsided within hours or days.

Recombinant human erythropoietin beta injection contraindications

Those who are highly sensitive to the active substance or any of the ingredients.
Patients with poorly controlled hypertension.

Precautions for recombinant human erythropoietin beta injection

Rocoman should be used with caution in athletes and should be used with caution in patients with refractory anemia accompanied by transformed budding, epilepsy, platelet elevation, and chronic liver failure. Folic acid and vitamin B12 deficiency can reduce the effectiveness of rocoman, so this should be avoided.
To ensure that red blood cells are produced efficiently, all patients should be evaluated for iron levels before and during treatment. If necessary, patients can be treated with iron supplementation according to treatment guidelines.
Severe aluminum overload due to renal failure treatment may reduce the efficacy of Rocoman.
As the possibility of accelerating the progression of renal failure cannot be ruled out, this product should be used for the treatment of patients with renal sclerosis who have not received dialysis treatment.
It has been reported that erythropoietin treatment, including rocoman, can cause simple erythropoietic disorders by neutralizing anti-erythropoietin antibodies. These antibodies can cross-react with all erythropoietin proteins, so patients with suspected or confirmed presence of neutralizing erythropoietin antibodies should not switch to rocoman (see Adverse Reactions).
For patients with chronic renal failure, elevated blood pressure or exacerbation of existing hypertension may occur, especially when PCV increases rapidly. These blood pressure increases can be treated with drugs. If medication does not control the rise in blood pressure, it is recommended that Rocoman be temporarily discontinued. Regular monitoring of blood pressure is recommended, especially at the beginning of treatment, including between dialysis sessions. Encephalopathy-like symptoms of high blood pressure crisis may occur, which requires doctors' immediate attention and intensive medical care. Special attention should be paid to sudden stinging migraine-like headaches that may be a warning sign.
Patients with chronic renal failure may have moderate dose-dependent increases in platelet counts within the normal range during rocoman treatment, especially after intravenous administration. This situation will regress during continued treatment. Regular monitoring of platelet count during the first 8 weeks of treatment is recommended.
For patients with chronic renal failure, the maintenance hemoglobin concentration should not exceed the upper limit of the target hemoglobin concentration recommended in [Usage and Dosage]. It has been observed in clinical trials that administration of erythropoietin (ESAs) at target hemoglobin concentrations above 12 g / dl (7.5 mmol / l) increases the risk of death and severe cardiovascular events. Controlled clinical trials have shown that increasing the hemoglobin concentration through erythropoietin and exceeding the standards required to control anemia to treat anemia or avoid blood transfusion does not bring significant benefits to patients.
Platelet counts may be slightly elevated in preterm infants, especially between 12 and 14 days after birth, so platelet monitoring should be performed regularly.
Effects on tumor growth Erythropoietin (EPO) is a growth factor that primarily stimulates the production of red blood cells. The erythropoietin receptor may be expressed on the surface of various tumor cells. Like all growth factors, erythropoietin may stimulate the growth of various malignancies. In several controlled trials, erythropoietin has not been shown to improve overall survival or reduce the risk of tumor progression in patients with cancer anemia.
In controlled clinical trials, the use of rocoman and other erythropoietin drugs (ESAs) has shown:
-When the target hemoglobin concentration is> 14g / dl (8.7mmol / l), it will promote tumor growth and shorten the survival time of patients with advanced head and neck cancer who receive radiotherapy. l), it will promote the four-month disease progression of patients with advanced breast cancer undergoing chemotherapy and shorten their overall survival and increase their death-when the target hemoglobin concentration is 12 g / dl (7.5 mmol / l), it will increase Risk of death in patients with active-stage malignancies who have not received chemotherapy or radiation. This indicates that ESAs cannot be used in such patients.
Elevated blood pressure may be controlled by the drug. Therefore, it is recommended to monitor the blood pressure of patients, especially in the initial treatment stage of tumor patients.
For tumor patients, platelet counts and hemoglobin levels should be monitored regularly to maintain hemoglobin levels at 10-12 g / dL.
In patients with chronic renal failure, it is often necessary to increase the heparin dose during hemodialysis due to increased hematocrit. If heparinization is not optimal, it may block the dialysis system.
For patients with chronic renal failure at risk of bypass thrombosis, early bypass correction and prevention of thrombosis should be considered, such as taking acetylsalicylic acid.
Blood potassium and phosphate levels should be monitored regularly during Rocoman treatment. Elevated blood potassium levels have been reported in a small number of uremic patients treated with rocoman, but the causal relationship has not been clarified. If elevated or increasing blood potassium levels are observed, consider discontinuing use of rocoman until the blood potassium levels return to normal.
From the perspective of the risk / benefit of allogeneic blood transfusion, this product should be used with caution in patients who need to avoid allogeneic blood transfusion in particular.
Misuse of this product by health personnel can lead to excessive increase in hematocrit. This can lead to life-threatening cardiovascular system complications.
Rocoman in each prefilled syringe contains 0.3mg of phenylalanine excipient. Therefore, the treatment of patients with severe phenylpyruvate should be considered.
This product contains less than 1mmol of sodium (23mg) per prefilled needle, which is almost "sodium-free".

Recombinant human erythropoietin beta injection for pregnant and lactating women

There are no clinical research data on recombinant human erythropoietin- in pregnant women. Animal studies have shown that there is no direct or indirect harmful effect on pregnancy, embryo / fetal development, childbirth or postpartum development. For pregnant women medication should be used with caution.

Recombinant human erythropoietin beta injection for children

No related studies in children

Recombinant human erythropoietin beta injection for the elderly

No related studies in children

Drug interactions of recombinant human erythropoietin beta injection

So far, clinical results have not shown that this product interacts with other drugs.
Animal tests have shown that recombinant human erythropoietin-beta does not increase the bone marrow toxicity of cytostatic drugs such as etoposide, cisplatin, cyclophosphamide, and fluorouracil.

Recombinant human erythropoietin beta injection drug overdose

The indications for the treatment of this product are very wide, and no poisoning symptoms are observed even at higher serum concentrations.

Clinical trial of recombinant human erythropoietin beta injection

Erythropoietin is a growth factor that primarily stimulates the production of red blood cells. The erythropoietin receptor can be expressed on the surface of various tumor cells.
Five large controlled trials, including 2,833 patients, studied patient survival and tumor progression. Four of these were double-blind, placebo-controlled trials and one was an open trial. Two of the enrolled patients were receiving chemotherapy with a target hemoglobin concentration of 13 g / dl; the remaining three trials had a target hemoglobin concentration of 12 g / dl to 14 g / dl. For one of the open trials, there was no difference in overall survival between patients receiving the recombinant human erythroglobin treatment group and the control group. The overall survival risk ratio in the four placebo-controlled trials ranged from 1.25 to 2.47, with better results in the control group. These trials have shown that patients receiving various human tumor anaemia patients receiving recombinant human erythroglobin have a consistently unexplained statistically significant increase in mortality compared to the control group. Overall survival results cannot be explained well by the difference in the incidence of thrombosis and related comorbidities in patients receiving the recombinant human erythroglobin treatment group and the control group.
The meta-analysis included data from all patients with anemia tumors (n = 2301) treated with rocoman in 12 controlled trials, which showed that the overall risk ratio for survival was 1.13, with better results in the control group (95% CI 0.87, 1.46) . For patients with baseline hemoglobin levels 10g / dl (n = 899), the hazard ratio for survival was 0.98 (95% CI 0.68 to 1.40). A relative increased risk of thrombotic events was observed in the entire population (RR 1.62, 95% CI: 1.13, 2.31).
A systematic analysis of more than 9,000 cancer patients who participated in 57 trials was performed. A meta-analysis of overall survival showed that the hazard ratio was 1.08, with better results in the control group (95% CI: 0.99, 1.18; 42 trials, 8167 patients). Patients receiving recombinant human erythropoietin were at a higher risk for thrombotic events (RR 1.67, 95% CI: 1.35, 2.06, 35 trials, 6769 patients). Conclusions indicate that there may be significant harm to tumor patients receiving recombinant human erythropoietin. These conclusions can be applied to tumor patients receiving recombinant human erythropoietin therapy, and it is unclear whether it is suitable for patients receiving chemotherapy with a hemoglobin concentration of less than 13 g / dl, as there are almost no such patients in the analysis.
In extremely rare cases, anti-erythropoietin neutralizing antibodies with or without simple erythrocyte regeneration (PRCA) appear during recombinant human erythropoietin treatment.
The two clinical trials ML17616 (hematological tumors) conducted in the Chinese population are open, randomized, two parallel controlled studies designed to validate Rocoman® in the treatment of non-Hodgkin with low-grade malignant multiple myeloma The effectiveness and safety of anemia in adult patients with Lymphoma or chronic lymphocytic leukemia, with a relative erythropoietin deficiency, and undergoing antitumor chemotherapy. A total of 74 patients were randomly assigned to either the Rocoman® treatment group or the control group. Receive treatment for 12 weeks. Of these, 38 patients entered the Rocoman® treatment group and 36 patients entered the control group. Rokman® treatment starts at 150 IU / Kg body weight and is administered subcutaneously three times a week. The results showed that the effective rate of the ITT (intention-to-treat) group in the Rocoman® treatment group was 68.4%, compared with 36.1% in the control group; the effective rate in the PP (per-protocol population) group was 73.5%. The control group was 46.4%.
The changes of hemoglobin values before and after treatment in the two groups are listed in Tables 1 and 2.

ML17620 (solid tumor) is an open, randomized, two parallel controlled study, the main purpose of which is to verify the effectiveness and safety of Rocoman® in the prevention and treatment of anemia in adult solid tumor patients receiving platinum-based chemotherapy. A total of 121 patients were randomly enrolled in the rocoman® treatment group or control group. Receive treatment for 12 weeks. Of these, 61 patients entered the Rocoman® treatment group and 60 patients entered the control group. Rocoman® treatment starts at 150 IU / Kg body weight and is administered subcutaneously three times a week. The results of the study showed that the effectiveness of the Rocoman® treatment group: 47.5% of the ITT (intention-to-treat intention) treatment group and 61.7% of the PP group; the effectiveness of the control group: the ITT (intention-to-treat intention treatment) group 23.3%, PP (per-protocol population) 31.8%.
The changes of hemoglobin values before and after treatment in the two groups are shown in Tables 3 and 4.

Pharmacology and toxicology of recombinant human erythropoietin beta injection

Recombinant human erythropoietin- is consistent with the amino acid and carbohydrate synthesis of erythroglobin isolated from the urine of anemia patients.
Erythropoietin is a glycoprotein that stimulates the production of red blood cells by stimulating stem cell precursors, acting as a mitogen-stimulating factor and differentiation hormone.
The biological effects of recombinant human erythropoietin- were confirmed after intravenous and subcutaneous injection. After administration of recombinant human erythropoietin- in various carrier animal models (normal and uremic rats, erythrocytic mice, dogs), the total iron binding rate, the number of red blood cells, the level of hemoglobin, and the reticulocyte count increased. . In mouse spleen cell culture carrier experiments, it was found that after incubation with recombinant human erythropoietin-, the 3H-thymidine binding rate of nucleated red blood cells in the spleen increased. Human bone marrow cell culture investigations have shown that injection of recombinant human erythro- only stimulates erythrocyte production without affecting white blood cells. No human erythropoietin- has been found to have a toxic effect on human bone marrow or skin cells, nor has any preclinical or clinical investigation shown that recombinant human erythropoietin- has an effect on tumor progression.
Administration of a single dose of recombinant human erythropoietin- had no effect on the behavior and movement of mice, nor did it affect the dog's breathing and circulation.

Pharmacokinetics of recombinant human erythropoietin beta injection

Pharmacokinetics show that in healthy volunteers and patients with uremia, intravenous administration of recombinant human erythropoietin- has a half-life of 4-12 hours and a volume of distribution equivalent to 1-2 times the volume of plasma. Similar results have been found in uremic and normal rat animal experiments. Subcutaneous injection of recombinant human erythropoietin- into uremia patients delays absorption due to serum platelet concentration, reaching the maximum concentration on average 12-28 hours. The average half-life is 13-28 hours, which is longer than intravenous injection.
Bioavailability < br Compared with intravenous injection, the bioavailability of subcutaneous injection of recombinant human erythropoietin- is 23-42%.

Storage of recombinant human erythropoietin beta injection

This product should be stored and transported in the dark at 2 8 .
Keep medicines out of the reach of children.

Recombinant human erythropoietin beta injection packaging

2000IU / 0.3ml / piece, 4000IU / 0.3ml / piece, 5000IU / 0.3ml / piece, 6000IU / 0.3ml / piece, 10000IU / 0.6ml / piece: 6 pieces / box (pre-filled syringe).

Validity of recombinant human erythropoietin beta injection

24 months.

Recombinant human erythropoietin beta injection execution standard

Import Registration Standard: JS20100092