For the use of a Registered Medical Practitioner only
WarningChronic Kidney Disease · In controlled trials, patients experienced greater risks for death, serious adverse cardiovascular reactions, and stroke when administered erythropoiesis stimulating agents (ESAs) to target a hemoglobin level of greater than 12 g/dL · No trial has identified a hemoglobin target level, ESA dose, or dosing strategy that does not increase these risks. · Use the lowest erythropoietin dose sufficient to reduce the need for red blood cell (RBC) transfusions Perisurgery Erythropoietin increased the rate of deep venous thrombosis in patients not receiving prophylactic anticoagulation |
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. ESPOGENTM Inj. 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.
Composition
Each pre-filled syringe contains:
Recombinant human erythropoietin ……………………… 2,000 IU/0.5mL
Each pre-filled syringe contains:
Recombinant human erythropoietin ……………………… 3,000 IU/0.3mL
Each pre-filled syringe contains:
Recombinant human erythropoietin …………………….... 4,000 IU/0.4mL
Each pre-filled syringe contains:
Recombinant human erythropoietin ……………………… 6,000 IU/0.6mL
Each pre-filled syringe contains:
Recombinant human erythropoietin ……………………… 8,000 IU/0.8mL
Each pre-filled syringe contains:
Recombinant human erythropoietin ……………………...10,000 IU/1.0mL
Each vial contains:
Recombinant Human Erythropoietin ...............................10,000 IU/1.0 mL
Each vial contains:
Recombinant Human Erythropoietin............................... 20,000 IU/2.0 mL
Description
Colorless or bright light yellow solution filled in a colorless and transparent vial or pre-filled syringe
Clinical Pharmacology
Mechanism of Action
rhEPO is a hormone that is instrumental in the production of red cells from the erythroid tissues in the bone marrow. The majority of this hormone is produced in the kidney in response to hypoxia, with an additional 10% to 15% of synthesis occurring in the liver. rhEPO functions as a growth factor, stimulating the mitotic activity of the erythroid progenitor cells (erythrocyte burst-forming and colony-forming units) and early precursor cells. The hormone is also active as a differentiation factor that stimulates transformation of an erythrocyte colony-forming unit to a proerythroblast. Although the precise location for the production of erythropoietin in the kidney tubule is not totally conclusive, it has been suggested that tubular or interstitial cells function as the main site for localization of the hormone and its mRNA. Preliminary work has also identified the liver as the major site of erythropoietin production for the fetus.
Erythropoietin significantly increases peripheral hemopoietic progenitor cells including BF-U-E, CFU-GM and CFU-mix within one week of erythropoietin. An increase in hematocrit was noted within 3 to 4 weeks, depending on the dosage of erythropoietin administered. The latter progenitor cells (CFE-GM, CFU-mix) are not those normally associated with erythrocyte production. Thus, erythropoietin may affect both cell lineages (erythroid and myeloid) when given in therapeutic doses.
In normal subjects, plasma erythropoietin levels range from 0.01 to 0.03 IU/ml and increase up to 100 to 1000-fold during hypoxia or anemia. In contrast, in patients with chronic renal failure (CRF), production of erythropoietin is impaired, and this erythropoietin deficiency is the primary cause of their anemia.
Chronic renal failure is the clinical situation in which there is a progressive and usually irreversible decline in kidney function. Such patients may manifest the sequelae of renal dysfunction, including anemia, but do not necessarily require regular dialysis. Patients with end-stage renal disease (ESRD) are those patients with CRF who require regular dialysis or kidney transplantation for survival. Erythropoietin has been shown to stimulate erythropoiesis in anemic patients with CRF, including both patients on dialysis and those who do not require regular dialysis. The first evidence of a response to the three times weekly (UW) administration of erythropoietin is an increase in the reticulocyte count within 10 days, followed by increases in the red cell count, haemoglobin, 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 less than 2 weeks and may require up to 6 weeks in some patients. Once the hematocrit reaches the target range (30-33%), that level can be sustained by erythropoietin therapy in the absence of iron deficiency and concurrent illnesses.
The rate of hematocrit increase varies between patients and is dependent upon the dose of erythropoietin within a therapeutic range of approximately 50-300 IU/kg T.I.W. A greater biologic response is not observed at doses exceeding 300 IU/kg T.I.W. Other factors affecting the rate and extent of response include duration of therapy availability of iron stores, the base-line hematocrit, and the presence of concurrent medical problems.
Pharmacokinetics
Bioavailability of erythropoietin after subcutaneous administration ranges from 22 to 31%. While the elimination half-life of erythropoietin after an i.v. dose is 4 to 13 hours in chronic renal failure patients. The apparent half-life after a subcutaneous dose is 27 hours. Renal clearance ranges from 0.032 to 0.055 ml/min/kg. Volume of distribution estimates ranges from 0.021 to 0.063 I/kg. Within the therapeutic dose range, detectable levels of plasma erythropoietin are maintained for at least 24 hours. After subcutaneous administration of erythropoietin to patients with CRF, peak serum levels are achieved within 5-24 hours after administration and decline slowly thereafter. There is no apparent difference in half-life between patients not on dialysis whose serum creatinine levels were greater than 3, and patients maintained on dialysis. In normal volunteers, the half-life of intravenously administered erythropoietin is approximately 20% shorter than the halt-life in CRF patients. Some metabolic degradation occurs, with small amounts recovered in urine.
Indications and Usage
Treatment of anemia in chronic renal failure patients
Dosage and Administration
Erythropoietin may be administered either subcutaneously or intravenously, however, the intravenous route is usually preferred for patients on hemodialysis. The recommended starting dose ranged from 50-100 IU/kg, 3 times per week. Intravenous injection to be given over at least one to five minutes, depending on the total dose.
Individualize dosing to achieve and maintain hemoglobin levels between 10-12 g/dL. Dosage must be carefully controlled to avoid too fast an increase in haematocrit and haemoglobin, and recommended values should not be exceeded because of the increased risks of hypertension and thrombotic events. The dose of erythropoietin should be reduced as the hemoglobin approaches 12 g/dL or increases by more than 1 g/dL in any2-week period. If hemoglobin excursions occur outside the recommended range, the erythropoietin dose should be adjusted as described below. Individually titrate to achieve and maintain hemoglobin levels between 10 to 12 g/dL.
Starting Dose: 50 to 100 Units/kg TIW; IV or SC
Increase Dose by 25% If:
· Hemoglobin is <10 g/dL and has not increased by 1 g/dL after 4 weeks of therapy or
· Hemoglobin decreases below 10 g/dL
Reduce Dose by 25% When:
· Hemoglobin approaches 12 g/dL or,
· Hemoglobin increases > 1 g/dL in any 2-week period
The administration of erythropoietin is independent of the dialysis procedure. To obviate the need for additional venous acces, erythropoietin may be administered into the venous line at the end of the dialysis procedure. During therapy, hematological parameters should be monitored regularly.
For patients whose hemoglobin does not attain a level within the range of 10 to 12 g/dL despite the use of appropriate erythropoietin dose titrations over a12-week period:
· Use the lowest dose that will maintain a hemoglobin level sufficient to avoid the need for recurrent RBC transfusions.
· evaluate and treat for other causes of anemia.
· thereafter, hemoglobin should continue to be monitored and if responsiveness improves, erythropoietin dose adjustments should be made as described above; discontinue erythropoietin if responsiveness does not improve and the patient needs recurrent RBC transfusions.
Pretherapy Iron Evaluation: Prior to and during erythropoietin therapy, the patient's iron stores, including transferrin saturation (serum iron divided by iron binding capacity) and serum ferritin, should be evaluated. Transferrin saturation should be at least 20%, and ferritin should be at least 100 ng/mL. Virtually all patients will eventually require supplemental iron to increase or maintain transferrin saturation to levels that will adequately support erythropoiesis stimulated by erythropoietin.
Maintenance Dose: The maintenance dose must be individualized for each patient on dialysis. lack or loss of Response: If a patient fails to respond or maintain a response, an evaluation for causative factors should be undertaken. If the transferrin saturation is less than 20%, supplemental iron should be administered.
In any case, maximum dose should not exceed 200 IU/kg in any single day. 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.
When changing from one route of administration to the other, the same dose should be used and the haemoglobin should be followed carefully (e.g. weekly) so that appropriate changes in dose can be made to keep the haemoglobin within the target range.
Contraindications
· Hypersensitivity to the active substance or to any of the excipients and to mammalian cell-derived product.
· Uncontrolled hypertension
· Patients who develop antibody-mediated pure red cell aplasia (PRCA) following treatment with any erythropoietin preparation should not be administered with erythropoietin
· All contraindications associated with autologous blood predonation programmes should be respected in patients being supplemented with erythropoietin.
· Patients undergone surgery who for any reason cannot receive adequate antithrombotic prophylaxis.
Warnings and Precautions
· Patients with hypertension (Rise in blood pressure caused by erythropoietin administration has been recognized and hypertensive encephalopathy may arise.)
· Seizures have been observed, among patients with chronic renal failure (CRF) involved in clinical trials of erythropoietin. 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.
· Chronic hepatic failure patients with predisposition to allergy.
· Patients on erythropoietin therapy should have platelet counts measured on a regular basis until a stable level is achieved, and periodically thereafter.
· It has been reported, that blood viscosity increases with erythropoietin administration and thromboembolism may be exacerbated or induced in patients with myocardial, pulmonary and cerebral infraction, pulmonary embolism, cerebrovascular accident, or transient ischemia attack. In order to store autologous blood and after operation sufficient monitoring required.
· All other causes of anaemia (iron deficiency, haemolysis, blood loss, vitamin B12 or folate deficiencies) should be considered and treated prior to initiating therapy with erythropoietin. 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 erythropoietin, adequate iron stores should be assured.
· Very rarely, development of or exacerbation of porphyria has been observed in erythropoietin-treated patients.
· In order to improve the traceability of the erythropoiesis-stimulating agent (ESA) all measures necessary and possible to ensure it should be taken (e.g. exact information on the product used should be documented in an appropriate way). Furthermore, patients should only be switched from one ESA to another under appropriate supervision.
· Antibody-mediated pure red cell aplasia (erythroblastopenia) has rarely been reported after months to years of treatment with erythropoietins. As these cases are predominantly associated with the subcutaneous route of administration, erythropoietin is recommended to be administered to chronic renal failure patients by the intravenous route. In most of these patients who have pure red cell aplasia, antibodies to erythropoietins have been reported. Patients should be investigated if they develop sudden lack of efficacy. If no cause is identified (e.g. iron folate, or vitamin B12 deficiency, aluminum intoxication, infection or inflammation, blood loss, and haemolysis) a bone marrow examination should be considered. If PRCA is diagnosed, therapy with erythropoietin must be immediately discontinued and testing for erythropoietin antibodies should be considered. If antibodies to erythropoietin are detected, patients should not be switched to another product as anti-erythropoietin antibodies cross-react with other erythropoietins. In case of PRCA due to other causes appropriate therapy should be instituted.
· Patients with ventricular hemorrhage and intracerebral haemorrhage (Cerebral hemorrhage maybe exacerbated by erythropoietin administration).
· During therapy, hemoglobin and hematocrit should be regularly monitored (about once a week in the early phase of administration, once every other week in the maintenance phase) with sufficient care to avoid exceeding target of hemoglobin (≥12g/dl as hemoglobin or ≥ 36% as hematocrit). If excessive hematopoiesis is recognized, appropriate treatments including discontinuance of administration should be considered.
· Blood pressure in patients treated with erythropoietin, 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.
· Hyperkalemia may be caused by erythropoietin administration. If an elevated or rising serum potassium level is detected, then in addition to appropriate treatment of the hyperkalaemia, consideration should be given to ceasing erythropoietin administration until the serum potassium level has been corrected.
· 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.
· An increase in heparin dose during haemodialysis is frequently required during the course of therapy with erythropoietin as a result of the increased packed cell volume. Occlusion of the dialysis system is possible if heparinisation is not optimum.
· Erythropoietin is primarily a growth factor of erythropoiesis. However, the possibility that erythropoietin may act as a growth factor of tumor type, particularly such as myeloid malignancies cannot be excluded.
· In patients scheduled for major elective orthopaedic surgery the cause of anemia should be established and treated, before the start of erythropoietin treatment. Thrombotic events can be a risk in this population and this possibility should be carefully weighed against the benefit to be derived from the treatment in this patient group. Patients scheduled for major elective orthopaedic surgery should receive adequate antithrombotic prophylaxis, as thrombotic as vascular events may occur in surgical patients, especially in those with underlying cardiovascular disease.
Pregnancy & Lactation
Pregnancy Category C - ESPOGENTM should be administered only if benefit for the treatment exceeds potential risk.
Lactation - It is not known whether exogenous erythropoietin is excreted in human milk. Therefore, it should be used with caution in nursing women.
Pediatric Patients
Safety of Erythropoietin in children has not been established.
Geriatric Patients
Physiological function is generally lowered and cardiovascular complications such as hypertension increase in geriatric patients. Dosage and frequency should be appropriately adjusted by measuring blood pressure, haemoglobin, or haematocrit.
Effects on Ability to Drive and Use Machines
There are no reports.
Drug Interactions
No evidence exists that indicates that treatment with erythropoietin alters the metabolism of other drugs. Since cyclosporin is bound by RBCs there is potential for a drug interaction. If erythropoietin is given concomitantly with cyclosporin, blood levels of cyclosporin should be monitored and the dose of cyclosporin adjusted as the haematocrit rises.
No evidence exists that indicates an interaction between erythropoietin and G-CSF or GM-CSF with regard to haematological differentiation or proliferation of tumour biopsy specimens in vitro
Adverse Effects
Blood & Lymphatic System Disorders: Thrombocythaemia, polycythemia, Erythropoeitin antibody-mediated pure red cell aplasia (very rarely reported in <1/10,000 cases per patient year after months to years of treatment), Thrombocytosis, tachycardia, Coagualtion, Anemia defect Immune System Disorders: Anaphylactic reaction, Hypersensitivity
Nervous System Disorders: Headache, Seizures, Cerebral haemorrhage, Cerebrovascular accident, Hypertensive encephalopathy, Transient ischaemic attacks, aphasia and confusion, visual hallucinations.
Eye Disorders: Retinal thrombosis, conjunctivitis
Vascular Disorders: Dose-dependent increase in blood pressure or aggravation of existing hypertension, Deep vein thrombosis, Hypertension, Arterial thrombosis, Hypertensive crisis.
Kidney/genitourinary -Nephrotoxicity, no adverse effect on renal hemodynamics or progression of renal disease was noted in dialysis patients receiving erythropoietin therapy for 18-22 weeks, Hyperkalemia, hyperphosphataemia.
Respiratory, Thoracic, and Mediastinal Disorders: Pulmonary embolism including myocardial infarction and myocardial ischaemia, upper respiratory tract infection.
Gastrointestinal Disorders: Nausea,Vomiting, Diarrhoea, Constipation, abdominal pain.
Skin and Subcutaneous Tissue Disorders: Rash, itching, acne, Angioneurotic oedema, Urticaria, diaphoresis, pseudoporphyria cutanea tarda.
Spleen Disorders: Aggravation of splenomeagaly, splenic infarction.
Musculoskeletal, Connective Tissue, and Bone Disorders: Arthralgia, Myalgia
Congenital and Familial/Genetic Disorders: Porphyria
General Disorders and Administration Site Conditions: Pyrexia, Influenza-like illness, Malaise, Peripheral oedema
Pyrexia, Injection site reaction, Anti-erythropoietin antibody positive
Injury, Poisoning, and Procedural Complications: Shunt thromboses including dialysis equipment (e.g.Aneurysms)
Others: Splenomegaly
The frequencies may vary depending on the indication.
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).
In patients scheduled for major elective orthopaedic surgery, with a baseline haemoglobin of 10 to 13g/dl, the incidence of thrombotic/vascular events (most of which were deep vein thrombosis) in the overall patient population of the clinical trials appeared to be similar across the different erythropoietin dosing groups and placebo group, although the clinical experience is limited.
In patients with a baseline haemoglobin of >13 g/dl, the possibility that erythropoietin treatment may be associated with an increased risk of postoperative thrombotic/vascular events cannot be excluded.
If you experience any side effects, talk to your doctor or pharmacist or write to drugsafety@cipla.com. You can also report side effects directly via the National Pharmacovigilance Programme of India by calling on 18002677779 from within India and on +91 821-6643551 from outside India (except the USA and EU).
Overdose
The therapeutic margin of erythropoietin is very wide. Overdosage of erythropoietin 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.
Instruction for Use, Handling and Disposal
· ESPOGENTM should not be administered by intravenous infusion.
· Before use, let the drug to reach room temperature. This usually takes between 15 -30 minutes.
· The product should be discarded if the seal is broken, contains particles or is not clear
· The product is for single use only.
· Any unused product should be discarded.
· In patients on hemodialysis, it is recommendable ESPOGENTM be injected after hemodialysis. And it is desirable ESPOGENTM be injected slowly over more than 5 minutes to the patients with flu-like symptoms.
How Supplied
2,000 IU/0.5ml / prefilled syringe; 1 ;6 unit pack
3,000 IU/0.3ml / prefilled syringe; 1 ;6 unit pack
4,000 IU/0.4ml / prefilled syringe; 1 ;6 unit pack
6,000 IU/0.5ml / prefilled syringe; 1 ;6 unit pack
8,000 IU/0.6ml / prefilled syringe; 1 ;6 unit pack
10,000 IU/1.0ml / prefilled syringe; 1 ;6 unit pack
10,000 IU/1ml / vial; 1 ;10 unit pack
20,000 IU/2ml / vial; 1 ;10 unit pack
Storage Condition
Store in hermetic container between 2-8°C in refrigerator. Do not freeze or shake, protect from light. Keep out of reach of children.
Incompatibilities
In the absence of compatibility studies, this medicinal product must not be mixed with other medicinal products.
Shelf Life
24 months
· Issued date: February 7, 2018
· Revised date: June 12, 2019
· Drug Import Lic. No.: FFR-50-53
Manufactured by
LG Chem
151, Osongsaengmyeong 1-ro,
Osong-eup, Heungdeok-gu, Cheongju-si,
Chungcheongbuk-do, Korea
Imported by
LG Chem
Life Sciences India Pvt. Ltd.
Basement Commercial SCO No. 321,
Sector-29, Gurugram, Haryana-122001, India
CIN: U24231DL2002PTC116249;
E-mail: info@lgcli.co.in;
Website: www.lgcli.co.in;
Toll Free No.: 18001025648
Marketed by
Cipla
CIPLA LTD
Cipla House, Penninsula Business Park,
Ganpatrao Kadam Marg, Lower Parel,
Mumbai – 400 013 INDIA.