Welcome Epokine Per Prefilled-syringe or vial Injection (Recombinant human erythropoietin)   Naphro Med / Nephro Tech 1000, 2000, 3000, 4000, 10000 Units                          EPOKINE is a recombinant human erythropoietin, type-a, which is produced by CHEIL JEDANG Corporation, Korea. It is a glycoprotein hormone, which stimulates the division and differentiation of committed erythroid progenitors in the bone marrow. EPOKINE has the same biological and immunological effects as endogenous erythropoietin and contains the identical amino acid sequence of isolated neutral erythropoietin. COMPOSITION: Active Ingredient: Recombinant human erythropoietin --- 1,000 Units / 2,000 Units / 3,000 Units / 4,000 Units / 10,000 Units (Host: CHO cell, Vector: SV40) Stabilizer: Human serum albumin --- 2, 5mg / mL DESCRIPTION: EPOKINE is a sterile, colorless solution in glass containers (vial or Prefilled syringe). INDICATIONS: 1.      Treatment of Anemia of Chronic Renal Failure Patients EPOKINE is indicated in the treatment of anemia associated with chronic renal failure, including patients on dialysis and patients not on dialysis. EPOKINE is indicated to elevate or maintain the red blood cell level and to decrease the need for transfusions. 2.      Treatment of Anemia in Cancer Patients on Chemotherapy 3.      EPOKINE is indicated to elevate the red blood cell level to donate autologous blood. EPOKINE is also indicated to prevent from reducing of hemoglobin for the patients scheduled to major surgery who are not able to participate in an autologous blood donation program. [e.g., 1) low hemoglobin concentration. 2) Patients scheduled to major surgery, female needs more than 4 units of blood or meal needs more than 5 units of blood. 3) in case of short time before surgery to donate autologous blood]. DOSAGE AND ADMINISTRATION: 1.      Chronic Renal Failure (CRF) Patients EPOKINE is administered intravenously at an initial dose of 50 units/kg for 1~2 minutes three times a week. It can be given by either an intravenous or subcutaneous route for patients with CRF not on dialysis. The dose increase is dependent upon the initial response. The dose can be increased, if necessary, by 25 units / kg in 4-week period. If hemoglobin is increased more than 2g/dl at a dose of 50 units/kg, the frequency should be reduced to two times a week. To correct the anemia, the target concentration of hemoglobin is 10 g/dl (30% as haematocrit). When the anemia is corrected, EPOKINE is given as a maintenance dose of 25~50 units / kg two or three times a week. The target range of hemoglobin is 10~12 g/dl. The patients with pretreatment hemoglobin <6g/dl need higher maintenance dose than the patients with pretreatment hemoglobin > 8 g/dl. And the dose may be adjusted according to the age of patients. The unit dose of EPOKINE should not be exceed 200 units / kg, and the frequency should not be more than three times a week.  Prior to initiation of therapy or during the therapy, the patient’s iron stores should be evaluated, if necessary, iron should be supplied. If the patients are in aluminum intoxication or infected, delayed or diminished responses may be occurred. In patients with CRF not on dialysis, the maintenance dose must also be individualized according to the severity of anemia or age, however, the dose of 70~150 units / kg per week have been shown to maintain 36~38% of haematocrit for more than six months. 2.      Cancer patients on Chemotherapy The recommended initial dose of EPOKINE is 150 units / kg as a subcutaneous injection three times a week. If the response is unsatisfactory after 8 weeks of therapy, the dose can be increased up to 300 units / kg three times a week. If patients have not responded satisfactory to a EPOKINE dose of 300 units / kg three times per week, it is unlikely that they will respond to higher dose of EPOKINE. If the haematocrit exceeds 40%, the dose of EPOKINE should be withheld unit it falls to 36%. The dose of EPOKINE should be reduced by 25% when treatment is resumed or the dose is titrated to maintain the desired haematocrit. If the initial dose of EPOKINE includes a very rapid haematocrit response (e.g., an increase of more than 4% points in any 2-week period), the dose should be reduced. In general, patients with lower baseline serum erythropoietin levels responded more vigorously to EPOKINE than patients with higher erythropoietin levels. Although no specific serum erythropoietin level can be stipulated above which patients would be unlikely to respond to EPOKINE therapy, treatment of patients with grossly elevated serum erythropoietin levels higher than 200 mU /mL is not recommended. The haematocrit should be monitored on a weekly basis in patients receiving EPOKINE therapy until haematocrit becomes stable.   3.      Patients to be participated in autologous blood donation program Prior to major surgery, it is recommended to take autologous blood two times a week for 3 weeks. Based on previous studies, EPOKINE, can be given intravenously at a dose of 150-300 units / kg, two times a week for 3 weeks to elevate the red blood cell levels. The recommended maximum dose to promote erythropoiesis is 600 units / kg, two times a week for 3 weeks intravenously. The concentration of hemoglobin should be controlled weekly for the patients who are expected to require> 4 units of blood with pretreatment of hemoglobin> 11 g/dl (Hb i< 6.8mmol/L), the patients require >5 units of blood with pretreatment hemoglobin> 11g/dl (Hb <6.8 mmol/L), or the patients to be scheduled to surgery within 1 ~ 3 weeks. Iron supplementation All surgery patients being treated with EPOKINE should receive adequate iron supplementation (e.g., 200mg of iron preparations per day, P.O) throughout the course of therapy in order to support erythropoiesis and avoid depletion of iron stores. Iron supplementation should be initiated as soon as possible, several weeks before taking blood. PRECAUTIONS: 1.      Contraindications EPOKINE is contraindicated in patients with: 1)      Known hypersensitivity to the drug or to other erythropoietin products. 2)      Uncontrolled hypertension. 3)      Known hypersensitivity to mammalian cell-derived products or Albumin (Human). 2.      General Precautions EPOKINE should be administered with caution to following patients. 1)      Patients with hypertension (Blood pressure may rise or hypertensive encephalopothy may occur during  EPOKINE therapy.) 2)      Patients with known history of a hypersensitivity to drugs. 3)      Patients with known history of allergic reactions to drug. 4)      Patients with myocardial infarction, pulmonary infarction or cerebral embolus. 5)      Patients with cerebral bleeding or premature infant with cerebral bleeding. 3.      Adverse Reactions 1)      Shock: As shock has been reported, full observation should be taken. If the symptoms appear, the administration should be discontinued and an appropriate treatment should be taken. 2)      Cardiovascular: Hypertension, thrombosis of lacrimal duct or A-V shunt, and tachycardia have been reported rarely. 3)      Hypertensive encephalopothy: As hypertensive encephalopathy (shows headache, conscious disorder and seizures) and cerebral hemorrhage have been reported occasionally, the drug should be administered cautiously with observation of the trends of blood pressure and hematocrit during the therapy. 4)      Cerebral embolus: As cerebral embolus has been reported, full observation should be taken. If the symptoms appear, the administration should be discontinued and an appropriate treatment should be taken 5)      Skin: Itching, skin rash and decubitus have been reported 6)      Liver: Elevation in AST, ALT, LDH, AL-P and total bilirubin may occur occasionally. 7)      G.I.: Nausea, vomiting, anorexia, diarrhea, and abdominal pain may occur occasionally. 8)      Blood: Leukocytosis, eosinophilia have been reported occasionally. On occasion, granulocytopenia may be occurred in premature Infant. Increased serum kalium, BUN, creatinine and uric acid have been reported occasionally. 9)      Others: Cerebral hemorrage in the eyes, splenomegaly, nasal hemorrage, edema, headache, dizziness, fever, mild fever, fatigue, arthralgia, myalgia, bitter taste in mouth, tremor, and edema of eyelid may occasionally associated with EPOKINE therapy. 10)  Studies analyzed to date indicate that EPOKINE is generally well-tolerated. The adverse reactions reported are frequent sequelae from patient’s disease, and are not necessarily attributable to EPOKINE therapy. (1) Chronic Renal Failure Patients In double-blind, placebo-controlled studies involving over 300 patients with CRF, the reactions reported in greater than 5% of patients treated with EPOKINE during the blinded phase were: Patients Treated              PLACEBO-Treated Reaction                with EPOKINE (N=200)            Patients (N=135) Hypertension               24.0%                                       18.5% Headache                    16.0%                                       11.9% Arthralgias                   11.0%                                       5.9% Nausea                       10.5%                                       8.9% Edema                          9.0%                                       10.4% Fatigue                          9.0%                                       14.1% Diarrhea                        8.5%                                       5.9% Vomiting                       8.0%                                       5.2% Chest Pain                     7.0%                                       8.8% Skin Reaction                7.0%                                       11.9% (Administration site) Asthenia                        7.0%                                       11.9% Dizziness                       7.0%                                       12.6% Clotted Access              6.8%                                       2.3% Significant adverse reactions of concern in patients with CRF treated with in double-blinded, placebo-controlled trials occurred in the following percent of patients during the blinded phase of the studies: Seizure                          1.1%                                       1.1% CVA / TIA                   0.4%                                       0.6% MI                                0.4%                                       1.1% Death                            0%                                          1.7% In the EPOKINE studies in patients on dialysis (N=567), the incidence of the most frequently reported adverse reactions were: hypertension (0.75%), headache (0.40%), tachycardia (0.31%), nausea / vomiting (0.26%), clotted vascular access (0.25%), shortness of breath (0.14%), hyperkalemia (0.11%), and diarrhea (0.11%). Other reported reactions occurred at a rate of less than 0.10% of reaction per patient per year. Reactions reported to have occurred within several hours after administration of EPOKINE were rare, mild, and transient, and included flu-like symptoms such as arthralgias and myalgias. In all studies analyzed to date, EPOKINE administration was generally well-tolerated, irrespective of the route of administration. (2) Cancer patients on chemotherapy In double-blind, placebo-controlled studies of up to 3-month duration involving 131 cancer patients, adverse reactions with an incidence > 10% in either patients treated with EPOKINE or placebo-treated patients were as indicated below. Patients Treated              PLACEBO-Treated Reaction                        with EPOKINE (N=63)            Patients (N=68) Pyrexia                                     29%                             19% Diarrhea                                   21%                             7% Nausea                                    17%                             32% Vomiting                                  17%                             15% Edema                                     17%                             1% Asthenia                                   13%                             16% Fatigue                                     13%                             15% Shortness of breathe                 13%                             9% Paresthesia                               11%                             6% Upper respiratory infection        11%                             4% Dizziness                                  5%                               12% Trunk pain                                3%                               16% Although some statistically significant differences between patients treated with EPOKINE and placebo-treated patients were noted, the overall safety profile of EPOKINE appeared to be consistent with the disease process of advanced cancer. During double-blind and subsequent open-label therapy in which patients (N=72) were treated for up to 32 weeks with doses as high as 927 Units / kg, the adverse reaction profile of EPOKINE was consistent with the [progression of advanced cancer. Based on comparable survival data and on the percentage of patients treated with EPOKINE and placebo-treated patients who discontinued therapy due to death, disease progression or adverse reactions (22% and 13%, receptivity; p=0.25), the clinical outcome in patients treated with EPOKINE and placebo-treated patients 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 EPOKINE suggest that EPOKINE does not potentiate tumor growth. Nevertheless, as a growth factor, the possibility that EPOKINE may potentiate growth of some tumors, particularly myeloid tumors cannot be excluded. A randomized controlled phase IV study is currently ongoing to further evaluate this issue. The mean peripheral white blood cell count was unchanged following EPOKINE therapy compared to the corresponding value in the placebo-treated group. 4.      Warnings 1)      EPOK1NE treatment should be limited in anemic patients with CRF less than I0g/dl of hemoglobin (30% as hematocrit) or cancer patients with serum erythropoietin less than 200mU/mL. 2)      EPOKINE should not be used in patients with anemia from blood loss, hematocytopenia and aluminum intoxication. 3)      Special monitoring of patient’s history should be done to forecast shock or other responses. Low dosage should be allowed by intravenous route to determine a patient’s responsiveness to the administration of EPOKINE before initiation the therapy or resumption after withholding. 4)      During the EPOKINE therapy, hemoglobin concentration or hematocrit should be observed periodically (once a week at initial therapy, biweekly at maintenance therapy). Special caution should be taken not to result in excessive erythropoiesis (more than 12g/dl of hemoglobin or 36% of hematocrit). In case of excessive erythropoiesis, withholding of the drug or appropriate treatment should be taken. 5)      Hypertension and hypertensive encephalopathy have been reported in patients treated with EPOKINE, associated with a significant increase in hematocrit. Hematocrit increase may be occurred in case of discontinuation of the therapy. Blood pressure in patients treated with EPOKINE should be monitored carefully, particularly in patients with an underlying history of hypertension or cardiovascular disease. The dosage should be adjusted in patients with a fast rate of rise of hematocrit (greater than 4% in any two-week period) owing to the potential for an increased risk. 6)      Seizures have occurred in patients with CRF participating in EPOKINE clinical trials. In patients on dialysis, there was a higher incidence of seizures during the first 90 days of therapy (occurring in approximately 2.5% of patients) as compared with later timepoints. Seizures also have occurred in cancer patients on chemotherapy. In double blind, placebo-controlled trials, 3.2% (N=2/63) of patients treated with EPOKINE and 2.9% (N=2/68) of placebo-treated patients had seizures. Seizures in 1.6% (N=1/63) of patients treated with EPOKINE occurred in the context of a significant increase in blood pressure and hematocrit from baseline values. However, both patients treated with EPOKINE also had underlying CNS pathology, which may have been related to seizure activity. Given the potential for an increased risk of seizures during the therapy, blood pressure and the presence of premonitory neurologic symptoms should be monitored closely. 7)      The thrombotic events may be occurred such as myocardial infarction, pulmonary embolism, cerebrovascular accident or ischemic attack. The patients with vascular disease should be monitored cautiously. 8)      Since hyperkalemia may be occurred, the importance of compliance with dietary prescriptions should be reinforced. 9)      It may be occurred shunt infarct or residual blood in dialysis kit, so, carefully monitor the blood circulation in shunt or dialysis kit. 10)  In case of iron deficiency, adequate iron supplementation in order to support erythropoiesis should be done. 11)  EPOKINE is a growth factor that primarily stimulates red blood cell production. However, the possibility that EPOKINE can act as a growth factor for any tumor type, particularly myeloid malignancies, cannot be excluded. 5.      Usage in pregnant women The safety of EPOKINE in pregnant women has not been established. EPOKINE should be used during pregnancy only if potential benefit justifies the potential risk 6.      Pediatric Use The safety of EPOKINE in children have not been established. 7.      Geriatric Use When EPOKINE is administered to geriatric patients, dosage and frequency should be controlled on the basis of observed blood pressure, hemoglobin concentration or hematocrit. 8.      Precautions in administration 1)      Do not dilute or administer in conjunction with other drug solutions. 2)      Administer EPOKINE after dialysis in patients on dialysis and slowly inject for longer than 5minutes in patients with flu-like symptoms. 3)      EPOKINE should not be administered by intravenous infusion. 9.      Treatment of overdosage The dose response of EPOKINE depends upon the conditions of patient. In case of overdosage, hypertension may be occurred. If polycythemia is of concern, phlebotomy may be indicated to decrease the hematocrit. STORAGE AND EXPIRATION Storage: Store at 20 ~ 80 C protected from light. Expiration: 18 months PRESENTATION EPOKINE is supplied in pre filled-syringes or vials. EPOK!NE PREFILLED - Inj. 1000 Units / 2000 Units / 3000Units / 4000Units / 10,000 Units: Carton of 1, 6, and 10 syringes. EPOKINE - Inj. 2000 Units / 4000 Units / 10,000 Units: carton of 1,6 and 10 vials. Registration # Put-ups 023635 Epokine 2,000 IU Prefilled Syringe   023633 Epokine 4,000 IU Prefilled Syringe   023632 Epokine 10,000 IU Vials   Marketed in Pakistan by:   RenalCare Division of: RG Pharmaceutica (Pvt.) Ltd. Manufactured by: CHEILJEDANG Corporation 500, 5-Ga, Namdaemun-No, Chung-Ku, Seoul, Korea Tel: (02) 726-8628~30 Fax: (02) 726-8649
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