Epokine prefilled injection

Epokine

EPOKINE PREFILLED INJECTION 4,000 IU  is a recombinant human erythropoietin, type-α, which is produced by CJ Corp., Korea. It is a glycoprotein hormone which stimulates the division and differentiation of committed erythroid progenitors in the bone marrow.

EPOKINE PREFILLED INJECTION 4,000 IU  has the same biological and immunological effects as endogenous erythropoietin and contains the identical amino acid sequence of isolated natural erythropoietin.

COMPOSITION

Active Ingredient :

Recombinant human erythropoietin —- 4,000 Units/ 0.4 mL

(Host : CHO cell, Vector : pSVEp2neo)

DESCRIPTION

EPOKINE PREFILLED INJECTION 4,000 IU  is a sterile, colorless solution in glass containers (vial or prefilled syringe).

INDICATIONS

  1. Treatment of Anemia of Chronic Renal Failure Patients

EPOKINE PREFILLED INJECTION 4,000 IU  is indicated in the treatment of anemia associated with chronic renal failure, including patients on dialysis and patients not on dialysis. EPOKINE PREFILLED INJECTION 4,000 IU  is indicated to elevate or maintain the red blood cell level and to decrease the need for transfusions.

  1. Treatment of Anemia in Cancer Patients on Chemotherapy
  2. EPOKINE PREFILLED INJECTION 4,000 IU is indicated to elevate the red blood cell level to donate autologous EPOKINE PREFILLED INJECTION 4,000 IU  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 male 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
  2. Cancer Patients on Chemotherapy
  3. Patients to be participated in autologous blood donation program
  4. Chronic Renal Failure (CRF) Patients

EPOKINE PREFILLED INJECTION 4,000 IU  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. 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 2 g/㎗ 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/㎗ (30% as hematocrit). When the anemia is corrected, EPOKINE PREFILLED INJECTION 4,000 IU  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/㎗. The patients with the treatment hemoglobin < 6 g/㎗ need higher maintenance dose than the patients with pretreatment hemoglobin > 8 g/㎗. And the dose may be adjusted according to the age of patients. The unit dose of EPOKINE PREFILLED INJECTION 4,000 IU  should not be exceed of 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 hematocrit for more than six months.

  1. Cancer patients on chemotherapy

The recommended initial dose of EPOKINE PREFILLED INJECTION 4,000 IU  is 150 units/kg as a subcutaneous injection three times a week. If the response is unsatisfactory after 8 weeks of therapy, the dose of EPOKINE PREFILLED INJECTION 4,000 IU  can be increased up to 300 units/kg three times a week. If patients have not responded satisfactorily to a EPOKINE PREFILLED INJECTION 4,000 IU  dose of 300units/kg three times per week, it is unlikely that they will respond to higher doses of EPOKINE PREFILLED INJECTION 4,000 IU . If the hematocrit exceeds 40%, the dose of EPOKINE PREFILLED INJECTION 4,000 IU  should be withheld until it falls to 36%. The dose of EPOKINE PREFILLED INJECTION 4,000 IU  should be reduced by 25% when treatment is resumed or the dose is titrated to maintain the desired hematocrit. If the initial dose of EPOKINE PREFILLED INJECTION 4,000 IU  includes a very rapid hematocrit 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 PREFILLED INJECTION 4,000 IU  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 PREFILLED INJECTION 4,000 IU  therapy, treatment of patients with grossly elevated serum erythropoietin levels higher than 200 mU/mL is not recommended. The hematocrit should be monitored on a weekly basis in patients receiving EPOKINE PREFILLED INJECTION 4,000 IU  therapy until hematocrit becomes stable.

  1. Patients to be participate 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 PREFILLED INJECTION 4,000 IU  can be given intravenously at a dose of 150 – 300units/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 is controlled weekly for the patients who are expected to require > 4 units of blood with pretreatment of hemoglobin > 11 g/㎗ (Hb ℓ< 6.8mmol/L), the patients require > 5 units of blood with pretreatment hemoglobin > 11 g/㎗  (Hb ℓ< 6.8 mmol/L), or the patients to be scheduled to surgery within 1 ∼ 3 weeks. Iron supplimentation : All surgery patients being treated with EPOKINE PREFILLED INJECTION 4,000 IU  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 PREFILLED INJECTION 4,000 IU  is contraindicated in patients with :

  • Known hypersensitivity to the drug or to other erythropoietin
  • Uncontrolled
  • Known hypersensitivity to mammalian cell-derived products or Albumin (Human).
  1. Precautions

EPOKINE PREFILLED INJECTION 4,000 IU  should be administered with caution to the following patients.

  • Patients with hypertension (Blood pressure may rise or hypertensive encephalopathy may occur during EPOKINE PREFILLED INJECTION 4,000 IU )
  • Patients with known history of a hypersensitivity to drugs
  • Patients with known history of allergic reactions to drugs
  • Patients with myocardial infarction, pulmonary infarction or cerebral embolus
  • Patients with cerebral bleeding or premature infant with cerebral bleeding
  1. Adverse Reactions
  • Shock : As shock has been reported, full observation should be If the symptoms appear, the administration should be discontinued and an appropriate treatment should be taken.
  • Cardiovascular : Hypertension, thrombosis of lacrimal duct or A-V shunt, and tachycardia have been reported
  • Hypertensive encephalopathy : 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
  • Cerebral embolus : As cerebral embolus has been reported, full observation should be If the symptoms appear, the administration should be discontinued and an appropriate treatment should be taken.
  • Skin : Itching, skin rash and decubitus have been
  • Liver : Elevation in AST, ALT, LDH, AL-P and total bilirubin may occur
  • I. : Nausea, vomiting, anorexia, diarrhea, and abdominal pain may occur occasionally.
  • Blood : Leukocytosis, eosinophilia have been reported On occasion, granulocytopenia may be occurred in premature infant. Increased serum potassium, BUN, creatinine and uric acid have been reported occasionally.
  • 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 occur occasionally associated with EPOKINE PREFILLED INJECTION 4,000 IU
  • Studies analyzed to date indicate that EPOKINE PREFILLED INJECTION 4,000 IU is generally well-tolerated. The adverse reactions reported are frequent sequelae from patient’s disease and are not necessarily attributable to EPOKINE PREFILLED INJECTION 4,000 IU

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 PREFILLED INJECTION 4,000 IU  during the blinded phase were :    

     Patients-Treated               PLACEBO-Treated

           Reaction                with EPOKINE PREFILLED INJECTION 4,000 IU  (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(Administration site)7.0%                                     11.9%

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 PREFILLED INJECTION 4,000 IU  studies in patints 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 reactions per patient per year. Reactions reported to have occurred within several hours after administration of EPOKINE PREFILLED INJECTION 4,000 IU  were rare, mild, and transient, and included flu-like symptoms such as arthralgias and myalgias. In all studies analyzed to date, EPOKINE PREFILLED INJECTION 4,000 IU  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 PREFILLED INJECTION 4,000 IU  or placebo-treated patients were as indicated below.

 Patients-Treated             PLACEBO-Treated

           Reaction                with EPOKINE PREFILLED INJECTION 4,000 IU  (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 breath                     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 PREFILLED INJECTION 4,000 IU  and placebo-treated patients were noted, the overall safety profile of EPOKINE PREFILLED INJECTION 4,000 IU  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 U/kg, the adverse reaction profile of EPOKINE PREFILLED INJECTION 4,000 IU  was consistent with the progression of advanced cancer. Based on comparable survival data and on the percentage of patients treated with EPOKINE PREFILLED INJECTION 4,000 IU  and placebo-treated patients who discontinued therapy due to death, disease progression or adverse reactions (22% and 13%, respectively ; p=0.25), the clinical outcome in patients treated with EPOKINE PREFILLED INJECTION 4,000 IU  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 PREFILLED INJECTION 4,000 IU  suggest that EPOKINE PREFILLED INJECTION 4,000 IU  does not potentiate tumor growth. Nevertheless, as a growth factor, the possibility that EPOKINE PREFILLED INJECTION 4,000 IU  may potentiate growth of some tumors, particularly myeloid tumors, can not 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 PREFILLED INJECTION 4,000 IU  therapy compared to the corresponding value in the placebo-treated group.

  1. Warnings
  • EPOKINE PREFILLED INJECTION 4,000 IU treatment should be limited in anemic patients with CRF less than 10g/㎗ of hemoglobin (30% as hematocrit) or cancer patients with serum erythropoietin less than 200mU/mL.
  • EPOKINE PREFILLED INJECTION 4,000 IU should not be used in patients with anemia from blood loss, hematocytopenia and aluminum
  • 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 PREFILLED INJECTION 4,000 IU before initiation the therapy or resumption after
    • During the EPOKINE PREFILLED INJECTION 4,000 IU 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/㎗ of hemoglobin or 36% of hematocrit). In case of excessive erythropoiesis, withholding of the drug or appropriate treatment should be
    • Hypertension and hypertensive encephalopathy have been reported in patients treated with EPOKINE PREFILLED INJECTION 4,000 IU , associated with a significant increase in Hematocrit increase may be occurred in case of discontinuation of the therapy. Blood pressure in patients treated with EPOKINE PREFILLED INJECTION 4,000 IU 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
    • Seizures have occurred in patients with CRF participating in EPOKINE PREFILLED INJECTION 4,000 IU clinical 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 PREFILLED INJECTION 4,000 IU  and 2.9% (N=2/68) of placebo-treated patients had seizures. Seizures in 1.6% (N=1/63) of patients treated with EPOKINE PREFILLED INJECTION 4,000 IU  occurred in the context of a significant increase in blood pressure and hematocrit from baseline values. However, both patients treated with EPOKINE PREFILLED INJECTION 4,000 IU  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 eurologic symptoms should be monitored closely.
    • The thrombotic events may be occurred such as myocardial infarction, pulmonary embolism, cerebrovascular accident or ischemic The patients with vascular disease should be monitored cautiously.
    • Since hyperkalemia may be occurred, the importance of compliance with dietary prescriptions should be
    • It may be occurred shunt infarct or residual blood in dialysis kit, so, carefully monitor the blood circulation in shunt or dialysis kit
    • In case of iron deficiency, adequate iron supplementation in order to support erythropoiesis should be
    • EPOKINE PREFILLED INJECTION 4,000 IU is a growth factor that primarily stimulates red blood cell However, the possibility that EPOKINE PREFILLED INJECTION 4,000 IU  can act as a growth factor for any tumor type, particularly myeloid malignancies, cannot be excluded.
  1. Usage in pregnant women

The safety of EPOKINE PREFILLED INJECTION 4,000 IU  in pregnant women has not been established. EPOKINE PREFILLED INJECTION 4,000 IU  should be used during pregnancy only if potential benefit justifies the potential risk.

  1. Pediatric Use

The safety of EPOKINE PREFILLED INJECTION 4,000 IU  in children have not been established.

  1. Geriatric Use

When EPOKINE PREFILLED INJECTION 4,000 IU  is administered to geriatric patients, dosage and frequency should be controlled on the basis of observed blood pressure, hemoglobin concentration or hematocrit.

  1. Precautions in administration
  • Do not dilute or administer in conjunction with other drug
  • Administer EPOKINE PREFILLED INJECTION 4,000 IU after dialysis in patients on dialysis and slowly inject for longer than 5minutes in patients with flu-like
  • EPOKINE PREFILLED INJECTION 4,000 IU should not be administered by intravenous
  1. Treatment of overdosage

The dose response of EPOKINE PREFILLED INJECTION 4,000 IU  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 2∼8℃ protected from light.

Validity : 18 months from manufacturing date.

PRESENTATION

EPOKINE PREFILLED INJECTION 4,000 IU  is supplied in prefilled-syringes. Carton of 6 syringes.

CJ Corp.

Head office

500, 5-Ga, Namdaemun-No, Chung-Ku, Seoul, Korea

Tel : (02 726-8415∼18 Fax : (02) 726-8428

Plant

511, Dokpyong-Ri, Majang-Myon, Ichon-City, Kyonggi-Do, Korea

Tel : (031) 639-4270∼1 Fax : (031) 634-9824

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