Hema-Plus

Epoetin alfa (recombinant human erythropoietin).

The recombinant human erythropoietin is a glycoprotein, manufactured by recombinant DNA technology, has 165 amino acids. With a molecular weight of 30,400 Dalton, it is produced by mammalian cells into which the human erythropoietin gene has been introduced. The product contains the identical amino acid sequence of natural Erythropoietin.
Epoetin alfa is formulated as a sterile colorless liquid in an isotonic sodium chloride/sodium citrate buffered solution for intravenous or subcutaneous administration.
Hema-Plus 2000 (Prefilled Syringe): Each prefilled syringe of 1 mL contains 2000 international units (IU) of Recombinant Human Erythropoietin (Epoetin alfa).
Hema-Plus 2000 (0.5 mL in Prefilled Syringe): Each prefilled syringe of 0.5 mL contains 2000 international units (IU) of Recombinant Human Erythropoietin (Epoetin alfa).
Hema-Plus 4000: Each vial of 1 mL contains 4000 international units (IU) of Recombinant Human Erythropoietin (Epoetin alfa).
Hema-Plus 4000 (Prefilled Syringe): Each prefilled syringe of 0.4 mL contains 4000 international units (IU) of Recombinant Human Erythropoietin (Epoetin alfa).
Hema-Plus 5000 (Prefilled Syringe): Each prefilled syringe of 0.5 mL contains 5000 international units (IU) of Recombinant Human Erythropoietin (Epoetin alfa).
Hema-Plus 10000 (Prefilled Syringe): Each prefilled syringe of 1 mL contains 10000 international units (IU) of Recombinant Human Erythropoietin (Epoetin alfa).
Hema-Plus 40000 (Prefilled Syringe): Each mL of solution contains of 40000 IU of Epoetin alfa.
Excipients/Inactive Ingredients: Human albumin, sodium citrate, sodium chloride, citric acid and polysorbate 20 in water for injection.

PHARMACOLOGY: Endothelioid cells of the cortex of the kidney and the outer medulla seem to be responsible for Erythropoietin synthesis (Lacombe, 1988). After it is synthesized in the kidney and released into the circulation erythropoietin develops its hormonal action in the bone marrow by stimulating the development of erythroid progenitor cells into mature erythrocytes. The product stimulates not only the proliferation of erythropoietic progenitor cells, but also their differentiation.
During the maturation phase, hemoglobin values increase together with an acceleration of the erythroblast maturing process and an increase of reticulocytes, which are direct producers of erythrocytes.
At the cell level, it works as a polypeptidic hormone on the receptors of the progenitor erythroid cells. It can also work through a second messenger and internalize.
Various groups, among which Miller (1988), have studied erythropoietin's biochemical action upon its ligand at the cell level. Reports indicate that it can notably increase intracellular calcium levels.
Recombinant human erythropoietin stimulates proliferation and differentiation of erythroid progenitors which is clearly dependent on dose and duration of administration. The increase in reticulocyte count is followed by rises in hematocrit and hemoglobin levels. Tissue iron stores are mobilized during recombinant human erythropoietin therapy, and iron supplement to maintain erythropoiesis is recommended when serum ferritin <100 - 150 ng/mL and/or transferrin saturation is < 20%.
The therapy is not associated with any effects on the peripheral leukocyte or platelets counts.
Blood pressure may increase, particularly during induction therapy. Improvements in left ventricular function and cardiac output appear to be less likely in patients with preexisting hypertension or in those who develop hypertension during the therapy. The treatment with recombinant human erythropoietin has been successful with improvements in exercise capacity. It is also demonstrated that this treatment does not produce the progression of the chronic renal failure.
Chronic renal failure patients: The level of tissue oxygenation normally regulates production of endogenous serum of erythropoietin. Hypoxia and anemia generally increase the production of erythropoietin, which in turn stimulates erythropoiesis.
In normal subjects, plasma erythropoietin levels range from 0.01 to 0.03 mIU/mL and may increase up to 1000-fold during hypoxia or anemia. In contrast, in-patients suffering from chronic renal failure, 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 sequel of renal dysfunction; including anemia. Patients with end-stage renal disease are those patients with chronic renal failure who require regular dialysis or kidney transplantation for survival.
Erythropoietin has been shown to stimulate erythropoiesis in anemic patients with chronic renal failure, including both patients on dialysis and those who do not require regular dialysis.
The first evidence of a response to the three times weekly administration of erythropoietin is an increase in the reticulocyte count within 10 days, followed by increases in the red cell count, hemoglobin and hematocrit, usually within 2-6 weeks. Once the proposal target hematocrit (30-36%) is reached this level should be maintained provided there is no iron deficiency or other concomitant disease.
Cancer patients: Anemia in cancer patients may be related to the disease itself or the effect of concomitantly administered chemotherapeutic agents.
It is recommended that the endogenous serum erythropoietin level be evaluated prior to treatment, since available evidence suggests that patients with endogenous serum erythropoietin levels greater than 200 mIU/mL do not respond to the treatment.
Pharmacokinetics: Intravenous route: Research works conducted on patients after administration of multiple intravenous erythropoietin doses have revealed a half-life of approximately 4 hours in volunteers and a slightly longer half-life (approximately 5 hours) in patients with chronic renal failure. For the time being, a half-life of 6 hours is reported in children.
Subcutaneous route: Serum concentrations following subcutaneous injection are much lower than those following intravenous injection. Serum levels increase slowly and reach a peak 8 to 12 hours after subcutaneous dosing. The maximum concentration is always lower than the obtained with intravenous administration.

Treatment of anemia due to chronic renal disease: Hema-Plus is indicated for the treatment of anemia associated to chronic renal failure, including both, dialysis patients and predialysis patients. The product is indicated to elevate or maintain the red blood cell level as manifested by the hematocrit or hemoglobin determinations and to decrease the need for transfusions in these patients.
Prior to initiation of therapy the patient's iron stores, including transferrin saturation and ferritin, which should be at least 20% and 100 ng/mL, respectively, should be evaluated. Blood pressure has to be properly controlled and monitored very carefully during the treatment. The treatment should be considered in patients with a hematocrit less than 30%.
Treatment of cancer patients on chemotherapy: Hema-Plus is indicated for anemia in patients with non-myeloid malignancies where anemia is due to the effect of concomitantly administered chemotherapy for at least two months, and its purpose is to increase or preserve the level of erythrocytes in blood, shown or expressed through the hematocrit or hemoglobin level, and therefore reduce the number of transfusions these patients need.

RECOMMENDED DOSE: Chronic renal failure patients: Starting dose: Intravenous route: 40 IU/kg three times weekly, Subcutaneous route: 20 IU/kg three times weekly. These doses have proved to be effective and safe in increasing hematocrit levels and eliminating transfusion dependency and need for transfusions. The dose of Hema-Plus should be reduced when the hematocrit reaches the target range of 36%.
Hema-Plus may be administered subcutaneously or intravenously. In patients on dialysis, it can be administered as an intravenous bolus. While the administration of the product should be independent of the dialysis procedure, it may be administered intravenously at the end of such process.
Dose adjustment: After treatment with Hema-Plus, a period of 2 to 4 weeks should be allowed for the parent erythroid cells to mature and be released for circulation, so an increase of the hematocrit takes place at the end.
This adjustment should not be made more than once a month unless clinically indicated.
If the level of the hematocrit approaches 36% the dose should be reduced to be withheld over the target range. Otherwise, the treatment should be suspended until the hematocrit reaches the target range.
If the level of the hematocrit increases by more than 4 points in a two-week period, the dose should be reduced and then the levels of the hematocrit should be monitored twice weekly for a 2 to 6-week period, before applying the maintenance dose.
If an increase of 5-6 points in the level of the hematocrit is not achieved after an 8-week period, the dose should be increased and evaluated again after 2-4 weeks, and then again it can be increased after 4 to 6 week periods.
Maintenance dose: Although the maintenance dose should be individually established, an average maintenance dose may be of 60 IU/kg for patients on dialysis three times weekly.
Diminished or delayed response: Approximately 95% of chronic renal failure patients treated with Epoetin alfa have responded to the treatment. If any patient is not responding, the iron stores should be evaluated, together with any other possible anemia-related etiology.
Cancer patients on chemotherapy: The level of endogenous serum erythropoietin should be evaluated prior to treatment, since available evidence suggests that patients with endogenous serum erythropoietin levels greater than 200 mIU/mL are unlikely to respond to treatment.
Starting dose: The recommended starting dose is 150 IU/kg three times weekly or 40000 IU weekly, subcutaneous route.
Dose adjustment: If the response is not satisfactory in terms of reducing transfusion requirements or increasing hematocrit after 8 weeks of therapy, the dose can be increased in 50 or 100 IU three times weekly and re-evaluated response after 4-8 weeks.
If it is needed, a further increase of the dose from 50-100 IU is needed only up to 300 IU/kg, higher doses are not recommended.
General: If the target hemoglobin concentration exceeds 12 g/dL, the dose should be withheld until a concentration of 12 g/dL is reached. Upon re-initiation of the treatment, the dose should be reduced in 25% and then re-adjusted to maintain the target hemoglobin concentration.
When the treatment is suspended, the target hemoglobin concentration diminishes to approximately 0.5 g/dL per week.
MODE OF ADMINISTRATION: Hema-Plus can be administered subcutaneously or intravenously.

OVERDOSE AND TREATMENT: The maximum amount of Epoetin alfa that can be safely administered has not been determined. Erythropoietin doses of up 1500 IU/kg for three times a week have been administered without any direct toxic effect. This therapy can result in polycythemia if the hematocrit is not carefully monitored and the dose is not appropriately adjusted. If the hematocrit's value exceeds expected, treatment may be interrupted or maintain by using low doses.

Hema-Plus is contraindicated in: 1. Patients suffering from uncontrolled hypertension.
2. Patients who are hypersensitive to products derived from mammalian cells.
3. Patients hypersensitive to human albumin.

General: The essential purpose of Hema-Plus is not the solution of cases of severe anemia that call for immediate correction. This product may obviate the need for treatment with transfusion, but is not a substitute for emergency transfusions, whatever the case is. It is neither indicated to rectify anemia in these specifics groups of patients when the anemic condition are caused from factors other than chronic renal failure or chemotherapy in cancer patients.
Chronic renal disease patients: Hypertension: It is very important to control arterial hypertension in patients with renal disease. It is deemed advisable that the dose of Hema-Plus be decreased if the hematocrit level exceeds 4 points in any two-week period (see Adverse Reactions).
Seizure: Have been reported in one patient with chronic renal failure treated with Epoetin alfa. It is deemed advisable that the dose of Hema-Plus be decreased if the hematocrit level exceeds 4 points in any two-week period (see Adverse Reactions).
Thrombotic events: During hemodialysis, patients treated with Hema-Plus may require increased anticoagulation to prevent clotting of the artificial kidney (see Adverse Reactions).
Cancer patients: Other stimulating agents of the erythropoiesis report an increased incidence of thromboembolic reactions, some serious and mortal, in this group of patient. It has also been described, an increase of the mortality and increase of the risk of tumoral progression or recurrence in patients with cancer.
Hema-Plus is indicated in patient with symptomatic anemia associated to the chemotherapy and when the hemoglobin levels are inferior to 10 g/dL; its preventive use is not recommended in patient with normal hemoglobin levels at the beginning of the treatment with chemotherapy and/or radiotherapy.
In these patients, before beginning the treatment with Hema-Plus other causes should be discarded, as for example the iron deficit, bleeding and hemolysis.
There is no evidence that support the role of the hematopoietic agent on the improvement of survival and response to treatment.
However, an increased incidence of thrombotic vascular events (TVEs) has been observed in cancer patients treated with erythropoiesis-stimulating agents, risk-benefit should be carefully weighed in treatment with epoetin alfa in cancer patients and patients with an increased risk of thrombotic vascular events, such as obesity and patients with a prior history of TVEs (e.g. deep vein thrombosis or pulmonary embolism).

General: Parenteral intake of any biological product must be carefully controlled and care must be taken in cases of allergy or unexpected reactions. Clinical tests showed occasional cases of skin rash. However, no systemic allergic or anaphylactic reactions were observed.
Diminished or delayed response: If the patient fails to respond or maintain a response to doses in the target range, the following etiologies must be observed and evaluated: 1. Iron deficiency. All patients will eventually require additional iron therapy.
2. Underlying infectious, inflammatory or malignant processes.
3. Loss of occult blood.
4. Underlying hematological diseases, e.g., thalassemia, refractory anemia or other myelodysplastic disorders.
5. Vitamins or folic acid deficiency.
6. Hemolysis.
7. Aluminum intoxication.
8. Cystic fibrous osteitis.
9. Secondary hyperparathyroidism.
Hematology: Some very rare cases of patients treated with erythropoietin have shown an exacerbation of porphyry, although there is no evidence of such increase of porphyries metabolites in normal volunteers. Hema-Plus should, however, be used with caution in patients with porphyry.
** Pure Red Cell Aplasia (PRCA): Antibody-mediated pure red cell aplasia (PRCA) were reported after subcutaneous injection of Epoetin treatment for a long time mainly in chronic renal failure patients. Cases were reported in patients with Hepatitis C treated with interferon and ribavirin in combination with Epoetin.
In patients developing lack of efficacy defined by a decrease in haemoglobin with increased need for transfusions, a reticulocyte count should be obtained and typical causes of non-response should be investigated.
If reticulocyte index shows lower than 20000 per microliter or less than 0.5%, with regular level of blood platelet and white blood cell with no other causes, should also be monitored anti-erythropoietin antibodies and bone marrow for diagnosis of the PRCA.
Either unexplained loss of effect (LOE) or PRCA suspected, prompt to discontinue treatment with Hema-Plus. No other ESA therapy should be commenced because of the risk of cross-reaction. Other treatments such as blood perfusion etc should be considered.
Iron assessment: During the treatment with Hema-Plus, an absolute or functional iron deficiency may develop. A functional deficit with normal ferritin values and low transferrin saturation is due to the inability of iron fast mobilization of the store in order to sustain the erythropoiesis rate.
Prior to initiation of therapy the patient's iron stores, including transferrin saturation and ferritin, which should be at least 20% and 100 ng/ml, respectively, should be evaluated. All patients will need an iron supplement.

During pregnancy and postnatal periods, Hema-Plus should be administered only in cases of need and as long as the potential benefit justifies the potential risk for the fetus. No evidence has been found that Epoetin alfa can affect either the fetus, when administered during pregnancy, or the woman's fertility.
Laboratory evaluation: The hematocrit should be determined every week until the patient achieved the target value and the maintenance dosage has been established. After that a regular assessment most be instituted.

Patients with chronic renal failure: Epoetin alfa is generally well tolerated; the adverse events reported are frequent sequel of chronic renal failure and are not necessarily attributable to Epoetin alfa use. In patients with chronic renal failure the most important side events reported from the clinical point of view are hypertension, seizures, thrombotic event, headache, increases of heart rate, nausea, vomiting and hypercalcemia.
Hypertension: Increases in blood pressure have been reported in clinical trials, often during the first 90 days of therapy. Data from clinical trial with Epoetin alfa showed a trend of more reports of hypertensive adverse event in patients on dialysis with a faster rate of rise of hematocrit (greater than 4 points). However in a double blind clinical trial with Epoetin alfa the incidence of hypertension was the same in group, the treated and the control.
Seizures: Seizures have been reported in clinical trials and with an incidence of 5% in patients on dialysis treated with erythropoietin. Even though this is a relatively low figure, there appears to be a higher rate of seizures during the first 90 days of therapy.
Thrombotic events: During hemodialysis, patients treated with Hema-Plus may require increased anticoagulation to prevent clotting of the artificial kidney.
A relationship has not been established with statistical significance between an increase in hematocrit and the rate of thrombotic events (including thrombosis of the vascular access). Clotting of the vascular access has occurred at an annual rate of about 0.25 events per patient-year, which is not greater than non-treated patients on dialysis treatment are.
Serious events of thrombo-embolism, including migratory thrombophlebitis, pulmonary embolus microvascular thrombosis and retinal thrombosis have rarely been observed in patients treated with erythropoietin. The overall frequency has been 0.0001 events per patient-year.
Allergic reactions: There have been no reports of serious allergic reactions or anaphylaxis associated with Epoetin alfa.
Cancer patients on chemotherapy: In this group of patients the following adverse reactions had been reported with an incidence of 10%: fever, diarrhea, vomiting, dizziness, and respiratory infections.
Although some statistically significant differences between patients treated with erythropoietin and placebo-controlled patients were found, the overall safety profile of the product proves to be consistent with the process of an advanced neoplastic disease.

No evidence exists indicates that treatment with Epoetin alfa alters the metabolism of other drugs.
Do not administer intravenously, together with other drug solutions.

PREPARATION: 1. Do not shake. Shaking may denature the glycoprotein and render it biologically inactive.
2. Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration.
3. Using aseptic techniques, attach a sterile needle to a sterile syringe. Remove the flip off from the vial containing Hema-Plus, and wipe the rubber stopper with a disinfectant. Insert the needle into the vial, and withdraw into the syringe an appropriate volume of solution.
4. Do not dilute to any other container and do not administer together with other drug solutions.

Store at 2°C to 8°C. Do not freeze or shake.

Haematopoietic Agents / Supportive Care Therapy

B03XA01 - erythropoietin ; Belongs to the class of other antianemic preparations. Used in the treatment of anemia.

S