Treatment of anemia associated with chronic renal failure in adult hemodialysis, peritoneal dialysis and predialysis patients and pediatric patients on hemodialysis.

Treatment of anemia in cancer patients with non-myeloid malignancies (with or without chemotherapy) and prevention of anemia in cancer patients with non-myeloid malignancies who are undergoing treatment with a chemotherapeutic agent.

Treatment of anemia in HIV-infected patients being treated with zidovudine who have endogenous erythropoietin levels < 500 mU/mL.

Indicated in adult patients with mild to moderate anemia (hemoglobin >10 to <13 g/dl) scheduled for elective orthopedic surgery with an expected moderate blood loss (2-4 units or 900 to 1800 mL) to reduce exposure to allogeneic blood transfusions and to facilitate erythropoietic recovery).

Method of Administration

Epoetin alfa (EPREX) may be administered by intravenous or subcutaneous injection.

As for any parenterally administered drug, the injection solution should be inspected for particles and discoloration prior to administration. Do not shake, shaking may denature the glycoprotein, rendering it inactive.

Epoetin alfa (EPREX) in single use syringes contains no preservatives. Do not re-enter or re-use syringe. Discard unused portion.

Intravenous Injection: Epoetin alfa (EPREX) should be administered over at least one to five minutes,depending on the total dose. A slower injection may be preferable in patients who react to the treatment with flu-like symptoms. In hemodialysis patients, the injection should be administered into the fistula needle at the completion of a hemodialysis session. To rinse the tubing and ensure satisfactory injection of the product into the circulation, the injection should be followed by 10 mL of isotonic saline. Epoetin alfa (EPREX) should not be administered by intravenous infusion or mixed with other drugs.

Subcutaneous Injection: The maximum volume per injection site should be 1 mL. In case of larger volumes, more than one injection site should be used. The injections should be given in the limbs or the anterior abdominal wall.

Chronic Renal Failure Patients

In patients with chronic renal failure, epoetin alfa (EPREX) should only be administered by the intravenous route (see Special Warnings and Special Precautions for Use - Renal Failure Patients).

The following is only to be used in those situations where an HSA-containing formulation of epoetin alfa (EPREX) is available:

In patients with chronic renal failure, HSA-containing epoetin alfa (EPREX) should be administered by the intravenous route, where feasible. For those patients where intravenous access is not available, the risk of PRCA should be taken into consideration prior to the administration of HSA-containing epoetin alfa (EPREX) by the subcutaneous route (see Special Warnings and Special Precautions for Use - Renal Failure Patients).

The hemoglobin concentration should be 10 to 12 g/dL (6.21-7.45mmol/L) in adults and 9.5 to 11 g/dL (5.90-6.83 mmol/L) in children. In patients with chronic renal failure and clinically evident ischaemic heart disease or congestive heart failure, maintenance hemoglobin concentration should not exceed the upper limit of the target hemoglobin concentration.

Iron status should be evaluated prior to and during treatment and iron supplementation should be administered if necessary. Other causes of anemia [such as Vitamin B12 or folate deficiency] should be excluded before starting therapy with epoetin alfa (EPREX). Non- response to epoetin alfa (EPREX) therapy should prompt a search for causative factors. These include: iron, folate, or Vitamin B12 deficiency; aluminum intoxication, intercurrent infections, inflammatory or traumatic episodes, occult blood loss, hemolysis, and bone marrow fibrosis of any origin.

The following is only to be used in those situations where an HSA-containing formulation of epoetin alfa (EPREX) is available: epoetin alfa (EPREX) may be administered intravenously or subcutaneously. When changing the route of administration, the same dose should be used initially and then titrated to keep hemoglobin in the target range.

In the correction phase, the dose of epoetin alfa (EPREX) should be increased if the hemoglobin does not increase at least 1g/dL (0.62 mmol/L) per month.

A clinically significant increase in hemoglobin is usually not observed in less than 2 weeks and may require up to 6-10 weeks in some patients.

Once the target hemoglobin concentration is achieved, the dose should be decreased by 25 IU/kg/dose in order to avoid exceeding the target range. In addition, if the hemoglobin concentration exceeds 12 g/dL (7.45 mmol/L), therapy should be withheld.

Dose reductions may be made by omitting one of the weekly doses or by decreasing the amount of the each dose.

Adult Hemodialysis Patients

In patients on hemodialysis, epoetin alfa (EPREX) should only be administered by the intravenous route (see Special Warnings and Special Precautions for Use - Renal Failure Patients).

The following is only to be used in those situations where an HSA-containing formulation of epoetin alfa (EPREX) is available:

In patients on hemodialysis, HSA-containing epoetin alfa (EPREX) should be administered by the intravenous route, where feasible. For those patients where intravenous access is not available, the risk of PRCA should be taken into consideration prior to the administration of HSA-containing epoetin alfa (EPREX) by the subcutaneous route (see Special Warnings and Special Precautions for Use - Renal Failure Patients).

The treatment is divided into two stages:

Correction Phase: 50 IU/kg three times per week. When necessary, dose adjustments should be made in increments of 25 IU/kg three times per week at intervals of at least 4 weeks until the target hemoglobin concentration (10-12 g/dL [6.21-7.45 mmol/L] is achieved.

Maintenance Phase: The maintenance dose should be individualized for each chronic renal failure patient.. The recommended total weekly dose is between 75 and 300 IU/kg.

Available data suggests that patients with a baseline hemoglobin < 6 g/dL (3.73 mmol/L) may require higher maintenance doses than patients with a baseline hemoglobin >8 g/dL (>4.97 mmol/L).

Pediatric Hemodialysis Patients

In pediatric hemodialysis patients, epoetin alfa (EPREX) should only be administered by the intravenous route (see Special Warnings and Special Precautions for Use - Renal Failure Patients).

The treatment is divided into two stages:

Correction Phase: 50 IU/kg three times per week by the intravenous route. When necessary, dose adjustments should be made in increments of 25 IU/kg three times per week at intervals of at least 4 weeks until the target hemoglobin concentration (9.5-11 g/dL [5.90-6.83 mmol/L]) is achieved.

Maintenance Phase: Generally, children under 30 kg require higher maintenance doses than children over 30 kg and adults. For example, the following maintenance doses were observed in clinical trials after 6 months of treatment.

Weight (kg)	Median	Dose (IU/kg given 3x/week) Usual maintenance dose
< 10	100	75-150
10-30	75	60-150
> 30	33	30-100

Available data suggests that patients whose initial hemoglobin is very low (hemoglobin <6.8 g/dL [4.22 mmol/L]) may require higher maintenance doses than patients whose initial hemoglobin is higher (hemoglobin >6.8 g/dL [4.22 mmol/L]).

Adult Peritoneal Dialysis Patients

In peritoneal dialysis patients, epoetin alfa (EPREX) should only be administered by the intravenous route (see Special Warnings and Special Precautions for Use - Renal Failure Patients).

The following is only to be used in those situations where an HSA-containing formulation of epoetin alfa (EPREX) is available:

In peritoneal dialysis patients, HSA-containing epoetin alfa (EPREX) should be administered by the intravenous route, where feasible. For those patients where intravenous access is not available, the risk of PRCA should be taken into consideration prior to the administration of HSA-containing epoetin alfa (EPREX) by the subcutaneous route (see Special Warnings and Special Precautions for Use - Renal Failure

The treatment is divided into two stages:

Correction Phase: 50 IU/kg twice per week. When necessary, dose adjustments should be made in increments of 25 IU/kg twice per week at intervals of at least 4 weeks until the target hemoglobin concentration (10-12 g/dL [6.21-7.45 mmol/L]) is achieved.

Maintenance Phase: The usual dose to maintain the target hemoglobin (10-12 g/dL [6.21-7.45 mmol/L]) is between 25 and 50 IU/kg twice per week in two equal injections.

Adult Predialysis Patients [Adult Patients with End Stage Renal Insufficiency]

In patients with renal insufficiency not yet undergoing dialysis, epoetin alfa (EPREX) should only be administered by the intravenous route (see Special Warnings and Special Precautions for Use - Renal Failure Patients). The following is only to be used in those situations where an HSA-containing formulation of epoetin alfa (EPREX) is available:

In patients on hemodialysis, HSA-containing epoetin alfa (EPREX) should be administered by the intravenous route, where feasible. For those patients where intravenous access is not available, the risk of PRCA should be taken into consideration prior to the administration of HSA-containing epoetin alfa (EPREX) by the subcutaneous route (see Special Warnings and Special Precautions for Use - Renal Failure

The treatment is divided into two stages:

Correction Phase: 50 IU/kg three times per week. When necessary, dose adjustments should be made in increments of 25 IU/kg three times per week at intervals of at least 4 weeks until the target hemoglobin concentration (10-12 g/dL [6.21-7.45 mmol/L] is achieved.

Maintenance Phase: The usual dose to maintain the target hemoglobin is between 17 and 33 IU/kg three times per week.

The maximum dosage should not exceed 200 IU/kg 3 times per week.

Cancer Patients

The subcutaneous route of administration should be used.

The target hemoglobin concentration should be approximately 12 g/dL (7.45 mmol/L). Epoetin alfa (EPREX) may be administered for the treatment of anemia in adult cancer patients.

Epoetin alfa (EPREX) may be used to prevent anemia in adult patients beginning chemotherapy who have a low baseline hemoglobin level (< 10.5 g/dL [6.5 mmol/L]). Epoetin alfa (EPREX) may also be used to maintain hemoglobin levels in adult cancer patients who are at risk of developing anemia during chemotherapy. Such as patients who had a substantial decrease in hemoglobin during their first cycle of chemotherapy (e.g., a 1.0-2.0 g/dL [0.62-1.24 mmol/L]) decrease in hemoglobin if their baseline is 11-13 g/dL [6.83-8.07 mmol/L] or a decrease of > 2.0 g/dL[1.24 mmol/L] if their baseline hemoglobin is > 13 g/dL [8.07 mmol/L].

The initial dose for the maintenance of hemoglobin or treatment of anemia should be 150 IU/kg 3 times per week.

If after 4 weeks of treatment, the hemoglobin has increased by at least 1 g/dL (0.62 mmol/L) [or the reticulocyte count has increased 40,000 cells/mL above baseline] the dose should remain at 150 IU/kg.

If after 4 weeks of treatment the hemoglobin increase is <1 g/dL (0.62 mmol/L) [and the reticulocyte count has increased <40,000 cells/mL bove baseline] the dose should be increased to 300 IU/kg for an additional 4 weeks.

If after 4 weeks of additional therapy with 300 IU/kg, the hemoglobin has increased > 1 g/dL (0.62 mmol/L), [or the reticulocyte count has increased > 40,000 cells/mL] the dose should remain at 300 IU/kg.

If after 4 weeks of additional therapy with 300 IU/kg, the hemoglobin has increased <1 g/dL (0.62 mmol/L) [and the reticulocyte count has increased < 40,000 cell/mL above baseline], response is unlikely and treatment should be discontinued.

[The recommended dosing regimen is described in the following diagram:]

A rate of rise in hemoglobin of greater than 2g/dL (1.25 mmol/L) per month or hemoglobin levels of >14 g/dL (>8.7 mmol/L) should be avoided. If the hemoglobin is rising by more than 2 g/dL (1.25 mmol/L) per month, reduce the epoetin alfa (EPREX) dose by about 25-50% depending upon the rate of rise of hemoglobin. If the hemoglobin exceeds 14 g/dL (8.69 mmol/L), discontinue therapy until it falls below 12 g/dL (7.45 mmol/L) and then reinitiate epoetin alfa (EPREX) at a dose 25% below the previous dose.

Epoetin alfa (EPREX) therapy should continue until one month after the end of chemotherapy. However, the need to continue epoetin alfa (EPREX) therapy shoul be re-evaluated periodically.

Zidovudine Treated HIV-Infected Patients Prior to beginning epoetin alfa (EPREX), it is recommended that the endogenous serum erythropoietin level be determined prior to transfusion. Available data suggests that patients with endogenous serum erythropoietin levels > 500 mU/mL are unlikely to respond to therapy with epoetin alfa (EPREX).

The treatment is divided into two stages:

Correction Phase: 100 IU/kg three times per week by subcutaneous or intravenous route for 8 weeks. If the response is not satisfactory (i.e., reduced transfusion requirements of increased hemoglobin) after 8 weeks of therapy, the dose of epoetin alfa (EPREX) can be increased. Dose increases should be made in increments of 50-100 IU/kg three times per week at intervals of at least 4 weeks. If patients have not responded satisfactorily to an epoetin alfa (EPREX) dose of 300 IU/kg three times per week, it is unlikely that they will respond to higher doses.

Maintenance Phase: After the desired response is attained, the dose should be titrated to maintain the hematocrit between 30-35%, based on factors such as variations in zidovudine dose and the presence of intercurrent infections or inflammatory episodes. If the hematocrit exceeds 40%, the dose should be discontinued until the hematocrit decreases to 36%. When treatment is resumed, the dose should be reduced by 25% and then titrated to maintain the desired hematocrit

Adult Orthopedic Surgery Patients in an Autologous Pre-Donation Program

Iron status should be evaluated for all patients prior to treatment with epoetin alfa (EPREX). Iron deficiency, if present, should be corrected before allowing a patient to enroll in an autologous blood donation program. In anemic patients, the cause of anemia should be explored before starting therapy with epoetin alfa (EPREX).

All patients being treated with epoetin alfa (EPREX) should receive adequate iron supplementation (e.g.,200 mg oral elemental iron daily) throughout the course of epoetin alfa (EPREX) treatment. In order to achieve high iron stores prior to starting epoetin alfa (EPREX) therapy, iron supplementation should be started as soon as possible, even several weeks prior to initiating the autologous predeposit.

The intravenous route of administration should be used.

Epoetin alfa (EPREX) should be administered after the completion of each blood donation procedure.

Mildly anemic patients (hematocrit of 33-39% and/or hemoglobin 10-13 g/dL [6.21-8.07 mmol/L]) requiring predeposit [of >4 units] of blood should be treated with epoetin alfa (EPREX) at 600 IU/kg 2 times weekly for 3 weeks prior to surgery.

For those patients who require a lesser degree of erythropoietic stimulation, a dosage regimen of 150-300 IU/kg administered twice weekly has been shown to augment autologous pre-donation and to decrease the subsequent decline in hematocrit.

Orthopedic Perisurgery Patients (Without Autologous Blood Donation)

All patients should receive adequate iron replacement. Iron replacement (e.g., at least 200 mg of oral elemental iron daily) should be initiated no later than the beginning of treatment with epoetin alfa (EPREX) and should continue throughout the course of therapy.

The subcutaneous route of administration should be used. The recommended dosage regimen is 600 IU/kg epoetin alfa (EPREX) subcutaneously given weekly for three weeks (days -21,-14 and -7) prior to surgery and on the day of the surgery. In cases where there is a medical need to shorten the lead time before surgery to less than 3 weeks, 300 IU/kg subcutaneously should be given daily for 10 consecutive days prior to surgery, on the day of the surgery and for four days immediately after. 300 IU/kg/day is recommended for hemoglobin levels <13 g/dL (8.07 mmol/L).

Contraindications

Patients who develop antibody-mediated Pure Red Cell Aplasia (PRCA) following treatment with any erythropoetin should not receive epoetin alfa (EPREX) or any other erythropoetin (see Special Warnings and Special Precautions for Use - Renal Failure Patients).

Uncontrolled hypertension.

Known hypersensitivity to any of the components of this product.

All contraindications associated with autologous blood predonation programs should be respected in patients being supplemented with epoetin alfa (EPREX).

The use of epoetin alfa (EPREX) in patients scheduled for major elective orthopedic surgery and not participating in an autologous blood predonation program is contraindicated in patients with severe coronary, peripheral arterial, carotid, or cerebral vascular disease, including patients with recent myocardial infarction or cerebral vascular accident.

Patients who for any reason cannot receive adequate antithrombotic prophylaxis.

Special Warnings and Special Precautions for Use

Blood pressure should be adequately controlled prior to initiation of epoetin alfa (EPREX) therapy.

In all patients receiving epoetin alfa (EPREX), blood pressure should be closely monitored and controlled as necessary. Epoetin alfa (EPREX) should be used with caution in the presence of untreated, inadequately treated or poorly controllable hypertension. Particular attention should be paid to the development of unusual headaches or an increase in headaches as a possible warning signal.

It may be necessary to initiate or increase anti-hypertensive treatment during epoetin alfa (EPREX) therapy. If blood pressure cannot be controlled, epoetin alfa (EPREX) should be discontinued.

Epoetin alfa (EPREX) should be used with caution in patients with a history of seizures. Patients with conditions associated with thrombotic/vascular events should be closely monitored.

The safety of epoetin alfa (EPREX) has not been established in patients with hepatic dysfunction. Due to decreased metabolism, patients with hepatic dysfunction may have increased erythropoiesis with epoetin alfa (EPREX).

There may be a moderate dose-dependent rise in the platelet count, within the normal range, during treatment with epoetin alfa (EPREX). This regresses during the course of continued therapy. It is recommended that the platelet count should be regularly monitored during the first 8 weeks of therapy.

Renal Failure Patients
In chronic renal failure patients the rate of increase in hemoglobin should be approximately 1 g/dL (0.62 mmol/L) per month and should not exceed 2 g/dL (1.24 mmol/L) per month to minimize the risks of an increase in hypertension.

Antibody-mediated pure red cell aplasia (erythroblastopenia) has rarely been reported after months to years of treatment with erythropoietins. As the antibody-mediated PRCA cases are predominantly associated with the subcutaneous route of administration, epoetin alfa (EPREX) should only be administered to chronic renal failure patients by the intravenous route. [In those situations where an HSA-containing formulation of epoetin alfa (EPREX) is available: HSA-containing epoetin alfa (EPREX) should be administered by the intravenous route, where feasible. For those patients where intravenous access is not available, the risk of PRCA should be taken into consideration prior to the administration of HSA-containing epoetin alfa (EPREX) by the subcutaneous route]. In most of these patients who have pure red cell aplasia, antibodies to erythropoietins have been reported. In patients developing sudden lack of efficacy typical causes of non-response (e.g., iron folate, or Vitamin B12 deficiency, aluminum intoxication, infection or inflammation, blood loss, and hemolysis) should be investigated. If no cause is identified, a bone marrow examination should be considered. If PRCA is diagnosed, therapy with epoetin alfa (EPREX) 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. Other causes of pure red cell aplasia should be excluded, and appropriate therapy instituted (see Method of Administration and Contraindications). Chronic renal failure patients on epoetin alfa (EPREX) should have hemoglobin levels measured on a regular basis until a stable level is achieved and periodically thereafter. In order to ensure optimum response to epoetin alfa (EPREX), adequate iron stores should be assured, and folic acid and vitamin B12 deficiencies should be excluded prior to initiating therapy. In most cases, the ferritin values in the serum fall simultaneously with the rise in packed cell volume. Therefore, iron supplementation, e.g., 200-300 mg/day orally, (100-200 mg/day for pediatric patients) is recommended for chronic renal failure patients whose serum ferritin levels are below 100 ng/mL.

In patients with chronic renal failure and clinically evident ischemic heart disease or congestive heart failure, maintenance hemoglobin concentration should not exceed the upper limit of the target hemoglobin concentration as recommended under the Method of Administration.

Hyperkalemia has been observed in isolated cases. In chronic renal failure patients, correction of anemia may lead to increased appetite and potassium and protein intake. Dialysis prescriptions may have to be adjusted periodically to maintain urea, creatinine, and potassium in the desired range. Serum electrolytes should be monitored in chronic renal failure patients. If an elevated (or rising) serum potassium level is detected then consideration should be given to ceasing epoeitin alfa (EPREX) administration until hyperkalemia has been corrected. Based on information available to date, the use of epoetin alfa (EPREX) in predialysis [end stage renal insufficiency] patients does not accelerate the rate of progression of renal insufficiency.

As a result of an increase in packed cell volume, hemodialysis patients receiving epoetin alfa (EPREX) frequently require an increase in heparin dose during dialysis. If heparinization is not optimal, occlusion of the dialysis system is possible.

In some female chronic renal failure patients, menses have resumed following epoetin alfa (EPREX) therapy; the possibility of potential pregnancy should be discussed and the need for contraception evaluated.

Rarely, exacerbation of porphyria has been observed in epoetin alfa (EPREX) -treated patients with chronic renal failure. Epoetin alfa (EPREX) should be used with caution in patients with known porphyria.

Cancer Patients
Cancer patients on epoetin alfa (EPREX) should have hemoglobin levels measured on a regular basis until a stable level is achieved and periodically thereafter. In order to ensure optimum response to epoetin alfa (EPREX), adequate iron should be assured, and folic acid and vitamin B12 deficiencies should be excluded prior to initiating therapy. In most cases, the ferritin values in the serum fall simultaneously with the rise in packed cell volume. Therefore, iron supplementation, e.g., 200-300 mg/day orally is recommended for cancer patients whose serum ferritin levels are below 100 ng/mL.

Epoetin alfa (EPREX) is a growth factor that primarily stimulates red blood cell production. However, the possibility that epoeitin alfa can act as a growth factor for any tumor type, particularly myeloid malignancies, cannot be excluded.

HIV-Infected Patients
If HIV-infected patients fail to respond or maintain a response to epoetin alfa (EPREX), other etiologies including iron deficiency anemia should be considered and evaluated.

Adult Surgery Patients in an Autologous Pre-Donation Program
All special warnings and special precautions associated with autologous blood donation programs, especially routine volume replacement, should be respected in patients being supplemented with epoetin alfa (EPREX).

Adult Perisurgery Patients (Without Autologous Blood Donation)

In patients scheduled for major elective orthopedic surgery the cause of anemia should be established and treated, if possible, before the start of epoetin alfa (EPREX) treatment.

In patients scheduled for major elective orthopedic surgery thrombotic events can be a risk and the possibility should be carefully weighed against the benefit to be derived from the treatment in this patient group.

Patients scheduled for major elective orthopedic surgery should receive adequate antithrombotic prophylaxis, as thrombotic and vascular events may occur in surgical patients, especially in those with underlying cardiovascular disease. In addition, special precaution should be taken in patients with predisposition for development of DVTs. Moreover, in patients with a baseline hemoglobin of.>13 g/dL (8.07 mmol/L), the possibility that epoetin alfa (EPREX) treatment may be associated with an increased risk of postoperative thrombotic/vascular events cannot be excluded. Therefore, it should not be used in patients with baseline hemoglobin >13 g/dL (8.07 mmol./L).

The use of epoetin alfa (EPREX) is not recommended in perisurgery patients with a baseline hemoglobin of >13 g/dL (8.07 mmol/L).

Interaction with Other Medicinal Products and Other Forms Of Interaction

No evidence exists that indicates that treatment with epoetin alfa (EPREX) alters the metabolism of other drugs. However, since cyclosporin is bound by red blood cells there is potential for a drug interaction. If epoetin alfa (EPREX) is given concomitantly with cyclosporin, blood levels of cyclosporin should be monitored and the dose of cyclosporine adjusted as the hematocrit rises.

[No evidence exists that indicates an interaction between epoetin alfa (EPREX) and G-CSF or GM-CSF with regard to hematological differentiation or proliferation of tumor cells from biopsy specimens in vitro.]

[The effect of epoetin alfa (EPREX) may be potentiated by the simultaneous therapeutic administration of hematinic agent, such as ferrous sulphate, when a deficiency state exist.]

[Drugs that decrease erythropoiesis may decrease the response to epoetin alfa (EPREX).]

Pregnancy and Lactation

In animal studies, epoetin alfa (EPREX) has been shown to decrease fetal body weight, delay ossification and increase fetal mortality when given in weekly doses of approximately 20 times the recommended human weekly dose. These changes are interpreted as being secondary to decreased maternal body weight gain.

There are no adequate and well-controlled studies in pregnant women.

In chronic renal failure patients, epoetin alfa (EPREX) should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

See Reproduction Toxicology

Erythropoietin is present in human milk. However, it is not known whether epoetin alfa (EPREX) is distributed into human milk. Epoetin alfa (EPREX) should be used with caution in nursing women.

In pregnant or lactating surgical patients participating in an autologous blood predonation program, the use of epoetin alfa (EPREX) is not recommended.

Effects On Ability To Drive And Use Machines

Due to the increased risk of hypertension during the initial phase of epoetin alfa (EPREX) treatment, patients with chronic renal failure should use caution when performing potentially hazardous activities, such as driving or operating machinery, until the optimal maintenance dose of epoetin alfa (EPREX) has been established.

Undesirable Effects

"Flu-like" symptoms such as dizziness, drowsiness, headaches, joint pains, and feelings of weakness may occur, especially at the start of treatment.

Thrombocytosis has been observed but its occurrence is rare.

Thrombotic/vascular events, such as myocardial ischemia, myocardial infarction, cerebrovascular accidents (cerebral hemorrhage and cerebral infarction), transient ischemic attacks, deep venous thrombosis, arterial thrombosis, pulmonary emboli, aneurysms, retinal thrombosis, and clotting of an artificial kidney have been reported in patients receiving epoetin alfa (EPREX). However, a causal relationship between epoetin alfa (EPREX) therapy and these events has not been established.

Non-specific skin rashes have been described in association with epeotin alfa (EPREX).

Skin reactions at the injection site have been reported in EPREX-treated patients. These reactions occur more frequently in patients receiving subcutaneous therapy than in patients receiving intravenous therapy.

Patients complain of erythema, burning, and pain, usually mild to moderate, around the site of injection.

The development of immune reactions to epoetin alfa (EPREX) is rare.

Renal Failure Patients
The most frequent adverse reaction during treatment with epoetin alfa (EPREX) is a dose-dependent increase in blood pressure or aggravation of existing hypertension. [These increases in blood pressure can be treated with drugs. Moreover, monitoring of the blood pressure is recommended and particularly at start of therapy. The following reactions have also occurred in isolated patients with normal or low blood pressure: hypertensive crisis with encephalopathy-like symptoms (e.g., headaches and confused state) and generalized tonoclonal seizures, requiring the immediate attention of a physician and intensive medical care.] Particular attention should be paid to sudden stabbing migraine-like headaches as a possible warning signal.

Shunt thromboses have occurred in hemodialysis patients, especially in those who have a tendency to hypotension or whose arteriovenous fistulae exhibit complications (e.g., stenoses, aneurysms, etc.). [Early shunt revision and thrombosis prophylaxis by administration of acetylsalicylic acid, for example, is recommended in these patients.]

In chronic renal failure patients, pure red cell aplasia (erythroblastopenia) has very rarely been reported after months to years of treatment with erythopoietins. [see Special Warnings and Special Precautions For Use].

Cancer Patients
The overall safety profile in cancer patients treated with epoetin alfa (EPREX) is consistent with the disease process.

HIV-Infected Patients
The overall safety profile in HIV-infected patients treated with epoetin alfa (EPREX) is consistent with the disease process.

Adult Surgery Patients in an Autologous Pre-Donation Program
Independent of epoetin alfa (EPREX) treatment, thrombotic and vascular events may occur in surgical patients with underlying cardiovascular disease following repeated phlebotomy. Therefore, routine volume replacement should be performed in such patients in autologous blood donation programs.

Adult Perisurgery Patients (Without Autologous Blood Donation)
In patients scheduled for major elective orthopedic surgery, with a baseline hemoglobin of 10 to 13 g/dL, the incidence of thrombotic/vascular events (most of which were DVTs), in the overall patient population of the clinical trials, appeared to be similar across the different epoetin alfa (EPREX) dosing groups and placebo group, although the clinical experience is limited.
Moreover, in patients with baseline hemoglobin of >13 g/dL, the possibility that epoetin alfa (EPREX) treatment may be associated with an increased risk of postoperative thrombotic/vascular events cannot be excluded. Therefore, it should not be used in patients with baseline >13 g/dL (8.07 mmol/L).

Overdose

The therapeutic margin of epoetin alfa (EPREX) is very wide. Overdosage of epoetin alfa may produce effects that are extensions of the pharmacological effects of the hormone. Phlebotomy may be performed if excessively high hemoglobin levels occur. Additional supportive care should be provided as necessary.

Pharmaceutical Particulars

Incompatibilities
Do not dilute or transfer to any other container. Do not administer in conjunction with other drug solutions.

Special Precautions For Storage
Store at 2°C to 8°C [36° to 46°F]. Do not freeze or shake, and protect from light.

Keep out of reach of children.

CAUTION: Foods, Drugs, Devices and Cosmetics Act prohibits dispensing without prescription.

Manufactured by:
Vetter Pharma-Fertigungs GmbH & CoKG
Ravensburg, Germany
Under license from:
Cilag AG International
Schaffhausen, Switzerland
Imported by:
Johnson & Johnson (Phils.), Inc.
Edison Road, Bo. Ibayo
Parañaque City
Packed by:
Interphil Laboratories, Inc.
Canlubang Industrial Estate
Bo. Pittland, Cabuyao, Laguna
Exclusively distributed by:
Zuellig Pharma Corporation
Sen. Gil Puyat Avenue Makati City