Epogen

[Epoetin alfa]

Hematocrit in CRF patients should be measured twice a week; zidovudine-treated HIV-infected and cancer patients should have hematocrit measured once a week until hematocrit has been stabilized, and measured periodically thereafter.

Lack or Loss of Response

If the patient fails to respond or to maintain a response to doses within the recom-mended dosing range, the following etiologies should be considered and evaluated:

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1. Iron deficiency: Virtually all patients will eventually require supplemental
iron therapy (see IRON EVALUATION).

2. Underlying infectious, inflammatory, or malignant processes.

3. Occult blood loss.

4. Underlying hematologic diseases (ie, thalassemia, refractory anemia, or
other myelodysplastic disorders).

5. Vitamin deficiencies: Folic acid or vitamin B12.

6. Hemolysis.

7. Aluminum intoxication.

8. Osteitis fibrosa cystica.

In the absence of another etiology, the patient should be evaluated for evidence of PRCA and sera should be tested for the presence of antibodies to recombinant erythropoietins.

Iron Evaluation

During EPOGEN (r) therapy, absolute or functional iron deficiency may develop. Functional iron deficiency, with normal ferritin levels but low transferrin satura-tion, is presumably due to the inability to mobilize iron stores rapidly enough to support increased erythropoiesis. Transferrin saturation should be at least 20% and ferritin should be at least 100 ng/ mL. Prior to and during EPOGEN (r) therapy, the patient's iron status, including trans-ferrin saturation (serum iron divided by iron binding capacity), and serum ferritin should be evaluated.

Virtually all patients will eventually require supplemental iron to increase or maintain transferrin saturation to levels which will adequately support erythropoiesis stimulated by EPOGEN (r) . All surgery patients being treated with EPOGEN (r) should receive adequate iron supplementation throughout the course of therapy in order to support erythropoiesis and avoid depletion of iron stores.

Carcinogenesis, Mutagenesis, and Impairment of Fertility

Carcinogenic potential of EPOGEN (r) has not been evaluated. EPOGEN (r) does not induce bacterial gene mutation (Ames Test), chromosomal aberrations in mammalian cells, micronuclei in mice, or gene mutation at the HGPRT locus. In female rats treated IV with EPOGEN (r) , there was a trend for slightly increased fetal wastage at doses of 100 and 500 Units/ kg.

Pregnancy

Category C

EPOGEN (r) has been shown to have adverse effects in rats when given in doses 5 times the human dose. There are no adequate and well-controlled studies in pregnant women. EPOGEN (r) should be used during pregnancy only if potential benefit justifies the potential risk to the fetus. In studies in female rats, there were decreases in body weight gain, delays in appearance of abdominal hair, delayed eyelid opening, delayed ossification, and decreases in the number of caudal vertebrae in the F1 fetuses of the 500 Units/ kg group. In female rats treated IV, there was a trend for slightly increased fetal wastage at doses of 100 and 500 Units/ kg. EPOGEN (r) has not shown any adverse effect at doses as high as 500 Units/ kg in pregnant rabbits (from day 6 to 18 of gestation).

Nursing Mothers

Postnatal observations of the live offspring (F1 generation) of female rats treated with EPOGEN (r) during gestation and lactation revealed no effect of EPOGEN (r) at doses of up to 500 Units/ kg. There were, however, decreases in body weight gain, delays in appearance of abdominal hair, eyelid opening, and decreases in the number of caudal vertebrae in the F1 fetuses of the 500 Units/ kg group. There were no EPOGEN (r) -related effects on the F2 generation fetuses. It is not known whether EPOGEN (r) is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when EPOGEN (r) is administered to a nursing woman.

Pediatric Use

See WARNINGS: PEDIATRIC USE.

Pediatric Patients on Dialysis:

EPOGEN (r) is indicated in infants (1 month to 2 years), children (2 years to 12 years), and adolescents (12 years to 16 years) for the treatment of anemia associated with CRF requiring dialysis. Safety and effective-ness in pediatric patients less than 1 month old have not been established (see CLINICAL EXPERIENCE: CHRONIC RENAL FAILURE, PEDIATRIC PATIENTS ON DIALYSIS). The safety data from these studies show that there is no increased risk to pediatric CRF patients on dialysis when compared to the safety profile of EPOGEN (r) in adult CRF patients (see ADVERSE REACTIONS and WARNINGS). Published literature 30-33 provides supportive evidence of the safety and effectiveness of EPOGEN (r) in pediatric CRF patients on dialysis.

Pediatric Patients Not Requiring Dialysis

Published literature 33,34 has reported the use of EPOGEN (r) in 133 pediatric patients with anemia associated with CRF not requiring dialysis, ages 3 months to 20 yearsâ treated with 50 to 250 Units/ kg SC or IVâ QW to TIW. Dose-dependent increases in hemoglobin and hematocrit were observed with reductions in transfusion requirements.

Pediatric HIV-infected Patients

Published literature 35,36 has reported the use of EPOGEN (r) in 20 zidovudine-treated anemic HIV-infected pediatric patients ages 8 months to 17 yearsâ treated with 50 to 400 Units/ kg SC or IVâ 2 to 3 times per week. Increases in hemoglobin levels and in reticulocyte countsâ and decreases in or elimination of blood transfusions were observed.

Pediatric Cancer Patients on Chemotherapy

Published literature 37,38 has reported the use of EPOGEN (r) in approximately 64 anemic pediatric cancer patients ages 6 months to 18 yearsâ treated with 25 to 300 Units/ kg SC or IVâ 3 to 7 times per week. Increases in hemoglobin and decreases in transfusion requirements were noted.

Chronic Renal Failure Patients

Patients with CRF Not Requiring Dialysis

Blood pressure and hematocrit should be monitored no less frequently than for patients maintained on dialysis. Renal function and fluid and electrolyte balance should be closely monitored, as an improved sense of well-being may obscure the need to initiate dialysis in some patients.

Hematology

Sufficient time should be allowed to determine a patient's responsiveness to a dosage of EPOGEN (r) before adjusting the dose. Because of the time required for erythropoiesis and the red cell half-life, an interval of 2 to 6 weeks may occur between the time of a dose adjustment (initiation, increase, decrease, or discontin-uation) and a significant change in hematocrit. In order to avoid reaching the suggested target hematocrit too rapidly, or exceed-ing the suggested target range (hematocrit of 30% to 36%), the guidelines for dose and frequency of dose adjustments (see DOSAGE AND ADMINISTRA-TION) should be followed.

For patients who respond to EPOGEN (r) with a rapid increase in hematocrit (eg, more than 4 points in any 2-week period), the dose of EPOGEN (r) should be reduced because of the possible association of excessive rate of rise of hematocrit with an exacerbation of hypertension. The elevated bleeding time characteristic of CRF decreases toward normal after correction of anemia in adult patients treated with EPOGEN (r) . Reduction of bleeding time also occurs after correction of anemia by transfusion.

Laboratory Monitoring

The hematocrit should be determined twice a week until it has stabilized in the suggested target range and the maintenance dose has been established. After any dose adjustment, the hematocrit should also be determined twice weekly for at least 2 to 6 weeks until it has been determined that the hematocrit has stabilized in response to the dose change. The hematocrit should then be monitored at regular intervals. A complete blood count with differential and platelet count should be performed regularly.

During clinical trials, modest increases were seen in platelets and white blood cell counts. While these changes were statistically significant, they were not clinically significant and the values remained within normal ranges.

In patients with CRF, serum chemistry values (including blood urea nitrogen [BUN], uric acid, creatinine, phosphorus, and potassium) should be monitored regularly. During clinical trials in adult patients on dialysis, modest increases were seen in BUN, creatinine, phosphorus, and potassium. In some adult patients with CRF not on dialysis treated with EPOGEN (r) , modest increases in serum uric acid and phosphorus were observed. While changes were statistically significant, the values remained within the ranges normally seen in patients with CRF.

Diet

As the hematocrit increases and patients experience an improved sense of well-being and quality of life, the importance of compliance with dietary and dialysis prescriptions should be reinforced. In particular, hyperkalemia is not uncommon in patients with CRF. In US studies in patients on dialysis, hyperkalemia has occurred at an annualized rate of approximately 0.11 episodes per patient-year of EPOGEN (r) therapy, often in association with poor compliance to medication, diet, and/ or dialysis.

Dialysis Management

Therapy with EPOGEN (r) results in an increase in hematocrit and a decrease in plasma volume which could affect dialysis efficiency. In studies to date, the result-ing increase in hematocrit did not appear to adversely affect dialyzer function 9,10 or the efficiency of high flux hemodialysis. 11 During hemodialysis, patients treated with EPOGEN (r) may require increased anticoagulation with heparin to prevent clotting of the artificial kidney.

Patients who are marginally dialyzed may require adjustments in their dialysis pre-scription. As with all patients on dialysis, the serum chemistry values (including BUN, creatinine, phosphorus, and potassium) in patients treated with EPOGEN (r) should be monitored regularly to assure the adequacy of the dialysis prescription.

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