Procrit

[Epoetin alfa]

Iron Evaluation:

During PROCRIT therapy, absolute or functional iron deficiency may develop. Functional iron deficiency, with normal ferritin levels but low transferrin saturation, 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 PROCRIT therapy, the patient's iron status, including transferrin 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 PROCRIT. All surgery patients being treated with PROCRIT should receive adequate iron supplementation throughout the course of therapy in order to support erythropoiesis and avoid depletion of iron stores.

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Carcinogenesis, Mutagenesis, and Impairment of Fertility:

Carcinogenic potential of PROCRIT has not been evaluated. PROCRIT 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 intravenously with PROCRIT, there was a trend for slightly increased fetal wastage at doses of 100 and 500 Units/ kg.

Pregnancy

Category C:

PROCRIT has been shown to have adverse effects in rats when given in doses five times the human dose. There are no adequate and well-controlled studies in pregnant women. PROCRIT 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 intravenously, there was a trend for slightly increased fetal wastage at doses of 100 and 500 Units/ kg. PROCRIT 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 PROCRIT during gestation and lactation revealed no effect of PROCRIT 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 PROCRIT related effects on the F2 generation fetuses. It is not known whether PROCRIT is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when PROCRIT is administered to a nursing woman.

Pediatric Use:

See WARNINGS, Pediatric Use.

Pediatric Patients on Dialysis:

PROCRIT 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 effectiveness 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 PROCRIT in adult CRF patients (see ADVERSE REACTIONS and WARNINGS).

Published literature 30-33 provides supportive evidence of the safety and effectiveness of PROCRIT in pediatric CRF patients on dialysis.

Pediatric Patients Not Requiring Dialysis:

Published literature 33,34 has reported the use of PROCRIT in 133 pediatric patients with anemia associated with CRF not requiring dialysis, ages 3 months to 20 years, treated with 50 to 250 Units/ kg SC or IV, Q. W. to T. I. W. 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 PROCRIT in 20 zidovudine-treated anemic HIV-infected pediatric patients ages 8 months to 17 years, treated with 50 to 400 Units/ kg SC or IV, 2 to 3 times per week (T. I. W.). Increases in hemoglobin levels and in reticulocyte counts, and decreases in or elimination of blood transfusions were observed.

Pediatric Cancer Patients on Chemotherapy:

Published literature 37,38 has reported the use of PROCRIT in approximately 64 anemic pediatric cancer patients ages 6 months to 18 years, treated with 25 to 300 Units/ kg SC or IV, 3 to 7 times per week (T. I. W.). Increases in hemoglobin and decreases in transfusion require-ments 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 PROCRIT before adjusting the dose. Because of the time required for erythropoiesis and the red cell half-life, an interval of 2-6 weeks may occur between the time of a dose adjustment (initiation, increase, decrease, or discontinuation) and a significant change in hematocrit. In order to avoid reaching the suggested target hematocrit too rapidly, or exceeding the suggested target range (hematocrit of 30-36%), the guidelines for dose and frequency of dose adjustments (see "DOSAGE AND ADMINISTRATION") should be followed. F

or patients who respond to PROCRIT with a rapid increase in hematocrit (e. g., more than 4 points in any two-week period), the dose of PROCRIT 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 patients treated with PROCRIT. 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 2-6 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 patients on dialysis, modest increases were seen in BUN, creatinine, phosphorus, and potassium. In some patients with CRF not on dialysis, treated with PROCRIT, 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 U. S. studies in patients on dialysis, hyperkalemia has occurred at an annualized rate of approximately 0.11 episodes per patient-year of PROCRIT therapy, often in association with poor compliance to medication, diet and/ or dialysis.

Dialysis Management:

Therapy with PROCRIT results in an increase in hematocrit and a decrease in plasma volume which could affect dialysis efficiency. In studies to date, the resulting 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 PROCRIT may require increased anticoagulation with heparin to prevent clotting of the artificial kidney.

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

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