CLINICAL PHARMACOLOGY
MECHANISM OF ACTION
Aranesp® stimulates erythropoiesis by the same mechanism as endogenous erythropoietin. A primary growth factor for erythroid development, erythropoietin is produced in the kidney and released into the bloodstream in response to hypoxia. In responding to hypoxia, erythropoietin interacts with progenitor stem cells to increase red blood cell (RBC) production. Production of endogenous erythropoietin is impaired in patients with chronic renal failure (CRF), and erythropoietin deficiency is the primary cause of their anemia. Increased hemoglobin levels are not generally observed until 2 to 6 weeks after initiating treatment with Aranesp® (see DOSAGE AND ADMINISTRATION: Dose Adjustment). In patients with cancer receiving concomitant chemotherapy, the etiology of anemia is multifactorial.
PHARMACOKINETICS
The pharmacokinetics of Aranesp® were studied in patients with CRF and cancer patients receiving chemotherapy.
Over the therapeutic range of 0.45 to 4.5 mcg/kg, pharmacokinetic measures (Cmax, half-life, AUC) were linear with respect to dose, and no evidence of accumulation was observed beyond an expected < 2-fold increase in blood levels when compared to the initial dose.
Following SC administration, absorption is slow and rate limiting. The observed half-life in CRF patients, which reflected the rate of absorption, was 49 hours (range: 27 to 89 hours). Following IV administration to these patients, Aranesp® serum concentration-time profiles are biphasic, with a distribution half-life of approximately 1.4 hours and the mean terminal half-life of 21 hours. Post SC administration in CRF patients' peak concentrations occur at 34 hours (range: 24 to 72 hours), whereas cancer patients' peak concentrations are at 90 hours (range: 71 to 123 hours).
When administered by IV administration, the terminal half-life of Aranesp® is approximately 3-fold longer than Epoetin alfa. The bioavailability of Aranesp® as measured in CRF patients after SC administration is 37% (range: 30% to 50%).
CLINICAL STUDIES
Throughout this section of the package insert, the Aranesp® study numbers associated with the nephrology and cancer clinical programs are designated with the letters "N" and "C", respectively.
CHRONIC RENAL FAILURE PATIENTS
The safety and effectiveness of Aranesp® have been assessed in multicenter studies. Two studies evaluated the safety and efficacy of Aranesp® for the correction of anemia in adult patients with CRF, and two studies assessed the ability of Aranesp® to maintain hemoglobin concentrations in adult patients with CRF who had been receiving other recombinant erythropoietins.
DE NOVO USE OF ARANESP®
In two open-label studies, Aranesp® or Epoetin alfa were administered for the correction of anemia in CRF patients who had not been receiving prior treatment with exogenous erythropoietin. Study N1 evaluated CRF patients receiving dialysis; Study N2 evaluated patients not requiring dialysis (predialysis patients). In both studies, the starting dose of Aranesp® was 0.45 mcg/kg administered once weekly. The starting dose of Epoetin alfa was 50 U/kg 3 times weekly in Study N1 and 50 U/kg twice weekly in Study N2. When necessary, dosage adjustments were instituted to maintain hemoglobin in the study target range of 11 to 13 g/dL. (Note: The recommended hemoglobin target is lower than the target range of these studies. See DOSAGE AND ADMINISTRATION: General for recommended clinical hemoglobin target.) The primary efficacy endpoint was the proportion of patients who experienced at least a 1.0 g/dL increase in hemoglobin concentration to a level of at least 11.0 g/dL by 20 weeks (Study N1) or 24 weeks (Study N2). The studies were designed to assess the safety and effectiveness of Aranesp® but not to support conclusions regarding comparisons between the two products.
In Study N1, the hemoglobin target was achieved by 72% (95% CI: 62%, 81%) of the 90 patients treated with Aranesp® and 84% (95% CI: 66%, 95%) of the 31 patients treated with Epoetin alfa. The mean increase in hemoglobin over the initial 4 weeks of Aranesp® treatment was 1.10 g/dL (95% CI: 0.82 g/dL, 1.37 g/dL). In Study N2, the primary efficacy endpoint was achieved by 93% (95% CI: 87%, 97%) of the 129 patients treated with Aranesp® and 92% (95% CI: 78%, 98%) of the 37 patients treated with Epoetin alfa. The mean increase in hemoglobin from baseline through the initial 4 weeks of Aranesp® treatment was 1.38 g/dL (95% CI: 1.21 g/dL, 1.55 g/dL).
CONVERSION FROM OTHER RECOMBINANT ERYTHROPOIETINS
Two studies (N3 and N4) were conducted in adult patients with CRF who had been receiving other recombinant erythropoietins and compared the abilities of Aranesp® and other erythropoietins to maintain hemoglobin concentrations within a study target range of 9 to 13 g/dL. (Note: The recommended hemoglobin target is lower than the target range of these studies. See DOSAGE AND ADMINISTRATION: General for recommended clinical hemoglobin target.) CRF patients who had been receiving stable doses of other recombinant erythropoietins were randomized to Aranesp®, or to continue with their prior erythropoietin at the previous dose and schedule. For patients randomized to Aranesp®, the initial weekly dose was determined on the basis of the previous total weekly dose of recombinant erythropoietin. Study N3 was a double-blind study conducted in North America, in which 169 hemodialysis patients were randomized to treatment with Aranesp® and 338 patients continued on Epoetin alfa. Study N4 was an open-label study conducted in Europe and Australia in which 347 patients were randomized to treatment with Aranesp® and 175 patients were randomized to continue on Epoetin alfa or Epoetin beta. Of the 347 patients randomized to Aranesp®, 92% were receiving hemodialysis and 8% were receiving peritoneal dialysis.
In Study N3, a median weekly dose of 0.53 mcg/kg Aranesp® (25th, 75th percentiles: 0.30, 0.93 mcg/kg) was required to maintain hemoglobin in the study target range. In Study N4, a median weekly dose of 0.41 mcg/kg Aranesp® (25th 75th percentiles: 0.26, 0.65 mcg/kg) was required to maintain hemoglobin in the study target range.
CANCER PATIENTS RECEIVING CHEMOTHERAPY
The safety and effectiveness of Aranesp® in reducing the requirement for RBC transfusions in patients undergoing chemotherapy was assessed in a randomized, placebo-controlled, double-blind, multinational study (C1). This study was conducted in anemic (Hgb </= 11 g/dL) patients with advanced, small cell or non-small cell lung cancer, who received a platinum-containing chemotherapy regimen. Patients were randomized to receive Aranesp® 2.25 mcg/kg (n = 156) or placebo (n = 158) administered as a single weekly SC injection for up to 12 weeks. The dose was escalated to 4.5 mcg/kg/week at week six, in subjects with an inadequate response to treatment, defined as less than 1 g/dL hemoglobin increase. There were 67 patients in the Aranesp® arm who had their dose increased from 2.25 to 4.5 mcg/kg/week, at any time during the treatment period.
Efficacy was determined by a reduction in the proportion of patients who were transfused over the 12 week treatment period. A significantly lower proportion of patients in the Aranesp® arm, 26% (95% CI: 20%, 33%) required transfusion compared to 60% (95% CI: 52%, 68%) in the placebo arm (Kaplan-Meier estimate of proportion; p < 0.001 by Cochran - Mantel - Haenszel test). Of the 67 patients who received a dose increase, 28% had a 2 g/dL increase in hemoglobin over baseline, generally occurring between weeks 8 to 13. Of the 89 patients who did not receive a dose increase, 69% had a 2 g/dL increase in hemoglobin over baseline, generally occurring between weeks 6 to 13.
Studies were conducted that evaluated doses of Aranesp® ranging from 0.5 mcg/kg to 8.0 mcg/kg administered weekly. Data from these studies indicate that there is a dose response relationship with respect to hemoglobin response. The minimally effective starting dose with respect to reducing transfusion requirements was 1.5 mcg/kg/week, with a plateau observed at 4.5 mcg/kg/week.
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