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Pharmacology: Chronic Renal Failure Patients: Endogenous production of erythropoietin is normally regulated by the level of tissue oxygenation. 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 Units/mL and increase up to 100- to 1000-fold during hypoxia or anemia. In contrast, in patients with chronic renal failure (CRF), production of erythropoietin is impaired, and this erythropoietin deficiency is the primary cause of their anemia.
Erythropoietin has been shown to stimulate erythropoiesis in anemic patients with CRF, including both patients on dialysis and those who do not require regular dialysis. The first evidence of a response to the three times weekly (TIW) 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 to 6 weeks. Once the hematocrit reaches the suggested target range (30% to 36%), that level can be sustained by erythropoietin therapy in the absence of iron deficiency and concurrent illnesses.
The rate of hematocrit increase varies between patients and is dependent upon the dose of erythropoietin, within a therapeutic range of approximately 50 to 300 Units/kg. The factors affecting the rate and extent of response include availability of iron stores, the baseline hematocrit, and the presence of concurrent medical problems.
Cancer Patients on Chemotherapy: Anemia in cancer patients may be related to the disease itself or the effect of concomitantly administered chemotherapeutic agents. Erythropoietin has been shown to increase hematocrit and decrease transfusion requirements after the first month of therapy (months 2 and 3), in anemic cancer patients undergoing chemotherapy.
Zidovudine-treated HIV-infected Patients: Responsiveness to erythropoietin in HIV-infected patients is dependent upon the endogenous serum erythropoietin level prior to treatment. Patients with endogenous serum erythropoietin levels ≤500 mUnits/mL, and who are receiving a dose of zidovudine ≤4200 mg/week, may respond to erythropoietin therapy. Patients with endogenous serum erythropoietin levels >500 mUnits/mL do not appear to respond to erythropoietin therapy. Response to erythropoietin in zidovudine-treated HIV-infected patients is manifested by reduced transfusion requirements and increased hematocrit.
Pharmacodynamics: Clinical Effects: Chronic Renal Failure Patients: Response to erythropoietin was consistent across all studies. In the presence of adequate iron stores (see Iron Evaluation), the time to reach the target hematocrit is a function of the baseline hematocrit and the rate of hematocrit rise.
The rate of increase in hematocrit is dependent upon the dose of erythropoietin administered and individual patient variation.
Once the target hematocrit (32% to 38%) was achieved, statistically significant improvements were demonstrated for most quality of life parameters measured, including energy and activity level, functional ability, sleep and eating behavior, health status, satisfaction with health, sex life, well-being, psychological effect, life satisfaction, and happiness.
Adult Patients on Dialysis: The clinical studies were conducted, involving IV administration to anemic patients of erythropoietin therapy. In the three largest of these clinical trials, the median maintenance dose necessary to maintain the hematocrit to 30% to 36% was approximately 75 Units/kg TIW.
Patients with CRF Not Requiring Dialysis: The clinical trials with erythropoietin were conducted in patients with CRF not on dialysis. These patients responded to erythropoietin therapy in a manner similar to that observed in patients on dialysis. Patients with CRF not on dialysis demonstrated a dose-dependent and sustained increase in hematocrit when erythropoietin was administered by either an IV or SC route, with similar rates of rise of hematocrit when erythropoietin was administered by either route.
Zidovudine-treated HIV-infected Patients: Erythropoietin has been studied in clinical trials enrolling anemic (hematocrit <30%), HIV-infected (AIDS) patients receiving concomitant therapy with zidovudine. Erythropoietin reduced the mean cumulative number of units of blood transfused per patient by approximately 40% as compared to the placebo group.
In a 6 month open-label erythropoietin study, patients responded with decreased transfusion requirements and sustained increases in hematocrit and hemoglobin with doses of erythropoietin up to 300 Units/kg TIW.
Cancer Patients on Chemotherapy: Erythropoietin has been studied in a series of placebo-controlled, double blind trials in anemic cancer patients. Within this group, patients were treated with concomitant non cisplatin-containing chemotherapy regimens and cisplatin-containing chemotherapy regimens. Patients were randomized to erythropoietin 150 Units/kg or placebo subcutaneously TIW for 12 weeks.
Erythropoietin therapy was associated with a significantly (p <0.008) greater hematocrit response than in the corresponding placebo-treated patients.
Surgery Patients: Erythropoietin has been studied in a placebo-controlled, double-blind trial enrolling patients scheduled for major, elective orthopedic hip or knee surgery who were expected to require ≥2 units of blood and who were not able or willing to participate in an autologous blood donation program. All patients received oral iron and a low-dose post-operative warfarin regimen.
Treatment with erythropoietin 300 Units/kg significantly (p = 0.024) reduced the risk of allogeneic transfusion in patients with a pretreatment hemoglobin of >10 to ≤13 g/dL.
Efficacy of recombinant human erythropoietin alfa (Renogen) in Indian Patients: The efficacy and safety of erythropoietin was evaluated in open label, 12 weeks, phase III confirmatory trial conducted in Indian patients for the treatments of anemia due to chronic kidney disease. This multicenter study enrolled patients both on dialysis and those not on dialysis with a hematocrit of 24%. Patients were evaluated for rise in hematocrit and reticulocyte count after erythropoietin administration at the baseline and 2-weeks. The patients were also evaluated for achieving the target hematocrit >33% at 12 weeks of drug administration in a dose of 50-150 IU/kg three times in a week. The safety of Erythropoietin was assessed by reporting spontaneous and serious adverse events and laboratory investigations for liver and kidney functions.
There was significant mean increase in hematocrit of 2.63% and reticulocyte of 1.07% (corrected for hematocrit) after 2 weeks of drug administration. 63.2% of patients achieved the target hematocrit of 33% or more at 12 weeks of erythropoietin administration. The remaining 36.8% patients showed an increase in hematocrit till the end of study. No patients required blood transfusion during the treatment with Recombinant Human Erythropoietin Alfa (Renogen).
There was no alteration in liver and kidney functions after erythropoietin administration as assessed by laboratory investigations. The drug was well tolerated in all the patients and no significant adverse effects reported with erythropoietin in this study.
Pharmacokinetics: Intravenously administered erythropoietin is eliminated at a rate consistent with first order kinetics with a circulating half-life ranging from approximately 4 to 13 hours in adult patients with CRF. Within the therapeutic dose range, detectable levels of plasma erythropoietin are maintained for at least 24 hours. After SC administration of erythropoietin to patients with CRF, peak serum levels are achieved within 5 to 24 hours after administration and decline slowly thereafter.
The pharmacokinetic profile of erythropoietin in children and adolescents appears to be similar to that of adults. Limited data are available in neonates.
Toxicology: Preclinical Pharmacology: In-vivo bioassay was performed to assess the potency of recombinant human erythropoietin alfa (Renogen) in swiss albino mice based on European Pharmacopoeia requirements. Reticulocyte count was analyzed using parallel line assay. The analysis revealed that the Intas recombinant human erythropoietin alfa (Renogen) and the standard erythropoietin are comparable in specific biological activities.
Toxicity Studies: Acute toxicity studies were conducted in rats and mice by administering I.V. and S.C. single dose of erythropoietin. There was no death or any adverse effect in the animals at all dose levels. In repeat dose subacute toxicity studies in rats and mice a dose of 30, 300, 3000 IU/kg was administered for a period of 28 days by SC and IV routes. The animals were examined for body weight changes, food consumption, hematology, blood chemistry and histopathological examination of body organs. There was no abnormality detected in any of the parameters in both the species. Erythropoietin was well tolerated in low, medium and high dose levels in these studies.
rHu EPO was also evaluated for local irritation and allergenecity by conducting primary irritation test in rabbits and allergic contact sensitization in guinea pigs. The test drug was well tolerated and there was no evidence of any irritation in animals.
