Erythropoietin dosing

The availability of erythropoietin has had a significant positive impact for patients with chronic renal failure. Erythropoietin consistently improves the hematocrit and hemoglobin level and usually eliminates the need for transfusions in these patients. An increase in reticulocyte count is usually observed in about 10 days and an increase in hematocrit and hemoglobin levels in 2-6 weeks. Most patients can maintain a hematocrit of about 35% with erythropoietin doses of 50-150 IU/kg intravenously or subcutaneously three times a week. Failure to respond to erythropoietin is most commonly due to concurrent iron deficiency, which can be corrected by giving oral iron. Folate supplementation may also be necessary in some patients. 

In selected patients, erythropoietin may also be useful for the treatment of anemia due to primary bone marrow disorders and secondary anemias. This includes patients with aplastic anemia and other bone marrow failure states, myeloproliferative and myelodysplastic disorders, multiple myeloma and perhaps other chronic bone marrow malignancies, and the anemias associated with chronic inflammation, AIDS, and cancer. Patients with these disorders who have disproportionately low serum erythropoietin levels for their degree of anemia are most likely to respond to treatment with this growth factor. Patients with endogenous erythropoietin levels of less than 100 IU/L have the best chance of response, though patients with erythropoietin levels between 100 and 500 IU/L respond occasionally. These patients generally require higher erythropoietin doses (150-300 IU/kg three times a week) to achieve a response, and responses are often incomplete. 

Kato A, et al. Effect of weekly or successive iron supplementation on erythropoietin doses in patients receiving hemodialysis. Nephron 2001 89 110-112. 

Patients with anemia secondary to chronic kidney disease are ideal candidates for epoetin alfa therapy. The response in predialysis, peritoneal dialysis, and hemodialysis patients is dependent on the severity of renal failure, erythropoietin dose and route of administration, and iron availability. The subcutaneous route of administration is preferred to the intravenous route because absorption is slower and the amount of drug required is reduced by 20 to 40%. 

Port RE, Mehls O. Erythropoietin dosing in children with chronic kidney disease based on body size or on hemoglobin deficit Pediatr Nephrol 2009 24(3) 435-7. 

Subcutaneous versus intravenous erythropoietin or darbepoetin is usual, which may reduce overall doses and be more physiologic. 

The response to erythropoietin products must be monitored closely to prevent adverse effects associated with these agents. The common adverse effects experienced include hypertension and thrombosis. Concomitant drugs with the same adverse-effect profile may increase a patient s risk for these complications. Also, the patient s overall survival may be decreased if the hemoglobin level is titrated to above the recommended 11 to 12 g/dL (110-120 g/L or 6.82-7.44 mmol/L) value. Therefore, it is important to follow the dosing and titration scheme recommended by the NCCN and summarized in... 

Fig. 63-4. Patients should have their hemoglobin evaluated at least every 2 weeks. If in that time period the hemoglobin value rises 1 g/dL (10 g/L or 0.62 mmol/L) or greater, then the dose should be reduced by 25%. In addition, the dose of an erythropoietin agent should be held in patients who have a hemoglobin value equal to or greater than 12 g/dL (120 g/L or...

TABLE 63-4. Erythropoietin Products and Their Usual Doses for Anemia from Cancer/Chemotherapy and CKD... 

Although EPO deficiency is the primary cause of CKD anemia, iron deficiency is often present, and it is essential to assess and monitor the CKD patient s iron status (NKF-K/DOQI guidelines). Iron stores in patients with CKD should be maintained so that transferrin saturation (TSAT) is greater than 20% and serum ferritin is greater than 100 ng/mL (100 mcg/L or 225 pmol/L). If iron stores are not maintained appropriately, epoetin or darbepoetin will not be effective, and most CKD patients will require iron supplementation. Oral iron therapy can be used, but it is often ineffective, particularly in CKD patients on dialysis. Therefore, intravenous iron therapy is used extensively in these patients. Details of the pharmacology, pharmacokinetics, adverse effects, interactions, dose, and administration of erythropoietin and iron products have been discussed previously. 

Besides anemia associated with cancer and CKD, anemia of chronic disease can result from inflammatory processes and occurs commonly in autoimmune disorders such as rheumatoid arthritis and systemic lupus erythematosus. In treating these types of anemia of chronic disease, the most important principle is treating the underlying disease. These patients also may have iron deficiency and should be treated in the manner already discussed. Erythropoietin therapy such as epoetin-alfa therapy at a dose of 150 units/kg three times a week also may be used in these patients. 

Do not exceed more than 1 g/dL (10 g/L or 0.62 mmol/L) every 2 weeks when using erythropoietin products to increase hemoglobin. Otherwise, decrease the dose of the erythropoietin product. 

Bone marrow suppression ZDV Onset Few weeks to months Symptoms Fatigue, risk of T bacterial infections due to neutropenia anemia, neutropenia 1. Advanced HIV 2. High dose ZDV 3. Preexisting anemia or neutropenia 4. Concomitant use of bone marrow suppressants Avoid in patients with high risk for bone marrow suppression avoid other suppressing agents monitor CBC with differential at least every 3 months Switch to another NRTI D/C concomitant bone marrow suppressant, if possible for anemia Identify and treat other causes consider erythropoietin treatment or blood transfusion, if indicated for neutropenia Identify and treat other causes consider filgrastim treatment, if indicated... 

To date, three pharmaceutical companies have entered clinical trials with PHD inhibitors for the treatment of anemia with the most advanced being FG-2216. In clinical studies, compound 2 (likely FG-2216) showed a dose- and time-dependent elevation of plasma erythropoietin after oral administration [66]. Healthy volunteers were orally administered various doses of compound 2 and serum erythropoietin (EPO) concentrations were measured at various times. Compound 2 increased serum EPO levels in a dose-dependent manner and, following administration of the 20 mg/kg dose, a 5-fold increase of EPO levels was observed after 12 h. In the same patent application, the effect of 2 on anemic predialysis patients with no previous rh-EPO exposure was also disclosed. Patients were treated with 2 three times/week for 4 weeks (no dose reported) and the hemoglobin levels were assessed on day 42. The patients who received treatment showed a mean increase in hemoglobin of 1.9 g/dL from baseline values, whereas subjects who received placebo showed a mean decrease of 0.35 g/dL from baseline levels. These data suggest for the first time that an oral PHD inhibitor could be effective for the treatment of anemia. 

Further details of the above study were discussed in U.S. EPA (1994). After the last exposure, methemoglobin levels were elevated in a dose-dependent manner 17 ppm, 0% to 2.9% (no different from controls) 45 ppm, 2.2% to 5.4% and 87 ppm, 4.2% to 23%. The animals exposed at 45 and 87 ppm were anemic with decreases in RBC counts, hemoglobin content, MCHb concentration, and hematocrit, and accompanying increases in erythropoietin foci, reticuloendothelial cell hypertrophy, and hemosiderin deposition in the spleen. The animals in the 87-ppm exposure group were judged cyanotic. In the 17-ppm exposure group, effects were limited to mild splenic congestion. 

Treatment of anemia related to zidovudine therapy in HIV-infected patients To elevate or maintain the red blood cell level (as manifested by the hematocrit or hemoglobin determinations) and to decrease the need for transfusions in these patients when the endogenous erythropoietin level is less than or equal to 500 milliunits/mL and the dose of zidovudine is less than or equal to 4200 mg/week. Treatment of anemia in cancer patients on chemotherapy Jreatment of anemia in patients with nonmyeloid malignancies where anemia is due to the effect of concomitantly administered chemotherapy. It is intended to decrease the need for transfusions in patients who will be receiving chemotherapy for a minimum of 2 months. 

Initial dose - For patients with serum erythropoietin levels 500 milliunits/mL or less who are receiving a dose of zidovudine 4,200 mg/week or less, the recommended starting dose is 100 units/kg as an IV or subcutaneous injection 3 times/week for 8 weeks. 

Epoetin Alfa [Erythropoietin/ EPO] (Epogen/ Procrit) [Recombinant Human Erythropoietin] WARNING Use lowest dose possible may be associated w/1 CV, thromboembolic events /or mortality D/C if Hgb >12 g/dL Uses CRF associated anemia zidovudine Rx in HIV-infected pts, CA chemo -1- transfusions associated w/ surgery Action Induces ery-thropoiesis Dose Adul Peds. 50-150 Units/kg IV/SQ 3x/wk adjust dose q4-6wk PRN Surgery 300 Units/kg/d x 10 d before to 4 d after -I dose if Hct 36% or Hgb, T > 12 g/dL or Hgb t >1 g/dL in 2-wk pmod hold dose if Hgb >12 g/dL Caution [C, +] Contra Uncontrolled HTN Disp Inj SE HTN, HA, fatigue, fever, tach, NA Interactions None noted EMS Monitor ECG for hypokalemia (peaked T waves) t risk of CV thrombotic events OD May cause HA, dizziness, SOB and polycythemia symptomatic and supportive... 

WARNING Anaphylactic Rxns w/ use use only if oral Fe not possible administer where resuscitation techniques available Uses Fe deficiency when cannot supl PO Action Fe supl Dose Adul. Iron defic anemia Estimate Fe deficiency, give 25-100 mg IM/IV /d until total dose total dose (mL) = [-.0442 x (desired Hgb - observed Hgb) x LBW] + (0.26 x LBW) Iron replacement, blood loss Total dose (mg) = blood loss (mL) x Hct (as decimal fraction) max 100 mg/d Peds >4 mo. As for adults max 0.5 mL (wt <5 kg), 1 mL (5-10 kg), 2 mL (>10 kg) p dose IM or direct IV Caution [C, M] Contra Anemia w/o Fe deficiency. Disp Inj SE Anaphylaxis, flushing, dizziness, inj site inf Rxns, metallic taste Interactions X Effects W/ chloramphenicol, X absorption of oral Fe EMS Anaphylactic Rxns common taking oral Fe t risk of tox and SEs OD May cause N/V, HA, muscle/joint pain and fev symptomatic and supportive Iron Sucrose (Venofer) [Iron Supplement] Uses Fe deficiency anemia w/ chronic HD in those receiving erythropoietin Actions Fe r lacement. Dose 5 mL (100 mg) IV on dialysis, 1 mL (20 mg)/min max Caution [C, M] Contra Anemia w/o Fe deficiency Disp Inj SE Anaphylaxis, -1- BP, cramps, N/V/D, HA Interactions i Absorption OF oral Fe supls EMS See Iron Dextran OD See Iron Dextran... 

Recombinant human erythropoietin for intravenous or subcutaneous injection is available as epoetin alfa, epoetin beta and since 2001 as darbe-poeitin alfa. Epoetin alfa and epoetin beta have different carbohydrate moieties. When administered intravenously the elimination half-life of epoetin alfa is approximately 10 hours. Subcutaneous bioavailability is 20-50% of IV and peak concentrations are achieved after some 20 hours. The recommended initial dose is 50-100 units/kg three times a week in patients with chronic renal failure. 

Advantage over erythropoietin is decreased frequency of dosing... 

Amgen has recently introduced darbe-poetin Aranesp), a long-acting version of human erythropoietin. With two additional N-linked carbohydrate chains, darbepoetin contains more sialic acid than epoetin alfa and has an approximately threefold longer half-life, which leads to less frequent dosing than epoetin alfa. Darbepoetin is approved for both the treatment of anemia due to chronic renal failure and the treatment of chemotherapy-induced anemia. 

In the past, large doses of androgens were employed in the treatment of refractory anemias such as aplastic anemia, Fanconi s anemia, sickle cell anemia, myelofibrosis, and hemolytic anemias. Recombinant erythropoietin has largely replaced androgens for this purpose. 

Tsiara SN, Chaidos A, Gouva M, Christou L, Panteli K, Kapsali E, Bourantas KL. Successful treatment of refractory anemia with a combination regimen containing recombinant human erythropoietin, low-dose methylpred-nisolone and nandrolone. J Exp Clin Cancer Res 2004 23 47-52. 

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