NKF KDOQI GUIDELINES 2000
IV. Administration of Epoetin
When Epoetin was administered during the initial clinical trials in the United States to patients with CKD, it was not known whether it would be effective and at what dose. Therefore, to assure that 100% of the dose would be available to stimulate erythropoiesis, Epoetin was administered intravenously. Subsequently, pharmacokinetic studies noted that subcutaneous (SC) administration provided elevated blood levels of Epoetin longer than the same dose given intravenously. In most countries outside of the United States, Epoetin is administered subcutaneously to most CKD patients. When the data from the many studies comparing IV to SC Epoetin are analyzed, the SC route of administration is as effective or more effective in the majority of patients than if Epoetin is given IV. Therefore, the Anemia Work Group recommends that SC Epoetin be the preferred route of administration.
Route of Administration of Epoetin
A. Epoetin should be administered subcutaneously (SC) in CKD and peritoneal dialysis patients. (Opinion)
B. The most effective route of Epoetin administration is SC in hemodialysis patients. (Opinion)
C. When Epoetin is given SC, the site of injection should be rotated with each administration. (Opinion)
Initial Epoetin Administration
A. SC Administration (Evidence)
1. When Epoetin is given SC to adult patients, the dose should be 80 to 120 units/kg/wk (typically 6,000 units/wk) in two to three doses per week.
2. Pediatric patients <5 years old frequently require higher doses (300 units/kg/wk) than older pediatric patients and adults.
B. IV Administration (Evidence)
If the initial administration of Epoetin is IV for hemodialysis patients, the dose should be 120 to 180 units/kg/wk (typically 9,000 units/wk), given in three divided doses.
RATIONALE FOR GUIDELINES 11 AND 12
Route of Administration of Epoetin
For normal subjects as well as CKD patients, SC administration of Epoetin has more favorable pharmacodynamics than IV administration,209-213 despite the incomplete absorption of Epoetin following SC administration (bioavailability approximately 20%). On the other hand, because of the greater discomfort patients experience from SC compared to IV injections, it is likely that Epoetin would always be administered intravenously to hemodialysis patients, were it not for the relatively high cost of Epoetin.
In CKD and peritoneal dialysis patients, it is inconvenient as well as costly to administer Epoetin intravenously. In addition, veins need to be protected from venipuncture so that they are available for future hemodialysis access sites. Therefore, SC administration of Epoetin is preferable in these patients.
Numerous studies have examined the variation in effectiveness of Epoetin related to whether it is administered SC or IV. Thirty-six published studies on this topic involving 2,028 patients showed that, on average, the dose of Epoetin required to maintain a given Hct at 33% was lower (range, 0% to 68%) when Epoetin was administered subcutaneously compared to intravenously.103,145,170,212-245 Two recent studies confirm the variability of response whether Epoetin is given SC or IV. In the largest study to date, a parallel group study in US male veterans, on average, the dose of Epoetin needed to maintain the Hct between 30% and 33% was more than 30% lower with SC than IV administration.246 However, 23% of the 208 patients required more Epoetin when switched from IV to SC administration. A European study noted that when the route of administration in 15 patients was shifted from SC to IV (which differs from the protocol of most comparative studies), there was no difference in the mean thrice weekly dose of Epoetin or mean Hct during 6 months of therapy at each route of administration.247
Although most of the available studies had relatively small sample sizes and often had other methodological limitations, the aggregate data suggest several conclusions.
1. In a group of patients, such as all patients receiving hemodialysis in a dialysis center, administration of Epoetin via the SC route appears to be more efficient than IV administration, ie, target Hgb and/or Hct levels are able to be maintained with a lower weekly Epoetin dose (15% to 50% lower) when the SC route is used.
2. The frequent administration of Epoetin appears to be more efficient, ie, administration of Epoetin on a two to three times per week basis appears to allow lower total weekly doses than administration once per week. However, the administration of Epoetin on a daily basis is no more effective than administration three times per week.33,106 Thus, from a physiologic standpoint, Epoetin therapy should be initiated subcutaneously two to three times per week. Although two to three times per week SC administration is more efficient than once weekly administration, once weekly administration is more convenient for many CKD patients. In addition, Medicare currently does not reimburse for Epoetin use in CKD patients who are not dialysis dependent unless it is given in the physicians office. (Home administration currently is not reimbursed for Medicare patients.) The Anemia Work Group strongly encourages a change in this policy. Once the target Hgb/Hct has been achieved, it may be possible, for purposes of convenience, to administer Epoetin SC once weekly, or less often, in CKD, peritoneal dialysis, and hemodialysis patients.
There are insufficient data in the literature to make a recommendation for a specific site of administration of Epoetin. Therefore, it would seem prudent to rotate the site of injection with each administration.
Dose of Epoetin
When selecting the initial dose of Epoetin, the goal is to achieve the target Hgb/Hct within a 2- to 4-month period (corresponding to the lifespan of red blood cells in CKD) through the induction of a slow, steady increase of the Hgb/Hct. Ideally, that dose will turn out to be the dose necessary to maintain the Hgb/Hct at the target value.248
Since it is not possible to accurately predict the fraction of patients who will respond adequately to any dose of Epoetin, it will be necessary to monitor each patients response to optimize the dose of Epoetin (see recommendation in Guideline 15: Monitoring of Hemoglobin/ Hematocrit During Epoetin Therapy).
In pediatric PD patients, the median weekly Epoetin dose required to maintain a target Hct of 28% to 30% was 136 units/kg/wk in those older than 15 years.
A higher dose requirement for pediatric patients <5 years has been noted in two multicenter trials.170,249 The basis for this difference has not been established. On the other hand, 19 of 22 children (peritoneal dialysis , hemodialysis , and chronic kidney function impairment ) between the ages of 4 months to 16 years (mean, 9 years) achieved target Hgb (9 to 11 g/dL) after 4 months of 50 U/kg of Epoetin given SC, twice weekly.23
Switching From Intravenous to Subcutaneous Epoetin
A. For hemodialysis patients who are being switched from IV to SC administration of Epoetin but have not yet achieved the target Hgb/Hct, the total weekly IV dose should be administered SC in two to three divided doses. (Evidence)
B. For hemodialysis patients who are being switched from IV to SC administration of Epoetin after achieving the target Hgb/Hct, the initial weekly SC dose should be two-thirds the weekly IV dose. (Opinion) Subsequent dose adjustments should be made as recommended in Guideline 16: Titration of Epoetin Dosage.
Rationale In the majority of hemodialysis patients, the erythropoietic response to a particular Epoetin dose will be greater with SC than with IV administration.212,215,221,225,232,239 Simple conversion of the IV dose to a SC dose in patients who are not yet at the desired target Hgb/Hct will, therefore, in most patients, produce a subsequent increase in the Hgb/Hct.
|Table IV-7. Advantages of Subcutaneous Versus Intravenous Epoetin Administration|
|Advantages of Subcutaneous Epoetin Administration|
|1. Most patients require less Epoetin via SC compared to IV route.|
|2. When given SC, Epoetin may be administered in many patients one to two times per week, thus reducing administration cost to facility.|
|Advantages of IV Epoetin Administration|
|1. No patient discomfort.|
|2. Most clinical experience (in the United States).|
Studies have indicated that Epoetin requirements are, on average, about 15% to 50% less with SC dosing than with IV dosing.212,215,221,225,232,239 Therefore, to avoid an unwanted increase in Hgb/Hct, approximately a 33% reduction in weekly dose should be made when converting from IV to SC administration if a stable target Hgb/Hct has already been achieved (see Guideline 11: Route of Administration of Epoetin). There is tremendous clinical variability, however, and some patients may require more Epoetin when administered SC compared to IV.232 Careful monitoring of the response to Epoetin therapy and individual titration of the dose will be necessary after conversion of hemodialysis patients from IV to SC administration of Epoetin to achieve and maintain the target Hgb/Hct. If, after conversion, the weekly SC dose is greater than the previous weekly IV dose, the IV route of Epoetin administration should be resumed.
Strategies for Initiating and Converting to Subcutaneous Epoetin Administration
The use of the strategies listed below is suggested to increase patient acceptance of SC administration of Epoetin: (Opinion)
When patients begin dialysis treatments, continue Epoetin administration subcutaneously.
Educate hemodialysis patients on the advantages of SC administration (improved Hgb/Hct response and economic savings).
Establish a unit-wide policy under which all hemodialysis patients are started on SC administration at the same time.
Use the smallest possible gauge needle for injection (eg, 29 gauge).
Use a multidose Epoetin preparation that contains benzyl alcohol.
Divide the doses (a smaller volume for injection may reduce discomfort).
Administer a single, weekly injection to patients receiving a small dose.
Rotate injection sites between upper arm, thigh and abdominal wall areas.
Encourage patients to self-administer Epoetin when possible.
Rationale It is impractical to administer Epoetin to CKD or PD patients intravenously, for reasons of staff and patient convenience. It is reasonable to continue SC administration after hemodialysis is initiated.
Successful implementation of SC Epoetin in hemodialysis units can be facilitated by several actions. Patients should be educated regarding the improved Hgb/Hct response, that is, achieving the target Hgb/Hct with less Epoetin.
Once all patients in a dialysis unit have been educated about the rationale for SC Epoetin administration (summarized in Table IV-7), it may be helpful to switch all patients from IV to SC at the same time. Otherwise, patients who have been used to receiving IV Epoetin who are reluctant to change to SC Epoetin might undermine efforts to put new hemodialysis patients on SC Epoetin.
Considering the drawbacks of frequent needle sticks, efforts should be undertaken to minimize discomfort associated with SC administration. Stinging may be associated with SC injection of Epoetin alfa, and has been attributed to the presence of a citrate buffer in the single-use vial. The multidose vial of Epoetin alfa contains the preservative benzyl alcohol, which acts as a local anesthetic and reduces the stinging. This preparation has been better tolerated than the single-use vial when Epoetin alfa is given SC.250
Additional strategies to minimize discomfort include use of the smallest gauge needle possible; a small injection volume, which can be accomplished by using the 10,000 units/mL multidose vial and administering Epoetin in three divided doses per week, or, for those patients requiring small doses (eg, <3,000 units/wk), reducing the frequency of administration to once weekly. Patients could be encouraged to participate in their own care by doing self-injections of Epoetin. Patients can control some of the discomfort that may accompany SC injections by controlling the speed of delivery of the injection. HCFA reimbursement policy will need to be altered so that self-injections outside of the dialysis unit are covered by Medicare.
Monitoring of Hemoglobin/Hematocrit During Epoetin Therapy
For purposes of monitoring response to Epoetin, Hgb/Hct should be measured every 1 to 2 weeks following initiation of treatment or following a dose increase or decrease, until a stable target Hgb/Hct and Epoetin dose have been achieved. Once a stable target Hgb/Hct and Epoetin dose have been achieved, Hgb/Hct should be monitored every 2 to 4 weeks. (Opinion)
Rationale There are no reported studies that have systematically compared different protocols (ie, different frequencies of Hgb/Hct measurements) for monitoring the Hgb/Hct response to Epoetin therapy. Therefore, a single most clinically and/or cost-effective protocol cannot be based on data reported in the medical literature. With the doses of Epoetin recommended in these guidelines, and with optimal iron stores, the absolute rise in Hgb can be expected to be about 0.3 g/dL (0.2 to 0.5 g/dL) per week (hematocrit rise of 1% per week [typical response range, 0.5% to 1.5% per week]).65,73,103,251-254 The dose-response range is wide, however. Weekly testing of Hgb/Hct is recommended following initiation of Epoetin, or an Epoetin dose adjustment, to detect changes in Hgb/Hct. Less frequent testing (ie, only every 2 weeks or monthly) could miss the very rapid erythropoietic response or the poor response and prevent an earlier dose adjustment. More frequent testing is not necessary (see Guideline 16: Titration of Epoetin Dosage).
Titration of Epoetin Dosage
If the increase in Hct after initiation of Epoetin therapy or after a dose increase has been <2 percentage points over a 2- to 4-week period, the dose of Epoetin should be increased by 50%. If the absolute rate of increase of Hgb/Hct after initiation of Epoetin therapy or after a dose increase exceeds 3 g/dL (or 8 Hct percentage points) per month (eg, an increase from a Hgb 7 to 10 g/dL or Hct change from 20% to 28%), or if the Hgb/Hct exceeds the target Hgb/Hct, reduce the weekly dose of Epoetin by 25%. When the weekly Epoetin dose is being increased or decreased, a change may be made in the amount administered in a given dose and/or the frequency of dosing (if given SC). (Opinion)
Rationale Several regimens have been described for adjusting the Epoetin dose until a target Hgb/Hct and stable maintenance Epoetin dose have been achieved. There are no reported studies, however, which have systematically compared different Epoetin dose adjustment protocols. Therefore, a single most effective and/or cost-effective protocol cannot be based on data reported in the medical literature. The dose adjustment strategies the Anemia Work Group recommends are similar to those which have been used safely and effectively in clinical trials.65,73,251,253 The Epoetin dose increases recommended will also avoid unnecessary delays in obtaining a desired erythropoietic response.
A recommendation as to whether Epoetin should be withheld (ie, not given for some period of time) before reducing the Epoetin dose cannot be based on data from the medical literature. A distinction, though, should be made between the "rapid responder" (ie, a patient whose Hct has increased >8 percentage points in a month) and the patient who approaches the target Hgb/Hct gradually. In the former case, Epoetin should be withheld if the target has been reached and resumed 1 to 2 weeks later at 75% of the original dose, or maintained at the same dose but at a reduced frequency, if given SC. When the rate of rise in Hgb/Hct has been slower and the target range is about to be exceeded, withholding Epoetin can result in a "roller-coaster" effect. Therefore, in the latter instance, the dose should either be reduced or the frequency of SC administration should be reduced rather than omitting Epoetin therapy in order to stabilize and maintain the Hgb/Hct in the target range.
Inability to Tolerate Subcutaneous Epoetin;
IV Epoetin Dose
When a hemodialysis patient is unable to tolerate SC administration of Epoetin, IV administration should be used. The IV Epoetin dose should be 50% higher than the SC dose, if known, or 120 to 180 units/kg/wk (typically 9,000 units/week), given in three divided doses. (Opinion)
Rationale Despite the best efforts of physicians and dialysis staff to educate patients regarding the value of SC Epoetin administration and to minimize discomfort associated with SC administration, there may be some patients who will not accept SC administration. This may be true, for example, in the case of the occasional patient who requires very large doses of Epoetin, since SC administration of a large volume can be painful, or in the patient who develops recurrent ecchymoses and hematomas. When IV Epoetin is required, the weekly dose should be given in divided doses during each dialysis treatment. Once weekly IV administration of Epoetin results in a lower Hgb/Hct response, and a 25% increase in Epoetin requirements, compared with three times per week administration.255 If Epoetin is given IV, it is best to inject it into either the arterial or venous blood lines (ie, the "ports") at any time during the hemodialysis procedure. Injection of Epoetin into the venous drip chamber of the Fresenius delivery system should be avoided since this can result in "trapping" and incomplete mixing with the patients blood.256
On average, studies have shown comparable Hgb/Hct response with a SC dose which is two thirds of the IV dose. Therefore, the IV Epoetin dose should be 50% higher than the SC dose.103
Intraperitoneal Epoetin Administration
For peritoneal dialysis patients in whom SC or IV administration of Epoetin is not feasible, intraperitoneal (IP) administration may be considered. IP administration must be done into a dry abdomen or one with a minimal amount of dialysate.
IP dose requirements may be higher than those associated with IV or SC administration. (Evidence)
Rationale Epoetin administered into the abdominal cavity will be diluted if mixed with dialysate, thus slowing its absorption.257 Perhaps for this reason, Epoetin doses are higher with IP administration, if mixed with dialysate, than with either IV or SC administration210; a "dry" abdomen results in better absorption.257 For example, in pediatric patients, if Epoetin is administered intraperitoneally into a full dialysate dwell volume, absorption of Epoetin is less than 50% of that attained with SC administration, but absorption is enhanced if instilled with a small amount (50 mL) of dialysate.258 Therefore, in pediatric patients, if IP administration of Epoetin is used, it is best to infuse it into a "dry" abdomen or one with a minimal amount of dialysate.
Epoetin Dosage Perioperatively or During Intercurrent Illness
A decision to continue or increase the Epoetin dose must be made on an individual basis in patients receiving Epoetin who undergo surgery, develop significant acute intercurrent illness, or require transfusion of red blood cells for acute blood loss. (Opinion)
Rationale Anecdotal observations suggest that the erythropoietic response to Epoetin may be reduced in patients who have significant intercurrent illness (infection, malignancy, inflammatory diseases) or who undergo surgery.29,259-262 There are no studies available which support a specific recommendation as to whether the Epoetin dose should be discontinued, maintained, or increased to try to obtain a particular erythropoietic response in such patients, particularly upon hospitalization, or in patients in whom red blood cell transfusions are required for acute blood loss. Continuation of Epoetin at a dose at least equal to that which the patient was receiving prior to development of an acute illness or surgery may allow for more prompt resumption of erythropoiesis once the intercurrent illness has resolved.
Following successful renal transplantation, erythropoietin production by the transplanted kidney is often delayed for up to 8 to 30 days,263-265 so full correction of anemia may not occur for 2 to 3 months after surgery. There are no data indicating that Epoetin administration during the immediate posttransplant period is of benefit.
© 2001 National Kidney Foundation, Inc