Drug Criteria & Outcomes: Darbepoetin alfa Formulary Evaluation

By Jenny S. Owen, PharmD
Written as a PharmD candidate at Samford University, Birmingham, AL

Erythropoiesis-stimulating factors

Darbepoetin alfa (Aranesp)
Epoetin alfa (Epogen)

Background

The most significant cause of anemia in chronic renal failure (CRF) is reduced erythrocyte production. With advanced renal disease, the production and release of erythropoietin (EPO), a glycoprotein released in response to hypoxia and anemia, are diminished further.

The kidney is responsible for the production of approximately 90% of the total EPO in the body; the liver produces the remainder. Under normal conditions, hypoxia and anemia trigger the release of EPO, which then stimulates red blood cell production within the bone marrow. However, the production of EPO decreases as renal damage progresses.

Treatment options include the use of recombinant EPO, which is a major advancement in the treatment of anemia in patients with CRF.

Dialysis may improve erythrokinetics, but it rarely restores the hematocrit/hemoglobin to normal levels and does not correct the anemia.

Mechanism of action

Both epoetin alfa and darbepoetin alfa are erythropoiesis-stimulating factors having the same mechanism of action as endogenous EPO. Endogenous EPO stimulates proliferation and maturation of committed erythroid progenitors to increase production of red blood cells and accelerates the release of reticulocytes from the bone marrow.

Darbepoetin alfa is closely related to the erythropoietin that is produced in Chinese hamster ovary cells by recombinant DNA technology. It is a 165-amino acid glycoprotein that contains five N-linked oligosaccharide chains. The approximate molecular weight is 37,000 daltons.

Epoetin alfa is a 165-amino acid glycoprotein manufactured by recombinant DNA technology. The molecular weight is 30,400 daltons and contains identical amino acid sequence as isolated natural erythropoietin.

Although there are similarities between these two erythropoiesis-stimulating factors, one difference distinguishes darbepoetin from epoetin. Darbepoetin has two additional N-glycosylation chains, which increase the terminal half-life approximately three-fold after IV administration and at least two-fold after subcutaneous administration.

Pharmacokinetics

Pharmacokinetic parameters are summarized in Table 1.

Indications

Darbepoetin and epoetin are both indicated for:

  • Treatment of anemia associated with chronic renal failure.
  • CRF patients on dialysis and patients not on dialysis.

Epoetin has additional indications:

  • Treatment of anemia that is due to zidovudine therapy in HIV-infected patients.
  • Treatment of chemotherapy-induced anemia in patients with non-myeloid malignancies.
  • Treatment of anemia in patients scheduled to undergo elective, noncardiac, nonvascular surgery to reduce the need for allogeneic blood transfusions.

Dosing

Dosing information for darbepoetin and epoetin can be found in Tables 2, 3, and 4.

Contraindications

Darbepoetin

  • Uncontrolled hypertension
  • Known hypersensitivity to the active substance or excipients (albumin and polysorbate)

Epoetin

  • Uncontrolled hypertension
  • Known hypersensitivity to mammalian cell-derived products
  • Known hypersensitivity to albumin

Adverse effects

The adverse effects reported are typically associated with CRF, or recognized complications of dialysis, and may not necessarily be attributable to the darbepoetin or epoetin. In all studies, the most frequently reported adverse reactions with darbepoetin were congestive heart failure, sepsis, and cardiac arrhythmia. Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of darbepoetin cannot be directly compared to rates in the clinical trials of epoetin and may not reflect the rates observed in practice. In a comparative trial of darbepoetin and epoetin, the adverse effects were shown to be similar. Adverse effect information is summarized in Tables 5 and 6.

Drug interactions

Darbepoetin. Due to new drug status, formal drug interaction studies have not been performed.

Epoetin. In clinical trials, no evidence of drug interactions were found.

Recommended monitoring

Darbepoetin

Hemoglobin should be determined weekly until stable.

After dose adjustments, hemoglobin should be determined weekly for at least four weeks or until it has stabilized. The hemoglobin should then be monitored at regular intervals.

In order to ensure effective erythropoiesis, iron status should be evaluated before and during treatment.

Blood pressure should be controlled adequately before initiation of therapy. Blood pressure should be monitored closely and controlled aggressively.

Premonitory neurologic symptoms should be monitored closely and the dose of darbepoetin should be decreased if the hemo-globin increase exceeds 1.0 g/dL in any two-week period; the relationship between seizure and rate of rise of hemoglobin is uncertain.

BUN, creatinine, phosphorous, and potassium and should be monitored in all patients with chronic renal failure.

Epoetin

Blood pressure should be monitored closely and controlled aggressively.

Premonitory neurologic symptoms should be monitored closely. The dose of epoetin should be decreased if the hematocrit increase exceeds four points in any two-week period since the relationship between seizure and rate of rise of hemoglobin is uncertain.

In order to ensure effective erythropoiesis, iron status should be evaluated before and during treatment.

Hematocrit should be determined twice a week until it has stabilized and a maintenance dose is achieved.

After any dose adjustment, hematocrit should be measured weekly for at least two to six weeks.

CBC with differential should be performed regularly.

BUN, Creatinine, phosphorous, and potassium should be monitored in all patients with chronic renal failure.

Precautions/warnings

Darbepoetin

Individualize dose if patient is not yet on dialysis.

Pregnancy Category C

Carcinogenic potential has not been studied.

Safety and efficacy in pediatric patients have not been established.

It is not known whether darbepoetin is excreted in breast milk.

Seizures have occurred in clinical trials

Darbepoetin may have to be decreased if hemo-globin increase exceeds 1.0 g/dL in any two-week period.

Patients with uncontrolled hypertension should not be treated with darbepoetin.

Hemoglobin increases of greater than 1.0 g/dL during any two-week period are associated with increased incidence of cardiac arrest, neurologic events, exacerbation of hypertension, congestive heart failure, vascular thrombosis, ischemia, and infarction.

Epoetin

Multi-dose formulations contain benzyl alcohol, which has been reported to be associated with an increased incidence of neurological and other complications in premature infants that are sometimes fatal. Single-use formulations that do not contain benzyl alcohol can be used in pediatric patients.

Pregnancy Category C

It is not known whether epoetin is excreted in breast milk.

Carcinogenic potential has not been studied.

Seizures have occurred in clinical trials.

Patients with uncontrolled hypertension should not be treated with epoetin.

Hematocrit of more than 42% increases mortality.

Allergies

Darbepoetin

The incidence of antibody development has not been adequately determined.

There are rare reports of potentially serious allergic reactions, including skin rash and urticaria.

Epoetin

There are no reports of potentially serious allergic reactions or anaphylaxis.

There are rare reports of potentially serious allergic reactions, including urticaria with associated respiratory symptoms or circumoral edema or urticaria.

There has been no evidence for development of antibodies.

Potential for medication errors

Potential for confusion of these two drugs does exist. Care should be taken to assure that verbal or written orders clearly specify the drug and dosage regimen intended.

Storage and stability

Darbepoetin

  • Store at 2-8° Celsius (36-46° F).
  • Do not freeze or shake.
  • Protect from light.

Epoetin

  • Store at 2-8° Celsius (36-46° F).
  • Do not freeze or shake.

Preparation and administration

Vigorous shaking may denature glycoprotein, making it biologically inactive.

Inspect the vials visually for any particulate matter or discoloration before administration. (Discard if particulate matter is present.)

Dilution is not required.

Do not administer drug in conjunction with another drug.

Darbepoetin is packaged as a single-dose vial (no preservatives), so discard any unused portion.

Epoetin is packaged as single- and multi-dose (contains preservatives) vials. Only the multi-dose vial can be used again, but it will expire 21 days after first entry.

Supply options

The supply options available for darbepoetin and epoetin are listed in Tables 7 and 8.

Cost comparison based on equivalent doses

The cost comparison presented here is based on a hypothetical situation, which best portrays the epoetin usage at Huntsville (AL) Hospital. Costs were calculated based on a 5,000 U dose of epoetin three times a week and a 40 mcg dose of darbepoetin once weekly.

Relative costs were calculated for three different lengths of stay, assuming 16 patients were on the drug per month for each time period. The cost comparison was based upon the equivalent dosage regimens of darbepoetin and epoetin. For example, comparing eight to nine days of therapy, the cost for epoetin was only $204, whereas the cost for darbepoetin was $289. The patient would receive four doses of epoetin and two doses of darbepoetin before being discharged. The effects from darbepoetin would last for several days after discharge before another dose is due; thus, hospital costs would include some expense that would normally be addressed in the outpatient setting. Similar cost savings to the hospital can be realized when calculating drug costs for other time periods.

Based on Huntsville Hospital drug use and cost data and length-of-stay figures, use of epoetin in recommended dosage regimens would be less costly overall to the hospital than darbepoetin. Estimated annual cost avoidance by not using darbepoetin is approximately $25,000.

Clinical Studies

Study No. 1: Locatelli F, et al. Novel erythropoiesis stimulating protein for treatment of anemia in chronic renal insufficiency. Kidney Int 2001;60:741-747.

Background: Darbepoetin (novel erythropoiesis stimulating protein) is a glycoprotein with a half-life that is three times longer than epoetin (recombinant human erythropoietin). The darbepoetin contains two additional N-glycosylation sites compared to epoetin, which gives darbepoetin a longer half-life.

Study purpose: To determine whether darbepoetin is effective for treating patients with anemia due to chronic renal failure, not yet on dialysis, at a reduced dosing frequency compared to epoetin.

Study design: Multi-center, randomized open-label study.

Study patients and procedure: 166 patients epoetin-naïve patients with CRF were randomized in a 3:1 ratio, to receive darbepoetin (n = 129; 0.45 mcg/kg once a week) or epoetin (n = 37; 50 U/kg twice a week) administered subcutaneously.

Inclusion criteria: Age 18 years or older; diagnosis of CRF; had not received epoetin 12 weeks before the first dose of study drug; hemoglobin concentration less than 11.0 g/dL; adequate iron stores, vitamin B12, and folate levels; and a CrCl of less than 30 mL/min.

Exclusion criteria: Uncontrolled hypertension, congestive heart failure, hematologic disorders, systemic infection, or inflammatory disease, or other disorder that could interfere with the response to darbepoetin or epoetin.

Length of study: 24 weeks.

Primary endpoint: Proportion of patients obtaining a hemoglobin response during the treatment period of 24 weeks, which was defined as an increase in hemoglobin of > to 1.0 g/dL.

Secondary endpoint: Safety was assessed by monitoring the incidence of adverse effects, hematology, iron status, vital signs, and antibody formation to darbepoetin or epoetin.

Results: For the primary endpoint, the increase in hemoglobin (defined as an increase of > 1.0 g/dL) was achieved by 93% of patients in the darbepoetin group and 92% of patients in the epoetin group.

For the secondary endpoint, darbepoetin and epoetin had similar safety profiles.

One hundred seven of 129 (83%) in the darbepoetin group and 24 of 37 (65%) in the epoetin group experienced at least one adverse event. Overall, it seems that patients who received darbepoetin had slightly more adverse events (see Table 9).

Conclusion: Darbepoetin and epoetin both have similar efficacy in treating anemia in chronic renal failure.

Both darbepoetin and epoetin have similar safety profiles; however, darbepoetin demonstrates a slightly higher incidence of adverse events in clinical trials.

One difference between these two erythropoiesis-stimulating factors is that darbepoetin has the same efficacy when used once a week compared to epoetin, which usually is dosed two to three times a week.

Limitations of the study:

  • Small sample sizes
  • Unequal sample sizes between groups
  • No P values or alpha values were given so statistical significance could not be determined.
  • Both the subjects and the investigators knew which treatments were being given to specific subjects.
  • The majority of study participants were white males; the study does not encompass the general population.
  • No power value given.
  • The study was sponsored by Amgen, manufacturer of darbepoetin. This could have influenced the presentation of the study results.

Study No. 2: Nissenson AR, et al. Novel erythropoiesis stimulating protein (NESP) safely maintains hemoglobin concentration levels in hemodialysis patients as effectively as erythropoietin (rHuEPO) when administered once weekly. J Am Soc Nephrol 2000;11:252A.

Study purpose: To determine if darbepoetin is safe and effective in maintaining hemoglobin when administered at a reduced frequency when compared with epoetin.

Study design: Double-blind, randomized study

Study patients and procedure: A total of 570 hemodialysis patients were randomized (1:2) to receive IV darbepoetin once weekly plus placebo two times weekly, or to continue to receive IV epoetin three times a week.

Primary endpoint: Change in hemoglobin levels from the baseline to the evaluation period, which were weeks 20-28.

Results: Mean change for darbepoetin was 0.16 (+ 0.97) g/dL; the mean change for epoetin was 0.0 + 1.0 g/dL. The difference was only 0.16 g/dL.

Conclusion: Darbepoetin maintains hemoglobin as safely and effectively as epoetin. Darbepoetin’s less frequent dosing schedule (once weekly vs. three times weekly for epoetin) will benefit both patients and health care professionals.

Limitations of the study:

  • Only an abstract is available.
  • No P value or alpha values were given; statistical significance could not be determined.
  • The study was sponsored by Amgen.
  • Clinical trials are currently in progress to investigat darbepoetin for various other indications.

Recommendation

Epoetin alfa is the current erythropoiesis-stimulating factor that is used in treating chronic renal failure patients with anemia in Huntsville Hospital. According to current studies comparing darbepoetin to epoetin, these two erythropoiesis-stimulating factors have similar efficacy and safety profiles with differences in pharmacokinetics. Darbepoetin, when administered intravenously and subcutaneously, has approximately three times the terminal half-life compared to epoetin.

Thus, darbepoetin can be administered once a week for patients on dialysis and once every other week for patients not on dialysis.

Although darbepoetin has the advantage of being administered less frequently, other considerations should be considered. First, epoetin has many Food and Drug Administration-approved indications, including treatment of anemia in HIV-infected patients and cancer patients on chemotherapy, and reduction of allogenic blood transfusion in surgery patients; currently, darbepoetin is approved only for use in chronic renal failure patients with anemia.

Second, epoetin is approved for use in the pediatric population, whereas darbepoetin therapy in pediatrics has not been established.

Third, because of darbepoetin’s long half-life and once-weekly dosing, the patient will be discharged before the next dose is due in many cases. Under those conditions, the hospital will absorb some drug costs that normally would be incurred in the outpatient setting.

Lastly, darbepoetin, based upon equivalent doses, is more costly compared to epoetin if less epoetin equivalent is administered in patients whose hospital stay is seven to 12 days. If the patient’s hospital stay is only five to six days, then it would be slightly more costly to use epoetin. If the patient’s stay were only a few days, epoetin would be less costly.

Thus, the final recommendation is that epoetin should continue as the recombinant erythropoietin of choice for inpatients at Huntsville Hospital and darbepoetin should be available on a non-formulary status. If darbepoetin is ordered, the pharmacist will notify the physician that a similar epoetin regimen should be used for inpatients.

Resources

• Locatelli F, et al. Novel erythropoiesis stimulating protein for treatment of anemia in chronic renal insufficiency. Kidney Int 2001; 60:741-747.

• Nissenson AR, et al. Novel erythropoiesis stimulating protein (NESP) safely maintains hemoglobin concentration levels in hemodialysis patients as effectively as erythropoietin (rHuEPO) when administered once weekly. J Am Soc Nephrol 2000: 11:252A.

• Epogen package insert. Thousand Oaks, CA: Amgen; 1999.

• Personal Communication. Hall, Cindy. Pharmacy buyer. Huntsville Hospital System Pharmacy. February 2002.

• Aranesp (monograph in electronic version). MICROMEDEX Healthcare series. Englewood, CO: MICROMEDEX; 2001.

• Epogen (monograh in electronic version). MICROMEDEX Healthcare series. Englewood, CO: MICROMEDEX; 2001.

• Hudson, JQ, Johnson, CA. Chronic renal failure. In: Koda-Kimble MA, Young LY, eds. Applied Therapeutics. 7th ed. Baltimore, MD: Lippincott Williams and Wilkins; 2001:1-30.