Darbepoetin Alfa

Pronunciation

(dar be POE e tin AL fa)

U.S. Brand Names

Aranesp®

Synonyms

Erythropoiesis Stimulating Protein

Generic Available

Canadian Brand Names

Aranesp®

Use

Treatment of anemia associated with chronic renal failure (CRF), including patients on dialysis (ESRD) and patients not on dialysis; anemia associated with chemotherapy for nonmyeloid malignancies

Pregnancy Risk Factor

Pregnancy Implications

There are no adequate and well-controlled studies in pregnant women. Darbepoetin alfa should be used in a pregnant woman only if potential benefit justifies the potential risk to the fetus.

Lactation

Excretion in breast milk unknown/use caution

Contraindications

Hypersensitivity to darbepoetin or any component of the formulation (including polysorbate 80 and/or albumin); uncontrolled hypertension

Warnings/Precautions

Erythropoietic therapies may be associated with an increased risk of cardiovascular and/or neurologic events in chronic renal failure. Darbepoetin alfa should be managed carefully; avoid hemoglobin increases >1 g/dL in any 2-week period, and do not exceed a target level of 12 g/dL. Prior to and during therapy, iron stores must be evaluated. Supplemental iron is recommended if serum ferritin <100 mcg/mL or serum transferrin saturation <20%.

Use with caution in patients with hypertension or with a history of seizures. If hypertension is difficult to control, reduce or hold darbepoetin alpha. Not recommended for acute correction of severe anemia or as a substitute for transfusion. Consider discontinuing in patients who receive a renal transplant.

Prior to treatment, correct or exclude deficiencies of vitamin B12 and/or folate, as well as other factors which may impair erythropoiesis (aluminum toxicity, inflammatory conditions, infections). Poor response should prompt evaluation of these potential factors, as well as possible malignant processes, occult blood loss, hemolysis, and/or bone marrow fibrosis. Pure red cell aplasia (PRCA) with associated neutralizing antibodies to erythropoietin has been reported, predominantly in patients with CRF. Patients with loss of response to darbepoetin alfa should be evaluated. Discontinue treatment in patients with PRCA secondary to neutralizing antibodies to erythropoietin.

Due to the delayed onset of erythropoiesis, darbepoetin is of no value in the acute treatment of anemia. Safety and efficacy in patients with underlying hematologic diseases have not been established, including porphyria, thalassemia, hemolytic anemia, and sickle cell disease. Risk of thrombosis, including pulmonary embolism, increased in cancer patients. Do not shake solution; vigorous shaking may denature darbepoetin alfa, rendering it biologically inactive. Safety and efficacy in pediatric patients have not been established.

Adverse Reactions

Note: Frequency of adverse events cited in patients with CRF or cancer and may be, in part, a reflection of population in which the drug is used and/or associated with dialysis procedures.

>10%:

Cardiovascular: Hypertension (4% to 23%), hypotension (22%), edema (21%), peripheral edema (11%), arrhythmia (10%)

Central nervous system: Fatigue (9% to 33%), fever (9% to 19%), headache (12% to 16%), dizziness (8% to 14%)

Gastrointestinal: Diarrhea (16% to 22%), constipation (5% to 18%), vomiting (15%), nausea (14%), abdominal pain (12%)

Neuromuscular & skeletal: Myalgia (21%), arthralgia (11% to 13%)

Respiratory: Upper respiratory infection (14%), dyspnea (12%), cough (10%)

Miscellaneous: Infection (27%)

1% to 10%:

Cardiovascular: Angina/chest pain (6% to 8%), fluid overload (6%), CHF (6%), thrombosis (6%), MI (2%)

Central nervous system: Seizure (<1% to 1%), stroke (1%), TIA (1%)

Dermatologic: Pruritus (8%), rash (7%)

Endocrine & metabolic: Dehydration (5%)

Local: Injection site pain (7%)

Neuromuscular & skeletal: Back pain (8%), weakness (5%), limb pain (10%)

Respiratory: Bronchitis (6%), pulmonary embolism (1%)

Miscellaneous: Vascular access thrombosis (8%, annualized rate 0.22 events per patient year), vascular access infection (6%), influenza-like symptoms (6%), vascular access hemorrhage (6%)

Overdosage/Toxicology

The maximum amount of darbepoetin which may be safely administered has not been determined. However, cardiovascular and neurologic adverse events have been correlated to excessive and/or rapid rise in hemoglobin. Phlebotomy may be performed if clinically indicated.

Drug Interactions

No data available

Ethanol/Nutrition/Herb Interactions

Ethanol: Should be avoided due to adverse effects on erythropoiesis.

Stability

Store at 2°C to 8°C (36°F to 46°F). Do not freeze or shake. Protect from light. Do not dilute or administer with other solutions.

Compatibility

Do not dilute or administer with other solutions.

Mechanism of Action

Induces erythropoiesis by stimulating the division and differentiation of committed erythroid progenitor cells; induces the release of reticulocytes from the bone marrow into the bloodstream, where they mature to erythrocytes. There is a dose response relationship with this effect. This results in an increase in reticulocyte counts followed by a rise in hematocrit and hemoglobin levels. When administered SubQ or I.V., darbepoetin's half-life is ~3 times that of epoetin alfa concentrations.

Pharmacodynamics/Kinetics

Onset of action: Increased hemoglobin levels not generally observed until 2-6 weeks after initiating treatment

Absorption: SubQ: Slow

Distribution: Vd: 0.06 L/kg

Bioavailability: CRF: SubQ: ~37% (range: 30% to 50%)

Half-life elimination: CRF: Terminal: I.V.: 21 hours, SubQ: 49 hours; Note: Half-life is ~3 times as long as epoetin alfa

Time to peak: SubQ: CRF: 34 hours (range: 24-72 hours); Cancer: 90 hours (range: 71-123 hours)

Dosage

Adults:

Anemia associated with CRF: I.V., SubQ: Initial: 0.45 mcg/kg once weekly; titrate to response; some patients may respond to doses given once every 2 weeks

Unlabeled dosing:

Every 2-weeks: 0.75 mcg/kg every 2 weeks (Toto, 2004)

Every 4-weeks: 0.75 mcg/kg every 2 weeks; once titrated, multiply dose by 2 and give every 4 weeks (Jadoul, 2004).

Anemia associated with chemotherapy: SubQ: Initial: 2.25 mcg/kg once weekly; with inadequate response: 4.5 mcg/kg once weekly

Unlabeled dosing:

Every 2 weeks:

Initial: 200 mcg every 2 weeks; inadequate response: 300 mcg every 2 weeks (Thames, 2003)

Initial: 3 mcg/kg every 2 weeks; inadequate response: 5 mcg/kg every 2 weeks (Vadhan-Raj, 2003)

Every 3 weeks (front load): Initial:

4.5 mcg/kg every week until desired Hgb obtained; maintenance: 4.5 mcg/kg (or titrated dose) every 3 weeks (Hesketh, 2004)

Initial: 325 mcg every week until desired Hgb obtained; maintenance: 325 mcg every 3 weeks (Hesketh, 2004)

Treatment goals: Note: Titration may be required to limit rises of Hgb to <1 g/dL over any 2-week interval and to reach a Hgb concentration not to exceed 12 g/dL.

Inadequate response: Increase dose; refer to individual dosing regimens for adjustment when Hgb increase <1 g/dL after 4-6 weeks

Excessive response: Hold dose and/or decrease dose by 25%

Decrease dose by 25% when Hgb increases >1 g/dL in any 2-week period or Hgb increases and approaches 12 g/dL in any 2-week period

Hold dose, then decrease dose by 25% when Hgb increases despite previous dose decrease (hold until Hgb decreases) or when Hgb 13g/dL (hold until Hgb 12 g/dL)

Conversion from epoetin alfa to darbepoetin alfa: See table.

Note:

Conversion From Epoetin Alfa to Darbepoetin Alfa

Previous Dosage of Epoetin Alfa (units/week)	Darbepoetin Alfa Dosage (mcg/week)	Darbepoetin Alfa Dosage (mcg/every 2 weeks)
<2500	6.25	12.5
2500-4999	12.5	25
5000-10,999	25	50
11,000-17,999	40	80
18,000-33,999	60	120
34,000-89,999	100	200
90,000	200	400
Note: In patients receiving epoetin alfa 2-3 times per week, darbepoetin alfa is administered once weekly. In patients receiving epoetin alfa once weekly, darbepoetin alfa is administered once every 2 weeks.

Dosage adjustment in renal impairment: Dosage requirements for patients with chronic renal failure who do not require dialysis may be lower than in dialysis patients. Monitor patients closely during the time period in which a dialysis regimen is initiated, dosage requirement may increase.

Administration

May be administered by SubQ or I.V. injection. Do not shake; vigorous shaking may denature darbepoetin alfa, rendering it biologically inactive. Do not dilute or administer in conjunction with other drug solutions. Discard any unused portion of the vial; do not pool unused portions. Discontinue immediately if signs/symptoms of anaphylaxis occur.

Monitoring Parameters

Hemoglobin (weekly until maintenance dose established and after dosage changes; monitor at regular intervals once hemoglobin is stabilized); iron stores (prior to and during therapy)

Dietary Considerations

Supplemental iron intake may be required in patients with low iron stores.

Patient Education

Inform prescriber of all prescriptions, OTC medications, herbal products, vitamins, or dietary supplements you are taking, and any allergies you have. Do not take any new medication during therapy without consulting prescriber. This medication can only be administered by infusion or injection (if self-administered, follow exact directions for injection and needle disposal). You will need frequent blood tests to determine appropriate dosage. Avoid alcohol and do not make significant changes in your dietary iron without consulting prescriber. Check your blood pressure as frequently as recommended and report any significant changes. May cause nausea or vomiting (small, frequent meals, frequent mouth care, sucking lozenges, or chewing gum may help); diarrhea (boiled milk, buttermilk, or yogurt may help); constipation (increased dietary fruit, fiber, fluids, and increased exercise may help); or dizziness, fatigue, or headache (use caution when driving or engaging in tasks that require alertness until response to drug is known). Report signs of edema (swollen extremities, respiratory difficulty); sudden onset of acute headache, back pain, or chest pain; muscle tremors or weakness; cough or signs of respiratory infection; or other adverse effects. Pregnancy/breast-feeding precautions: Inform prescriber if you are or intend to become pregnant. Consult prescriber if breast-feeding.

Anesthesia and Critical Care Concerns/Other Considerations

Recently, a prospective, randomized, double-blind, placebo-controlled, multicenter trial was performed in critically-ill patients (Corwin, 2002) assessing the efficacy of recombinant human erythropoietin in reducing red blood cell transfusions. Patients were enrolled from December 1998 through June 2001. Over thirteen hundred ICU (medical, surgical, or medical/surgical) patients were randomized to receive placebo or 40,000 units of erythropoietin subcutaneously on ICU day 3 and then weekly for patients who remained in the hospital. Each patient's physician determined the need for red blood cell transfusion. The mean baseline hemoglobin was 9.97 g/dL in each group. Patients receiving erythropoietin were less likely to receive transfusions. The mean number of units transfused per patient in the placebo group was 3 and in the erythropoietin group was 2.4. The erythropoietin group had a 19% reduction in total units of red blood cells transfused. Mortality and adverse clinical events were not significantly different between groups. The authors concluded that weekly administration of erythropoietin in critically-ill patients reduces red blood cell transfusions and increases hemoglobin. The authors also suggest that further study is needed to determine whether use of erythropoietin results in improved clinical outcomes. In addition, data on cost effectiveness would be helpful.

A restrictive transfusion approach (Hebert, 1999) was described in a transfusion trial that was published after Corwin's trial was underway. Hebert and his group evaluated a restrictive transfusion strategy (transfuse if hemoglobin <7 g/dL to maintain between 7 and 9 g/dL) versus a liberal strategy (transfuse if hemoglobin <10 g/dL to maintain between 10 and 12 g/dL). The restrictive approach to transfusion was at least as effective as, and possibly superior to, a liberal transfusion policy in critically-ill patients. The exception to this may be patients with acute myocardial infarction and unstable angina.

Dental Health: Effects on Dental Treatment

No significant effects or complications reported

Dental Health: Vasoconstrictor/Local Anesthetic Precautions

No information available to require special precautions

Mental Health: Effects on Mental Status

May cause sedation or dizziness

Mental Health: Effects on Psychiatric Treatment

Nausea, vomiting, and diarrhea are common; use caution with lithium, valproic acid, and SSRIs

Dosage Forms

Injection, solution, with human albumin 2.5 mg/mL [preservative free, single-dose vial]: 25 mcg/mL (1 mL); 40 mcg/mL (1 mL); 60 mcg/mL (1 mL); 100 mcg/mL (1 mL); 150 mcg/0.75 mL (0.75 mL); 200 mcg/mL (1 mL); 300 mcg/mL (1 mL)

Injection, solution, with human albumin 2.5 mg/mL [preservative free, prefilled syringe]: 25 mcg/0.42 mL (0.42 mL); 40 mcg/0.4 mL (0.4 mL); 60 mcg/0.3 mL (0.3 mL); 100 mcg/0.5 mL (0.5 mL); 200 mcg/0.4 mL (0.4 mL); 300 mcg/0.6 mL (0.6 mL); 500 mcg/mL (1 mL)

References

Besarab A, Bolton WK, Browne JK, et al, "The Effects of Normal as Compared With Low Hematocrit Values in Patients With Cardiac Disease Who Are Receiving Hemodialysis and Epoetin,"N Engl J Med, 1998, 339(9):584-90.

Corwin HL, Gettinger A, Pearl RG, et al, "Efficacy of Recombinant Human Erythropoietin in Critically Ill Patients: A Randomized Controlled Trial,"JAMA, 2002, 288(22):2827-35.

Egrie JC and Browne KJ, "Development and Characterization of Novel Erythropoiesis Stimulation Protein (NESP),"Brit J Cancer, 2001, 84(Suppl 1):3-10.

Hebert PC, Wells G, Blajchman MA, et al, "A Multicenter, Randomized, Controlled Clinical Trial of Transfusion Requirements in Critical Care. Transfusion Requirements in Critical Care Investigators, Canadian Critical Care Trials Group,"N Engl J Med, 1999, 340(6):409-17.

Hesketh PJ, Arena F, Patel D, et al, "A randomized Controlled Trial of Darbepoetin Alfa Administered as a Fixed or Weight-Based Dose Using a Front-Loading Schedule in Patients With Anemia Who Have Nonmyeloid Malignancies,"Cancer, 2004, 100(4):859-68.

Jadoul M, Vanrenterghem Y, Foret M, et al, "Darbepoetin Alfa Administered Once Monthly Maintains Haemoglobin Levels in Stable Dialysis Patients,"Nephrol Dial Transplant, 2004, 19(4):898-903.

Thames W, Yao B, Scheifele A, et al, "Drug Use Evaluation (DUE) of Darbepoetin Alfa in Anemic Patients Undergoing Chemotherapy Supports a Fixed Dose of 200 mcg Q2W Given Every 2 Weeks (Q2W)," Asco Annual Meeting, 2003.

Toto RD, Pichette V, Brenner R, et al, "Darbepoetin Alfa Effectively Treats Anemia in Patients With Chronic Kidney Disease With de novo Every-Other-Week Administration,"Am J Nephrol, 2004, 24(4):453-60.

Vadhan-Raj S, Mirtsching B, Charu V, et al, "Assessment of Hematologic Effects and Fatigue in Cancer Patients With Chemotherapy-Induced Anemia Given Darbepoetin Alfa Every Two Weeks,"J Support Oncol, 2003, 1(2):131-8.

International Brand Names

Aranesp® (AT, BE, CA, CH, DE, DK, ES, FI, FR, GB, IE, IL, IT, NL, NO, PT, SE); Aranest® (ES); Nespo® (IT)