darbepoetin alfa (Rx)

>10%

Cancer patients

• Fatigue (33%)
• Diarrhea (22%)
• Edema (21%)
• Fever (19%)
• Dizziness (14%)
• Arthralgia (13%)
• Headache (12%)
• Death (10%)

Chronic renal failure patients

• Infectious disease (24%)
• Hyper/Hypotension (20%)
• Spasm (17%)
• Upper respiratory infection, Headache (15%)
• Diarrhea, Vomiting (14%)
• Nausea (11%)
• Peripheral edema, Dyspnea (10%)
• Abdominal pain (10%)

1-10%

Cancer patients

• Myalgia (8%)
• Hypertension (3.7%)
• Pneumonia (3%)
• Dyspnea (2%)
• Vomiting (2%)
• Pulmonary embolism (1.3%)

Chronic renal failure patients

• Arthralgia, Cough, Fatigue (9%)
• Limb pain (8%)
• Dizziness, Fever (7%)
• Death (6%)
• Edema (6%)
• Anemia, DVT, red cell aplasia (5.6%)
• Cardiac arrest, Cardiac dysrhythmia, Congestive heart failure (5%)
• Myocardial infarction, CVA (2%)

<1%

Cancer patients

• Hypertensive encephalopathy (0.6%)
• Seizure (0.6%)

Chronic renal failure patients

• Hypertensive encephalopathy (<1%)
• Seizure (<1%)
• Transient ischemic attack (<1% )

Frequency Not Defined

Tumor progression

Venous thromboembolism

Immune hypersensitivity reaction (rare )

Injection site thrombosis

Contraindications

Uncontrolled hypertension

Hypersensitivity to any component

Pure red cell aplasia (PRCA) that begins after treatment with darbepoetin alfa or other erythropoietin protein drugs

Cautions

Increased mortality, myocardial infarction, stroke, and thromboembolism: Using ESAs to target a hemoglobin level of greater than 11 g/dL increases the risk of serious adverse cardiovascular reactions and has not been shown to provide additional benefit (see Black Box Warnings)

Hypertensive encephalopathy and seizures reported in patients with CKD; appropriately control hypertension prior to initiation of and during treatment; reduce or withhold Aranesp if blood pressure becomes difficult to control; advise patients of importance of compliance with antihypertensive therapy and dietary restrictions

For lack or loss of hemoglobin response to therapy, initiate a search for causative factors (eg, iron deficiency, infection, inflammation, bleeding); if typical causes of lack or loss of hemoglobin response are excluded, evaluate for PRCA; in absence of PRCA, follow dosing recommendations for management of patients with insufficient hemoglobin response to therapy

Use caution in known porphyria, sickle cell anemia, thalassemia

Serious allergic reactions, including anaphylactic reactions, angioedema, bronchospasm, skin rash, and urticaria may occur; immediately and permanently discontinue therapy and administer appropriate therapy if a serious allergic or anaphylactic reaction occurs

Decrease dose if Hgb increase exceeds 1 g/dL in any 2 wk period

Increased mortality and/or increased risk of tumor progression or recurrence in patients with cancer

Increases the risk for seizures in patients with CKD; increase monitoring of these patients for changes in seizure frequency or premonitory symptoms

If severe anemia and low reticulocyte count develop during treatment, withhold therapy and evaluate for pure red cell aplasia

Blistering and skin exfoliation reactions including erythema multiforme and Stevens-Johnson Syndrome (SJS)/Toxic Epidermal Necrolysis (TEN), reported in the post-marketing setting; discontinue therapy immediately if a severe cutaneous reaction, such as SJS/TEN, suspected

Two different excipients available: polysorbate 80 or human albumin

May use supplemental iron if serum ferritin <100 mcg/L [0.225 pmol/L] or serum transferrin saturation <20%

IV route preferred for patients on hemodialysis

Patients may require adjustments in their dialysis prescriptions after initiation of therapy; patients receiving treatment may require increased anticoagulation with heparin to prevent clotting of extracorporeal circuit during hemodialysis

Autoinjector for SC administration only

Dose increase no more frequently than once monthly

Pure red cell aplasia

• Cases of PRCA and severe anemia, with or without other cytopenias that arise following development of neutralizing antibodies to erythropoietin reported predominantly in patients with CKD receiving ESAs by subcutaneous administration; also reported in patients receiving therapy for anemia related to hepatitis C treatment (indication not approved)
• If severe anemia and low reticulocyte count develop during treatment, withhold therapy and evaluate patients for neutralizing antibodies to erythropoietin; contact Amgen (1-800-77-AMGEN) to perform assays for binding and neutralizing antibodies
• Permanently discontinue therapy in patients who develop PRCA following treatment; do not switch patients to other ESAs

Pregnancy

Limited available data on pregnant women are insufficient to determine a drug-associated risk of major birth defects or miscarriage; in animal reproductive and developmental toxicity studies, drug increased early post-implantation loss at doses approximating clinical recommended starting doses; consider benefits and risks for the mother and possible risks to fetus when prescribing to a pregnant woman

Animal data

• When Aranesp was administered intravenously during organogenesis to pregnant rats (gestational days 6 to 15) and rabbits (gestational days 6 to 18), there was no evidence of embryofetal toxicity or other adverse outcomes at intravenous doses tested, up to 20 mcg/kg/day; no significant placental transfer was observed in rats; placental transfer was not evaluated in rabbits
• In a peri/postnatal development study, pregnant female rats received therapy intravenously every other day from implantation (day 6) throughout pregnancy and lactation (day 23); the lowest dose tested, 0.5 mcg/kg, did not cause fetal toxicity; this dose is approximately equivalent to clinical recommended starting dose; at maternal doses of 2.5 mcg/kg and higher, pups had decreased fetal body weights, which correlated with a slight increase in the incidence of fetal deaths, as well as delayed eye opening and delayed preputial separation; the offspring (F1 generation) of treated rats were observed postnatally; rats from F1 generation reached maturity and were mated; no treatment related effects were apparent for their offspring (F2 generation fetuses)

Lactation

There is no information regarding presence of drug in human milk, effects on breastfed child, or on milk production; the developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for therapy and any potential adverse effects on breastfed child from drug or from underlying maternal condition

Pregnancy Categories

A: Generally acceptable. Controlled studies in pregnant women show no evidence of fetal risk.

B: May be acceptable. Either animal studies show no risk but human studies not available or animal studies showed minor risks and human studies done and showed no risk.

C: Use with caution if benefits outweigh risks. Animal studies show risk and human studies not available or neither animal nor human studies done.

D: Use in LIFE-THREATENING emergencies when no safer drug available. Positive evidence of human fetal risk.

X: Do not use in pregnancy. Risks involved outweigh potential benefits. Safer alternatives exist.

NA: Information not available.

Mechanism of Action

Recombinant human erythropoietin with sialic acid additions to enhance stability; stimulates erythropoiesis via division & differentation of progenitor cells in bone marrow to induce the release of reticulocytes from the bone marrow into the bloodstream to become erythrocytes.

Pharmacokinetics

Half-Life: 46 hr (SC), 21 hr (IV)

Peak Plasma Time: 34 hr (SC)

Vd: 0.06 L/kg

Absorption: Slow (SC)

Bioavailability: 37% (SC; adults); 54% (SC; children)

IV Incompatibilities

Do not dilute or administer with other solutions

IV Administration

May be administered SC or IV bolus

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

Storage

Store at 2-8°C (36-46°F)

Do not freeze or shake

Protect from light