Darbepoetin – Uses, Dosage, Side Effects, Interaction

Darbepoetin alfa injection is used to treat anemia (a lower-than-normal number of red blood cells) in people with chronic? kidney failure? (a condition in which the kidneys? slowly and permanently stop working over a period of time). Darbepoetin alfa injection is also used to treat anemia caused by chemotherapy? in people with certain types of cancer. Darbepoetin alfa cannot be used in place of a red blood cell transfusion to treat severe? anemia and has not been shown to improve tiredness or poor well-being? that may be caused by anemia. Darbepoetin alfa is in a class of medications called erythropoiesis-stimulating agents (ESAs). It works by causing the bone marrow? (soft tissue inside the bones where blood is made) to make more red blood cells

Darbepoetin alfa is a re-engineered form of erythropoietin containing 5 amino acid changes (N30, T32, V87, N88, T90) resulting in the creation of 2 new sites for N-linked carbohydrate addition. It has a 3-fold longer serum half-life compared to epoetin alpha and epoetin beta. It stimulates erythropoiesis (increases red blood cell levels) by the same mechanism as rHuEpo (binding and activating the Epo receptor) and is used to treat anemia, commonly associated with chronic kidney? failure and cancer chemotherapy. Darbepoetin is marketed by Amgen under the trade name Aranesp.

Mechanism of action

Darbepoetin alfa stimulates erythropoiesis by the same mechanism as endogenous erythropoietin. Erythropoietin interacts with progenitor stem cells to increase red cell production. The binding of erythropoietin to the erythropoietin receptor leads to receptor dimerization, which facilitates the activation of JAK-STAT signaling pathways within the cytosol. Activated STAT (signal transducers and activators of transcription) proteins are then translocated to the nucleus where they serve as transcription factors that regulate the activation of specific genes involved in cell division or differentiation.

Darbepoetin alfa is used in the treatment of anemia. It is involved in the regulation of erythrocyte differentiation and the maintenance of a physiological level of circulating erythrocyte mass.

Indications

• For the treatment of anemia (from renal? transplants or certain HIV treatments)
• Anemia
• Treatment of anemia in patients with non-myeloid malignancies where anemia is due to the effect of concomitant myelosuppressive chemotherapy.

Use in Cancer

Darbepoetin alfa is approved to treat:

• Anemia is caused by myelosuppressive chemotherapy used for certain types of cancer.

Contraindications

• inadequate folic acid
• inadequate vitamin B12
• porphyria
• anemia from inadequate iron
• high blood pressure
• significant uncontrolled high blood pressure
• a heart attack?
• a clot in the lung
• sudden and serious symptoms of heart failure? called acute? decompensated heart failure
• a stroke?
• obstruction of a blood vessel by a blood clot
• a blood clot
• blood clot in a deep vein? of the extremities
• seizures
• visible water retention
• a blood clot in a vascular access device
• pure red cell aplasia
• Aluminum poisoning, severe Bleeding, severe or Bone marrow fibrosis? (osteoporosis? cystic) Folic acid deficiency, Infections, inflammation?, cancer Iron deficiency, or Vitamin B12 deficiency—This may cause a delay in response to treatment.
• Blood clots (history of) or other problems with the blood or Congestive heart failure or Heart attack, history of or Heart bypass surgery or Heart or blood vessel disease or Stroke, history of or Thrombosis?, at risk for—The chance of side effects may be increased.
• Bone marrow problems (eg, hemolytic anemia, sickle cell anemia, porphyria, thalassemia?)—The use of darbepoetin alfa injection has not been established in patients with these conditions.
• Hypertension? (high blood pressure), uncontrolled or Pure red cell aplasia (rare bone marrow disease)—Should not be used in patients with these conditions.
• Seizures, history of—Use with caution. May make this condition worse.

Dosage?

Strengths: 25 mcg/mL; 40 mcg/mL; 60 mcg/mL; 100 mcg/mL; 200 mcg/mL; 300 mcg/mL; 40 mcg/0.4 mL; 60 mcg/0.3 mL; 100 mcg/0.5 mL; 150 mcg/0.3 mL; 200 mcg/0.4 mL; 500 mcg/mL; 300 mcg/0.6 mL; 150 mcg/0.75 mL; 25 mcg/0.42 mL; 10 mcg/0.4 mL

Anemia Associated with Chronic Renal Failure?

Chronic Kidney Disease? (CKD?) Patients Not on Dialysis:

• Initial dose: 0.45 mcg/kg IV or subcutaneously once every 4 weeks as appropriate
• Initiate treatment only when hemoglobin? is less than 10 g/dL, the rate of hemoglobin decline indicates the likelihood of requiring RBC transfusion, and reducing the risk of alloimmunization and/or other RBC transfusion-related risks is a goal.

CKD Patients on Dialysis:

• Initial dose: 0.45 mcg/kg IV or subcutaneously once a week or 0.75 mcg/kg once every 2 weeks as appropriate
• Initiate treatment when hemoglobin is less than 10 g/dL.
• IV route is recommended for patients on hemodialysis.

Anemia Associated with Chemotherapy

• Initial dose: 2.25 mcg/kg subcutaneously once a week or 500 mcg subcutaneously once every 3 weeks
• Duration of therapy: Until completion of the chemotherapy course
• Initiate treatment if hemoglobin is less than 10 g/dL and a minimum of 2 additional months of chemotherapy is planned.
• Use the lowest dose necessary to avoid RBC transfusions.

Pediatric Dose for Anemia Associated with Chronic Renal Failure

Less than 18 Years:
Initial dose:

• Chronic Kidney Disease (CKD) Patients Not on Dialysis: 0.45 mcg/kg IV or subcutaneously once a week or 0.75 mcg/kg once every 2 weeks
• CKD Patients on Dialysis: 0.45 mcg/kg IV or subcutaneously once a week
• Initiate treatment when hemoglobin is less than 10 g/dL.

Dose Adjustments

All chronic kidney disease (CKD) patients:

• May increase dose no more than every 4 weeks; may decrease dose more frequently. Avoid frequent dose adjustments.
• If hemoglobin increases by more than 1 g/dL in 2 weeks, reduce the dose by 25% or more as needed to reduce rapid responses.
• If hemoglobin has not increased by more than 1 g/dL after 4 weeks of therapy, increase the dose by 25%.
• For patients who do not respond adequately over a 12-week escalation period, further dose increases are unlikely to improve response and may increase risks. Use the lowest dose that will maintain a hemoglobin level sufficient to reduce the need for RBC transfusions.
• Evaluate other causes of anemia. Discontinue if responsiveness does not improve.

CKD patients on dialysis:

• If hemoglobin approaches or exceeds 11 g/dL, reduce or interrupt the dose of this drug.

CKD patients not on dialysis:

• If hemoglobin exceeds 10 g/dL, reduce or interrupt the dose and use the lowest dose sufficient to reduce the need for RBC transfusions.

Pediatric CKD patients:

• If hemoglobin approaches or exceeds 12 g/dL, reduce or interrupt the dose of this drug.

Conversion from epoetin alfa to this drug in CKD patients on dialysis:

• Maintain the route of administration when converting.
• Administer this drug once weekly in patients who were receiving epoetin alfa 2 to 3 times weekly; administer once every 2 weeks in patients who were receiving epoetin alfa once weekly.
• Previous weekly epoetin alfa dose (units/week): Darbepoetin alfa dose (mcg/week)
• Less than 1500: Adults: 6.25; Pediatric: Unknown
• 1500 to 2499: Adults: 6.25; Pediatric: 6.25
• 2500 to 4999: Adults: 12.5; Pediatric: 10
• 5000 to 10999: Adults: 25; Pediatric: 20
• 11000 to 17999: Adults: 40; Pediatric: 40
• 18000 to 33999: Adults: 60; Pediatric: 60
• 34000 to 89999: Adults: 100; Pediatric: 100
• 90000 or greater: Adults: 200; Pediatric: 200

Conversion from epoetin alfa to this drug in CKD patients not on dialysis:

• Refer to doses for CKD patients on dialysis. Dose conversion does not accurately estimate the once-monthly dose of this drug.

All chemotherapy patients:

• If hemoglobin increases greater than 1 g/dL in 2 weeks or reaches a level needed to avoid RBC transfusion, reduce the dose by 40%.
• If hemoglobin exceeds a level needed to avoid RBC transfusion, withhold the dose until hemoglobin approaches a level where RBC transfusions may be required and reinitiate at a dose 40% below the previous dose.
• If hemoglobin increases by less than 1 g/dL and remains below 10 g/dL after 6 weeks of therapy, increase the dose to 4.5 mcg/kg/week, if on the weekly dosing schedule. If on the every 3-week dosing schedule, no dose adjustment is recommended.
• If there is no response as measured by hemoglobin levels or if RBC transfusions are still required after 8 weeks of therapy, or if the chemotherapy course is complete, discontinue this drug.

Side Effects

The Most Common

• cough?
• stomach pain
• redness, swelling, bruising, itching, or a lump at the spot where you injected darbepoetin alfa
• rash
• itching
• difficulty breathing or swallowing
• wheezing
• hoarseness
• swelling of the face, throat, tongue, lips, eyes, hands, feet, ankles, or lower legs
• fast pulse
• excessive tiredness
• lack of energy
• dizziness
• fainting
• pale skin

More common

• Accumulation of pus
• arm, back, or jaw pain
• blurred vision
• breathing problems (irregular, noisy, or trouble when resting)
• chest pain, discomfort, tightness, or heaviness
• chills
• confusion
• cough producing mucus
• decrease in the amount of urine
• diarrhea
• dilated neck veins
• dizziness, fainting, or lightheadedness
• dry mouth
• fast, slow, or irregular heartbeat
• fatigue or tiredness (extreme or unusual)
• fever
• headache
• nausea
• pain, tenderness, swelling, or warmth over the injection site
• pounding in the ears
• rapid breathing
• rapid or pounding pulse
• skin discoloration at the injection site
• stomach pain
• sunken eyes
• sweating
• swelling of the ankles, face, fingers, feet, hands, or lower legs
• thirst
• trouble with breathing
• unconsciousness
• vomiting
• weight gain
• wrinkled skin

Rare

• Anxiety
• difficulty with speaking (slow speech or unable to speak)
• double vision
• seizures
• trouble with thinking
• trouble with walking
• unable to move the arms, legs, or face muscles (including numbness and tingling)
• Fever
• hives, itching, skin rash
• pale skin
• sore throat
• Blistering, peeling, or loosening of the skin
• cough
• joint or muscle pain
• red, irritated eyes
• red skin lesions, often with a purple center
• sores, ulcers, or white spots in the mouth or on the lips

Drug Interactions

Pregnancy and Lactation

AU TGA pregnancy category: B3
US FDA pregnancy category: Not assigned

Pregnancy

Studies in animals have shown evidence of an increased occurrence of fetal damage, the significance of which is considered uncertain in humans. The limited data available on use in pregnant women is insufficient to know this drug’s risks, including the risk of fetal harm or reproductive effects. Animal reproduction studies showed increased early post-implantation loss at doses about equal to the usual human starting dose.

Lactation

Darbepoetin alfa is biologically and immunologically indistinguishable from erythropoietin, a normal component of human milk. IV darbepoetin has been given safely to newborn infants in doses much larger than those expected to appear in breast milk.

There is no information regarding this drug on the presence of human milk, its effects on a breastfed infant, or its effects on milk production.
Consider the developmental and health benefits of breastfeeding along with the mother’s clinical need for this medication as well as any potential adverse effects from this drug or the underlying maternal condition.

References