Darbepoetin – Uses, Dosage, Side Effects, Interaction

Darbepoetin alfa is a recombinant form of human erythropoietin used to increase the differentiation of progenitor cells to red blood cells in the treatment of anemia. Human erythropoietin with 2 aa substitutions to enhance glycosylation (5 N-linked chains), 165 residues (MW=37 kD). Produced in Chinese hamster ovary (CHO) cells by recombinant DNA technology.

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:

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

You Might Also Read  What Is Evabotulinumtoxina? Indications, Contraindications
You Might Also Read  Bevacizumab; Uses, Dosage, Side Effects, Drug Interactions
You Might Also Read  Isavuconazole; Uses, Dosage, Side Effects, Interactions, Pragnancy

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.

How should this medicine be used?

Darbepoetin alfa injection comes as a solution (liquid) to inject subcutaneously (just under the skin) or intravenously (into a vein). It is usually injected once every 1 to 4 weeks. Follow the directions on your prescription label carefully, and ask your doctor or pharmacist to explain any part you do not understand. Use darbepoetin alfa injection exactly as directed. Do not use more or less of it or use it more often than prescribed by your doctor.

Your doctor will start you on a low dose of darbepoetin alfa injection and adjust your dose depending on your lab results and on how you are feeling. Your doctor may also tell you to stop using darbepoetin alfa injection for a time. Follow these instructions carefully.

Darbepoetin alfa injection will help to control your anemia only as long as you continue to use it. It may take 2-6 weeks or longer before you feel the full benefit of darbepoetin alfa injection. Continue to use darbepoetin alfa injection even if you feel well. Do not stop using darbepoetin alfa injection without talking to your doctor.

Darbepoetin alfa injections may be given by a doctor or nurse, or your doctor may decide that you can inject darbepoetin alfa yourself, or that you may have a friend or relative give the injections. You and the person who will be giving the injections should read the manufacturer’s information for the patient that comes with the darbepoetin alfa injection before you use it for the first time at home. Ask your doctor to show you or the person who will be injecting the medication how to inject it.

Darbepoetin alfa injection comes in prefilled syringes and in vials to be used with disposable syringes. If you are using vials of darbepoetin alfa injection, your doctor or pharmacist will tell you what type of syringe you should use. Do not use any other type of syringe because you may not get the right amount of medication.

Do not shake the darbepoetin alfa injection. If you shake the darbepoetin alfa injection it may look foamy and should not be used.

Always inject darbepoetin alfa injection in its own syringe. Do not dilute it with any liquid and do not mix it with any other medications.

You can inject darbepoetin alfa injection anywhere on the outer area of your upper arms, and your stomach except for the 2-inch (5-centimeter) area around your navel (belly button), the front of your middle thighs, and the upper outer areas of your buttocks. Choose a new spot each time you inject darbepoetin alfa. Do not inject darbepoetin alfa into a spot that is tender, red, bruised, or hard, or that has scars or stretch marks.

If you are being treated with dialysis (treatment to remove waste from the blood when the kidneys are not working), your doctor may tell you to inject the medication into your venous access port (the place where dialysis tubing is connected to your body). Ask your doctor if you have any questions about how to inject your medication.

Always look at the darbepoetin alfa injection solution before injecting it. Be sure that the prefilled syringe or vial is labeled with the correct name and strength of medication and an expiration date that has not passed. If you are using a vial, check to be sure that it has a colored cap, and if you are using a prefilled syringe, check that the needle is covered with the grey cover and that the yellow plastic sleeve has not been pulled over the needle. Also check that the solution is clear and colorless and does not contain lumps, flakes, or particles. If there are any problems with your medication, call your pharmacist and do not inject it.

Do not use prefilled syringes, disposable syringes, or vials of darbepoetin alfa injection more than once. Dispose of used syringes in a puncture-resistant container. Ask your doctor or pharmacist how to dispose of the puncture-resistant container.

What special precautions should I follow?

Before using darbepoetin alfa injection,

  • tell your doctor and pharmacist if you are allergic to darbepoetin alfa, epoetin alfa (Epogen, Procrit), any other medications, or any of the ingredients in darbepoetin alfa injection. Ask your pharmacist or check the Medication Guide for a list of the ingredients. If you will be using the prefilled syringes, tell your doctor if you or the person who will be injecting the medication is allergic to latex.
  • tell your doctor if you have or have had high blood pressure, and if you have ever had pure red cell aplasia (PRCA; a type of severe anemia that may develop after treatment with an ESA such as darbepoetin alfa injection or epoetin alfa injection). Your doctor may tell you not to use darbepoetin alfa injection.
  • tell your doctor and pharmacist what prescription and nonprescription medications, vitamins, nutritional supplements, and herbal products you are taking or plan to take. Your doctor may need to change the doses of your medications or monitor you carefully for side effects.
  • tell your doctor if you have or have ever had seizures. If you are using darbepoetin alfa injection to treat anemia caused by chronic kidney disease, tell your doctor if you have or have ever had cancer.
  • tell your doctor if you are pregnant, plan to become pregnant, or are breastfeeding. If you become pregnant while using darbepoetin alfa injection, call your doctor.
  • before having surgery, including dental surgery, tell your doctor or dentist that you are being treated with darbepoetin alfa injection. It is especially important to tell your doctor that you are using darbepoetin alfa injection if you are having coronary artery bypass graft (CABG) surgery or surgery to treat a bone problem. Your doctor may prescribe an anticoagulant (‘blood thinner’) to prevent clots from forming during surgery.

References