Darbepoetin alfa

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Darbepoetin alfa
Clinical data
AHFS/Drugs.com monograph
MedlinePlus a604022
Licence data EMA:Link, US FDA:link
Pregnancy cat.
Legal status
Identifiers
CAS number 11096-26-7 YesY
ATC code B03XA02
DrugBank DB00012
UNII 15UQ94PT4P N
Chemical data
Formula C815H1317N233O241S5 
Mol. mass 18396.1 g/mol
 N (what is this?)  (verify)

Darbepoetin alfa (rINN) /dɑrbəˈpɔɪtɨn/ is a synthetic form of erythropoietin. It stimulates erythropoiesis (increases red blood cell levels) and is used to treat anemia, commonly associated with chronic renal failure and cancer chemotherapy. Darbepoetin is marketed by Amgen under the trade name Aranesp.

The drug was approved in September 2001 by the Food and Drug Administration for treatment of anemia in patients with chronic renal failure by intravenous or subcutaneous injection.[1] In June 2001, it had been approved by the European Medicines Agency for this indication as well as the treatment of anemia in cancer patients undergoing chemotherapy.[2]

Dr. Reddy's Laboratories launched darbepoetin alfa in India under the brand name ‘Cresp’ in August 2010. This is the world’s first generic darbepoetin alfa. Cresp has been approved in India.

Darbepoetin is produced by recombinant DNA technology in modified Chinese hamster ovary cells.[3] It differs from endogenous erythropoietin (EPO) by containing two more N-linked oligosaccharide chains. It is an erythropoiesis-stimulating 165-amino acid protein.

Contraindications[edit]

Use of darbepoetin alfa is contraindicated in patients with hypersensitivity to the drug, pre-existing uncontrolled hypertension, and pure red cell aplasia.[4]

Adverse effects[edit]

Darbepoetin alfa has black box warnings in the United States for increased risk of death, myocardial infarction, stroke, venous thromboembolism, thrombosis of vascular access, and tumor progression or recurrence. To avoid side effects, it is recommended for patients with chronic renal failure or cancer to use the lowest possible dose needed to avoid red blood cell (RBC) transfusions.[5]

In addition to those listed in the black box warning, use of darbepoetin alfa also increases the risk of cardiovascular problems, including cardiac arrest, arrhythmia, hypertension and hypertensive encephalopathy, congestive heart failure, ischemia, and edema.[4] A recent study has extended these findings to treatment of patients exhibiting cancer-related anemia (distinct from anemia resulting from chemotherapy).[6] Other reported adverse reactions include increased risk of seizure, hypotension, fever, chest pains, nausea and myalgia.

Pregnancy and lactation[edit]

Darbepoetin alfa is a Pregnancy Category C drug in the United States.[4] Pregnant women who are taking darbepoetin alfa may enroll in Amgen’s Pregnancy Surveillance Program (800-772-6436).[5]

It is not known if darbepoetin alfa is excreted in breast milk. Mothers who choose to breast-feed are advised to use caution.[4]

Mechanism of action[edit]

Darbepoetin alfa binds to the erythropoietin receptor on erythroid progenitor cells, stimulating RBC production and differentiation.[4]

Safety advisories in anemic cancer patients[edit]

Amgen sent a "dear doctor" letter in January, 2007, that highlighted results from a recent anemia of cancer trial, and warned doctors to consider use in that off-label indication with caution.

Amgen advised the U.S. Food and Drug Administration (FDA) as to the results of the DAHANCA 10 clinical trial. The DAHANCA 10 data monitoring committee found that 3-year loco-regional control in subjects treated with Aranesp was significantly worse than for those not receiving Aranesp (p=0.01).

In response to these advisories, the FDA released a Public Health Advisory[7] on March 9, 2007, and a clinical alert[8] for doctors on February 16, 2007, about the use of erythropoeisis-stimulating agents (ESAs) such as epoetin alfa (marketed as Epogen) and darbepoetin alfa. The advisory recommended caution in using these agents in cancer patients receiving chemotherapy or off chemotherapy, and indicated a lack of clinical evidence to support improvements in quality of life or transfusion requirements in these settings.

In addition, on March 9, 2007, drug manufacturers agreed to new black box warnings about the safety of these drugs. On November 8, 2007, additional black box warnings were included on the Aranesp label, at the request of the FDA.

On March 22, 2007, a congressional inquiry into the safety of erythropoeitic growth factors was reported in the news media. Manufacturers were asked to suspend drug rebate programs for physicians and to also suspend marketing the drugs to patients.

According to the 2010 update to clinical practice guidelines from the American Society of Clinical Oncology (ASCO) and the American Society of Hematology (ASH), use of ESAs such as darbepoetin alfa in cancer patients is appropriate when following stipulations outlined in FDA-approved labeling.[9]

Society and culture[edit]

Like EPO, darbepoetin alfa has the potential to be abused by athletes seeking a competitive advantage. Its use during the 2002 Winter Olympic Games to improve performance led to the disqualification of cross-country skiers Larisa Lazutina and Olga Danilova of Russia and Johann Mühlegg of Spain from their final races.[10]

Economics[edit]

Epogen and Aranesp had more than $6 billion in combined sales in 2006. Procrit sales were about $3.2 billion in 2006.

References[edit]

  1. ^ Jay P. Siegel (2001-09-17). "Product Approval Information - Licensing Action". United States Food and Drug Administration. Archived from the original on 2006-10-22. Retrieved 2007-01-27. 
  2. ^ "European Public Assessment Report (Abstract)" (PDF). European Medicines Agency. 2001-06-08. Retrieved 2007-01-27. 
  3. ^ Smith, R E; Jaiyesimi, I A; Meza, L A; Tchekmedyian, N S; Chan, D; Griffith, H; Brosman, S; Bukowski, R; Murdoch, M; Rarick, M; Saven, A; Colowick, A B; Fleishman, A; Gayko, U; Glaspy, J (16 June 2001). "Novel erythropoiesis stimulating protein (NESP) for the treatment of anaemia of chronic disease associated with cancer". British Journal of Cancer 84 (s1): 24–30. doi:10.1054/bjoc.2001.1749. Retrieved 31 October 2014. 
  4. ^ a b c d e "Darbepoetin Alfa (Lexi-Drugs)". LexiComp. Retrieved 29 October 2014.
  5. ^ a b "Prescribing Information: Aranesp ® (darbepoetin alfa) injection, for intravenous or subcutaneous use". Amgen Inc. Thousand Oaks, CA. Retrieved 3 November 2014. 
  6. ^ Pollack, Andrew (2007-01-26). "Amgen Finds Anemia Drug Holds Risks in Cancer Use". The New York Times. Retrieved 2007-01-27. 
  7. ^ "FDA Public Health Advisory: Erythropoiesis-Stimulating Agents (ESAs): Epoetin alfa (marketed as Procrit, Epogen), Darbepoetin alfa (marketed as Aranesp)". Archived from the original on 2007-05-28. Retrieved 2007-06-05. 
  8. ^ "Information for Healthcare Professionals: Erythropoiesis Stimulating Agents (ESA)". Archived from the original on 2007-05-15. Retrieved 2007-06-05. 
  9. ^ Rizzo, J. Douglas; Brouwers, Melissa; Hurley, Patricia; Seidenfeld, Jerome; Arcasoy, Murat O; Spivak, Jerry L; Bennett, Charles L; Bohlius, Julia; Evanchuk, Darren; Goode, Matthew J; Jakubowski, Ann A; Regan, David H; Somerfield, Mark R (November 2010). "ASCO-ASH Clinical Practice Guideline Update on the Use of Epoetin and Darbepoetin in Adult Patients With Cancer". Journal of Clinical Oncology 28 (33): 4996–5010. 
  10. ^ McGrath, Matt; Portal, Gaetan (30 January 2002). "New drugs give cheats the edge". BBC News. Retrieved 3 November 2014.