Tuesday, November 24, 2009

Another Black Box: Aranesp, Epogen, Procrit, What you should know about drugs that tell your body to make more red blood cells

Erythropoiesis Stimulating Agents (ESAs) tell your body to make more red blood cells. Drugs in this class include:

• Aranesp (darbopoetin alfa)
• Epogen (epoetin alfa)
• Procrit (epoetin alfa)
• There are other brand names & epoetin variants marketed worldwide

The Good News First . . .

Twenty years ago we didn’t have synthetic medications to treat anemia. Depending on the cause anemia was often treated through diet, by administering supplementary iron or vitamin B12, and frequently, by blood transfusions. The 1980's was a decade of concern over the safety of our blood supply due to blood borne pathogens such as Hepatitis B and C and the HIV virus. New technologies in recombinant DNA allowed science to explore and develop innovative alternative therapies.

In 1989, Epogen (epoetin alfa), the first of a class of drugs called erythropoiesis stimulating agents (abbreviated as “ESAs”), was approved by the FDA in the United States to treat patients suffering from anemia due to chronic kidney disease. Epogen was eventually joined by similar ESAs called Aranesp and Procrit and treatment was eventually broadened to include patients suffering from anemia related to chemotherapy.

The benefit to both groups was that they no longer needed to rely on frequent blood transfusions to treat their anemia. ESAs directly influence the body to speed up the production of its own red blood cells by introducing a synthetic version of the hormone erythropoietin. Erythropoietin is a chemical messenger of sorts with the specific mission of instructing our bone marrow to produce more red blood cells. Epogen, Aransep, and Procrit are easily given by a simple injection under the skin from one to three times per week.

So what exactly is anemia? Anemia results when we don’t have enough healthy red blood cells called erythrocytes circulating in our bloodstream. Healthy red blood cells are vital; they carry a protein called hemoglobin which picks up molecules of oxygen from our lungs and delivers it to the tissues throughout our body. We don’t store oxygen in our body but we use it continuously, and our body’s demand for oxygen is constant as oxygen molecules literally fuel every basic function that each cell in our body must perform.

Symptoms of Anemia. Moderate to severe anemia can cause symptoms of weakness, fatigue, shortness of breath, rapid/irregular heartbeat and pale skin. Milder or chronic anemia may cause subtle symptoms or no symptoms at all.

Erythropoietin. This hormone is a chemical messenger with several functions relating to the manufacture of red blood cells, preserving their lifespan in the body, and enhancing the growth of blood vessels. As we develop before birth, erythropoietin is active within our livers. After we are born, erythropoietin is manufactured and released by cells in the kidney.

Kidneys and Anemia. People often don’t think of a relationship between the kidneys and anemia, but when you carefully consider it, it makes sense for the kidney to have this function. Like a waste-water treatment plant adds chemicals based on the scientific observations of the plant technicians, the kidneys have specialized cells that detect decreased oxygen levels in the blood circulating through them, and as a result, these specialized cells release erythropoietin to enhance red blood cell formation and longevity. If the kidneys become diseased and fail, this system of checks and balances is impaired or lost. When ESAs, or synthetic erythropoietin, was first introduced in 1989, the drug was intended specifically for the benefit of patients in kidney failure.

Chemotherapy and Anemia. Cancer cells are bizarre mutant cells that divide rapidly. therefore, malignant tumors can grow large very quickly. The goal of chemotherapy is to target those rapidly-dividing bizarre cells and kill them. Other “good” rapidly-dividing cells in our body get caught in the cross-fire and are also damaged by chemo drugs. Hair is lost when rapidly-dividing cells in the roots are targeted by the chemo drugs. Other fast-growing cells affected by chemotherapy are in the digestive tract; that’s why mouth sores, nausea, and vomiting are a common consequence of chemo. The body’s rapidly dividing blood cells (red cells, white cells, and platelets) are also among the good cells that fall prey to chemotherapy. The anemia that results from chemotherapy is not caused by a lack of erythropoietin, but ESAs were approved by the FDA in 1993 to treat anemia to reduce the amount of blood transfusions necessary for patients suffering from chemotherapy-induced anemia.

Sobering News about ESAs . . .

All medications have both benefits and risks. In the U.S. the FDA places "black box warnings" on the medication labels and inserts of drugs when research suggests there is a risk of serious adverse effects. The first black box warning for ESAs appeared in March of 2007. Eight months later in November 2007, the black box warning was emphatically strengthened by the FDA.

Both the chronic renal failure and chemotherapy patients were found to have some increased risks when using ESAs. Patients with certain types of cancer were found to be at risks of tumor progression and decreased survival when taking ESAs to increase red blood cell production. Chronic renal failure patients were found to be at increased risk of developing heart attack, stroke, blood clots, heart failure and death if their ESA dose was high enough to cause them to make more than recommended number of red blood cells.

The FDA’s guidance to physicians was very specific on the recommended dosage to achieve good results without increasing patients’ risks for a bad outcome. Further, their guidance suggested that physicians specifically discuss the risks and benefits of these medications with their patients.

What’s Inside the Black Box . . . guidance for physicians about prescribing:

For patients with cancer: ESAs should only be used to treat anemia caused by chemotherapy—not to treat anemia from any other cause. After chemotherapy is finished, ESAs should no longer be used. Risks of tumor progression and decreased survival were noted in some clinical trials. The FDA strongly recommends that healthcare professionals discuss these risks with their patients before this therapy is started.

For anemic patients with chronic renal failure: Treat with the lowest level of the drug which will maintain hemoglobin levels within the target range of less than 12 g/dL. The established goal for this group is to maintain hemoglobin between 10-12 g/dL, because the risk for death and serious cardiovascular events increases when higher hemoglobin levels are achieved on ESA therapy. Further, it’s recommended that ESA therapy be discontinued if the patient’s hemoglobin levels remain so low that blood transfusions are still required.

What the FDA recommends for physicians and other healthcare professionals to discuss with their patients:

1. The primary goal of treatment with erythropoiesis stimulating agents (ESA) is to increase the number of red blood cells in order to avoid receiving blood transfusions.
2. These medications require at least two weeks of treatment before there is an increase in the number of red blood cells, and the dose may be adjusted periodically, but not more often than every four weeks.
3. ESAs increase the patient’s chance of blood clots and the risk of dying may be greater in certain circumstances.
4. Patients should keep appointments for blood tests so hemoglobin levels can be monitored.
5. Patients should monitor their blood pressure and call their healthcare provider for changes outside of the range that has been established for them.
6. Call the healthcare provider if they experience any of the following symptoms:
  • Pain and/or swelling in the legs
  • Worsening in shortness of breath
  • Increases in blood pressure
  • Dizziness or loss of consciousness
  • Extreme tiredness
  • Blood clots in hemodialysis vascular access ports

What the FDA wants patients to know about treatment with Aranesp, Epogen and Procrit . . .

Patients with cancer who are currently using or considering the use of an ESA should know the following:
• ESAs may shorten your survival time or may cause your tumors to grow faster.
• ESAs should only be used to treat anemia caused by chemotherapy and not other anemia from other causes in patients with cancer
• ESAs should not be used to treat the symptoms of anemia, such as fatigue or improve the quality of life in patients with cancer. The goal of treatment with ESAs is to avoid blood transfusions
• Treatment with an ESA should be stopped after you complete your course of chemotherapy.

Patients with chronic kidney failure (this includes both patients on dialysis and those not on dialysis) who are currently using an ESA should know the following:
• Your hemoglobin level should be checked regularly to make sure it stays between 10 and 12 g/dL.
• ESAs can increase your chance of heart attack, stroke, blood clots, heart failure, and death when they are given to maintain higher hemoglobin levels.
• If you are not responding to treatment with an ESA (your hemoglobin levels are not increasing) ask your doctor if you need to be checked for other causes of anemia.

Report Adverse Reactions to the FDA: Healthcare professionals are to report adverse and unexpected reactions with these meds to the FDA MedWatch reporting program online or by phone: 1-800-332-1088.

Links to more information about ESAs:

• Comprehensive information about ESAs from the U.S. Centers for Medicaid and Medicare Services: www.cms.hhs.gov/determinationprocess/downloads/id203d.pdf
• Kidney Disease and Anemia: http://kidney.niddk.nih.gov/kudiseases/pubs/anemia/
• Anemia and Kidney Disease: http://www.aakp.org/aakp-library/Anemia-in-Chronic-Kidney-Disease/
A plus: Anemia and Kidney Disease from Anemia.org: http://www.anemia.org/patients/information-handouts/kidney-disease/
• ESA use for anemia in cancer patients: http://www.medscape.com/viewarticle/571464

.(All rights reserved, Carolyn Cooper, MPH, RN, 2009)  .. . .

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