Increased Worldwide Focus on the Safety of Drugs Used To Treat Chemotherapy-Related Anemia

Over the past month, there was considerable press coverage regarding the safety and proper use of epoetin alfa (marketed as Epogen® & Procrit®) and darbepoetin (marketed as Aranesp®). Both drugs are erythropoiesis-stimulating agents (ESAs).

This controvery began between December 2006 and February 2007, when the U.S. Food and Drug Administration (FDA) was made aware of several studies in cancer patients that showed higher mortality or shorter time to tumor progression in patients randomized to receive an ESA as compared to placebo. Some of the trials dosed patients in the ESA treatment group to achieve hemoglobin levels ≥ 12 g/dl (higher than recommended on the ESAs drug box labeling). Other trials included anemic patients who were not on chemotherapy or radiotherapy. These studies were discussed at a May 10, 2007 meeting of the Oncology Drug Advisory Committee of the FDA (ODAC). The ODAC recommended additional restrictions in the labeling for ESAs including: (i) specific tumor types for which adverse safety signals were observed with the use of an ESA, (ii) instructions for hemoglobin trigger level-based dose modification/suspension, and (iii) instruction to discontinue use of ESAs upon completion of chemotherapy.

With respect to cancer the FDA recommendations to healthcare professionals include the following:

• ESAs shortened the overall survival and/or time-to-tumor progression in patients with various cancers;

• Risks of shortened survival and tumor progression have not been excluded when ESAs are dosed with the intent to achieve hemoglobin levels <12g/dL;

• Use the lowest dose of [Aranesp/EPOGEN/PROCRIT] needed to avoid red blood cell transfusions. Do not exceed the upper safety limit for hemoglobin levels of 12 g/dL;

• Reduce the ESA dose by 25% when hemoglobin reaches a level needed to avoid transfusion;

• Withhold dosing with an ESA when hemoglobin level exceeds 12 g/dL;

• Restart dosing at 25% below the previous dose when the hemoglobin approaches a level where transfusions may be required;

• Use ESAs only for the treatment of anemia due to concomitant myelosuppressive chemotherapy;

• Discontinue treatment with an ESA following the completion of a course of chemotherapy; and

• Use of ESAs in cancer patients have not been demonstrated in controlled clinical trials to improve the symptoms of anemia, quality of life, fatigue, or well-being.

The FDA also provided patient counseling guidance to healthcare professionals with respect to the use of ESAs. As part of a risk minimization plan, the FDA announced that it is developing a patient “Medication Guide” to better communicate the risks and benefits of ESA use to patients. Physicians and other healthcare professionals were advised by the FDA to discuss the following talking points with their patients:

• 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.

• ESAs require at least 2 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 4 weeks.

• ESAs increase the patient’s chance of blood clots and the risk of dying may be greater in certain circumstances

• Patients should keep appointments for blood tests so hemoglobin levels can be monitored.

• Patients need to monitor their blood pressure and contact their doctor if there are any changes outside of the range that has been established for them.

• Patients should contact their doctor if they experience any of the following symptoms:

o Pain and/or swelling in the legs;
o Worsening in shortness of breath;
o Increases in blood pressure;
o Dizziness or loss of consciousness;
o Extreme tiredness; and
o Blood clots in hemodialysis vascular access ports

On June 26, 2008 -in a surprising announcement – the European Medicines Agency (EMEA) urged oncologists to favor blood transfusions over ESAs. Although these popular drugs have been used to treat cancer-related anemia for close to 20 years and have become a mainstay of therapy, the new recommendation is encouraging clinicians to reverse this common practice. The EMEA committee for Medicinal Products for Human Use (CHMP) recommendation is based upon its review of new data from studies that showed an increased risk for tumor progression, venous thromboembolism, and shorter overall survival in patients who received ESAs. “In cancer patients with a reasonably long life expectancy, the benefit of using epoetins does not outweigh the risk of tumor progression and shorter overall survival,” the committee noted in a statement. There are many U.S. doctors who believe that there is simply not enough data to conclude that ESAs are unsafe. Despite that fact, the ESA controversy is likely to continue until definitive fact-based evidence is fully developed.

Sources:

• Information on Erythropoiesis Stimulating Agents (ESA)(marketed as Procrit, Epogen, and Aranesp), Center For Drug Evaluation and Research, U.S. Food & Drug Administration (website information).
• Questions and Answers On Epoteins and the Risk of Tumour Growth and Blood Clots in the Veins (Adobe PDF Document), European Medicines Agency Press Release, June 26, 2008.
• New Study Probes Safety of Erythropoiesis-Stimulating Agents (Free Registration Required to View), by Allison Gandey, Medscape Medical News, Medscape Today, June 10, 2008 (online article includes two videos).
• European Regulators Say Transfusions Safer Than ESAs in Cancer (Free Registration Required to View), by Allison Gandey, Medscape Medical News, Medscape Today, June 30, 2008.