Thank you for the opportunity to provide a response to Dr. Tumber’s letter (Botulinum Toxin Type A Therapy and Human Serum Albumin). Dr. Tumber has correctly identified the continuing need to educate patients on human serum albumin (HSA). As with any drug product or excipient, proper education and dissemination of information to patients is the basis for appropriate and ethical clinical practice. This is particularly important in regard to products derived from human tissue, such as HSA. It is for this reason that HSA has undergone intense scrutiny to ensure its safe use in clinical practice.
The concerns of Dr. Tumber focus mainly on two issues: hypersensitivity reactions and viral and prion transmission. Each of these issues will be addressed in this letter.
Each 100-U vial of Botox® (Allergan, Inc. Irvine, CA) contains 100 U purified botulinum toxin type A neurotoxin complex, 0.5 mg human albumin, and 0.9 mg sodium chloride in a sterile, vacuum-dried form without a preservative. The HSA used in Botox® is purchased from Talecris Biotherapeutics, Inc. (Research Triangle Park, NC), who acquired the contributed assets of the worldwide plasma business from the Biologic Products Division of Bayer HealthCare AG (Berkeley, CA) and became operational April 1, 2005.
*Although it would be difficult to distinguish between hypersensitivity reactions to botulinum toxin and HSA, both Botox® and Plasbumin® (Talecris Biotherapeutics, Inc., Research Triangle Park, NC) product monographs mention the rarity of hypersensitivity reactions.1,2The Botox® product monograph states, “Serious and/or immediate hypersensitivity reactions have been rarely reported. These reactions include anaphylaxis, urticaria, soft tissue edema, and dyspnea.” The Plasbumin®-25 monograph states, “Adverse reactions to albumin are rare. Such reactions may be allergic in nature or due to high plasma protein levels from excessive albumin administration. Allergic manifestations include urticaria, chills, fever, and changes in respiration, pulse and blood pressure.”
The expected plasma levels reached after both Plasbumin® and Botox® administration would be quite different. Plasbumin® is packaged as 5%, 20%, and 25% formulations (5–25 g/100 ml) and is administered intravenously. Although no pharmacokinetic information for HSA is included in the product labeling, the expected plasma levels of HSA after Plasbumin® administration would be several orders of magnitude higher than after an intramuscular or intradermal Botox® injection containing 0.5 mg HSA per 100 U. Although any given patient has the potential to have a hypersensitivity reaction to any drug or excipient, these occurrences, regardless of cause, are rarely reported with Botox®.
The safety of HSA in clinical practice has been well documented. Correctly pasteurized HSA preparations have an excellent safety record in regard to virus and prion protein transmission (Bayer HealthCare written communication, November 2005). Safety and quality of the product are ensured through complete screening and documentation of donors, purification and viral-removal procedures, and extensive pathogen detection assays.
The plasma used by Talecris Biotherapeutics is source plasma from US donors that meets all US license criteria for source plasma, as specified in the US Code of Federal Regulations. Individual donations and plasma pools are screened and must be found nonreactive or negative for numerous viruses and antigens, including the hepatitis B virus antigen, human immunodeficiency virus (HIV)-1 p24 antigen, and antibodies to both HIV and hepatitis C virus. Donated plasma is also screened using viral nucleic acid testing for HIV, hepatitis B and C viruses, and parvovirus B19 genetic material. Each donation is also required to be less than or equal to two times the upper limit of the normal range for alanine aminotransferase levels using Food and Drug Administration–approved test methods.
A high margin of safety from the risk of viral transmission is achieved by using a combination of virus removal by means of the Cohn fractionation process (including cold ethanol precipitation, centrifugation, and/or filtration of human plasma) and inactivation through chemical treatment and pasteurization for 10 h at 60°C. These specific manufacturing steps are reported to be capable of eliminating and inactivating a wide range of viruses and have been demonstrated to remove spiked hamster-adapted scrapie prion protein and transmissible spongiform encephalopathy infectivity. To confirm removal of pathogenic prion proteins during the manufacturing process, a patented Western blot assay was developed that has confirmed the removal of spiked transmissible spongiform encephalopathy infectivity.
On August 17, 1999, the Food and Drug Administration issued a Guidance for Industry regarding precautionary measures to reduce the risk of possible transmission of Creutzfeldt-Jakob disease and new variant Creutzfeldt-Jakob disease to recipients of blood products.3The guidance document notes that plasma derivatives are unlikely to transmit disease in humans because of (1) the dilution factor of the infectious agent in a large plasma pool, (2) the less efficient intravenous and intramuscular route of inoculation, and (3) the rigors of the plasma pool manufacturing process. The document also states that no transmission of Creutzfeldt-Jakob or new variant Creutzfeldt-Jakob disease by human blood products or plasma derivatives has been documented to date. We are not aware of any subsequent reports of the transmission of any viral or prion disease associated with the use of HSA. As a precaution, the following warning statement appears on all products containing plasma-derived albumin:
This product contains albumin, a derivative of human blood. Based on effective donor screening and product manufacturing processes, it carries an extremely remote risk for transmission of viral diseases. A theoretical risk for transmission of Creutzfeldt-Jakob disease (CJD) also is considered extremely remote. No cases of transmission of viral diseases or CJD have ever been identified for albumin.
Bayer first licensed albumin on October 21, 1942. It is estimated that between 1980 and 1991, approximately 20 million individuals received 951 tons of albumin and plasma protein fractions. To date, there has not been a single, confirmed, documented case of viral or prion transmission to any recipient of albumin reported to Talecris.
We appreciate the concern on the part of Dr. Tumber regarding this issue and would like to reiterate that despite the proven safety record of HSA, proper awareness on the part of both physician and patient is necessary for ethical medical treatment with Botox®.
*Allergan, Inc., Irvine, California. email@example.com