Docket Management
Docket: 00N-1269 - Labeling for Human Prescription Drug/Biologic Products
Comment Number: EC -18

Accepted - Volume 4

Comment Record
Commentor Mr. ROBERT MARTIN, MS, CFNP Date/Time 2001-05-11 23:53:28
Category Health Professional

Comments for FDA General
1. General Comments I would like to make comment that I am whole heartedly against the FDA's package labeling of Celecoxib (Celebrex), Maxide, Ziac, HCTZ, and Lasix in regard to the drugs potential for allergenicity in patients allergic to sulfonamide antibiotics. Quite frankly, I would be interested in seeing the scientific data that the FDA utilized in making this decision. The science of the mechanism of allergenicity of sulfonamide antibiotics decries any possibility for cross-reactivity between celecoxib, HCTZ, Furosemide, or any other nonaromatic amine sulfonamide (NA sulfonamide) containing compounds in patients known to be allergic to arommatic amine sulfonamides (AA sulfonamides). Did the FDA even consider the biochemistry involved in the mechanism of this immunologic reaction? Or did the FDA simply view the ill-defined term sulfonamide, and decide to blanket a vast segment of the population denying them the benefits of these medications without applying good science? Ladies and Gentleman, it is the 21st century; the science is there for heavenís sake. Use it. This is not the middle ages. The fact that you might have drawn conclusions from such superficial and subjective observations, is dumbfounding. We use empirical evidence, objective data, and the scientific method to come to critical conclusions. Please, do so here. By taking this stance, your agency has opened the door for frivolous and misplaced law suits against healthcare providers, denied millions of patients medications that can improve their quality of life and health, and have short-changed both yourselves and the American people. It is my opinion that this misplaced contraindication places an unnecessary burden on both the physician and the millions of patients who should be allowed to benefit from these medications, and feel confident that they are safe in doing so. Please take into consideration the following abstracts and citations that support my position. Thank you. 1) Should celecoxib be contraindicated in patients who are allergic to sulfonamides? Revisiting the meaning of 'sulfa' allergy. Knowles S, Shapiro L, Shear NH. Clinical Pharmacology, Department of Medicine, Sunnybrook & Women's Health Sciences Centre, Toronto, Canada. Celecoxib, a selective cyclo-oxygenase-2 inhibitor, is a diaryl-substituted pyrazole derivative containing a sulfonamide substituent. Because of this structural component, celecoxib is contraindicated for use in patients who have demonstrated allergic reactions to sulfonamides. However, there is a lack of data demonstrating cross-reactivity among sulfonamide medications. A sulfonamide is any compound with an SO2NH2 moiety. The major difference between sulfonamide antimicrobials and other sulfonamide-containing medications such as furosemide, thiazide diuretics and celecoxib, is that sulfonamide antimicrobials contain an aromatic amine group at the N4 position. This allows for division of the sulfonamides into 2 groups: aromatic amines (i.e., sulfonamide antimicrobials) and nonaromatic amines. In addition, sulfonamide antimicrobials contain a substituted ring at the N1-position; this group is not found with nonaromatic amine-containing sulfonamides. Adverse reactions to sulfonamide antimicrobials include type I, or immunoglobulin (Ig) E-mediated reactions, hypersensitivity syndrome reactions, and severe skin reactions such as toxic epidermal necrolysis. The aromatic amine portion of the sulfonamide antimicrobial is considered to be critical in the development of latter 2 reactions. In susceptible individuals, the hydroxylamine metabolite is unable to be detoxified leading to a cascade of cytotoxic and immunological events that eventually results in the adverse reaction. Since celecoxib does not contain the aromatic amine, adverse reactions such as hypersensitivity syndrome reactions and toxic epidermal necrolysis would not be expected to occur at the same frequency as they do with sulfonamide antimicrobials. Similarly, for IgE-mediated reactions, the N1-substituent and not the sulphonamide moiety is important in determining specificity to antibodies. Celecoxib and other nonaromatic amine-containing sulfonamide medications do not contain the N1-substituent. Cross-reactivity among the various sulfonamide-containing medications has also not been substantiated by published case reports. In fact, conflicting information exists in the literature. Reports showing lack of cross-reactivity balance the few case reports suggesting cross-reactivity. Cross-reactivity between sulfonamide medications should be based on scientific data, including chemistry, metabolism, immune responses and clinical data. Based on the current information, there is no documentation for cross-reactivity between sulfonamide antimicrobials and other sulfonamide medications, such as celecoxib. 2) Immunologic tolerability profile of celecoxib. Patterson R, Bello AE, Lefkowith J. Department of Medicine, Northwestern University, Chicago, Illinois, USA. Celecoxib is primarily an inhibitor of cyclooxygenase (COX) 2 and, at therapeutic concentrations in humans, does not inhibit the COX-1 isoenzyme. The present meta-analyses explore the incidence of allergic reactions with celecoxib in patients in the North American and international arthritis trials, in patients with a history of hypersensitivity reactions to sulfonamides, and in patients receiving medications containing sulfonamides. Data were obtained from 11,008 patients in 14 double-masked trials of celecoxib in arthritis ranging from 4 to 24 weeks in duration. Results demonstrate that the incidence of allergic reactions with celecoxib was not statistically different from that seen with placebo or active comparators (nonsteroidal anti-inflammatory drugs [NSAIDs]) when data from the entire cohort were analyzed. The subset of patients with a history of sulfonamide hypersensitivity reactions had a 3-fold to 6-fold higher incidence of dermatologic reactions than did the entire arthritis trial cohort. Although dermatologic reactions occurred with greater frequency in patients with a history of sulfonamide hypersensitivity, the trend was consistent across all 3 treatment groups (celecoxib, NSAIDs, and placebo). According to these data and structural and metabolic differences between sulfonamides, the potential for cross-allergenicity between celecoxib and other sulfonamide-containing medications appears comparable to that of placebo and nonsulfonamide-containing NSAIDs. Additionally, the risk of allergic reactions with celecoxib appears comparable to that of placebo and comparator NSAIDs. Prospective trials are needed to confirm these findings. 3) There is gross inconsistancy in reporting true drug reactions leading to misdiagnosis and mislabeling of patients as allergic. Roujeau JC, Guillaume JC, Revuz J, Touraine R. Related Reporting adverse drug reactions. Lancet. 1985 Nov 30;2(8466):1244. Ladies and gentleman, science supports these conclusions, I hope you will as well. Best Regards, Robert Martin, MS, CFNP

EC -18