Detail-Document #260601 −This Detail-Document accompanies the related article published in− PHARMACIST’S LETTER / PRESCRIBER’S LETTER June 2010 ~ Volume 26 ~ Number 260601 Cross-Reactivity of Sulfonamide Drugs Background designed trials that show that sulfonamides from An estimated 3% of patients develop allergic different groups cross-react. An alternative theory reactions to sulfonamide antibiotics.1 The most to sulfonamide cross-reactivity is that patients common type of reaction is a maculopapular rash. allergic to one drug may be at higher risk for Rarely, patients develop life-threatening reactions being allergic to other, even structurally unrelated, like anaphylaxis, Stevens-Johnson syndrome, or drugs.6 toxic epidermal necrosis. For many years, there This hypothesis was tested in a retrospective has been debate in the medical community cohort study by Strom et al (n=20,226) that whether all sulfa drugs should be avoided in evaluated the incidence of allergic reactions patients allergic to sulfonamide antibiotics. This following initiation of sulfonamide nonantibiotic document discusses the different classifications of drugs.6 Patients that had previously experienced sulfonamide drugs and the risks for cross- an allergic reaction to a sulfonamide antibiotic reactivity. A chart listing sulfonamide drugs by had a higher occurrence of allergic reactions than their chemical subclass is also included. did patients with no history of hypersensitivity to sulfonamide antibiotics (9.9% versus 1.6%, How are Sulfa Drugs Classified? adjusted odds ratio 2.8; 95% confidence interval, A sulfonamide is any compound that contains 2.1 to 3.7). However, patients with a prior sulfa 2 a SO2NH2 moiety. Sulfonamides are divided into allergy were even more likely to have an allergic three different groups based on chemical reaction to penicillin, obviously a structurally structure. The first group, the sulfonylarylamines, unrelated drug, than they were to a sulfonamide have a sulfonamide moiety directly attached to a nonantibiotic. Additionally, the risk of an allergic benzene ring with an unsubstituted amine (-NH2) reaction after receiving a sulfonamide moiety at the N4 position.2 This group consists nonantibiotic was HIGHER in patients with a primarily of the sulfonamide-type antibiotics as history of penicillin allergy than in those with a well as three protease inhibitors (amprenavir history of hypersensitivity to sulfonamide [Agenerase], darunavir [Prezista], and antibiotics. fosamprenavir [Lexiva]).3-5 The second group, the Some experts also argue that cross-reactivity nonsulfonylarylamines, also have a sulfonamide isn’t possible between the sulfonylarylamines and moiety attached to a benzene ring or other cyclic the other types of sulfonamides because of structure, but they do not have an amine group at structural differences.2,7 The one structural the N4 position. The third group, known as the similarity found among the three groups, the sulfonamide moiety-containing drugs, have a SO2NH2 moiety, hasn’t been shown to interact sulfonamide group that is not connected to a with the immune system.7 However, there are at benzene ring like in the other groups. The specific least two known types of allergic reactions related agents included in these three groups are to the sulfonylarylamine structure that require summarized in the attached table. functional groups NOT present in the nonsulfonylarylamines or sulfonamide moieties. The Cross-Reactivity Controversy The first, type 1 immunological reaction, Several case reports suggest patients that are requires the presence of a heterocyclic ring at the allergic to sulfonamides from one group (e.g., sulfonamide-N1 position.2,7 This reaction is sulfonylarylamines) may be at increased risk for immunoglobulin (Ig) E mediated, presents usually developing an allergic reaction to a sulfonamide within one to three days after initiation of from another group.2 This is known as cross- medication, and is commonly associated with a reactivity. However, there is no data from well maculopapular eruption or an urticarial rash.2 More. Copyright © 2010 by Therapeutic Research Center Pharmacist’s Letter / Prescriber’s Letter ~ P.O. Box 8190, Stockton, CA 95208 ~ Phone: 209-472-2240 ~ Fax: 209-472-2249 www.pharmacistsletter.com ~ www.prescribersletter.com (Detail-Document #260601: Page 2 of 4) More serious reactions including angioedema, similarity is unknown, there have been reports of hypotension, and anaphylaxis may also occur, cross-sensitivity between sulfonamides and especially with repeat exposure.2,7 dapsone, a sulfone.1,9 The second, more common hypersensitivity Cross-reactivity between dapsone and reaction, requires the presence of an unsubstituted sulfonylarylamines appears to be especially amine group at the N4 position.2,7,8 Cytochrome prevalent in human immunodeficiency virus P-450 oxidation of the N4 arylamine results in the (HIV) infected individuals, who are already at a formation of cytotoxic or immunogenic much higher risk of allergic reaction to hydroxylamine and nitrosamine metabolites.7,8 sulfonamides.1,9 The package labeling of dapsone This reaction usually develops seven to 14 days does not address the issue of cross-sensitivity with after initiation of drug therapy and resolves upon sulfonamides. However, experts state that discontinuation of medication.2 Presentation dapsone may be considered in HIV-infected consists of a fever and a nonurticarial rash that patients with mild hypersensitivity reactions to may progress to erythema multiforme and multi- trimethoprim-sulfamethoxazole (Bactrim, organ toxicity. Septra).9 The difference in chemical structure between Agents containing sulfur, sulfites, sulfates, and the sulfonylarylamines and other types of saccharin often confuse clinicians about their sulfonamides implies that cross-reactivity is potential for cross-reactivity with sulfonamides. unlikely. However, T-cell mediated immune Medications that contain sulfur such as response to the unmetabolized, nonhaptenated amoxicillin (Amoxil), captopril (Capoten), parent sulfonamide antibiotic has been reported to omeprazole (Prilosec), ranitidine (Zantac), occur occasionally.7 It is unknown whether T-cell spironolactone (Aldactone), and sulindac recognition is related to the sulfonamide moiety or (Clinoril) are not sulfonamides and do not cross- some other functional group. Until the react.1 Sulfites (sulfur dioxide, sodium sulfite, mechanism behind T-cell recognition is more sodium bisulfite, potassium bisulfite, sodium clearly understood, cross-reactivity between metabisulfite, and potassium metabisulfite) are sulfonylarylamines and the other types of used in foods and drugs (e.g., EpiPen, Pred Forte, sulfonamides remains theoretically possible. Garamycin injectable, etc) as antioxidants.1,10 The protease-inhibitors amprenavir and They are also chemically unrelated to fosamprenavir are sulfonamides with an N4 sulfonamides and there is no risk of cross- arylamine, like the sulfonylarylamine antibiotics. sensitivity. However, sulfites may cause their The product labeling for these agents state that the own reactions such as dyspnea, wheeziness, and potential for cross-sensitivity with other chest tightness in patients with asthma.10 Sulfates sulfonamides is unknown, but they should be used (e.g., zinc sulfate, morphine sulfate, etc) are also with caution in people with sulfonamide allergy.3-5 not chemically related to sulfonamides. Saccharin In initial clinical trials, 16 patients with a history is an O-toluene sulfonamide derivative. This of sulfonamide allergy were prescribed artificial sweetener is an ingredient in many amprenavir.2 Five (31%) of these patients liquids and tablets, but is not required to appear in developed a rash which resulted in discontinuation drug labeling.1,10 Dermatologic reactions and of amprenavir in two patients. In a clinical study cross-reactivity with sulfonamide antibiotics have with fosamprenavir used as the only protease been reported. The American Academy of inhibitor, rash occurred in 20% of patients with a Pediatrics recommends that children with history of sulfonamide allergy compared to 33% sulfonamide allergy avoid saccharin [Evidence of patients with no history of sulfonamide level C, Consensus].10 allergy.4 Other drugs (e.g., some local anesthetics, Commentary dapsone, and procainamide) do not contain a The majority of available evidence suggests sulfonamide moiety; but, like the that nonsulfonylarylamine and sulfonamide sulfonylarylamines, contain an N4 arylamine.7 moiety-containing drugs need not be routinely The same is true for sunscreens that contain para- avoided in patients with a history of allergy to amino-benzoic acid (PABA) derivatives.1 sulfonylarylamines.2,6,7 Although the Although the significance of this structural nonsulfonylarylamines and sulfonamide moieties More. Copyright © 2010 by Therapeutic Research Center Pharmacist’s Letter / Prescriber’s Letter ~ P.O. Box 8190, Stockton, CA 95208 ~ Phone: 209-472-2240 ~ Fax: 209-472-2249 www.pharmacistsletter.com ~ www.prescribersletter.com (Detail-Document #260601: Page 3 of 4) may cause allergic reactions themselves, because Example desensitization protocols are available at of the stereospecificity of the reaction associated http://depts.washington.edu/madclin/providers/pro with sulfonylarylamines, cross-reactivity is tocols/Rapid_Oral_Bactrim_des.pdf and http:// unlikely.7 The question that remains unanswered www.aidsetc.org/aidsetc?page=cm-1001_sulfa is the mechanism behind T-cell