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Detail-Document #211113
−This Detail-Document accompanies the related article published in− PHARMACIST’S LETTER / PRESCRIBER’S LETTER
November 2005 ~ Volume 21 ~ Number 211113 Sulfa Drugs and the Sulfa-allergic Patient
*Health Canada Product Labeling Listed by Exception*
Sulfonamide-Containing Agents: Summary of Cross-Reactivity Information
Drug FDA
Comments1,2,12
Labeling
Recommendations in
Sulfonamide
Allergy1,2,12
Sulfonylarylamines
Antibiotics
Sulfadiazine,
Contraindications include ophthalmic (sodium sulfacetamide), topical (silver sulfadiazine [SSD, Silvadene]), and vaginal products (triple sulfa, sulfanilamide) in addition to oral and Protease Inhibitors
Amprenavir (Agenerase) Precaution6
Labeling cautions that the potential for cross-sensitivity with these agents and sulfonamides is unknown. These agents should be used with caution in patients with a sulfonamide Nonsulfonylarylamines
Carbonic Anhydrase Inhibitors
Acetazolamide (Diamox) Contraindicated,
Labeling warns that due to severe reactions to sulfonamides, sensitizations may recur when a sulfonamide is readministered regardless of route of administration. This warning includes the ophthalmic preparations (brinzolamide and dorzolamide) because they are absorbed Two case reports suggest a connection between an anaphylactic reaction with acetazolamide Copyright 2005 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 #211113: Page 2 of 8)
Comments1,2,12
Labeling
Recommendations in
Sulfonamide
Allergy1,2,12
Nonsulfonylarylamines (cont.)
Cyclooxygenase 2 (COX-2) Inhibitors
Celecoxib (Celebrex)
In case reports, celecoxib and valdecoxib have been suggested to cross-react with other Valdecoxib (Bextra) Contraindicated sulfonamides. Incidence of allergic reactions to celecoxib was evaluated in three meta-analyses. Combined findings concluded that the risk of cross-reactivity between celecoxib and other sulfonamides is no greater than that seen with placebo or other comparators. Rofecoxib is a sulfone, not a sulfonamide, cross-sensitivity is likely not a concern. Loop Diuretics
Bumetanide (Bumex)
Some sources recommend that if a diuretic is used in a patient with a history of sulfonamide allergy, the first dose should be reduced and given under medical supervision. Referral to an also listed as warning by allergist may be warranted for patients who have had a severe allergic reaction to a Health Canada) sulfonamide. Ethacrynic acid does not contain a sulfa group and is a possible alternative in Torsemide (Demadex) Contraindicated Bumetanide and furosemide product labeling contain statements that patients may also be allergic to these drugs if they are allergic to sulfonamides. One case report suggests cross-sensitivity between furosemide and other sulfonamides. Torsemide is contraindicated in patients allergic to sulfonylureas because its chemical structure is a pyridine sulfonylurea. However, none of the product labeling for sulfonylureas contain statements regarding the use of torsemide. One patient that developed angioedema with torsemide treatment was later found to be sulfonamide-allergic. Copyright 2005 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 #211113: Page 3 of 8)
Comments1,2,12
Labeling
Recommendations in
Sulfonamide
Allergy1,2,12
Nonsulfonylarylamines (cont.)
Sulfonylureas
Chlorpropamide (Diabinese)
There is one case report of contact dermatitis with tolbutamide in a patient with sensitivity to sulfanilamide vaginal cream. After discontinuation of tolbutamide, therapy was changed to chlorpropamide which was tolerated without difficulty. There is also one case report which describes an allergic reaction to glyburide in a patient with a known allergy to Micronase) Tolbutamide (Orinase) (Apo-Tolbutamide – Canada)
Tolazamide (Tolinase) None
Thiazides and Related Compounds
Chlorothiazide (Diuril)
Some sources recommend that if a diuretic is used in a patient with a history of sulfonamide allergy, the first dose should be reduced and given under medical supervision. Referral to an allergist may be warranted for patients who have had a severe allergic reaction to a sulfonamide. Ethacrynic acid does not contain a sulfa group and is a possible alternative in Case reports suggest cross-reactivity between indapamide and sulfonamide antibiotics. (Lozide – Canada) Metolazone (Mykrox, Other Agents
Probenecid (Benemid)
(Benuryl – Canada) Sulfasalazine (Azulfidine) Contraindicated (Also in Sulfasalazine is broken down in the gut into sulfapyridine and 5-aminosalicylic acid (mesalamine). Sulfasalazine is contraindicated because sulfapyridine is a sulfonylarylamine Copyright 2005 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 #211113: Page 4 of 8)
Comments1,2,12
Labeling
Recommendations in
Sulfonamide
Allergy1,2,12
Nonsulfonylarylamines (cont.)
Other Agents (cont.)
Tamsulosin (Flomax) Precaution13
Cross-reactivity in sulfa-allergic patient rarely reported. Cautious use recommended with serious or life-threatening sulfa allergy.13 Tipranavir (Aptivus) Precaution10 The potential for cross-sensitivity between drugs in the sulfonamide class and tipranavir (a protease inhibitor) is unknown.10 Sulfonamide Moiety-Containing Drugs
5-HT Antagonists
Naratriptan (Amerge)
Sulfonamide group not on benzene ring, FDA concluded no risk of cross-reactivity. A retrospective chart review evaluated patients with a sulfonamide allergy receiving sumatriptan. No allergic reactions were reported during sumatriptan therapy. Other Agents
Ibutilide (Corvert) None
(Sotacor – Canada) Topiramate (Topamax) Zonisamide (Zonegran) Contraindicated11 One small study showed no risk of cross-reactivity when zonisamide was used in patients allergic to sulfonylarylamines. Users of this document are cautioned to use their own professional judgment and consult any other necessary or appropriate sources prior to making clinical judgments based on the content of this document. Our editors have researched the information with input from experts, government agencies, and national organizations. Information and Internet links in this article were current as of the date of publication. Copyright 2005 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 #211113: Page 5 of 8)
Cross-Reactivity of Sulfonamide Drugs
Lead authors: Sherri K. Boehringer, Pharm.D., BCPS Background
following initiation of sulfonamide nonantibiotic An estimated 3% of patients develop allergic drugs.3 Patients that had previously experienced an reactions to sulfonamide antibiotics.1 The most allergic reaction to a sulfonamide antibiotic had a common type of reaction is a maculopapular rash. higher occurrence of allergic reactions than did Rarely, patients develop life-threatening reactions patients with no history of hypersensitivity to like anaphylaxis, Stevens-Johnson syndrome, or sulfonamide antibiotics (9.9% versus 1.6%, toxic epidermal necrosis. For many years, there has adjusted odds ratio 2.8; 95% confidence interval, been debate in the medical community whether all 2.1 to 3.7). However, patients with a prior sulfa sulfa drugs should be avoided in patients allergic to allergy were even more likely to have an allergic reaction to penicillin, obviously a structurally unrelated drug, than they were to a sulfonamide How are Sulfa Drugs Classified?
nonantibiotic. Additionally, the risk of an allergic A sulfonamide is any compound that contains a reaction after receiving a sulfonamide antibiotic SO2NH2 moiety.2 Sulfonamides are divided into was HIGHER in patients with a history of penicillin three different groups based on chemical structure. The first group, the sulfonylarylamines, have a hypersensitivity to sulfonamide antibiotics. sulfonamide moiety directly attached to a benzene Some experts also argue that cross-reactivity ring with an unsubstituted amine (-NH2) moiety at isn’t possible between the sulfonylarylamines and the N4 position.2 This group consists primarily of the other types of sulfonamides because of the sulfonamide-type antibiotics as well as two structural differences.2,4 The one structural protease inhibitors (amprenavir [Agenerase] and similarity found among the three groups, the fosamprenavir [Lexiva]). The second group, the SO2NH2 moiety, hasn’t been shown to interact with nonsulfonylarylamines, also have a sulfonamide the immune system.4 However, there are at least moiety attached to a benzene ring or other cyclic two known types of allergic reactions related to the structure, but they do not have an amine group at sulfonylarylamine structure that require functional the N4 position. The third group, known as the groups NOT present in the nonsulfonylarylamines sulfonamide-moiety containing drugs, have a sulfonamide group that is not connected to a The first, type 1 immunological reaction, benzene ring like in the other groups. The specific requires the presence of a heterocyclic ring at the agents included in these three groups are sulfonamide-N1 position.2,4 This reaction is immunoglobulin (Ig) E mediated and presents usually within one to three days after initiation of The Cross-Reactivity Controversy
medication and is commonly associated with a Several case reports suggest patients that are maculopapular eruption or an urticarial rash.2 More allergic to sulfonamides from one group (e.g., sulfonylarylamines) may be at increased risk for hypotension, and anaphylaxis may also occur, developing an allergic reaction to a sulfonamide from another group.2 This is known as cross- The second, more common hypersensitivity reactivity. However, there is no data from well reaction, requires the presence of an unsubstituted designed trials that show that sulfonamides from amine group at the N4 position.2,4,5 Cytochrome P- different groups cross-react. An alternative theory 450 oxidation of the N4 arylamine results in the to sulfonamide cross-reactivity is that patients allergic to one drug may be at higher risk for being hydroxylamine and nitrosoamine metabolites.4,5 allergic to other, even structurally unrelated, drugs.3 This reaction usually develops seven to 14 days This hypothesis was tested in a retrospective after initiation of drug therapy and resolves upon cohort study by Strom et al (n=20,226) that discontinuation of medication.2 Presentation evaluated the incidence of allergic reactions consists of a fever and a nonurticarial rash that may Copyright 2005 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 #211113: Page 6 of 8)
progress to erythema multiforme and multi-organ hypersensitivity reactions to trimethoprim- sulfamethoxazole (Bactrim, Septra). 8 The difference in chemical structure between the Agents containing sulfur, sulfites, sulfates, and sulfonylarylamines and other types of sulfonamides saccharin often confuse clinicians about their implies that cross-reactivity is unlikely. However, potential for cross-reactivity with sulfonamides. T-cell mediated immune response to the Medications that contain sulfur such as amoxicillin unmetabolized, nonhaptenated parent sulfonamide (Amoxil), captopril (Capoten), omeprazole antibiotic has been reported to occur occasionally.4 (Prilosec), ranitidine (Zantac), spironolactone It is unknown whether T-cell recognition is related (Aldactone), and sulindac (Clinoril) are not to the sulfonamide moiety or some other functional sulfonamides and do not cross-react.1 Sulfites group. Until the mechanism behind T-cell (sulfur dioxide, sodium sulfite, sodium bisulfite, recognition is more clearly understood, cross- potassium bisulfite, sodium metabisulfite, and reactivity between sulfonylarylamines and the other potassium metabisulfite) are used in foods and types of sulfonamides remains theoretically drugs (e.g., Epipen, Pred Forte, Garamycin possible. injectable, etc.) as antioxidants.1,9 They are also The protease-inhibitors amprenavir and chemically unrelated to sulfonamides and there is fosamprenavir are sulfonamides with an N4 no risk of cross-sensitivity. However, sulfites may arylamine, like the sulfonylarylamine antibiotics. cause their own reactions such as dyspnea, The product labeling for these agents state that the wheeziness, and chest tightness in patients with potential for cross-sensitivity with other asthma.9 Sulfates (e.g., zinc sulfate, morphine sulfonamides is unknown, but they should be used sulfate, etc) are also not chemically related to with caution in people with sulfonamide allergy.6,7 In initial clinical trials, 16 patients with a history of sulfonamide derivative. This artificial sweetener is sulfonamide allergy were prescribed amprenavir.2 an ingredient in many liquids and tablets, but is not Five (31%) of these patients developed a rash which required to appear in drug labeling.1,9 Dermatologic resulted in discontinuation of amprenavir in two reactions and cross-reactivity with sulfonamide patients. In a clinical study with fosamprenavir antibiotics have been reported. The American used as the only protease inhibitor, rash occurred in Academy of Pediatrics recommends that children 20% of patients with a history of sulfonamide with sulfonamide allergy avoid saccharin [Evidence allergy compared to 33% of patients with no history Other drugs (e.g., some local anesthetics, Commentary
dapsone, and procainamide) do not contain a The majority of available evidence suggests that sulfonamide moiety, but like the sulfonylarylamines nonsulfonylarylamine and sulfonamide moiety- contain an N4 arylamine.4 The same is true for containing drugs need not be routinely avoided in sunscreens that contain para-amino-benzoic acid (PABA) derivatives.1 Although, the significance of this structural similarity is unknown, there have nonsulfonylarylamines and sulfonamide moieties been reports of cross-sensitivity between may cause allergic reactions themselves, because of sulfonamides and dapsone, a sulfone.1,8 the stereospecificity of the reaction associated with Cross-reactivity between dapsone and sulfonylarylamines, cross-reactivity is unlikely.4 sulfonylarylamines appears to be especially The question that remains unanswered is the prevalent in human immunodeficiency virus (HIV) mechanism behind T-cell recognition, and whether infected individuals, who are already at a much it is related to the sulfonamide functional group.4 higher risk of allergic reaction to sulfonamides.1,8 Unfortunately, the product labeling of many The package labeling of dapsone does not address nonantibiotic sulfonamide agents does not correlate the issue of cross-sensitivity with sulfonamides. with what is known scientifically. For instance, However, experts state that dapsone may be many diuretics are either contraindicated or contain considered in HIV-infected patients with mild warnings regarding their use in patients with a history of sulfonamide allergy (see table).1,2 The Copyright 2005 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 #211113: Page 7 of 8)
inconsistency between product labeling and Level Definition
available evidence is likely because some of these High-quality randomized controlled trial (RCT) agents (e.g., hydrochlorothiazide) were marketed High-quality meta-analysis (quantitative systematic review) many years before these newer theories refuting The inconsistency between product labeling and scientific evidence places clinicians in a difficult position. The routine avoidance of sulfonamide- containing drugs in patients with a history of sulfa compromise patient care. However, to ignore the product labeling recommendations places clinicians Adapted from Siwek J, et al. How to write an evidence-based clinical Patient-specific factors should be considered review article. Am Fam Physician 2002;65:251-8. when evaluating the risk of an allergic reaction.1 Allergic reactions may be less common in infants References
and the elderly, in theory because the immune 1. Which medications to avoid in patients with sulfa allergy? Pharmacist’s Letter / Prescriber’s Letter system is immature or senescent. Factors that may predict drug allergy include a family or personal 2. Johnson KK, Green DL, Rife JP, Limon L. history of drug allergy, some concurrent illnesses Sulfonamide cross-reactivity: fact or fiction? Ann (e.g., HIV), and slow acetylator phenotype.1 One 3. Strom BL, Schinnar R, Apter AJ, et al. Absence of theory called the “danger hypothesis” suggests that cross-reactivity between sulfonamide antibiotics and sulfonamide nonantibiotics. N Engl J Med predisposition and environmental stress (e.g., infection) cause the immune system to become 4. Brackett CC, Singh H, Block JH. Likelihood and activated resulting in an immune response to mechanisms of cross-allergenicity between sulfonamide antibiotics and other drugs containing a sulfonamide functional group. Pharmacotherapy Ultimately, clinicians will need to make the decision of whether to initiate sulfonamide drugs in 5. Slatore CG, Tilles SA. Sulfonamide hypersensitivity. sulfa allergic patients on a case by case basis. Immunol Allergy Clin North Am 2004;24:477-90. Prescribing information for Agenerase. Some experts support using nonsulfonylarylamine GlaxoSmithKline, Research Triangle Park, NC and/or sulfonamide moiety-containing medications in patients allergic to sulfonylarylamines if alternative therapy with structurally unrelated Research Triangle Park, NC 27709. July 2005. compounds is not possible [Evidence level C; 8. Holtzer CD, Flaherty JF Jr, Coleman RL. Cross- reactivity in HIV-infected patients switched from expert opinion].2 Exceptions include patients with trimethoprim-sulfamethoxazole to dapsone. serious allergic reactions and/or multiple 9. American Academy of Pediatrics. “Inactive“ ingredients in pharmaceutical products: Update (subject review). 1997 (information current as of Users of this document are cautioned to use their own professional judgment and consult any other necessary or http://www.pediatrics.org/cgi/content/full/99/2/268. appropriate sources prior to making clinical judgments based on the content of this document. Our editors have researched 10. Prescribing information for Aptivus. Boehringer the information with input from experts, government agencies, Ingelheim Pharmaceuticals, Inc., Ridgefield, CT and national organizations. Information and Internet links in this article were current as of the date of publication. 11. Prescribing information for Zonegran. Eisai Inc., Levels of Evidence
12. Compendium of Pharmaceuticals and Specialties In accordance with the trend towards Evidence-Based Medicine, we are citing the LEVEL OF EVIDENCE
www.pharmacists.ca. (Accessed October 19, 2005). 13. Prescribing information for Flomax. Boehringer Ingelheim Pharm. Ridgefield, CT 06877. Oct. 2005. Copyright 2005 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 #211113: Page 8 of 8)
Cite this Detail-Document as follows: Sulfa drugs and the sulfa-allergic patient. Pharmacist’s Letter/Prescriber’s
Letter 2005;21(11):211113.

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