Cross-Reactivity of Sulfonamide Drugs

Detail-Document #260601 −This Detail-Document accompanies the related article published in−

PHARMACIST’S LETTER / PRESCRIBER’S LETTER June 2010 ~ Volume 26 ~ Number 260601

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 recognition, and (for HIV-infected patients). whether it is related to the sulfonamide functional group.7 Users of this document are cautioned to use their own Unfortunately, the product labeling of many professional judgment and consult any other necessary nonantibiotic sulfonamide agents does not or appropriate sources prior to making clinical correlate with what is known scientifically. For judgments based on the content of this document. Our instance, many diuretics are either contraindicated editors have researched the information with input or contain warnings regarding their use in patients from experts, government agencies, and national with a history of sulfonamide allergy (see table).1,2 organizations. Information and Internet links in this The inconsistency between product labeling and article were current as of the date of publication. available evidence is likely because some of these agents (e.g., hydrochlorothiazide) were marketed Levels of Evidence many years before these newer theories refuting In accordance with the trend towards Evidence-Based cross-reactivity were developed. Medicine, we are citing the LEVEL OF EVIDENCE for the statements we publish. The inconsistency between product labeling and scientific evidence places clinicians in a Level Definition difficult position. The routine avoidance of A High-quality randomized controlled trial (RCT) High-quality meta-analysis (quantitative sulfonamide-containing drugs in patients with a systematic review) history of sulfa allergy can unnecessarily B Nonrandomized clinical trial complicate or compromise patient care. However, Nonquantitative systematic review to ignore the product labeling recommendations Lower quality RCT places clinicians at risk of liability. Clinical cohort study Case-control study Patient-specific factors should be considered Historical control 1 when evaluating the risk of an allergic reaction. Epidemiologic study Allergic reactions may be less common in infants C Consensus and the elderly, in theory because the immune Expert opinion system is immature or senescent. Factors that D Anecdotal evidence In vitro or animal study may predict drug allergy include a family or Adapted from Siwek J, et al. How to write an evidence-based personal history of drug allergy, some concurrent clinical review article. Am Fam Physician 2002;65:251-8. illnesses (e.g., HIV), and slow acetylator phenotype.1 One theory called the “danger hypothesis” suggests that co-stimulatory signals Project Leaders in preparation of this Detail- such as genetic predisposition and environmental Document: Sherri K. Boehringer, Pharm.D., stress (e.g., infection) cause the immune system to BCPS (Original 2005), Stacy A. Hester, R.Ph., become activated resulting in an immune response BCPS, Assistant Editor (May 2010 update) to otherwise well-tolerated drugs.8 Ultimately, clinicians will need to make the References decision of whether to initiate sulfonamide drugs 1. Which medications to avoid in patients with sulfa in sulfa allergic patients on a case by case basis. allergy? Pharmacist’s Letter/Prescriber’s Letter 2000;16(7):160708. Some experts support using nonsulfonylarylamine 2. Johnson KK, Green DL, Rife JP, Limon L. and/or sulfonamide moiety-containing Sulfonamide cross-reactivity: fact or fiction? Ann medications in patients allergic to Pharmacother 2005;39:290-301. sulfonylarylamines if alternative therapy with 3. Product information for Agenerase. structurally unrelated compounds is not possible GlaxoSmithKline, Research Triangle Park, NC 2 27709. November 2005. [Evidence level C; expert opinion]. Exceptions 4. Product information for Lexiva. GlaxoSmithKline, include patients with serious allergic reactions Research Triangle Park, NC 27709. April 2010. and/or multiple medication allergies.2 In some 5. Product information for Prezista. Tibotec. Raritan, situations, sulfa desensitization may be necessary. NJ 08869. January 2010. 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 4 of 4)

6. Strom BL, Schinnar R, Apter AJ, et al. Absence of 9. Holtzer CD, Flaherty JF Jr, Coleman RL. Cross- cross-reactivity between sulfonamide antibiotics reactivity in HIV-infected patients switched from and sulfonamide nonantibiotics. N Engl J Med trimethoprim-sulfamethoxazole to dapsone. 2003;349:1628-35. Pharmacotherapy 1998;18:831-5. 7. Brackett CC, Singh H, Block JH. Likelihood and 10. American Academy of Pediatrics. “Inactive“ mechanisms of cross-allergenicity between ingredients in pharmaceutical products: Update sulfonamide antibiotics and other drugs containing (subject review). 1997 (information current as of a sulfonamide functional group. Pharmacotherapy May 12, 2010). Available at: 2004;24:856-70. http://www.pediatrics.org/cgi/content/full/99/2/268. 8. Slatore CG, Tilles SA. Sulfonamide (Accessed May 12, 2010). hypersensitivity. Immunol Allergy Clin North Am 2004;24:477-90.

Cite this Detail-Document as follows: Cross-reactivity of sulfonamide drugs. Pharmacist’s Letter/Prescriber’s Letter 2010;26(6):260601.

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Allergic Cross-reactivity Among Beta-lactam Antibiotics: An Update

Introduction Immediate/accelerated reactions typically Beta-lactams are first-line treatments for a occur within one hour (immediate) or one to number of common infections. Patients allergic to 72 hours (accelerated) after administration of a penicillins are often treated as also being allergic penicillin. These reactions are mediated by to cephalosporins. Historical data have suggested penicillin-specific IgE antibodies. Clinical signs that up to 10% of patients allergic to penicillins of an immediate or accelerated reaction include are also allergic to cephalosporins.1,2 In addition, anaphylaxis, a drop in blood pressure, swelling of cross-reactivity with penicillins and carbapenems the larynx, wheezing, angioedema, and hives or an has been cited at nearly 50%, with little scientific itchy rash. data to back up the claim. It’s easy to see why Late reactions tend to occur more than penicillin-allergic patients might be prescribed a 72 hours after exposure to a penicillin. As second-line therapy that is less effective, more previously mentioned, these are sometimes expensive, more toxic, or has a broader spectrum referred to as type II, III, and IV reactions. Type of activity than necessary.3 More recent data II reactions are mediated by IgG antibodies and suggest that the true incidence of allergic cross- complement. Clinical signs include increased red reactivity between the penicillins and other beta- blood cell and platelet clearance by the lactam antibiotics is much lower than originally lymphoreticular system. Type III reactions are reported.3,4 This is important for a number of mediated by IgG and IgM immune complexes. reasons, including the fact that some non beta- Clinical signs include serum sickness and tissue lactam alternative therapies, such as macrolides injury. Type IV reactions are mediated through for otitis media, are no longer preferred options an unknown mechanism. A clinical sign is due to high bacterial resistance rates.5 This contact dermatitis. document reviews the types of penicillin allergies, Idiopathic reactions also tend to occur after assesses current data on true cross-reactivity 72 hours of exposure to a penicillin. Idiopathic between penicillins and other beta-lactams, and reactions are mediated through unknown provides treatment considerations. mechanisms. Clinical signs include a maculopapular or morbilliform rash which can Types of Penicillin Allergies progress to Stevens-Johnson syndrome. Approximately 10% of the population will An example of an idiopathic reaction is the report a history of an allergy to penicillin. rash that can occur following administration of However, up to 90% of these individuals will be drugs such as ampicillin and amoxicillin in able to tolerate treatment with a penicillin and patients with an Epstein-Barr virus (EBV) further, will not have a positive skin test. The infection. The risk appears to be highest in 9 designation of “penicillin allergy” is not necessary patients who receive ampicillin. This rash for these individuals.3,6 typically occurs seven to 14 days after beginning Several types of allergic reactions to antibiotic therapy. It is described as a red, itchy, penicillins are described in the medical maculopapular rash, involving primarily the upper literature.7,8 One method of classifying penicillin extremities and trunk. The rash can be allergies is as follows: accompanied by fever, swelling of the lips and  immediate/accelerated (type I reactions); eyelids, diarrhea, and joint pain. Patients who develop this rash are likely to be able to tolerate  late (type II, III, and IV reactions); 3,9,10  other (idiopathic reactions). penicillins in the future.

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Diagnosis of a Penicillin Allergy Unfortunately, minor determinant skin testing is Prior to treating a patient who reports a not standardized and can vary from place to place. penicillin allergy, a thorough history of the patient’s allergy should be obtained. Examples of Cephalosporin Cross-reactivity questions the patient should be asked include the Studies performed in the 1960s and 1970s following:3,8 suggested that the rate of cross-reactivity between  How old were you when the reaction penicillins and cephalosporins was as high as occurred? 50%.13 However, early cephalosporins may have  Please describe the reaction. been contaminated with trace amounts of 6  When did the reaction occur? After the first penicillins, and the rate of cross-reactivity has dose? After the tenth dose? traditionally been cited as 8% to 10%. Note that  How was the penicillin administered? Orally? people with a penicillin allergy, compared to those Intravenously? without a penicillin allergy, are three times more likely to have an adverse effect to an unrelated  Were you taking any other medications at the 4 same time? drug.  When the penicillin was stopped, what Current data suggest that the rate of cross- happened? reactivity between penicillins and cephalosporins  Have you since taken a penicillin, is probably less than 1% (approximately 0.1% of patients without skin test-confirmed penicillin cephalosporin, carbapenem, or monobactam? allergy, 0.1% for those with mild reactions to Only immediate or accelerated penicillin penicillin, and 2% for patients who are penicillin allergies (IgE-mediated) can be diagnosed with skin test positive). This cross-reactivity is likely penicillin skin testing. Results from studies determined by the sharing of identical R-group suggest that just 10% to 20% of patients who side chains and not the beta-lactam structure report a penicillin allergy will have a positive 3,4,6 8,11 itself. penicillin skin test. However, patients with a In general, the rate of allergic cross-reactivity negative penicillin skin test can still be allergic to is highest between penicillins and first-generation penicillins. In most of these cases, the allergy is a cephalosporins. The risk for cross-reactivity may late or idiopathic type reaction. reach almost 40% between penicillins and Skin testing is the best method for diagnosing cephalosporins with identical R-group side an IgE-mediated penicillin allergy. Skin testing is chains.6 Penicillins and cephalosporins with usually performed by an allergist. It typically which have the same R-group side chains include involves placement of positive (histamine) and the following:3,6 negative (saline) controls, and then an epidermal or intracutaneous prick test. If the penicillin prick  amoxicillin, cefadroxil, cefprozil test is negative, an intradermal skin test is done.  ampicillin, cefaclor, cephalexin Anaphylaxis can occur with skin testing. Therefore, providers performing penicillin skin Carbapenem and Monobactam Cross- testing must be prepared to quickly treat patients reactivity who have anaphylactic reactions. Other tests, Cross-reactivity between penicillins and such as patch testing, radioallergosorbent tests, carbapenems (i.e., imipenem, meropenem, and enzyme-linked immunoassay, are less ertapenem, or doripenem) has been reported. In reliable.3 early studies, the cross reactivity of penicillin and 14 Current recommendations for penicillin skin imipenem was cited at 47%, but more recent testing are to administer both the major studies estimate the likelihood of cross-reactivity 15 determinant (benzylpenicilloyl-polylysine [Pre- to be close to 1%. The large difference in Pen]) of penicillin allergy, and the minor reaction rates is thought to be because of a small determinant (e.g., penicillin G).3,7 The terms patient population and methods of taking allergy 12 major and minor determinant refer to the amount histories in the early studies. of drug that is metabolized to that component.12 Meropenem cross-reactivity is estimated at Allergic reactions are linked to the minor 0.9% in studies, although conservative statistical 16,17 determinant in a large majority of cases.11 estimates cite a rate of 5.2% or less. More. . . Copyright © 2013 by Therapeutic Research Center 3120 W. March Lane, Stockton, CA 95219 ~ Phone: 209-472-2240 ~ Fax: 209-472-2249 www.PharmacistsLetter.com ~ www.PrescribersLetter.com ~ www.PharmacyTechniciansLetter.com (PL Detail-Document #291002: Page 3 of 5)

There are no studies of ertapenem or a penicillin ten years ago will not presently have a doripenem cross-reactivity in patients with a positive skin test.3 penicillin allergy. Those who report immediate or accelerated Cross-reactivity between penicillins and reactions to semisynthetic penicillins such as aztreonam, a monobactam, does not generally amoxicillin or ampicillin may be able to tolerate occur.3 However, aztreonam and ceftazidime other penicillins. Skin testing with penicillin may have the same R-group side chain. Therefore the be helpful to determine this.3 potential for cross-reactivity to aztreonam exists Historically, data suggested that patients who in patients allergic specifically to reported an immediate or accelerated reaction to a ceftazidime.3,12,18 In addition, aztreonam should penicillin (or are skin test positive to penicillin) be used cautiously in cystic fibrosis patients should not receive a cephalosporin. However reporting hypersensitivities to beta-lactam with certain precautions (see below), some antibiotics.12,19 second, third, and fourth generation agents may be able to be safely administered to patients with an Treatment Recommendations immediate or accelerated reaction to a penicillin.4 Ideally, all patients who report symptoms (The manufacturer of the fifth generation consistent with an IgE-mediated reaction to cephalosporin, ceftaroline, advises caution in penicillins would be evaluated by an allergist or beta-lactam allergic patients until more data are immunologist. This could help reduce the available on the potential for cross-reactivity.)20 unnecessary use of more broad-spectrum Since side chain similarity appears to be important antibiotics. In the absence of skin testing, the in allergic cross-reactivity between the penicillins risks and benefits of different treatment options and cephalosporins, those with an immediate or must be weighed.6 accelerated reaction to amoxicillin should not In general, patients who report symptoms receive cefadroxil or cefprozil without consistent with an immediate or accelerated desensitization and those with an immediate or reaction (type I) to penicillin (or are skin test accelerated reaction to ampicillin should not positive to penicillin) should not receive any receive cefaclor or cephalexin without penicillin, unless they undergo desensitization desensitization.6 (also called induction of drug tolerance).3 Usually Administration of a cephalosporin to a patient desensitization is a last resort if a penicillin is the who reports an immediate or accelerated penicillin treatment of choice for an infection and no allergy (or is skin test positive to penicillin) acceptable nonpenicillin alternatives are available. should be done cautiously. There is not good Desensitization involves incremental doses of an evidence that cephalosporin skin testing will oral penicillin every 15 minutes for a total of predict IgE-mediated reactions to cephalosporins. nearly four hours before a full dose (oral or IV) is Providers may opt for rapid desensitization to the given. An example of a penicillin desensitization cephalosporin, or for a graded challenge. For protocol is available in Morbidity and Mortality graded challenge with oral cephalosporins, 10% Weekly Report found at of the first dose is administered, followed one http://www.cdc.gov/std/treatment/2006/penicillin- hour later by the full dose, under observation, in allergy.htm#skintesting. the absence of a reaction. For graded challenge Individuals with vague or distant histories of with intravenous cephalosporins, 1% of the full penicillin allergy may be candidates for receiving dose is administered, then 10% of the full dose, penicillins via graded challenge, although it is then the full dose, separated by one hour each, important to note that up to one-third of these under observation, in the absence of a reaction.6 individuals will have a positive skin test.3 Carbapenems can be used in patients who (Graded challenge does not modify an report an immediate or accelerated type reaction individual’s immune response, it is simply a more with a penicillin (or are skin test positive to cautious way of administering the drug.)6 penicillin), after optional skin testing and a graded Penicillin allergies are likely to wane over time. challenge.3,15-17 For example, about 80% of patients who report For example, if a patient needs to be skin symptoms of an IgE-mediated allergic reaction to tested with imipenem, a concentration of 0.5 mg/mL of imipenem-cilastatin should be used. More. . . Copyright © 2013 by Therapeutic Research Center 3120 W. March Lane, Stockton, CA 95219 ~ Phone: 209-472-2240 ~ Fax: 209-472-2249 www.PharmacistsLetter.com ~ www.PrescribersLetter.com ~ www.PharmacyTechniciansLetter.com (PL Detail-Document #291002: Page 4 of 5)

If the skin test is negative, some studies have used Conclusion a graded challenge: 1% of the dose in the first The incidence of allergic cross-reactivity hour, 10% of the dose in the second hour, and a among beta-lactam antibiotics appears to be less full imipenem-cilastatin dose in the third hour if than historically thought. Ideally, all patients who no reaction has occurred.15 report symptoms consistent with an IgE-mediated Skin testing for meropenem should be reaction to penicillins would be evaluated by an performed with a concentration of 1 mg/mL. allergist or immunologist. This could help reduce Then, one of two equally safe graded challenge the unnecessary use of more broad spectrum regimens can be chosen: 1% of the dose in the antibiotics.3,4,6,7 first hour, then 10% of the dose in the second A patient’s allergy history should be carefully hour, and the full dose in the third hour if no obtained and the decision about which antibiotic reaction occurs in the first or second hour; or 10% class to administer should be based on this of the dose in the first hour, and the full dose in information. Under certain conditions, patients the second hour if no reaction occurs in the first with an IgE-mediated penicillin allergy may be hour.16 able to safely receive a cephalosporin, particularly In some cases, it may be preferable to use an second, third, and fourth generation antibiotic from a different drug class (a non beta- cephalosporins.3,6 lactam) for patients with penicillin allergy. The carbapenems and aztreonam pose little However, the latest treatment guidelines for risk to patients with a true type I penicillin allergy infections such as sinusitis and acute otitis media in most cases, although skin testing and graded recommend against the routine use of some challenge is recommended prior to treatment with alternatives such as macrolides due to an increase carbapenems.3 in resistance. For more information, see our PL Detail-Document, Should Macrolides Be Used for Respiratory Tract Infections? Users of this PL Detail-Document are cautioned to use their own professional judgment and consult any other Treatments for patients reporting a necessary or appropriate sources prior to making cephalosporin allergy may also be chosen based clinical judgments based on the content of this on R-group side-chain similarities. Patients with document. Our editors have researched the an immediate or accelerated allergy to a information with input from experts, government cephalosporin should not receive a cephalosporin agencies, and national organizations. Information and with the same R-group side chain without internet links in this article were current as of the date desensitization to that drug.3 For example, a of publication. patient with an IgE-mediated reaction to cefuroxime should not receive cefoxitin.3 Likewise, a patient with an IgE-mediated reaction Project Leader in preparation of this PL Detail- to ceftriaxone should not receive cefotaxime or Document: Stacy A. Hester, R.Ph., BCPS, cefpodoxime.3 A cephalosporin with a different Assistant Editor side chain may be able to be used safely. However, consideration should be given to the use of either rapid desensitization or graded challenge, References depending on the severity of the reaction.3,4 1. Kelkar PS, Li JT. Cephalosporin allergy. N Engl J Patients who report an immediate or Med 2001;345:804-9. 2. Romano A, Gueant-Rodriguez RM, Viola M, et al. accelerated allergy to ceftazidime should not Cross-reactivity and tolerability of cephalosporins in receive aztreonam, since these drugs have patients with immediate hypersensitivity to identical R-group side chains.3 As previously penicillins. Ann Intern Med 2004;141:16-22. mentioned, aztreonam should be used cautiously 3. Joint Task Force on Practice Parameters. Drug allergy: an updated practice parameter. Ann in cystic fibrosis patients reporting 12,19 Allergy Asthma Immunol 2010;105:259-73. hypersensitivities to beta-lactam antibiotics. 4. Pichichero ME. A review of evidence supporting If a patient has a documented immediate or the American Academy of Pediatrics accelerated reaction to a carbapenem, use of recommendation for prescribing cephalosporin another agent from that particular class should be antibiotics for penicillin-allergic patients. Pediatrics 2005;115:1048-57. avoided until more data are available. More. . . Copyright © 2013 by Therapeutic Research Center 3120 W. March Lane, Stockton, CA 95219 ~ Phone: 209-472-2240 ~ Fax: 209-472-2249 www.PharmacistsLetter.com ~ www.PrescribersLetter.com ~ www.PharmacyTechniciansLetter.com (PL Detail-Document #291002: Page 5 of 5)

5. PL Detail-Document, Should Macrolides Be Used 12. Frumin J, Gallagher JC. Allergic cross-sensitivity for Respiratory Tract Infections? Pharmacist’s between penicillin, carbapenem, and monobactam Letter/Prescriber’s Letter. August 2013. antibiotics: what are the chances? Ann 6. Solensky R, Banerji A, Bloomberg GR, et al. Pharmacother 2009;43:304-15. Cephalosporin administration to patients with a 13. Daulat S, Solensky R, Earl HS, et al. Safety of history of penicillin allergy. May 1, 2009. cephalosporin administration to patients with http://www.aaaai.org/Aaaai/media/MediaLibrary/PD histories of penicillin allergy. J Allergy Clin F%20Documents/Practice%20and%20Parameters/ Immunol 2004;113:1220-2. Cephalosporin-administration-2009.pdf. (Accessed 14. Saxon A, Adelman DC, Patel A, et al. Imipenem September 10, 2013). cross-reactivity with penicillin in humans. J Allergy 7. Executive summary of disease management of Clin Immunol 1988;82:213-7. drug hypersensitivity: a practice parameter. Joint 15. Romano A, Viola M, Gueant-Rodriguez RM, et al. Task Force on Practice Parameters, the American Imipenem in patients with immediate Academy of Allergy, Asthma and Immunology, the hypersensitivity to penicillins. N Engl J Med American Academy of Allergy, Asthma and 2006;354:2835-7. Immunology, and the Joint Council of Allergy, 16. Romano A, Viola M, Gueant-Rodriguez RM, et al. Asthma and Immunology. Ann Allergy Asthma Brief communication: tolerability of meropenem in Immunol 1999;83(6 Pt 3):665-700. patients with IgE mediated hypersensitivity to 8. Salkind AR, Cuddy PG, Foxworth JW. The rational penicillins. Ann Intern Med 2007;146:266-9. clinical examination. Is this patient allergic to 17. Atanaskovic-Markovic M, Gaeta F, Medjo B, et al. penicillin? An evidence-based analysis of the Tolerability of meropenem in children with IgE- likelihood of penicillin allergy. JAMA mediated hypersensitivity to penicillins. Allergy 2001;285:2498-505. 2008;63:237-40. 9. Ikediobi NI, Tyring SK. Cutaneous manifestations 18. Robinson JL, Hameed T, Carr S. Practical aspects of Epstein-Barr virus infection. Dermatol Clin of choosing an antibiotic for patients with a 2002;20:283-9. reported allergy to an antibiotic. Clin Infect Dis 10. Trcka J, Seitz CS, Brocker EB, et al. 2002;35:26-31. Aminopenicillin-induced exanthema allows 19. Moss RB. Sensitization to aztreonam and cross- treatment with certain cephalosporins or reactivity with other beta-lactam antibiotics in high- phenoxymethyl penicillin. J Antimicrob Chemother risk patients with cystic fibrosis. J Allergy Clin 2007:60:107-11. Immunol 1991;87:78-88. 11. Rosario NA, Grumach AS. Allergy to beta-lactams 20. Product information for Teflaro. Forest. St. Louis, in pediatrics: a practical approach. J Pediatr (Rio MO 63045. July 2013. J) 2006;82(5 Suppl):S181-8.

Cite this document as follows: PL Detail-Document, Allergic Cross-reactivity Among Beta-lactam Antibiotics: An Update. Pharmacist’s Letter/Prescriber’s Letter. October 2013.

Evidence and Recommendations You Can Trust…

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Detail-Document #260601 −This Detail-Document accompanies the related article published in− PHARMACIST’S LETTER / PRESCRIBER’S LETTER June 2010 ~ Volume 26 ~ Number 260601

Sulfa Drugs and the Sulfa-allergic Patient

Healthcare providers often have questions about whether or not certain drugs can be used in a patient with a sulfa allergy. There are three different classifications of sulfa drugs, or sulfonamides, based on chemical structure: sulfonylarylamines (includes sulfa antibiotics), nonsulfonylarylamines, and sulfonamide moiety-containing drugs.2 About 3% of individuals have an allergy to the sulfa antibiotics, such as sulfamethoxazole. Most commonly, this manifests as a maculopapular rash.1 Generally, nonsulfonylarylamines and sulfonamide moiety-containing drugs need not be avoided in people with allergies to sulfa antibiotics.2 Available evidence suggests that cross-sensitivity (also called cross-reactivity) is unlikely between the three different sulfa chemical classes. However, individuals with allergic reactions to sulfonylarylamine antibiotics may be more likely to experience allergic reactions to the other types of sulfonamides. This is probably because these patients have a predisposition for allergies instead of cross- sensitivity with sulfonylarylamine antibiotics.14 It should be noted that sulfates, sulfur, and sulfites are chemically unrelated to sulfonamides and do not cross-react.1 It’s important to note that package labeling doesn’t always match up with available evidence regarding cross-sensitivity of these drugs. It’s a good idea to investigate the patient’s drug allergy history and check the evidence for cross-sensitivity before ruling out a needed therapy. The following chart lists sulfa drugs according to classification based on chemical structure. (See description of each chemical class following the chart.b) Information from the product labeling regarding administration to patients with sulfa drug allergy and additional clinical evidence is also included.

Sulfonamide-Containing Agents: Summary of Cross-Sensitivity Information Drug1,2,c FDA Product Labeling Comments1,2 Recommendations in Sulfonamide Allergya Sulfonylarylamines Antibiotics Sulfadiazine Contraindicated Contraindications include ophthalmic (sodium sulfacetamide), topical (silver Sulfamethoxazole sulfadiazine [SSD, Silvadene]), and vaginal products (triple sulfa, sulfanilamide) Sulfapyridine in addition to oral and parenteral preparations. Sulfisoxazole Protease Inhibitors Amprenavir (Agenerase) Precaution Labeling cautions that the potential for cross-sensitivity with these agents and Darunavir (Prezista) Precaution sulfonamides is unknown. These agents should be used with caution in patients with a sulfonamide allergy.3,5 Fosamprenavir (Lexiva) Precaution In clinical studies with darunavir plus ritonavir, there was a similar incidence of (Telzir – Canada) rash in patients with and without a history of sulfonamide allergy.4

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 5)

Drug1,2,c FDA Product Labeling Comments1,2 Recommendations in Sulfonamide Allergya Nonsulfonylarylamines Carbonic Anhydrase Inhibitors Acetazolamide (Diamox) Contraindicated, warning Labeling warns that due to severe reactions to sulfonamides, sensitizations may (Precaution-Health Canada)6 recur when a sulfonamide is readministered regardless of route of administration. Brinzolamide (Azopt) Warning (U.S./Canada Azopt) This warning includes the ophthalmic preparations (brinzolamide and (Azarga13=brinzolamide/timolol) (Contraindicated-Health Canada)13 dorzolamide) because they are absorbed systemically.

Dorzolamide (Trusopt) Warning Two case reports suggest a connection between an anaphylactic reaction with Methazolamide (Neptazane) Warning acetazolamide and sulfonamide allergy. 6 (Apo-Methazolamide-Canada) (Precaution-Health Canada)

Cyclooxygenase 2 (COX-2) Inhibitors Celecoxib (Celebrex) Contraindicated In case reports, celecoxib has been suggested to cross-react with other 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 with placebo or other comparators.

Loop Diuretics Bumetanide (Bumex) Warning Some sources recommend that if a diuretic is used in a patient with a history of (Burinex – Canada) (Contraindication and warning- sulfonamide allergy, the first dose should be reduced and given under medical Health Canada)7 supervision. Referral to an allergist may be warranted for patients who have had Furosemide (Lasix) Precaution a severe allergic reaction to a sulfonamide. Ethacrynic acid does not contain a Torsemide (Demadex) Contraindicated in patients allergic sulfa group and is a possible alternative in sulfonamide-allergic patients.

to sulfonylureas 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. 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 5)

Drug1,2,c FDA Product Labeling Comments1,2 Recommendations in Sulfonamide Allergya Nonsulfonylarylamines (cont.) Sulfonylureas Chlorpropamide (Diabinese) None There is one case report of contact dermatitis with tolbutamide in a patient with (Apo-Chlorpropamide – sensitivity to sulfanilamide vaginal cream. After discontinuation of tolbutamide, Canada) therapy was changed to chlorpropamide, which was tolerated without difficulty. Glimepiride (Amaryl) Warning There is also one case report that describes an allergic reaction to glyburide in a (Contraindicated-Health Canada)8 patient with a known allergy to sulfamethoxazole. Glipizide (Glucotrol) None Glyburide (DiaBeta, others) Warning (Contraindicated-Health Canada)9 Tolbutamide (Orinase) None (Apo-Tolbutamide – Canada) Tolazamide (Tolinase) None Thiazides and Related Compounds Chlorothiazide (Diuril) Contraindicated Some sources recommend that if a diuretic is used in a patient with a history of Chlorthalidone (Hygroton) Contraindicated sulfonamide allergy, the first dose should be reduced and given under medical (Apo-Chlorthalidone – supervision. Referral to an allergist may be warranted for patients who have had Canada) a severe allergic reaction to a sulfonamide. Ethacrynic acid does not contain a Hydrochlorothiazide Contraindicated sulfa group and is a possible alternative in sulfonamide-allergic patients.

Indapamide (Lozol) Contraindicated Case reports suggest cross-reactivity between indapamide and sulfonamide (Lozide – Canada) antibiotics. Metolazone (Mykrox, Warning Zaroxolyn) (No recommendation per Health Canada) Other Agents Mafenide (Sulfamylon) Contraindication, precaution It is not known whether there is cross sensitivity to other sulfonamides.10 Probenecid (Benemid) None -- (Benuryl – Canada) Sulfasalazine (Azulfidine) Contraindicated Sulfasalazine is broken down in the gut into sulfapyridine and 5-aminosalicylic (Salazopyrin – Canada) acid (mesalamine). Sulfasalazine is contraindicated because sulfapyridine is a sulfonylarylamine that is systemically absorbed.

(Detail-Document #260601: Page 4 of 5)

Drug1,2,c FDA Product Labeling Comments1,2 Recommendations in Sulfonamide Allergya Nonsulfonylarylamines (cont.) Other Agents (cont.) Tamsulosin (Flomax) Precaution Cross-reactivity in sulfa-allergic patients rarely reported. Cautious use (No recommendations per Health recommended with serious or life-threatening sulfa allergy.11 Canada) Tipranavir (Aptivus) Precaution The potential for cross-sensitivity between drugs in the sulfonamide class and tipranavir (a protease inhibitor) is unknown.12 Sulfonamide Moiety-Containing Drugs 5-HT Agonists Naratriptan (Amerge) None Sulfonamide group not on benzene ring, FDA concluded no risk of cross- Sumatriptan (Imitrex) None 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 -- Sotalol (Betapace) None -- (Sotacor – Canada) Topiramate (Topamax) None -- Zonisamide (Zonegran) Contraindicated One small study showed no risk of cross-reactivity when zonisamide was used in patients allergic to sulfonylarylamines. a. Information from U.S. product labeling current at time of publication. Health Canada product labelling listed by exception. b. A sulfonamide is any compound that contains a S02NH2 moiety. Sulfonamides are divided into three different groups based on chemical structure. The first group, the sulfonyarylamies, have a sulfonamide moiety directly attached to a benzene ring with an unsubstituted amine (-NH2) moiety at the N4 position. The second group, the nonsulfonylarylamines, also have a sulfonamide moiety attached to a benzene ring or other cyclic structure, but they do not have an amine group at the N4 position. The third group, known as the sulfonamide moiety-containing drugs, have a sulfonamide group that is not connected to a benzene ring like in the other groups.2 c. Chart may not include all sulfa drugs currently marketed in the U.S. or Canada.

(Detail-Document #260601: Page 5 of 5)

Users of this document are cautioned to use their own 5. Product information for Lexiva. GlaxoSmithKline, professional judgment and consult any other necessary Research Triangle Park, NC 27709. April 2010. or appropriate sources prior to making clinical 6. eCPS [Internet]. Ottawa (ON): Canadian Pharmacists Association; c2010. Carbonic judgments based on the content of this document. Our anhydrase inhibitor CPhA monograph (Revised editors have researched the information with input from November 2005). http://www.e-therapeutics.ca. experts, government agencies, and national (Accessed May 7, 2010). organizations. Information and Internet links in this 7. eCPS [Internet]. Ottawa (ON): Canadian article were current as of the date of publication. Pharmacists Association; c2010. Burinex monograph. http://www.e-therapeutics.ca (Accessed Project Leaders in preparation of this Detail- May 7, 2010). Document: Sherri K. Boehringer, Pharm.D., BCPS 8. Product monograph for Amaryl. Sanofi-aventis. (Original), Stacy A. Hester, R.Ph., BCPS, Assistant Laval, QC H7L 4A8. August 7, 2008. 9. Product monograph for DiaBeta. Sanofi-aventis. Editor (May 2010 update) Laval, QC H7L 4A8. June 2008. 10. Product information for Sulfamylon. UDL. Rockford, References IL 61103. April 2006. 1. Which medications to avoid in patients with sulfa 11. Product information for Flomax. Boehringer allergy? Pharmacist’s Letter/Prescriber’s Letter Ingelheim Pharm. Ridgefield, CT 06877. April 2009. 2000;16(7):160708. 12. Product information for Aptivus. Boehringer 2. Johnson KK, Green DL, Rife JP, Limon L. Ingelheim Pharmaceuticals, Inc., Ridgefield, CT Sulfonamide cross-reactivity: fact or fiction? Ann 06877. June 2009. Pharmacother 2005;39:290-301. 13. Product monograph for Azarga. Alcon Canada. 3. Product information for Agenerase. Mississauga, ON L5N 8C7. August 2009. GlaxoSmithKline, Research Triangle Park, NC 14. Strom BL, Schinnar R, Apter AJ, et al. Absence of 27709. November 2005. cross-reactivity between sulfonamide antibiotics and 4. Product information for Prezista. Tibotec. Raritan, sulfonamide nonantibiotics. N Engl J Med NJ 08869. January 2010. 2003;349:1628-35.

Cite this Detail-Document as follows: Sulfa drugs and the sulfa-allergic patient. Pharmacist’s Letter/Prescriber’s Letter 2010;26(6):260601.

Evidence and Advice You Can Trust…

Opioid Intolerance Decision Algorithm

―For help with dose conversion, please see our chart, “Equianalgesic Dosing of Opioids for Pain Management.”―

When patients say they’re allergic to an opioid, are all opioid analgesics off limits? The key is getting a detailed description of the reaction. Answer the questions below and follow the instructions to find the best options for your patient.

• Check the symptoms the patient describes, and follow the instructions in the far right column. Flushing, itching, hives, sweating, and/or mild hypotension only Go to A Itching, flushing, or hives at injection or application site only Go to A Severe hypotension Go to B Skin reaction other than itching, flushing, or hives (e.g., rash) Go to B Breathing, speaking, or swallowing difficulties Go to B Swelling of face, lips, mouth, tongue, pharynx, or larynx Go to B

A. These symptoms may be due to a pseudoallergy. It’s a result of histamine release, a pharmacologic side effect of some opioids. Options for this patient include:

1. A nonopioid analgesic (e.g., acetaminophen, an NSAID) 2. Avoidance of codeine, morphine, and meperidine, the opioids most commonly associated with pseudoallergy 3. Use of a more potent opioid less likely to release histamine. Potency, from lower to higher: meperidine

B. This patient may have experienced a true allergy. Options for this patient include:

1. A nonopioid analgesic (e.g, acetaminophen, an NSAID) 2. An opioid in a chemical class different from the one to which the patient reacted, with close monitoring:*

Phenylpiperidines: meperidine (Demerol), fentanyl (Duragesic, Actiq, Sublimaze), sufentanil (Sufenta), remifentanil (Ultiva)

Diphenylheptanes: methadone (Dolophine), propoxyphene (Darvon)

Morphine group: morphine, codeine, hydrocodone (Vicodin, Lorcet), oxycodone (Percocet, OxyContin), oxymorphone (Numorphan), hydromorphone (Dilaudid), nalbuphine (Nubain), butorphanol (Stadol), levorphanol (Levo-Dromoran), pentazocine (Talwin)

* Tramadol (Ultram, etc. [U.S.]; Zytram XL, etc. [Canada]) is contraindicated in patients with opioid allergy per U.S. and Canadian product labeling.23,26 There is not good evidence for cross-sensitivity of tramadol with opioids. However, experts recommend using tramadol only for patients who have mild reactions to opioids. The product labeling for tapentadol (Nucynta [U.S.]) does not contain this same contraindication, but the FDA considers tapentadol structurally related to tramadol.27 Experts also suggest cautious use of tapentadol in patients with opioid allergy.

(Page 2 of 4)

Detail-Document #220201 −This Detail-Document accompanies the related article published in−

PHARMACIST’S LETTER / PRESCRIBER’S LETTER February 2006 ~ Volume 22 ~ Number 220201

Analgesic Options for Patients with Allergic-Type Opioid Reactions

Background Methadone and propoxyphene are in the Opioid allergy is a common patient complaint. diphenylheptane class.4 And meperidine and But true allergy is rare.1 Upon questioning, it fentanyl are phenylpiperidines. often becomes clear the “allergy” is only a side Patients allergic to one opioid are thought to be effect, such as stomach upset. But when the less likely to react to an opioid in a different symptoms are those associated with allergic-type structural class.4 But because true allergy is rare, reactions (e.g., hives), there’s a need to determine there’s not enough information to assess the which, if any, opioid is safe. To choose a safe chance of cross-reactivity.10, 13 alternative, a thorough description of the reaction It’s important to note there is evidence patients and an understanding of opioid reactions are can be allergic to more than one narcotic class. needed. For example, IgE antibodies isolated from a patient allergic to morphine were able to bind to Types of Reactions to Narcotics fentanyl.14 Morphine antibodies have also shown Most allergic-type reactions to opioids involve some reactivity with methadone and meperidine. codeine, morphine, or meperidine.1 A common type of reaction to these opioids is pseudoallergy. Diagnosis of Opioid Allergy Symptoms can resemble a true allergy, but are It’s important to take steps to avoid labeling caused by histamine release from cutaneous mast nonallergic patients allergic.1 If the nature and cells, a nonimmunologic effect.2 Symptoms of cause of the reaction are not clarified, opioids may pseudoallergy include itching, flushing, and be withheld unnecessarily. Even if the reaction is sweating.3 Hives, increased heart rate, and low found to be opioid-related, information from the blood pressure can be due to pseudoallergy,1 but history can be used to choose a safer opioid.4 For are also seen with true allergy.4,5 example, history of tolerability of other opioids Unlike true allergy, prior exposure to the can be a clue to the mechanism of the reaction, opioid or related opioid is not necessary. and guide narcotic choice. In vitro and clinical data suggest risk of Patients should be asked about symptoms, and pseudoallergy depends on the concentration of the foods and other medications ingested several opioid at the mast cell.2,4 This is dependent on hours before the reaction.15 Also inquire about opioid potency, dose, and route of administration. preceding activities, and the possibility of bites or True allergy to opioids seems to be IgE- stings. Medical records pertaining to the reaction, mediated or T-cell mediated.5-7 Allergic skin if available, should be reviewed. Alternate reactions to opioids include hives, maculopapular diagnoses (e.g., hereditary angioedema, rash, erythema multiforme,8 and pustular rash.9 scombroid fish poisoning, carcinoid syndrome) Bronchospasm is thought to represent true allergy should be considered. only.10 Reports suggest angioedema is usually a Elevated total IgE levels during the acute manifestation of true allergy, but pseudoallergy is reaction suggest true allergy.4 But IgE could be also possible.7,11,13 elevated for reasons unrelated to drug allergy.16 Tests for IgE to specific opioids have been Narcotic Cross-reactivity developed,10 but are not readily available. There are three main opioid structural classes. Skin testing has been suggested before using a One structurally similar group is comprised of structurally unrelated opioid in a patient with a morphine, codeine, hydrocodone, oxycodone, serious opioid reaction.4 But false-positive results oxymorphone, hydromorphone, nalbuphine, due to pharmacologic histamine release have been butorphanol, levorphanol, and pentazocine.12 documented with codeine, morphine, and More. . . Copyright © 2006 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 #220201: Page 3 of 4) meperidine.17 Patch testing may produce false- labeling.23,26 There is not good evidence for cross- negative results.7 sensitivity of tramadol with opioids. However, History is the most important diagnostic tool.15 experts recommend using tramadol only for Patients requiring a detailed workup should be patients who have mild reactions to opioids. The referred to an allergist or immunologist. product labeling for tapentadol (Nucynta [U.S.]) does not contain this same contraindication, but Choosing an Analgesic the FDA considers tapentadol structurally related When choosing an analgesic for a patient with to tramadol.27 Experts also suggest cautious use a history of an allergic-type opioid reaction, the of tapentadol in patients with opioid allergy. benefits of an opioid must be weighed against the Propoxyphene and codeine are not recommended risk of a serious reaction. due to poor efficacy.24 Pentazocine (Talwin) If the reaction is only flushing, itching, should be avoided due to psychiatric side effects sweating, hives, and/or mild hypotension, the (e.g., dysphoria).19,24,25 Patients with mild to opioid can usually be continued with an moderate pain may be best served by antihistamine or dose reduction [Evidence level C; acetaminophen or an NSAID.4,24 expert opinion].3,4,18 Because pseudoallergic reactions appear to be Conclusions a function of opioid dose and potency, consider Most patients who say they’re allergic to an use of a higher potency opioid [Evidence level C; opioid have only experienced a side effect. For expert opinion]. Start with a low dose [Evidence patients with a history of allergic-type reaction, level C; expert opinion].18 If possible, avoid options include a nonopioid or a carefully chosen parenteral administration, or slow the opioid. Potential risks and benefits must be administration rate [Evidence level C; expert considered. 2 opinion]. Some patients have a reaction under the Users of this document are cautioned to use their own fentanyl patch. For these patients, spraying professional judgment and consult any other necessary triamcinolone nasal spray (Nasacort) to the area or appropriate sources prior to making clinical before patch application may be helpful [Evidence judgments based on the content of this document. Our 19 editors have researched the information with input level C; expert opinion]. from experts, government agencies, and national It’s prudent to assume other reactions (e.g., organizations. Information and Internet links in this rash, severe hypotension, bronchospasm, article were current as of the date of publication. angioedema) have an allergic mechanism. If an opioid is necessary, choose one in a different Levels of Evidence structural class if possible, and monitor the patient In accordance with the trend towards Evidence-Based 1,4 closely [Evidence level C; expert opinion]. Medicine, we are citing the LEVEL OF EVIDENCE When choosing an alternative opioid, consider for the statements we publish. the risks, benefits, and practicality of the drug. Level Definition For example, the fentanyl patch (Duragesic) is A High-quality randomized controlled trial (RCT) best reserved for chronic pain due to its slow High-quality meta-analysis (quantitative onset of action.20 Duragesic and the fentanyl systematic review) lozenge (Actiq) are for patients who’ve been B Nonrandomized clinical trial Nonquantitative systematic review taking, at minimum, morphine 60 mg daily or Lower quality RCT 21,22 equivalent for a week. Both methadone Clinical cohort study (Dolophine) and levorphanol (Levo-Dromoran) Case-control study must be dosed cautiously. Their long half-lives Historical control Epidemiologic study can cause drug accumulation and CNS and C Consensus respiratory depression with repeated dosing. And Expert opinion remember that meperidine should be limited to D Anecdotal evidence short-term use because of its neurotoxic side In vitro or animal study effects.20 Tramadol (Ultram, etc. [U.S.]; Zytram Adapted from Siwek J, et al. How to write an evidence-based clinical review article. Am Fam Physician 2002;65:251-8. XL, etc. [Canada]) is contraindicated in patients with opioid allergy per U.S. and Canadian product More. . . Copyright © 2006 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 #220201: Page 4 of 4)

Project Leader in preparation of this Detail- 14. Baldo BA, Pham NH, Zhao Z. Chemistry of drug Document: Melanie Cupp, Pharm.D., BCPS allergenicity. Curr Opin Allergy Clin Immunol 2001;1:327-35. 15. Joint Task Force on Practice Parameters. The References diagnosis and management of anaphylaxis: an 1. Gilbar PJ, Ridge AM. Inappropriate labeling of updated practice parameter. J Allergy Clin patients as opioid allergic. J Oncol Pharm Practice Immunol 2005;115(3 Suppl):S483-523. 2004;10:177-82. 16. Emanuel IA. In vitro testing for allergy diagnosis. 2. VanArsdel PP. Pseudoallergic drug reactions. Otolaryngol Clin North Am 2003;36:879-93. Introduction and general review. Immunol Allergy 17. Nasser SMS, Ewan PW. Opiate-sensitivity: Clin North Am 1991;11:635-44. clinical characteristics and the role of skin prick 3. Middleton RK, Beringer PM. Anaphylaxis and drug testing. Clin Exp Allergy 2001;31:1014-20. allergies. In: Koda-Kimble MA, Young LY, Kradjan 18. Nutescu E, Hunt C, Teeters J. Multidisciplinary WA, et al., eds. Applied Therapeutics: the clinical approach to improving allergy documentation. Am use of drugs. 8th ed. Philadelphia: Lippincott J Health-Syst Pharm 1998;55:364-8. Williams & Wilkins, 2005. 19. Otis JA, Fudin J. Use of long-acting opioids for the 4. Crabe Erush S. Narcotic allergy. P&T management of chronic pain. U.S. Pharmacist 1996;21:250-2, 292. 2005;30(3 Suppl):1-14. www.uspharmacist.com/ 5. Harle DG, Baldo BA, Coroneos NJ, Fisher MM. index.asp?page=ce/10163/default.htm (Accessed Anaphylaxis following administration of January 13, 2006). papaveretum. Case report: Implication of IgE 20. Reisner L, Koo PJS. Pain and its management. antibodies that react with morphine and codeine, In: Koda-Kimble MA, Young LY, Kradjan WA, et and identification of an allergenic determinant. al., eds. Applied Therapeutics: the clinical use of th Anesthesiology 1989;71:489-94. drugs. 8 ed. Philadelphia: Lippincott Williams & 6. Estrada JL, Puebla MJ, deUrbina JJ, et al. Wilkins, 2005. Generalized eczema due to codeine. Contact 21. Fentanyl transdermal system (Duragesic) Dermatitis 2001;44:185. prescribing information. Titusville, NJ: Janssen 7. Mohrenschlager M, Glockner A, Jessberger B, et Pharmaceutical Products, LP. February 2005. al. Codeine caused pruritic scarlatiniform Available at: exanthemata: patch test negative but positive to http://www.duragesic.com/active/janus/en_US/asse oral provocation test. Br J Dermatol 2000;143:663- ts/common/company/pi/duragesic.pdf. (Accessed 4. January 19, 2006). 8. Cooper SM, Shaw S. Dihydrocodeine: a drug 22. Oral transmucosal fentanyl (Actiq) prescribing allergy diagnosed by patch testing. Contact information. Salt Lake City, UT: Cephalon, Inc. Dermatitis 2000;42:307-8. 2004. Available at: 9. Machet L, Martin L, Machet MC, et al. Acute http://www.actiq.com/physicians/aboutbtcp/default. generalized exanthematous pustulosis induced by asp. (Accessed January 19, 2006). dextropropoxyphene and confirmed by patch 23. Product information for Ultram. PriCara. Raritan, testing. Acta Dermatol Venereol 2000;80:224-5. NJ 08869. September 2009. 10. Fisher MM, Harle DG, Baldo BA. Anaphylactoid 24. Sachs CJ. Oral analgesics for acute nonspecific reactions to narcotic analgesics. Clin Rev Allergy pain. Am Fam Phys 2005;71:913-8. 1991;9:309-18. 25. Inturrisi CE. Clinical pharmacology of opioids for 11. Vidal C, Perez-Leiros P, Bugarin R, Armisen M. pain. Clin J Pain 2002;18:S3-13. Fever and urticaria to codeine. Allergy 26. Product monograph for Zytram XL. Purdue 2000;55:416-7. Pharma. Pickering, ON L1W 3W8. March 2009. 12. Baumann TJ. Analgesic selection when the patient 27. Product information for Nucynta. PriCara. Raritan, is allergic to codeine. Clin Pharm 1991;10:658. NJ 08869. March 2010. 13. Anibarro B, Vila C, Seoane FJ. Urticaria induced by meperidine allergy. Allergy 2000;55:305.

Cite this Detail-Document as follows: Analgesic options for patients with allergic-type opioid reactions. Pharmacist’s Letter/Prescriber’s Letter 2006;22(2):220201.

Evidence and Advice You Can Trust…

(Detail-Document #260601: Page 1 of 2)

Investigating Possible Drug Allergy or Sensitivity

Drug allergies noted on a patient’s chart or medication profile can be somewhat nebulous, with no description or just a single word such as “rash” or “nausea” describing the event. This may lead to inappropriate avoidance of the offending drug or other drugs, compromising or unnecessarily complicating patient care. For example, a patient with a codeine allergy and no specific reaction noted on his or her profile might receive inferior pain relievers such as propoxyphene, when the reaction is simply an upset stomach. On the flipside, it’s important to have accurate documentation of allergies so other drugs that could cause a reaction can be avoided. For some drugs such as aspirin, a sensitivity reaction may not be an actual allergy. Aspirin sensitivity involves symptoms that are respiratory in nature, such as rhinitis and worsening of asthma, or skin manifestations, such as urticaria and angioedema. Aspirin sensitivity is due to COX-1 inhibition, and not to an actual immune response. Because NSAIDs also inhibit COX-1, patients who have aspirin sensitivity are likely to also have sensitivity to NSAIDs. However, the chance for cross-reactivity between aspirin and NSAIDs in a patient with a true allergic reaction to either is less likely.

Prior to treating patients who report a drug allergy, a thorough history of the patient’s allergy should be obtained. Example questions the patient should be asked are included below. However, keep in mind there are times when a patient will require intricate diagnosis and testing for drug allergies, such as when skin testing for penicillin-specific IgE is indicated.

Be aware that the significance of responses to these questions can vary according to the drug that caused the reaction. Also be aware that individuals who have an allergy to one drug are more likely to have other drug allergies than those who aren’t allergic to any drugs at all.

Is there any medicine you cannot take for any reason? By what route did you receive the drug? (Identifying all problematic drugs, whether due to allergy or intolerance, is important. In some instances, a perceived "intolerance" problem may be minimized or avoided with counseling [e.g., take with food] or modification of therapy [e.g., dosage reduction].)

Why was the medication prescribed?

How long ago did the reaction occur? (The longer the time from the original administration of an allergen to the next administration, the less chance an IgE-mediated, or Type I, reaction will recur. This includes reactions such as hives and anaphylaxis. About 70% of people with penicillin allergy lose their allergy after five to ten years.)

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Can you describe the reaction? How was the reaction managed? (The most common allergic reaction to a drug is measles-like rash. Symptoms that could be suggestive of anaphylaxis include sense of warmth, flushing, itching, hives, facial or throat swelling, asthma or wheezing, nausea or vomiting, light headedness from low blood pressure, or abdominal cramping.)

How soon after taking the drug did your reaction occur? (Onset of drug allergy usually happens several days to several months after starting a drug. Anaphylaxis usually occurs within one hour after a drug is taken.)

When the offending drug was stopped, what happened? (An allergic reaction should subside within several days to weeks after the drug is stopped.)

Were you taking any other medications, including OTCs or supplements, at the same time the reaction occurred? Had you ingested any type of food that may have caused the reaction? (Consider the possibility that the reaction could have been related to the pharmacological action of, or reaction to, another substance.)

Have you since taken the SAME drug? If so, what happened?

Have you taken a SIMILAR drug since the reaction happened? If so, what happened? (Consider asking a patient who had a reaction to penicillin if he or she has taken a cephalosporin, or a patient who had a reaction to an opioid if he or she has taken a different opioid.)

Have you ever had the SAME reaction with a DIFFERENT drug?

Technician Training Tutorial: Drug Allergies

Making sure that you have a patient’s up-to-date allergy information is a vital step in helping to ensure safe medication use. In fact, more than 200,000 people are treated in emergency rooms each year for drug allergies. The range of “allergic” reactions that patients experience can vary widely. Around one in ten reported side effects are actually drug allergies. Some patients will report side effects, like nausea or upset stomach, as allergies. But these reactions aren’t allergies at all. Other drug reactions, such as swelling and shortness of breath, ARE allergies. These reactions can indicate that certain drugs may cause life- threatening reactions in certain patients. A true drug allergy happens as a result of activity of the immune system. Allergic reactions can occur as soon as a drug is taken, or days after. The different types of antibodies that are involved determine how long the reaction takes. Reactions indicating a true drug allergy include hives, rash, difficulty breathing, speaking, or swallowing, wheezing, and severe low blood pressure. A severe allergic reaction that includes these symptoms is sometimes referred to as “anaphylaxis” or an “anaphylactic reaction.” Anaphylaxis can be deadly. Compared to drugs taken orally, drugs that are either injected or applied to the skin are more likely to cause allergic reactions. Besides the wide range of reactions that can be reported by patients, specific drugs that can or can’t be used in a patient with a particular allergy can be confusing. Allergies to aspirin, opioids (e.g., codeine, hydrocodone, morphine, etc.), penicillins (e.g., amoxicillin, Augmentin, Clavulin [Canada]), and sulfa drugs (sulfamethoxazole, which is in Septra and Bactrim DS) are among the most commonly reported. Penicillin is THE most common drug allergy and is reported by about one in ten patients. About one in ten adults with asthma have an allergy to aspirin. Essentially, evaluating the appropriateness of therapy for patients with drug allergies involves determining if the reaction is actually an allergy, and which drugs, if any, should be avoided. Usually, when a patient has a true allergy to a drug or class of drugs, the pharmacist can recommend another drug that will treat the patient’s condition safely.

A new patient, Katherine Katz, comes in to your pharmacy. You ask her for all the usual information, including drug allergies. She says that she is allergic to penicillin and Tylenol #3 and hands you the following prescription.

Prescription interpretation: Keflex 500 mg twice daily for ten days. When you enter this prescription into the pharmacy computer system, you get a warning that the patient could have an allergic reaction to Keflex. You know that cephalexin is not a penicillin, but you advise the pharmacist that Ms. Katz has a penicillin allergy.

What additional information do you need to get from Ms. Katz? Ask Ms. Katz what type of reaction she had. The pharmacist will need this information to decide whether her reactions were actually allergies, or just a side effect of the medication, or an intolerance to the drug.

Ms. Katz states that she had hives from penicillin and amoxicillin in the past and that Tylenol #3 makes her “very nauseous,” but she’s never had a rash or any other reaction to it.

What information should be entered into the computer based on Ms. Katz’s history? It is very important to keep good records of a patient’s reactions to drugs. In this case, “penicillin” should be entered as a drug allergy and a note can be added to Ms. Katz’s patient profile stating that she reports extreme nausea with Tylenol #3. Based on Ms. Katz’s description of her reaction, an allergy to Tylenol #3 should NOT be entered. The distinction between the two types of entries is important. Flagging penicillin as an allergy will ensure that the pharmacy computer system is also scanning Ms. Katz’s future prescriptions for drugs that are similar to penicillin, like amoxicillin or ampicillin, and will increase the likelihood of avoiding a future reaction to one of these meds. However, the same is not true of Tylenol #3, since Ms. Katz is reporting an intolerance or a side effect to this medication, and not a true drug allergy. Making a note in the computer alerts the pharmacist of this side effect and will prompt the pharmacist to recommend something that will help Ms. Katz avoid it in the future. For example, if Ms. Katz had a prescription for an opioid similar to codeine which is found in Tylenol #3, the pharmacist might recommend that she take the drug with food to minimize the nausea. Ask your pharmacist for guidance if you are unsure if patients are describing a true allergic reaction or a side effect or intolerance. It can sometimes be hard to differentiate between these.

When a patient reports an allergy to one drug, what other drugs should also be avoided? When a patient is allergic to a particular drug, it’s usually best for that drug to be avoided unless absolutely necessary. Drugs in the SAME CLASS should generally be avoided as well. We’ll use sulfa drugs to illustrate. For example, a patient who is allergic to Bactrim (sulfamethoxazole/trimethoprim) will probably also be allergic to other sulfa drugs, like sulfadiazine (Silvadene) and sulfisoxazole. Keep in mind that the term “sulfa drug” refers to drugs that are classified as sulfonamides, with a specific chemical structure. Sometimes, there’s confusion over whether or not an allergy to sulfa drugs means that a patient is also allergic to sulfate, as in morphine SULFATE. The chemical structure of sulfate is not the same as the structure of sulfonamides, so an allergic reaction isn’t expected.

What is allergic cross-reactivity? When a patient has had an allergic reaction to a particular drug, there’s a chance that he or she might also have an allergic reaction to drugs with a similar chemical structure. This is referred to as “cross- reactivity.” For example, cephalosporins (e.g. cephalexin [Keflex], cefuroxime [Ceftin, Zinacef], etc.) are chemically similar to penicillins. Around one out of 100 patients who are allergic to penicillin will have an allergic reaction to a cephalosporin drug. Carbapenem antibiotics (e.g., doripenem (Doribax), ertapenem [Invanz], imipenem [Primaxin], meropenem [Merrem]) and monobactam antibiotics (e.g., aztreonam [Azactam]) are also chemically similar to penicillins. Around one out of 100 people with a true penicillin allergy will have a reaction to a carbapenem. In the general population, the risk may be slightly less for monobactams. Cross-reactivity can also vary between different subgroups of the same drug class. Opioid analgesics are a good example. The opioid analgesic drug class can be subdivided into three distinct chemical/structural classes. Morphine, codeine, hydrocodone, and oxycodone are all in the same chemical class. Meperidine and fentanyl are in a different chemical class. Methadone and propoxyphene

are in yet another chemical class. For patients with opioid allergies, a good choice might be another opioid that is not in the same chemical class as the offending opioid. The pharmacist might recommend a drug from a chemical class other than the one the patient is allergic to. Some drugs that don’t have “sulfa” in the name might be dangerous for patients with sulfa allergy. These include celecoxib (Celebrex), some diuretics, some medications for HIV, and zonisamide (Zonegran). The risk for cross-reactivity in patients with sulfa allergies is variable with these drugs. The decision about whether it is okay to use drugs from a different class with a similar chemical structure can depend on how severe a patient’s reaction to a particular drug is and how badly they need to take the drug to which they may react. For example, a pharmacist might recommend against using Keflex in a patient who had a life-threatening allergic reaction with penicillin. On the other hand, using Keflex would be considered safer in a patient who only had a rash with penicillin. Alert your pharmacist to any drug allergy alerts that show up in your computer system, even if they do not seem to be for the same drug. The alert might be caused by a cross-reactivity between two drugs. An alternative drug might be better for the patient to avoid a potential reaction, as in the case of the patient with the life-threatening penicillin allergy above. Verify allergy information at every opportunity to make sure you have the most accurate and updated information possible in the computer to detect any potential reactions.

What if a patient MUST have a medication that he or she is allergic to? If a patient has had a serious allergic reaction to a medication that he or she MUST have, there are times when a “desensitization protocol” can be used. Desensitization involves initially giving a patient a very small amount of drug, and repeating administration with increasingly larger amounts. Eventually, normal doses of the drug can be tolerated. However, hypersensitivity to a drug will usually return after the course of treatment is stopped. Normally, desensitization is supervised by an allergist. There’s a chance that the patient could have a severe reaction at any time. Appropriate precautions, like ensuring immediate access to emergency medications, must be taken.

Although a skin reaction associated with use of a drug usually indicates an allergic reaction, there are exceptions. What are they? It’s possible for a patient to have a skin reaction, like flushing, hives, or itching, after taking a medication that he or she is NOT allergic to. One such reaction is called a “pseudoallergy.” Pseudoallergy can occur with drugs that cause the release of some inflammatory chemicals in the body, such as histamine. An example of pseudoallergy is a rash caused by infusion of the injectable antibiotic, vancomycin. This reaction is called “red man syndrome.” Patients will most often have a red rash on the neck and shoulders. Slowing the infusion rate of vancomycin in patients who have experienced red man syndrome can help prevent it from happening again. A histamine-related pseudoallergy can occur when patients take some opioids for pain, such as morphine. When this happens, certain opioids might need to be avoided, or an antihistamine (e.g., diphenhydramine [Benadryl], etc.) can be given to help minimize the reaction. Patients may also experience “photosensitivity” when taking some drugs. Photosensitivity is not necessarily an allergic reaction. This increased sensitivity of the skin to the sun’s effects can result in reddening of the skin or sunburn and is sometimes seen with sulfonamide antibiotics, isotretinoin (Accutane), and tetracyclines. Check out “Management of Common Skin Diseases” for examples of skin reactions to drugs that ARE NOT caused by allergies.

The pharmacist approaches Ms. Katz, and Ms. Katz explains that she had hives with penicillin. She says that it was probably 30 years ago since this happened. She also tells the pharmacist that she has had Keflex before with no problems. The pharmacist tells her that there is a small chance that she will

have a reaction with the Keflex, but that he feels comfortable dispensing it to her. She agrees that she is comfortable taking Keflex. The pharmacist tells Ms. Katz that if she has any kind of reaction, from hives to shortness of breath or swelling, to call her provider immediately.

Are food allergies important to know? Yes, although food allergies are only an issue with a few drugs. There are actually a few medications that are contraindicated in patients with certain food allergies. This is usually not because of the drug itself, but instead, because of the drug formulation. For example, Atrovent (ipratropium) and Combivent (ipratropium/albuterol) inhalers both contain soy lecithin as a suspending agent. Soy and peanuts are in the same plant family. Patients who are allergic to peanuts might also react to soy. The newer injectable drug Cleviprex (clevidipine), which is for blood pressure lowering, is formulated with both eggs and soy. It’s contraindicated in patients who have soy or egg allergies. Patients with egg or gelatin allergies shouldn’t get the intranasal flu vaccine, FluMist. Remember that latex allergy should also be noted. Some medication containers, like vial stoppers, contain latex. However, in the past decade or so, manufacturers have made drug packaging safer for patients with latex allergy. If a patient reports a food or latex allergy check with your pharmacist about the best way to enter this into the pharmacy computer system. Many systems allow food or other allergies to be entered in the same way as a drug allergy, so that the allergy can be checked against drugs that shouldn’t be used.

How does drug allergy monitoring differ in the hospital setting? In the hospital, a patient’s allergy information is usually recorded or entered into the computer system by a nurse or provider. However, pharmacists may need to request more information from the patient, a family member, or nurse, if more details such as the specific reaction are needed. Alert the pharmacist if you notice that drug allergy is missing from the patient’s profile, chart, med order, etc. No matter the practice setting, medications should not be dispensed until allergy information is provided. There are very rare exceptions to this rule. One exception would be for administration of life- saving medications when a patient is unconscious and allergy information is not immediately available, as for a trauma patient before family members have arrived. For this reason, patients who have experienced very severe allergic reactions should consider wearing a Medic Alert bracelet or necklace which lists his or her allergies. When you encounter patients who have very severe allergic reactions to drugs, remind them that the Medic Alert bracelet or necklace could provide that important information in an emergency situation.

Resources American Academy of Allergy, Asthma, and Immunology. Tips to remember: adverse reactions to medications and drug allergies. http://www.aaaai.org/patients/publicedmat/tips/adversereactions.stm. (Accessed March 15, 2009).

Allergic cross-reactivity among beta-lactam antibiotics: an update. Pharmacist’s Letter/Prescriber’s Letter 2009;25(4):250415.

Analgesic options for patients with allergic-type opioid reactions. Pharmacist's Letter/Prescriber's Letter 2006;22(2):220201.

Sulfa drugs and the sulfa-allergic patient. Pharmacist's Letter/Prescriber's Letter 2005;21(11):211113.