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Testing for hypersensitivity reactions to intravenous drug and biologic agents: Recommendations in product labels
S182 Abstracts
Testing for Hypersensitivity Reactions to Intravenous Drug and Biologic Agents: Recommendations in Product Labels H. Ko; Cber/obrr/dh, Food and Drug Administration, Rockville, MD. RATIONALE: Administration of intravenous agents may be associated with serious allergic reactions. It would be important to examine the recommendations on testing for hypersensitivity reactions in the use of available intravenous products that carry such risks. METHODS: Package inserts for marketed intravenous drug and biologic products were examined for information on the immunogenicity of the product, precautions before and after dosing, and recommendations on testing. RESULTS: The evaluation included 20 package inserts of blood-derived products (polyclonal antibodies and coagulation factors), monoclonal antibody products, volume expanders (dextrans), pharmaceuticals (iron, insulin, penicillin), and radiographic contrast media. Among the recommendations in these labels, skin testing is the most common, and appears in five product labels. Three labels recommend administering test doses prior to full dosing. Two package inserts advocate conjunctival testing, two propose screening for antibodies and two other labels state that skin testing is not suggested or required prior to dosing. The remaining labels are silent on testing for reactions. There is no uniform description of what constitutes a “positive” test and when a product should be avoided if it is observed. Despite “negative” tests, some patients may still experience reactions to the products. Desensitization procedures are described in three labels. CONCLUSIONS: Currently there is much variation in the recommendations on hypersensitivity testing for intravenous agents that carry reaction risks. Formulating recommendations for testing should be based on an evidence-based approach.
725
Comparison of an In-House Preparation of the Major Allergenic Determinant of Benzyl Penicillin G With the Commercially Produced Pre-Pen D. Matesic, E. Frigas, H. Kita, P. A. Harris, G. W. Volcheck, P. A. Markus, C. R. Weiler, D. E. Maddox, J. T. C. Li, R. G. Van Dellen, J. B. Hagan, J. H. Butterfield; Division of Allergic Diseases, Mayo Clinic, Rochester, MN. RATIONALE: The major determinant of benzyl penicillin G “PrePen™, is often unavailable for purchase. Therefore, there is a need to produce it in-house and validate its efficacy in the clinical setting. METHODS: In an IRB approved prospective study we evaluated both clinically and via skin testing, 206 consecutive surgical patients who reported in their preoperative questionnaires a history of allergy to penicillin. The skin testing was done using: an in-house preparation of penicilloyl polylysine (IPP), the commercial “Pre-Pen™” (CPP), an in-house preparation of the minor penicillin determinant (alkaline hydrolysis product of benzyl penicillin G) (mPD) and a “fresh mix of penicillin G”(fPD). RESULTS: Five patients did not react to histamine control and were dropped from the study. No patient reacted to mPD or fPD. Six patients had an immediate positive skin reaction to both IPP and CPP. In addition, one patient reacted only to IPP and other two only to CPP. These nine reactors received vancomycin for antibacterial prophylaxis perioperatively (ABPPO) without difficulty. Of othe192 patients who tested negative, 160 received for ABPPO cephalosporin and the remainder received clindamycin, cipro or ampicillin. Only five of cephalosporin treated patients developed rash or urticaria all easily controlled. There were no life-threatening reactions. CONCLUSIONS: In-house preparation of the major antigenic determinant of benzyl penicillin G is well tolerated and might be helpful for
726
J ALLERGY CLIN IMMUNOL FEBRUARY 2005
avoiding disruptions in the evaluation and management of patients resulting from short-falls in the production of commercially produced PrePen. Utility of Penicillin Major and Minor Determinants for Identification of Allergic Reactions to Cephalosporins P. A. Greenberger, J. C. Klemens; Division of Allergy-Immunology, Northwestern University, Chicago, IL. RATIONALE: The ability of penicillin major and minor determinants to detect anti-cephalosporin IgE antibodies remains controversial. It was our hypothesis that most or all antibodies could be detected by use of penicillin determinants and that negative skin tests in penicillin allergic patients would allow for safe cephalosporin administration. METHODS: From 1984-2004, 851 adult patients with convincing, equivocal or unknown histories of penicillin allergy were skin tested. PrePen (Hollister-Stier), K PCN G, benzylpenicilloate and benzylpenicilloyln-propylamine were used for prick and intradermal. If negative skin tests, patient received a test dose (1/1000 full dose) and then full dose. 156/851 (18.3%) patients who underwent skin testing received a subsequent cephalosporin. RESULTS: From the 156 patients, 6 patients were skin test positive; all 6 patients tolerated cephalosporins. Skin tests were negative in 142; 140 patients tolerated cephalosporins. One patient developed a rash after 1g of cefepime. One expired after a test dose but not secondary to anaphylaxis. Skin tests were indeterminate in 8 patients; 7 patients tolerated cephalosporins. One patient never received cephalosporin after skin testing. Patients with positive skin tests reacted to the following: Pre-Pen (3), K PCN G (2), and benzylpenicilloate (1). CONCLUSIONS: 1) Overall, 3.8% of patients who were skin test positive to penicillin determinants received a cephalosporin. 2) Only 1/142 (0.7%) had evidence for an allergic reaction to a cephalosporin with negative penicillin skin tests. 3) The negative predictive value using major and minor determinants is high for subsequent cephalosporin administration. 4) Three of 6 skin test positive patients reacted only to Pre-Pen. Funding: Ernest S. Bazley grant to Northwestern University
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Purpuric Dermatosis Due to Diltiazem
M. J. Fernandez-Bohorquez1, M. J. De Barrio1, E. Martin1, V. Agustin1, I. Longo2, T. Herrero1; 1Allergy Department, Hospital Gregorio Maranon, Madrid, SPAIN, 2Dermatology, Hospital Gregorio Maranon, Madrid, SPAIN. RATIONALE: Diltiazem is a calcium channel blocker that belongs to the benzothiacepine group. This drug is widely used in the treatment of arterial hypertension. It evoques frequent cutaneous eruptions but purpuric dermatosis are exceptional. METHODS: A 82 year- old woman received treatment with diltiazem. She experienced intense pruritus and a generalized widespread eruption after two months of therapy. The lesions consisted on well circumscribed erythemato- purpuric plaques of varying diameter. Some of them progressed into vesicles with residual pigmentation. Lesions resolved within 15 days after discontinuation of diltiazem and treatment with systemic corticosteroids and antihistamines. RESULTS: A cutaneous biopsy showed extravasated erythrocytes within the papillary dermis, and a perivascular lymphohistioytic infiltrate. Patch test with diltiazem(10% in DMSO) was positive (+++) 48 and 72 hours later. Patch tests in 10 control subjects were negative. CONCLUSIONS: 1. We report an exceptionally case of purpuric dermatosis due to diltiazem. 2. Patch-test was useful to the diagnosis. 3. The positive patch test and the anatomopathology finding support a Type IV hypersensitivity reaction.
Testing for Hypersensitivity Reactions to Intravenous Drug and Biologic Agents: Recommendations in Product Labels H. Ko; Cber/obrr/dh, Food and Drug Administration, Rockville, MD. RATIONALE: Administration of intravenous agents may be associated with serious allergic reactions. It would be important to examine the recommendations on testing for hypersensitivity reactions in the use of available intravenous products that carry such risks. METHODS: Package inserts for marketed intravenous drug and biologic products were examined for information on the immunogenicity of the product, precautions before and after dosing, and recommendations on testing. RESULTS: The evaluation included 20 package inserts of blood-derived products (polyclonal antibodies and coagulation factors), monoclonal antibody products, volume expanders (dextrans), pharmaceuticals (iron, insulin, penicillin), and radiographic contrast media. Among the recommendations in these labels, skin testing is the most common, and appears in five product labels. Three labels recommend administering test doses prior to full dosing. Two package inserts advocate conjunctival testing, two propose screening for antibodies and two other labels state that skin testing is not suggested or required prior to dosing. The remaining labels are silent on testing for reactions. There is no uniform description of what constitutes a “positive” test and when a product should be avoided if it is observed. Despite “negative” tests, some patients may still experience reactions to the products. Desensitization procedures are described in three labels. CONCLUSIONS: Currently there is much variation in the recommendations on hypersensitivity testing for intravenous agents that carry reaction risks. Formulating recommendations for testing should be based on an evidence-based approach.
725
Comparison of an In-House Preparation of the Major Allergenic Determinant of Benzyl Penicillin G With the Commercially Produced Pre-Pen D. Matesic, E. Frigas, H. Kita, P. A. Harris, G. W. Volcheck, P. A. Markus, C. R. Weiler, D. E. Maddox, J. T. C. Li, R. G. Van Dellen, J. B. Hagan, J. H. Butterfield; Division of Allergic Diseases, Mayo Clinic, Rochester, MN. RATIONALE: The major determinant of benzyl penicillin G “PrePen™, is often unavailable for purchase. Therefore, there is a need to produce it in-house and validate its efficacy in the clinical setting. METHODS: In an IRB approved prospective study we evaluated both clinically and via skin testing, 206 consecutive surgical patients who reported in their preoperative questionnaires a history of allergy to penicillin. The skin testing was done using: an in-house preparation of penicilloyl polylysine (IPP), the commercial “Pre-Pen™” (CPP), an in-house preparation of the minor penicillin determinant (alkaline hydrolysis product of benzyl penicillin G) (mPD) and a “fresh mix of penicillin G”(fPD). RESULTS: Five patients did not react to histamine control and were dropped from the study. No patient reacted to mPD or fPD. Six patients had an immediate positive skin reaction to both IPP and CPP. In addition, one patient reacted only to IPP and other two only to CPP. These nine reactors received vancomycin for antibacterial prophylaxis perioperatively (ABPPO) without difficulty. Of othe192 patients who tested negative, 160 received for ABPPO cephalosporin and the remainder received clindamycin, cipro or ampicillin. Only five of cephalosporin treated patients developed rash or urticaria all easily controlled. There were no life-threatening reactions. CONCLUSIONS: In-house preparation of the major antigenic determinant of benzyl penicillin G is well tolerated and might be helpful for
726
J ALLERGY CLIN IMMUNOL FEBRUARY 2005
avoiding disruptions in the evaluation and management of patients resulting from short-falls in the production of commercially produced PrePen. Utility of Penicillin Major and Minor Determinants for Identification of Allergic Reactions to Cephalosporins P. A. Greenberger, J. C. Klemens; Division of Allergy-Immunology, Northwestern University, Chicago, IL. RATIONALE: The ability of penicillin major and minor determinants to detect anti-cephalosporin IgE antibodies remains controversial. It was our hypothesis that most or all antibodies could be detected by use of penicillin determinants and that negative skin tests in penicillin allergic patients would allow for safe cephalosporin administration. METHODS: From 1984-2004, 851 adult patients with convincing, equivocal or unknown histories of penicillin allergy were skin tested. PrePen (Hollister-Stier), K PCN G, benzylpenicilloate and benzylpenicilloyln-propylamine were used for prick and intradermal. If negative skin tests, patient received a test dose (1/1000 full dose) and then full dose. 156/851 (18.3%) patients who underwent skin testing received a subsequent cephalosporin. RESULTS: From the 156 patients, 6 patients were skin test positive; all 6 patients tolerated cephalosporins. Skin tests were negative in 142; 140 patients tolerated cephalosporins. One patient developed a rash after 1g of cefepime. One expired after a test dose but not secondary to anaphylaxis. Skin tests were indeterminate in 8 patients; 7 patients tolerated cephalosporins. One patient never received cephalosporin after skin testing. Patients with positive skin tests reacted to the following: Pre-Pen (3), K PCN G (2), and benzylpenicilloate (1). CONCLUSIONS: 1) Overall, 3.8% of patients who were skin test positive to penicillin determinants received a cephalosporin. 2) Only 1/142 (0.7%) had evidence for an allergic reaction to a cephalosporin with negative penicillin skin tests. 3) The negative predictive value using major and minor determinants is high for subsequent cephalosporin administration. 4) Three of 6 skin test positive patients reacted only to Pre-Pen. Funding: Ernest S. Bazley grant to Northwestern University
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Purpuric Dermatosis Due to Diltiazem
M. J. Fernandez-Bohorquez1, M. J. De Barrio1, E. Martin1, V. Agustin1, I. Longo2, T. Herrero1; 1Allergy Department, Hospital Gregorio Maranon, Madrid, SPAIN, 2Dermatology, Hospital Gregorio Maranon, Madrid, SPAIN. RATIONALE: Diltiazem is a calcium channel blocker that belongs to the benzothiacepine group. This drug is widely used in the treatment of arterial hypertension. It evoques frequent cutaneous eruptions but purpuric dermatosis are exceptional. METHODS: A 82 year- old woman received treatment with diltiazem. She experienced intense pruritus and a generalized widespread eruption after two months of therapy. The lesions consisted on well circumscribed erythemato- purpuric plaques of varying diameter. Some of them progressed into vesicles with residual pigmentation. Lesions resolved within 15 days after discontinuation of diltiazem and treatment with systemic corticosteroids and antihistamines. RESULTS: A cutaneous biopsy showed extravasated erythrocytes within the papillary dermis, and a perivascular lymphohistioytic infiltrate. Patch test with diltiazem(10% in DMSO) was positive (+++) 48 and 72 hours later. Patch tests in 10 control subjects were negative. CONCLUSIONS: 1. We report an exceptionally case of purpuric dermatosis due to diltiazem. 2. Patch-test was useful to the diagnosis. 3. The positive patch test and the anatomopathology finding support a Type IV hypersensitivity reaction.