Anaphylaxis associated with omalizumab administration: Risk factors and patient characteristics

The omalizumab product label includes a black box warning for anaphylaxis. As of the end of 2016, there has been an estimated cumulative exposure of ∼31,000 patient-years in clinical trials and 819,000 patient-years in the postmarketing setting. Episodes of anaphylaxis have been observed in association with omalizumab use since the initial human studies and after its approval for allergic asthma in 2003. In 2016, Lieberman et al,1Lieberman P.L. Umetsu D.T. Carrigan G.J. Rahmaoui A. Anaphylactic reactions associated with omalizumab administration: analysis of a case-control study.J Allergy Clin Immunol. 2016; 138: 913-915.e2Abstract Full Text Full Text PDF PubMed Scopus (36) Google Scholar reported data from a postmarketing case-control study (The Pharmacosurveillance Data Repository of Patients With and Without History of Anaphylactic Reactions Subsequent to Xolair Dosing [X-PAND], N = 30) that examined cases of anaphylaxis related to omalizumab use. We now report on a larger sample size of 132 patients with potential anaphylaxis associated with omalizumab that was adjudicated by the same independent clinical expert; 96 (73%) were adjudicated as cases of anaphylaxis related to omalizumab (see Fig E1 in this article's Online Repository at www.jacionline.org). Demographic characteristics revealed a preponderance of female subjects (84%), and mean age of 40.5 (range 9-86) years. Omalizumab was prescribed for asthma in most patients (80%). A prior anaphylactic event unrelated to omalizumab was documented in 43% (n = 37) of patients who provided an anaphylaxis history. The most common symptoms reported during omalizumab-associated anaphylaxis involved the respiratory tract (95%, 91 of 96 patients). The majority of patients also reported experiencing cutaneous/angioedema symptoms (see Table E1 in this article's Online Repository at www.jacionline.org). The majority of anaphylactic reactions were observed during the first 2 (69%) or first 3 (72%) doses (see Table E2 in this article's Online Repository at www.jacionline.org). Time to onset of reaction following administration of omalizumab was documented in 81 cases of anaphylaxis (see Table E3 available in this article's Online Repository at www.jacionline.org). The reaction occurred within 60 minutes of omalizumab administration in the majority of cases (64%, 52 of 81); median time to anaphylactic reaction was 60 minutes. Treatment of anaphylaxis included use of antihistamines (69%, 66 of 96 patients), epinephrine (60%, 58 of 96 patients), systemic corticosteroids (57%, 55 of 96 patients), and inhaled beta-agonists (41%, 39 of 96 patients). Hospitalization was reported in 16 cases (17%). No treatment was needed in 2 cases (2%), and there was no information on treatment for 11 cases (11%). No case of anaphylaxis resulted in death. A comparison of our data with data previously reported by Limb et al2Limb S.L. Starke P.R. Lee C.E. Chowdhury B.A. Delayed onset and protracted progression of anaphylaxis after omalizumab administration in patients with asthma.J Allergy Clin Immunol. 2007; 120: 1378-1381Abstract Full Text Full Text PDF PubMed Scopus (144) Google Scholar and Lieberman et al1Lieberman P.L. Umetsu D.T. Carrigan G.J. Rahmaoui A. Anaphylactic reactions associated with omalizumab administration: analysis of a case-control study.J Allergy Clin Immunol. 2016; 138: 913-915.e2Abstract Full Text Full Text PDF PubMed Scopus (36) Google Scholar is provided in Fig 1. Data from the current analysis and that from the Limb et al2Limb S.L. Starke P.R. Lee C.E. Chowdhury B.A. Delayed onset and protracted progression of anaphylaxis after omalizumab administration in patients with asthma.J Allergy Clin Immunol. 2007; 120: 1378-1381Abstract Full Text Full Text PDF PubMed Scopus (144) Google Scholar study indicate that most cases (∼70%) of anaphylaxis occurred within the first 3 doses, while in the X-PAND study,1Lieberman P.L. Umetsu D.T. Carrigan G.J. Rahmaoui A. Anaphylactic reactions associated with omalizumab administration: analysis of a case-control study.J Allergy Clin Immunol. 2016; 138: 913-915.e2Abstract Full Text Full Text PDF PubMed Scopus (36) Google Scholar this number was 40% (Fig 1, A). All 3 studies suggest that a significant fraction of patients with omalizumab-associated anaphylaxis have a prior history of anaphylaxis unrelated to omalizumab (Fig 1, B) and that more than half of the anaphylactic events happened within 60 minutes of omalizumab administration (Fig 1, C). This dataset represents the largest number of adjudicated cases of anaphylaxis associated with omalizumab and is about 3 times the number of adjudicated anaphylaxis cases reported in our initial study.1Lieberman P.L. Umetsu D.T. Carrigan G.J. Rahmaoui A. Anaphylactic reactions associated with omalizumab administration: analysis of a case-control study.J Allergy Clin Immunol. 2016; 138: 913-915.e2Abstract Full Text Full Text PDF PubMed Scopus (36) Google Scholar These results suggest that a specific subpopulation of patients, that is, those with a prior history of anaphylaxis unrelated to omalizumab use, may be particularly prone to developing anaphylaxis with omalizumab administration. It is critical to note that this observation was unexpected. We are not aware of any prior report identifying risk factors for anaphylaxis against a specific drug or biologic agent, except when the risk factor includes IgE sensitization to a substance that cross reacts with the drug or biologic agent. Patients who have had episodes of anaphylaxis, particularly those in whom a causative agent can be identified (eg, with food or bee venom), are known to have a higher risk of recurrent episodes of anaphylaxis,3González-Pérez A. Aponte Z. Vidaurre C.F. Rodriguez L.A. Anaphylaxis epidemiology in patients with and patients without asthma: a United Kingdom database review.J Allergy Clin Immunol. 2010; 125: 1098-1104.e1Abstract Full Text Full Text PDF PubMed Scopus (168) Google Scholar, 4Kemp S.F. Lockey R.F. Wolf B.L. Lieberman P. Anaphylaxis. A review of 266 cases.Arch Intern Med. 1995; 155: 1749-1754Crossref PubMed Scopus (264) Google Scholar, 5Mullins R.J. Anaphylaxis: risk factors for recurrence.Clin Exp Allergy. 2003; 33: 1033-1040Crossref PubMed Scopus (203) Google Scholar but the mechanism by which prior anaphylaxis unrelated to omalizumab results in omalizumab-associated anaphylaxis is perplexing, especially because most omalizumab-associated anaphylactic events do not appear to be IgE mediated (eg, no IgE antiomalizumab antibodies have been detected in omalizumab-associated anaphylaxis in the limited number of patients analyzed).1Lieberman P.L. Umetsu D.T. Carrigan G.J. Rahmaoui A. Anaphylactic reactions associated with omalizumab administration: analysis of a case-control study.J Allergy Clin Immunol. 2016; 138: 913-915.e2Abstract Full Text Full Text PDF PubMed Scopus (36) Google Scholar An increased knowledge of omalizumab-associated anaphylaxis may add perspective to anaphylaxis associated with 2 other biologics that have recently been approved by the US Food and Drug Administration for treatment of severe asthma (mepolizumab and reslizumab).6Khan D.A. Hypersensitivity and immunologic reactions to biologics: opportunities for the allergist.Ann Allergy Asthma Immunol. 2016; 117: 115-120Abstract Full Text Full Text PDF PubMed Scopus (60) Google Scholar Both of these new biologics have been associated with anaphylaxis7CinqairPrescribing information. Teva Respiratory, LLC, Frazer (PA)2016Google Scholar, 8NucalaPrescribing information. GlaxoSmithKline, Research Triangle Park (NC)2017Google Scholar and it is possible that a small subset of individuals, particularly those with a prior history of anaphylaxis, may have a higher risk of developing anaphylaxis with any biologic prescribed for asthma and/or allergy. The Omalizumab Joint Task Force for managing the risk of anaphylaxis in omalizumab-treated patients previously recommended in 2007 that patients be kept under observation for 2 hours after the first 3 omalizumab injections, and 30 minutes after each subsequent injection, although this could be “modified based on a physician's clinical judgment after discussing risks with the patient.”9Cox L. Platts-Mills T.A. Finegold I. Schwartz L.B. Simons F.E. Wallace D.V. American Academy of Allergy, Asthma & Immunology/American College of Allergy, Asthma and Immunology Joint Task Force Report on omalizumab-associated anaphylaxis.J Allergy Clin Immunol. 2007; 120: 1373-1377Abstract Full Text Full Text PDF PubMed Scopus (227) Google Scholar A reexamination of these recommendations may be warranted based on collective data from adjudicated cases.1Lieberman P.L. Umetsu D.T. Carrigan G.J. Rahmaoui A. Anaphylactic reactions associated with omalizumab administration: analysis of a case-control study.J Allergy Clin Immunol. 2016; 138: 913-915.e2Abstract Full Text Full Text PDF PubMed Scopus (36) Google Scholar Updated recommendations might focus particularly on those patients who have a prior history of anaphylaxis. While we do not suggest changing the recommendations of maintaining vigilance for late-occurring reactions, our recent data suggest that late-occurring reactions (>60 minutes after injection as previously reported2Limb S.L. Starke P.R. Lee C.E. Chowdhury B.A. Delayed onset and protracted progression of anaphylaxis after omalizumab administration in patients with asthma.J Allergy Clin Immunol. 2007; 120: 1378-1381Abstract Full Text Full Text PDF PubMed Scopus (144) Google Scholar) are relatively rare with none of the adjudicated cases occurring beyond 24 hours. Nevertheless, cumulative data indicate that a large fraction of reactions occur within the first 3 doses, suggesting that clinicians might focus their attention on the initial doses of omalizumab, particularly in the first 30 to 60 minutes after the dose, and in a subset of patients, such as those with prior history of anaphylaxis. We anticipate that as more safety data are generated, and if similar patient characteristics are observed in patients with adjudicated episodes of anaphylaxis associated with all biologics used for asthma and allergy, a common set of recommendations for managing the risk of anaphylaxis might be developed for all biologics used for asthma and allergy. As the number and amount of biologics used for the treatment of asthma grow, understanding the risks of hypersensitivity and anaphylaxis associated with biologics is critical for responsible and safe use. Omalizumab, the most prescribed biologic for the treatment of asthma with over 14 years of worldwide postmarketing safety experience, has been shown to be safe with an appropriate risk-benefit profile and a small risk for anaphylaxis (0.1% to 0.2%), particularly in a subset of patients with a prior history of anaphylaxis. This information is valuable to clinicians, who must inform patients of the potential benefits and potential risks of treatment. We thank Dr Abdelkader Rahmaoui of Genentech, Inc, for his help in analyzing data for this project. Table E1Clinical signs and symptoms experienced during the anaphylactic eventSymptomAnaphylaxis cases, n (%)n = 96Cutaneous/angioedema, respiratory66 (69)Cutaneous/angioedema, respiratory, gastrointestinal12 (13)Cutaneous/angioedema, respiratory, cardiovascular8 (8)Cutaneous/angioedema, cardiovascular3 (3)Respiratory, cardiovascular3 (3)Cutaneous/angioedema, respiratory, gastrointestinal, cardiovascular1 (1)Respiratory, gastrointestinal, cardiovascular1 (1)Cutaneous/angioedema, gastrointestinal1 (1)Cardiovascular1 (1) Open table in a new tab Table E2Total omalizumab doses administered at time of anaphylactic eventNo. of dosesAnaphylaxis cases, n (%)n = 68∗Data missing for 28 patients.135 (51)212 (18)32 (3)4-2010 (15)21-405 (7)41-602 (3)>602 (3)∗ Data missing for 28 patients. Open table in a new tab Table E3Time to onset of event after omalizumab dosingTime to onsetAnaphylaxis cases, n (%)n = 81∗Data missing for 15 patients.<30 min35 (43)30-60 min17 (21)>60-90 min4 (5)>90-120 min5 (6)>2-6 h11 (14)>6-12 h3 (4)>12-24 h6 (7)>24 h0∗ Data missing for 15 patients. Open table in a new tab