Volume 120, Issue 6 , Pages 1378-1381, December 2007
Delayed onset and protracted progression of anaphylaxis after omalizumab administration in patients with asthma
Article Outline
Background
Risk of anaphylaxis is included in the prescribing information for omalizumab, but the nature of these reactions merits further elaboration.
Objective
To describe cases of anaphylaxis associated with omalizumab administration in patients with asthma.
Methods
We reviewed spontaneous postmarketing adverse event reports submitted to the US Food and Drug Administration's Adverse Event Reporting System database and to the manufacturers of omalizumab and cases published in the literature through December 2006. Diagnostic criteria for anaphylaxis outlined by the National Institute of Allergy and Infectious Diseases and the Food Allergy and Anaphylaxis Network were used to screen cases.
Results
One-hundred twenty-four cases of anaphylaxis associated with omalizumab administration in patients with asthma were identified. Many cases had a delayed onset of symptoms beyond 2 hours after dose administration. Many cases were also characterized by a protracted progression, with individual signs and symptoms of anaphylaxis staggered over hours. Review of the case reports did not reveal any predictive risk factors for the delayed onset or protracted progression of anaphylaxis.
Conclusion
Omalizumab-induced anaphylaxis may be characterized by a delayed onset and a protracted progression of symptoms.
Clinical implications
The unusual timing of anaphylaxis in these cases challenges our understanding of anaphylaxis. A delayed onset of symptoms and protracted progression of anaphylaxis should be taken into account when administering omalizumab.
Key words: Anaphylaxis, omalizumab
Abbreviations used: NIAID, National Institutes of Allergy and Infectious Disease, FAAN, Food Allergy and Anaphylaxis Network
Despite attempts to elucidate immunologic mechanisms and markers, anaphylaxis remains a clinical diagnosis. As new protein-based drug therapies are introduced into clinical practice, health care providers may expect to see an increase in the frequency of anaphylaxis with these therapies as well as a range of clinical presentations. In the case of omalizumab, the prescribing information includes a recent boxed warning1 regarding the risk of anaphylaxis, but omalizumab-induced anaphylaxis has not been previously well characterized in the literature. In this case series, we summarize the characteristics of 124 cases of anaphylaxis after omalizumab administration and describe an unusual feature of some of these cases in which the onset of anaphylaxis was delayed in onset and protracted in course. These cases served as the basis for recent changes to the prescribing information including the addition of a Boxed Warning, a Medication Guide with additional information regarding the risk of anaphylaxis, and the issuance of a Health Care Provider sheet on the US Food and Drug Administration Web site.2
Methods
We reviewed spontaneous adverse event reports submitted to the US Food and Drug Administration's Adverse Event Reporting System database and to the manufacturers of omalizumab from June 2003 to December 2006, as well as published cases in the literature.3, 4, 5 These data were voluntarily submitted to Adverse Event Reporting System, and no additional information was available. The estimated exposure to omalizumab over this period was about 57,300 patients. By using diagnostic criteria for anaphylaxis outlined by the 2006 Symposium on the Definition and Management of Anaphylaxis sponsored by the National Institute of Allergy and Infectious Disease/Food Allergy and Anaphylaxis Network,6 we identified 124 cases of anaphylaxis and categorized these cases by time to onset and other clinical features. Patients were required to have involvement of the skin, mucosal tissue, or both, and at least 1 of the following: (1) respiratory compromise or (2) a decrease in blood pressure or associated symptoms of end-organ dysfunction, and a temporal relationship to omalizumab administration with no other identifiable causes. Patients with isolated involvement of 1 organ system, such as hives or bronchospasm, were excluded. Cases with other probable allergen exposure as cause for anaphylaxis, such as peanut exposure in a patient with peanut allergy, were also excluded.
Results
We identified 124 cases of anaphylaxis to omalizumab (Table I). Eighty-three percent (101 of 121 cases with sex reported) of the patients were female, and the mean age was 43 years (range, 9-78 years). Thirty-nine percent (n = 48) of the cases were first-dose reactions. Approximately ⅓ (n = 44) occurred after the third dose or higher; in some of these cases, patients had been receiving omalizumab therapy for a year or more before the anaphylactic reaction. As reported, 89% (n = 110) displayed respiratory compromise, 14% (n = 17) developed hypotension or syncope, and 19% (n = 15) required hospitalization. No patients were intubated, although 1 patient was given ventilatory support via biphasic positive airway pressure.
Table I. Characteristics of 124 patients with asthma with anaphylaxis after omalizumab administration
| Characteristic | No. (%) |
|---|---|
| All anaphylaxis adverse events | 124 (100) |
| Pulmonary involvement | 110 (89) |
| Sex | |
 Female | 101 (82) |
| Male | 20 (16) |
| Unknown | 3 (2) |
| Hypotension or syncope | 17 (14) |
| Hospitalization | 19 (15) |
| Previous history of anaphylaxis | 30 (24) |
| Dose number | |
| First | 48 (39) |
| Second | 23 (19) |
| Third | 12 (10) |
| Greater than third | 32 (26) |
| Time to onset | |
| <30 min | 43 (35) |
| 30-60 min | 20 (26) |
| >60-90 min | 3 (2) |
| >90-120 min | 8 (6) |
| 2 to 6 h | 6 (5) |
| 6 to 12 h | 17 (14) |
| 12 to 24 h | 10 (8) |
| >24 h up to 4 d | 5 (5) |
| Unknown | 11 (9) |
| Rechallenge | |
| Patients rechallenged | 23 (19) |
| Patients rechallenged with recurrence of anaphylaxis | 18 (15) |
Time-to-onset of anaphylaxis varied widely, from minutes to days (Table I). Approximately 1/3 of cases (n = 43) occurred within 30 minutes of dose administration. Another 1/3 occurred from 30 minutes to 6 hours. The remainder (n = 33) presented more than 6 hours after dose administration, with 5% of cases (n = 6) exceeding 24 hours. Two of the 6 patients who had onset of anaphylaxis more than 24 hours after receiving omalizumab were rechallenged at later time points; both patients were reported to have positive drug rechallenges,2 although details of these challenges were not included in the case reports. Seven patients who were on their fourth dose or higher had a delay in onset of symptoms of 2 hours or more from time of injection.
In addition, 8% of patients (n = 10) experienced a protracted progression of symptoms. The timing and pattern of symptoms did not correspond to a biphasic pattern observed in other allergic responses. Several patients were reported to have itching or flushing, followed by bronchospasm minutes to hours later, then other manifestations such as generalized rash, angioedema, tachycardia, hypotension, or syncope minutes to hours beyond that. For example, a 54-year-old man experienced pruritus and ocular burning 1 hour after his first dose of omalizumab. Later that evening he developed shortness of breath and an asthma exacerbation. He developed angioedema the next day. He was treated with diphenhydramine and corticosteroids with resolution of his symptoms. Of the 33 cases with an onset of symptoms of greater than 6 hours, 4 had a protracted progression of symptoms. In contrast, other patients experienced a rapid progression of symptoms more typical of classic anaphylaxis. For example, a 44-year-old woman developed generalized pruritus, shortness of breath, wheezing, lightheadedness, and a drop in systolic blood pressure from 150 to 110 mmHg within 30 minutes of receiving a second injection of omalizumab. These symptoms promptly responded to epinephrine, bronchodilators, and diphenhydramine, and the patient was discharged to home from the clinic. Several cases illustrating the range of omalizumab-induced anaphylactic reactions are presented in more detail in this article's Online Repository at www.jacionline.org, as well as in previously published cases.3, 4, 5
The majority of patients appeared to respond readily to epinephrine once anaphylaxis was recognized. However, several patients required multiple doses of epinephrine, bronchodilators, and antihistamines to control symptoms. Review of the available demographic data, comorbid conditions, and other elements of medical history such as concomitant medications did not reveal any predictive factors for the delayed onset or protracted presentation of anaphylaxis. Twenty-four percent (n = 30) of patients were reported to have a history of anaphylaxis. The timing of symptoms also did not clearly correlate with the severity of the reaction, as indicated by requirement for hospitalization or multiple doses of epinephrine.
Discussion
Anaphylaxis is commonly considered to be an immediate systemic response to an agent, with signs and symptoms occurring simultaneously or in rapid sequence. In certain situations, a biphasic response may be observed, with a second wave of symptoms presenting generally within 8 hours of the initial event. These 124 cases of omalizumab-induced anaphylaxis challenge the typical model of anaphylaxis and are noteworthy for cases with delayed onset and protracted progression of symptoms.
Delay in onset of anaphylaxis has been previously reported in the literature for various allergenic triggers, such as foods7, 8, 9 and insect venom10 and for cases of food-dependent exercise-induced anaphylaxis.11 The literature on delayed drug-induced anaphylaxis is more limited. The most common example is allergen immunotherapy.12, 13 Rare instances of delayed-onset anaphylaxis have been reported for β-lactams14 and for intramuscular L-asparaginase.15 More recently, delayed anaphylaxis of as long as 24 hours after drug administration has been reported for several other mAb therapies, including infliximab,16 trastuzumab,17 daclizumab,18 basiliximab,19 and gemtuzumab ozogamicin.20 Most of these reports are presented in the manufacturers' drug product labels, but very few cases have been described in detail in the literature. The pathophysiology remains unclear, although given the range of presentations, multiple mechanisms may be responsible. The pharmacokinetic profiles of these antibody therapies may account partially for the delayed onset of symptoms. For example, omalizumab is administered as a subcutaneous injection and does not reach peak serum concentrations until an average of 7 to 8 days later. Also, omalizumab is supplied as a lyophilized powder that typically takes 15 to 20 minutes to dissolve, forming a viscous solution. Conceivably, incomplete reconstitution may alter absorption and lead to delayed reactions.
The protracted progression of anaphylaxis symptoms is another unusual feature of the omalizumab cases. Several previously published studies have also used the term “protracted anaphylaxis,” but in the sense of refractory or recurrent anaphylaxis.21, 22 These studies are primarily based on cases observed in an emergency department setting, where establishing general criteria for safe outpatient disposition in patients without longitudinal follow-up is a major concern. Although a few of the omalizumab cases were characterized by protracted, recurrent, or multiphasic anaphylaxis requiring repeated doses of epinephrine treatment, the more striking feature in our opinion was the gradual progression or escalation of symptoms staggered over hours. This protracted presentation may complicate the prompt diagnosis and management of anaphylaxis, particularly in a patient population that is atopic and has asthma at baseline. To our knowledge, these cases are the first description in the literature of drug-induced anaphylaxis following this pattern and timing of symptoms.
From these 124 cases, we were unable to identify potential risk factors for a delay in onset or protracted progression of anaphylaxis. The patients were mostly female, but the available drug usage data do not specify sex preference of drug use. Therefore, we do not know whether the female predominance reflects the typical patient profile for this drug or whether female sex is a risk factor for these types of reactions. The lack of any clear risk factors may also be a result of the limitations of spontaneous postmarketing reports, because these data were voluntarily submitted and no additional information was available. The possibility also remains that some of these subjects may have had other allergic exposures that were not recognized or reported. However, given the nature and number of reports from health care professionals, our overall impression of the cases remains the same. As clinical awareness increases and other cases of anaphylaxis are identified, more systematic study of potential risk factors may be possible.
Because postmarketing adverse reactions are reported voluntarily to the US Food and Drug Administration, the actual frequency of patients with delayed onset and protracted progression of omalizumab-induced anaphylaxis may differ from the estimates in this case series. The overall frequency of anaphylaxis calculated on the basis of these 124 spontaneously reported cases and on the manufacturer's estimate of patient exposure to omalizumab from the same period (time of marketing through December 2006) is ∼0.2%. This frequency is higher than that reported in the premarketing clinical trials database submitted for product registration in the United States, where the frequency was 0.1% (n = 3 of 3507 subjects).1 These cases of anaphylaxis were based on investigator ascertainment and judgment in relationship to the study drug and were not based on formal prespecified criteria. Of these 3 cases seen in premarketing clinical trials, 2 were from a pivotal safety study, which was a 6-month, randomized, double-blind, placebo-controlled trial (n = 1261 on omalizumab; n = 638 on placebo). In this trial, there were 5 additional patients reported to develop urticaria concomitant with bronchospasm after omalizumab administration.23 These patients were not reported as having anaphylaxis and are not included in the product label as having anaphylaxis. Of these 5 patients, interestingly, 1 patient, a 37-year-old woman, had a delayed onset of reaction, developing urticaria, flushing, and dyspnea the day after receiving the third dose.
The unusual features of these reactions certainly challenge conventional concepts about anaphylaxis and should be taken into consideration when treating patients with omalizumab. As the armamentarium of biological drug products increases, we expect that these types of anaphylactic reactions may become more commonplace. The clinical management issues that we now confront with omalizumab may set a precedent for diagnosis and treatment of anaphylaxis with similar drugs in the future.
Appendix. Supplementary data
Online Repository.
References
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- . Late-onset anaphylaxis to fermented soybeans: the first confirmation of food-induced, late-onset anaphylaxis by provocation test. Ann Allergy Asthma Immunol. 2005;94:402–406
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- . Delayed food-dependent, exercise-induced anaphylaxis. Allergy Asthma Proc. 2007;28:64–66
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- . Late systemic-allergic reactions to inhalant allergen immunotherapy. J Allergy Clin Immunol. 1988;82:287–290
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Disclosure of potential conflict of interest: The authors are employed by the US Food and Drug Administration.
The views expressed in this article are those of the authors and do not necessarily reflect the views or policies of the US Food and Drug Administration.
PII: S0091-6749(07)01781-2
doi:10.1016/j.jaci.2007.09.022
© 2007 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.
Refers to erratum:
- Correction
Volume 120, Issue 6 , Pages 1378-1381, December 2007
