American Academy of Allergy, Asthma & Immunology/American College of Allergy, Asthma and Immunology Joint Task Force Report on omalizumab-associated anaphylaxis
2007; Elsevier BV; Volume: 120; Issue: 6 Linguagem: Inglês
10.1016/j.jaci.2007.09.032
ISSN1097-6825
AutoresLinda Cox, Thomas A.E. Platts‐Mills, Ira Finegold, Lawrence B. Schwartz, F. Estelle R. Simons, Dana Wallace,
Tópico(s)Allergic Rhinitis and Sensitization
ResumoThe American Academy of Allergy, Asthma & Immunology and the American College of Allergy, Asthma and Immunology Executive Committees formed the Omalizumab Joint Task Force with the purpose of reviewing the Genentech Xolair (omalizumab) clinical trials and postmarketing surveillance data on anaphylaxis and anaphylactoid reactions. Using the definition of anaphylaxis proposed at a 2005 multidisciplinary symposia, the Omalizumab Joint Task Force concluded that 35 patients had 41 episodes of anaphylaxis associated with Xolair (omalizumab) administration between June 1, 2003, and December 31, 2005. With 39,510 patients receiving Xolair (omalizumab) during the same period of time, this would correspond to an anaphylaxis-reporting rate of 0.09% of patients. Of those 36 events for which the time of reaction was known, 22 (61%) reactions occurred in the first 2 hours after one of the first 3 doses. Five (14%) of the events after the fourth or later doses occurred within 30 minutes. Considering the timing of these 36 events, an observation period of 2 hours for the first 3 injections and 30 minutes for subsequent injections would have captured 75% of the anaphylactic reactions. The OJTF report provides recommendations for physicians who prescribe Xolair (omalizumab) on (1) the suggested wait periods after administration and (2) patient education regarding anaphylaxis. The American Academy of Allergy, Asthma & Immunology and the American College of Allergy, Asthma and Immunology Executive Committees formed the Omalizumab Joint Task Force with the purpose of reviewing the Genentech Xolair (omalizumab) clinical trials and postmarketing surveillance data on anaphylaxis and anaphylactoid reactions. Using the definition of anaphylaxis proposed at a 2005 multidisciplinary symposia, the Omalizumab Joint Task Force concluded that 35 patients had 41 episodes of anaphylaxis associated with Xolair (omalizumab) administration between June 1, 2003, and December 31, 2005. With 39,510 patients receiving Xolair (omalizumab) during the same period of time, this would correspond to an anaphylaxis-reporting rate of 0.09% of patients. Of those 36 events for which the time of reaction was known, 22 (61%) reactions occurred in the first 2 hours after one of the first 3 doses. Five (14%) of the events after the fourth or later doses occurred within 30 minutes. Considering the timing of these 36 events, an observation period of 2 hours for the first 3 injections and 30 minutes for subsequent injections would have captured 75% of the anaphylactic reactions. The OJTF report provides recommendations for physicians who prescribe Xolair (omalizumab) on (1) the suggested wait periods after administration and (2) patient education regarding anaphylaxis. At the 2007 American Academy of Allergy, Asthma and Immunology (AAAAI) Annual Meeting in San Diego, California, the AAAAI and American College of Allergy, Asthma and Immunology (ACAAI) Executive Committees formed the Omalizumab Joint Task Force (OJTF) with the purpose of reviewing the Genentech Xolair (omalizumab) clinical trials and postmarketing surveillance data on anaphylaxis and anaphylactoid reactions. The OJTF reviewed the data and prepared a report that included recommendations for physicians who prescribe Xolair (omalizumab). The OJTF gratefully acknowledges the AAAAI Board of Directors and the ACAAI Board of Regents for their review and support of this document. 1.Informed consent should be obtained from the patient after discussing the risks, benefits, and alternatives to Xolair (omalizumab).2.The patient should be educated regarding the signs, symptoms, and treatment of anaphylaxis (Table I).1The diagnosis and management of anaphylaxis: an updated practice parameter.J Allergy Clin Immunol. 2005; 115: S483-S523Abstract Full Text Full Text PDF PubMed Scopus (543) Google Scholar, 2Simons F.E. Anaphylaxis, killer allergy: long-term management in the community.J Allergy Clin Immunol. 2006; 117: 367-377Abstract Full Text Full Text PDF PubMed Scopus (192) Google ScholarTable IAnaphylaxis education sheetTreatment of anaphylaxis in the physician's office1The diagnosis and management of anaphylaxis: an updated practice parameter.J Allergy Clin Immunol. 2005; 115: S483-S523Abstract Full Text Full Text PDF PubMed Scopus (543) Google ScholarTreatment of anaphylaxis in the community2Simons F.E. Anaphylaxis, killer allergy: long-term management in the community.J Allergy Clin Immunol. 2006; 117: 367-377Abstract Full Text Full Text PDF PubMed Scopus (192) Google ScholarImmediate measuresPatient self-management after leaving the physician's officeAssess airway breathing, circulation, and orientationInformation sheet on anaphylaxis with specific information on Xolair (omalizumab)Inject epinephrine, 0.3 mg intramuscularly, in the vastus lateralis (lateral thigh)Epinephrine autoinjector (EpiPen duopak or Twinject)Activate emergency medical services (call 911 or local rescue squad)Anaphylaxis Emergency Action Plan (downloadable from www.AAAAI.org)Place patient in recumbent position and elevate the lower extremities, as toleratedAnaphylaxis wallet card (available from www.AAAAI.org at no charge to members and minimal charge for nonmembers)Establish and maintain airwayMedical identification jewelry tag (eg, MedicAlert bracelet)Administer oxygenEstablish an intravenous line for venous access and fluid replacement; keep open with normal salineConsider administration of nebulized albuterol, 2.5-5 mg in 3 mL of saline; repeat as necessaryConsider administration of ancillary medications, such as H1 antihistamine or a systemic corticosteroid Open table in a new tab 3.Patients should be prescribed and educated on the proper use of the epinephrine autoinjector and advised to carry this before Xolair (omalizumab) administration and for the next 24 hours after Xolair (omalizumab) administration.4.An assessment of the patient's current health status should be made before each injection to determine whether there were any recent health changes that might require withholding treatment. This assessment should include vital signs and some measure of lung function (eg, peak expiratory flow or FEV1).5.The OJTF recommends that patients be kept under observation for 30 minutes after each injection. This time should be extended for 2 hours for the first 3 injections based on the data reviewed by the OJTF, as well as suggested in the 2007 National Heart, Lung, and Blood Institute Expert Panel Report 3 "Guidelines for the diagnosis and management of asthma."3National Heart, Lung, and Blood Institute National Asthma Education and Prevention Program Expert Panel Report 3: guidelines for the diagnosis and management of asthma. National Heart, Lung, and Blood Institute, Bethesda (MD)2007Google Scholar However, this could be modified based on a physician's clinical judgment after discussing risks with the patient. Recombinant chimeric or fully humanized mAbs are increasingly part of medical treatment not only in chronic inflammatory and malignant disease but also in allergic disease. Hypersensitivity reactions to biologic agents, including anaphylaxis, have been well described.4Klastersky J. Adverse effects of the humanized antibodies used as cancer therapeutics.Curr Opin Oncol. 2006; 18: 316-320Crossref PubMed Scopus (72) Google Scholar, 5Baudouin V. Crusiaux A. Haddad E. Schandene L. Goldman M. Loirat C. et al.Anaphylactic shock caused by immunoglobulin E sensitization after retreatment with the chimeric anti-interleukin-2 receptor monoclonal antibody basiliximab.Transplantation. 2003; 76: 459-463Crossref PubMed Scopus (81) Google Scholar, 6Cheifetz A. Mayer L. Monoclonal antibodies, immunogenicity, and associated infusion reactions.Mt Sinai J Med. 2005; 72: 250-256PubMed Google Scholar Anaphylaxis has been reported with several different mAbs, including omalizumab. However, the prevalence is low (ie, ≤0.2%) for Xolair (omalizumab).7Genentech, Inc. Xolair (omalizumab) [product insert]. South San Francisco; 2007.Google Scholar Such reactions, in general, are least to most common with human (100% human), humanized (≥90% human), chimeric (75% human), and mouse (0% human) mAbs. They reportedly occur acutely (<4 hours) or in a delayed manner (up to 14 days) after an infusion6Cheifetz A. Mayer L. Monoclonal antibodies, immunogenicity, and associated infusion reactions.Mt Sinai J Med. 2005; 72: 250-256PubMed Google Scholar, 8Cheifetz A. Smedley M. Martin S. Reiter M. Leone G. Mayer L. et al.The incidence and management of infusion reactions to infliximab: a large center experience.Am J Gastroenterol. 2003; 98: 1315-1324Crossref PubMed Scopus (473) Google Scholar and can occur with the first or subsequent infusions.5Baudouin V. Crusiaux A. Haddad E. Schandene L. Goldman M. Loirat C. et al.Anaphylactic shock caused by immunoglobulin E sensitization after retreatment with the chimeric anti-interleukin-2 receptor monoclonal antibody basiliximab.Transplantation. 2003; 76: 459-463Crossref PubMed Scopus (81) Google Scholar In some cases IgE against an idiotypic, allotypic, or murine portion of the mAb has been identified by means of skin testing9Leonard P.A. Woodside K.J. Gugliuzza K.K. Sur S. Daller J.A. Safe administration of a humanized murine antibody after anaphylaxis to a chimeric murine antibody.Transplantation. 2002; 74: 1697-1700Crossref PubMed Scopus (31) Google Scholar or in vitro immunoassays, although typically one must wait for mAb levels in the circulation to diminish before such tests are performed. In other cases IgG-mediated hypersensitivity might be involved. When IgG anti-mAb is made against the biologic agent, the potency of the mAb can be diminished. Immune complexes formed between the mAb and the target antigen or spontaneous aggregates of the mAb preparation also could be involved. In one study of 14 infliximab infusion reactions, neither an increase in serum tryptase levels nor IgE levels against infliximab were detected. However, future reactions were avoided by decreasing the infusion rate and, in some cases, pretreating with antihistamines and glucocorticosteroids.8Cheifetz A. Smedley M. Martin S. Reiter M. Leone G. Mayer L. et al.The incidence and management of infusion reactions to infliximab: a large center experience.Am J Gastroenterol. 2003; 98: 1315-1324Crossref PubMed Scopus (473) Google Scholar Coadministration of immunosuppressive drugs (eg, in transplant recipients or in patients with cancer) is thought to diminish production of immune responses against the biologic agent. Xolair (omalizumab) is a humanized mAb that forms small immune complexes with target IgE. It lacks complement fixing activity but does bind to Fcγ receptors. In the case of omalizumab, the molecule is so extensively humanized that antibodies to the remaining mouse epitopes are unlikely but merit further study. Evidence has been presented that anaphylactic reactions related to another mAb, cetuximab, which is chimeric, occur in patients who have pre-existing IgE antibodies to the oligosaccharide galactose-α-1,3-galactose. This sugar is an important posttranslational modification on cetuximab. Xolair (omalizumab) is grown in a Chinese hamster ovary cell line that does not express the enzyme α-1,3-galactosyl transferase, and thus this mAb cannot contain galactose-α-1,3-galactose. However, mAbs produced in Chinese hamster ovary cell lines are glycosylated in the Golgi apparatus, and that glycosylation could theoretically be a target for pre-existing IgE antibody responses. Studies to exclude that possibility are currently being planned by Genentech. The excipients (sucrose, L-histidine hydrochloride monohydrate, L-histidine, and polysorbate20) in Xolair (omalizumab) are generally considered safe, but reactions to these are a remote possibility. Polysorbate, an additive used to promote the rapid solubilization of pharmaceuticals in aqueous solutions,10Kozutsumi D. Tsunematsu M. Yamaji T. Murakami R. Yokoyama M. Kino K. PS80 interferes with the antiallergic effect of Cry-consensus peptide, a novel recombinant peptide for immunotherapy of Japanese cedar pollinosis, at very low concentration through modulation of Th1/Th2 balance.Immunology. 2006; 118: 392-401Crossref PubMed Scopus (6) Google Scholar has been reported to cause hypersensitivity reactions.11Steele R.H. Limaye S. Cleland B. Chow J. Suranyi M.G. Hypersensitivity reactions to the polysorbate contained in recombinant erythropoietin and darbepoietin.Nephrology (Carlton). 2005; 10: 317-320Crossref PubMed Scopus (75) Google Scholar, 12Price K.S. Hamilton R.G. Anaphylactoid reactions in two patients after omalizumab administration after successful long-term therapy.Allergy Asthma Proc. 2007; 28: 313-319Crossref PubMed Scopus (118) Google Scholar An in vitro and in vivo immunologic evaluation of 2 patients who experienced anaphylaxis after 1 year of omalizumab treatment concluded that the likely cause was the excipient polysorbate.12Price K.S. Hamilton R.G. Anaphylactoid reactions in two patients after omalizumab administration after successful long-term therapy.Allergy Asthma Proc. 2007; 28: 313-319Crossref PubMed Scopus (118) Google Scholar Priorities should include the identification of the mechanism of these reactions and, if possible, the development of a screening test to identify patients at risk. This will require studies of serum samples from a series of patients who have had reactions. Allergy-immunology specialists who administer Xolair (omalizumab) in their offices or clinics and identify patients with anaphylaxis to Xolair (omalizumab) are in a unique position to provide detailed information about these reactions and to help their colleagues learn more about these rare events. The recently revised Xolair (omalizumab) product information sheet describes anaphylaxis-like reactions that occurred in up to 0.2% of subjects who received this medication, primarily for treatment of asthma.7Genentech, Inc. Xolair (omalizumab) [product insert]. South San Francisco; 2007.Google Scholar Possible mechanisms worth considering include antiallotypic or anti-idiotypic antibodies (IgE or IgG) against this reagent that were either pre-existing before drug administration or had developed after initial exposures or a response to the aggregated preparations of Xolair (omalizumab). Another possible mechanism is that an unrelated event happened to occur near the time of Xolair (omalizumab) administration (eg, accidental food allergen ingestion). However, there are insufficient laboratory data at present to ascertain which, if any, of these explanations relate to the Xolair (omalizumab)–associated events noted below. Risk assessment in individuals with anaphylaxis is potentially complex, even when the antigen has been identified and the specific effector mechanism through which it produces anaphylaxis is known. It is even more complex when the specific antigen has not yet been identified and when the mechanism is unknown.13Castells M. Desensitization for drug allergy.Curr Opin Allergy Clin Immunol. 2006; 6: 476-481Crossref PubMed Scopus (43) Google Scholar The OJTF reviewed a composite report provided by pharmaceutical firms that manufacture and market Xolair (omalizumab), Genentech and Novartis, dated May 3, 2006, that included the pivotal Xolair (omalizumab) clinical trials, as well as the postmarketing reports filed with the Food and Drug Administration between June 1, 2003, and December 31, 2005. Also reviewed was the information provided in the revised Xolair (omalizumab) package insert that included postmarketing reports from June 2003 until December of 2006. The OJTF members concentrated their review on the postmarketing data and combined the clearly anaphylactic cases with those with less severe reactions into one group, hereafter referred to as "anaphylaxis." During this period there were 46 cases of anaphylaxis reported. In addition, there were 55 potential anaphylactic events based on composite symptoms that were reported as being temporally associated with Xolair (omalizumab). There were a total of 101 patients and 106 events because a few patients had more than 1 event. The composite report included the summary of an independent expert hired by Genentech and Novartis to review the postmarketing surveillance data. Using a consensus panel's "emerging definition of anaphylaxis,"14Sampson H.A. Munoz-Furlong A. Campbell R.L. Adkinson Jr., N.F. Bock S.A. Branum A. et al.Second symposium on the definition and management of anaphylaxis: summary report—Second National Institute of Allergy and Infectious Disease/Food Allergy and Anaphylaxis Network symposium.J Allergy Clin Immunol. 2006; 117: 391-397Abstract Full Text Full Text PDF PubMed Scopus (1764) Google Scholar the reviewer concluded that 10 of the 42 cases of reported anaphylaxis and 8 of the 55 potential anaphylactic events fulfilled the stated definition of anaphylaxis, for a total of 18 cases. The revised product information sheet reported that at least 0.2% of the 57,300 patients who received Xolair (omalizumab) between June 2003 and December 2006 experienced anaphylaxis, but it did not specify the criteria used to define anaphylaxis. Using the definition of anaphylaxis proposed at the 2005 multidisciplinary symposia cosponsored by the National Institute of Allergy and Infectious Diseases and the Food Allergy and Anaphylaxis Network,14Sampson H.A. Munoz-Furlong A. Campbell R.L. Adkinson Jr., N.F. Bock S.A. Branum A. et al.Second symposium on the definition and management of anaphylaxis: summary report—Second National Institute of Allergy and Infectious Disease/Food Allergy and Anaphylaxis Network symposium.J Allergy Clin Immunol. 2006; 117: 391-397Abstract Full Text Full Text PDF PubMed Scopus (1764) Google Scholar the OJTF included all cases reported that included presentation of symptoms and findings that a clinician might reasonably consider to be anaphylaxis. Of the original 42 reported patients, the OJTF concluded that 27 patients and a total of 33 events might reasonably be categorized as anaphylaxis. Combining these 27 patients with the 8 of the 55 patients with potential anaphylaxis gave a total of 35 patients with 41 episodes of anaphylaxis associated with Xolair (omalizumab) administration. With 39,510 patients receiving Xolair (omalizumab) during the same period of time, this would correspond to an anaphylaxis-reporting rate of 0.09% of patients. All patients responded to treatment, and there were no fatalities or respiratory failures requiring intubation. A summary report was prepared with recommendations based on analysis of the timing and character of the 41 cases that occurred in the time period between June 1, 2003, and December 31, 2005. After the preparation of a summary report, the OJTF was provided with additional case reports from Genentech and Novartis dating from January 1, 2006, through December 2006. These additional reported events were from various sources, including patients and individuals who were not present at the time of the event and were often reported some time after the event. Confounding variables, incomplete information, predominant subjective symptoms, and a lack of objective medical observations prevented an accurate assessment of the number of diagnosable anaphylactic events. The pattern of timing and severity was similar to the cases reviewed in the summary report. The incidence of adverse events was about 0.2%, but because of the paucity of data, we were unable to judge which cases were truly anaphylaxis. There were no fatalities in any of the case reports dating from the pivotal trials to December of 2006. It was thus the OJTF's decision not to include these reports in the final tabulation. The OJTF analyzed the timing of the 41 (33 + 8) anaphylactic events (Table II). The timing of 5 events was unknown. Of those 36 events for which the time of reaction was known, 22 (61%) reactions occurred in the first 2 hours after one of the first 3 doses. Five (14%) of the events after the fourth or later doses occurred within 30 minutes. Considering the timing of these 36 events, an observation period of 2 hours for the first 3 injections and 30 minutes for subsequent injections would have captured 75% of the anaphylactic reactions. Advising the patient to have an epinephrine autoinjector will, hopefully, address reactions that occur outside the recommended observation period.Table IISummary of timing of Xolair (omalizumab) adverse reactionsTiming of the reactionFirst-third Xolair (omalizumab) dose (no. of events)Fourth or later Xolair (omalizumab) dose (no. of events)Total 12 h303Unknown325Total32941 Open table in a new tab When onset of reaction was noted to be longer than 2 hours, details were usually lacking, and "a few hours later" was often the only information available. The character and severity of these reactions included tongue swelling in a patient taking a β-blocker (emergency department treatment), "lingual angioedema" (no details provided), increased asthma symptoms and urticaria (resolved with outpatient treatment) and shortness of breath, watery itchy eyes, and a sensation of throat closing (emergency department treatment). Based on the data summarized above, the OJTF concluded that Xolair (omalizumab) should only be administered by a physician or other licensed health care provider who has been trained to recognize and treat anaphylaxis and who has available appropriate medications, equipment, and staff to respond to anaphylaxis.3National Heart, Lung, and Blood Institute National Asthma Education and Prevention Program Expert Panel Report 3: guidelines for the diagnosis and management of asthma. National Heart, Lung, and Blood Institute, Bethesda (MD)2007Google Scholar It would not be appropriate to administer Xolair (omalizumab) at home or in a facility that did not have appropriate staff and equipment to treat anaphylaxis. Direct observation for 2 hours after the first 3 Xolair (omalizumab) treatments, as suggested in the National Heart, Lung, and Blood Institute Expert Panel Report 3 asthma guidelines,1The diagnosis and management of anaphylaxis: an updated practice parameter.J Allergy Clin Immunol. 2005; 115: S483-S523Abstract Full Text Full Text PDF PubMed Scopus (543) Google Scholar and 30 minutes thereafter would seem to provide adequate periods of observation. These observation recommendations could be modified based on a physician's clinical judgment after the risks were discussed with the patient.
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