Incidence of Amiodarone Hypersensitivity in Patients with Previous Allergy to Iodine or Iodinated Contrast Agents

Umashankar Lakshmanadoss, M.D., John Lindsley, Pharm.D., Daryl Glick, B.S., Charles H. Twilley, Pharm.D., M.B.A., John J. Lewin, III, Pharm.D., M.B.A., and Joseph E. Marine, M.D. Study Objective. To determine the incidence and nature of allergic reactions to amiodarone in hospitalized patients with a listed allergy to iodine or iodinated radiocontrast agents. Design. Retrospective medical record review. Setting. Two academic medical centers. Patients. A total of 234 sequential hospitalized patients with a listed iodine and/or iodinated radiocontrast agent allergy who received oral or intravenous amiodarone between January 2006 and December 2010. Measurements and Main Results. Demographic and clinical data, as well as documentation of an allergic reaction to amiodarone, were collected for each patient from electronic medical records. Mean SD age was 69 12 years, and 51% were male. Of the 234 patients, 167 (71%) had a listed previous allergy to iodinated contrast agents, 55 (24%) to iodine, and 12 (5%) to both. Patients received an average inpatient total dose of 2.9 3.2 g of either oral (106 patients [45%]), intravenous (39 patients [17%]), or both oral and intravenous (89 patients [38%]) amiodarone. Only 1 (0.4%) of the 234 patients was identified as having a probable allergic reaction to amiodarone (score of 6 on the Naranjo adverse drug reaction probability scale). One additional patient receiving intravenous amiodarone experienced a rash that was determined to be caused by an antibiotic. All other patients received amiodarone without any identifiable allergic reactions. Conclusion. The incidence of hypersensitivity reaction to amiodarone in hospitalized patients with a listed allergy to iodine or iodinated contrast agents was less than 1%, and all identified reactions were without long-term sequelae. Allergy to iodine and iodinated contrast agents may not be a valid absolute contraindication to amiodarone administration in the inpatient setting. Key Words: iodine allergy, radiocontrast media allergy, amiodarone hypersensitivity, hospitalized patients. (Pharmacotherapy 2012;32(7):618622)

Amiodarone is a class III antiarrhythmic drug that is effective as therapy for both atrial and ventricular arrhythmias. Its primary effect is to block cardiac potassium and sodium channels, and it also exerts antisympathetic action and slows conduction in the atrioventricular node.1, 2

Amiodarone is commonly used in hospitalized patients with atrial fibrillation or life-threatening ventricular arrhythmias. Amiodarone contains 37.3% iodine by weight, and the current package labeling contains a contraindication for use in patients with a known

AMIODARONE HYPERSENSITIVITY IN PATIENTS WITH IODINE ALLERGY Lakshmanadoss et al 619 hypersensitivity to iodine.1 Despite the sometimes ambiguous nature of past iodine reactions, amiodarone is commonly prescribed and administered to hospitalized patients with a listed iodine allergy due to its efficacy and extensive list of indications. Limited published data exist to support or refute the use of amiodarone in patients with a documented iodine allergy (Table 1).35 Therefore, we sought to determine the incidence and nature of allergic reactions to amiodarone after administration to hospitalized patients with a listed allergy to iodine or iodinated radiocontrast agents. We hypothesized that few allergic reactions would be discovered in this population. Methods Study Protocol We retrospectively reviewed the electronic pharmacy databases of the two largest hospitals in the Johns Hopkins Health System (Johns Hopkins Hospital and Johns Hopkins Bayview Medical Center) to identify patients hospitalized between January 1, 2006, and December 31, 2010, with a listed previous allergy to iodine and/or iodinated contrast agents who also received oral or intravenous amiodarone during their hospital stay. The study protocol was approved by the Johns Hopkins University School of Medicine Institutional Review Board. Electronic medical records, including daily progress notes, consultation reports, and disStatistical Analysis Categoric variables are presented as numbers and percentages, and continuous variables are presented as mean SD. All analyses were performed using SAS software, version 9.2 (SAS Institute Inc., Cary, NC). Results A total of 234 patients, mean SD age 69 12 years, 51% male, were identified who met study inclusion criteria (Table 2). Of these patients, 167 (71%) had a recorded previous allergy to iodinated contrast agents, 55 (24%) to iodine, and 12 (5%) to both (Table 3). In 20 patients (8.5%), the recorded reaction was anaphylaxis; 34 patients (14.5%) experienced hives, and 180 patients (77%) had skin rashes or other nonspecified symptoms. Patients received an average inpatient total amiodarone dose of 2.9 3.2 g of oral (106 patients [45%]), intravenous (39 patients [17%]), or both oral and intravenous (89 patients [38%]) amiodarone. Eighty-eight patients (38%) were noted to have previous use of amiodarone that was continued on admission. The primary indication for amiodarone was ventricular arrhythmia in 34 patients (15%) and atrial fibrillation in 200 patients (85%). Two patients (0.9%) developed peripheral eosinophilia during treatment, but they did not have any clinical manifestation of an allergic reaction. Only 1 (0.4%) of the 234 patients was identified as having a probable allergic reaction to amiodarone (score of 6 on the Naranjo adverse charge summaries, were reviewed to obtain demographic and clinical information, and to search for any documentation of an allergic reaction to amiodarone. Baseline information was collected, including age, sex, medical history, indication for amiodarone use, history of autoimmune or allergic disorders, and any available details about the previous reaction to iodine or iodinated contrast agents. Data from the index hospital stay were collected, including principal admission diagnosis, history of previous use of amiodarone, indication for and route of administration of amiodarone, and cumulative dose administered. Medical records were evaluated for evidence of allergic reactions that followed the administration of amiodarone. Evidence of an allergic reaction was analyzed using the Naranjo adverse drug reaction probability scale.6

From the Division of Cardiology (Dr. Marine), Department of Medicine (Drs. Lakshmanadoss and Marine), and Department of Anesthesiology and Critical Care Medicine (Dr. Lewin), Johns Hopkins University School of Medicine, Baltimore, Maryland; the Department of Pharmacy, Johns Hopkins Hospital, Baltimore, Maryland (Drs. Lindsley and Lewin); the University of Maryland School of Pharmacy, Baltimore, Maryland (Mr. Glick); the Department of Pharmacy, Johns Hopkins Bayview Medical Center, Baltimore, Maryland (Dr. Twilley); and the Guthrie Clinic, Sayre, Pennsylvania (Dr. Lakshmanadoss). Dr. Lakshmanadoss and Dr. Lindsley contributed equally as first authors to this work. Presented as an abstract at the American Heart Association Scientific Sessions 2011, Orlando, Florida, November 1216, 2011. For reprints, visit https://caesar.sheridan.com/reprints/ redir.php?pub=10089&acro=PHAR. For questions or comments, contact Joseph E. Marine, M.D., Division of Cardiology, Johns Hopkins Hospital, Carnegie 568, 600 North Wolfe Street, Baltimore, MD 21287; e-mail: jmarine2@ jhmi.edu.

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Table 1. Published Reports of Amiodarone Administration in Seven Patients with Previous Iodine and/or Iodinated Radiocontrast Media Allergy Patient No. 1
3

Listed Allergy Iodine and iodinated contrast media Iodine Iodine Iodinated contrast media Iodinated contrast media Iodinated contrast media Iodinated radiocontrast media Skin rash Skin rash Skin rash

Reaction

Route of Administration Oral Oral Oral and intravenous Oral Oral Oral Oral

Allergic Reaction After Amiodarone Administration No reaction noted No reaction noted No reaction noted No reaction noted No reaction noted No reaction noted Swelling and tingling of lips

23 33 44 54 64 75

Anaphylaxis Near total hypersensitivity reaction with loss of conscious Severe throat swelling Facial urticaria

Table 2. Demographic and Clinical Characteristics of the 234 Study Patients Characteristic Age, mean SD (yrs) Male Coronary artery disease Hypertension Diabetes mellitus Cardiomyopathy Autoimmune disorders Allergy disorders
Data are no. (%) of patients except for age.

Table 3. Index Allergy and Amiodarone Use in the 234 Study Patients Value Listed index allergy Iodine allergy Iodinated contrast media allergy Both iodine and iodinated contrast media allergy Reaction to index allergen Anaphylaxis Hives Skin rash or other reaction Previous use of amiodarone Route of inpatient amiodarone Oral Intravenous Both oral and intravenous Mean total inpatient dose of amiodarone 55 (24) 167 (71) 12 (5) 20 34 180 88 106 39 89 2.9 (8.5) (14.5) (77) (38) (45) (17) (38) 3.2 g

Value 69 12 120 130 165 75 95 10 6 (51) (56) (71) (32) (41) (4) (3)

drug reaction probability scale6). This single case of a probable allergic reaction occurred in a 68year-old woman with a medical history significant for ischemic cardiomyopathy, hypertension, dementia, Charcot-Marie-Tooth disease, and abdominal aortic aneurysm who was admitted to the hospital for multilobar pneumonia and acute kidney injury. She had a listed history of iodine allergy, with the reaction being manifested as a rash. In the setting of sepsis, she developed atrial fibrillation with a rapid ventricular rate, which was treated with intravenous rate-controlling drugs. She continued to have tachycardia and developed hypoxemia requiring noninvasive ventilation and was loaded with intravenous amiodarone. After infusion of approximately 600 mg, the patient developed facial flushing, hives, worsening hypoxia, and tachycardia. Due to her history of iodine allergy, an allergic reaction to amiodarone was suspected to be the cause, and the drug was discontinued. She was treated with intravenous steroids and antihistamines, and her rash improved over the next 30 minutes. Amiodarone allergy was added to the patients medical record, and no rechallenge was undertaken. She recovered fully from the probable allergic reaction and required no further intervention.

Data are no. (%) of patients except for amiodarone dose.

One additional patient developed a diffuse morbiliform rash during his hospitalization during which amiodarone was given. He was 61 years old, with multiple chronic illnesses including valvular heart disease. He presented with atrial fibrillation and rapid ventricular response and was given intravenous amiodarone for 1 day. He had recently received several weeks of treatment with intravenous vancomycin and ceftriaxone for pneumonia. A review of his medical records showed that detection of the rash clearly preceded initiation of amiodarone. A dermatology consultant determined that the rash was most consistent with a reaction to antibiotics. Atrial fibrillation was managed with rate-control agents, and amiodarone was not added as an allergy. Therefore, we did not consider this event to represent a reaction to amiodarone (score of 0 on the Naranjo adverse drug reaction probability scale6).

AMIODARONE HYPERSENSITIVITY IN PATIENTS WITH IODINE ALLERGY Lakshmanadoss et al 621 All other patients received amiodarone without any identifiable allergic reactions. Discussion We retrospectively analyzed a large series of hospitalized patients with a listed allergy to iodine and/or iodinated radiocontrast agents who subsequently received amiodarone, and we found an extremely low incidence of allergic reaction to the drug (1 of 234 patients [0.4%]). The single patient with a probable reaction had no sequelae after cessation of amiodarone and treatment with steroids and antihistamines. Amiodarone is an effective antiarrhythmic drug used for the treatment of atrial and ventricular arrhythmias in hospitalized patients; however, it has been suggested that its use should be avoided in patients with an iodine or iodinated contrast media allergy. Hypersensitivity reactions to iodinated contrast media are seen in 12% of patients.7 Although controversy exists regarding the etiology of allergic reactions to iodine-containing products, most investigators believe that these reactions are nonimmunoglobulin E (IgE) mediated and that elemental iodine alone cannot act as an allergen.79 This view is supported by the observation that iodine is an element that is essential for the synthesis of thyroid hormones and that dietary iodine is ubiquitous in Western countries through consumption of iodized salt.10 Although anaphylactoid and anaphylactic reactions are characterized by similar clinical features, their underlying pathophysiologies differ. Anaphylaxis is an IgE-mediated reaction that is allergen specific. On initial exposure to the allergen, the immune system is sensitized, and allergen-specific IgE is produced. Subsequent exposures to the allergen then trigger mast cell and basophil degranulation, resulting in the release of vasoactive mediators that cause bronchospasm, hypotension, vasodilation, and/or urticaria. On the other hand, anaphylactoid reactions are nonspecific and defined as IgEindependent mast cell and basophil degranulation and, thus, are thought to be a result of direct stimulation of these cells.8 The view that reactions to iodine-containing agents are primarily nonIgE mediated is based on several findings. First, anaphylactoid reactions can occur in patients who have not been exposed previously to iodinated contrast material and, therefore, do not require the sensitization step.7 In addition, when intradermal skin tests were performed on a group of patients who had a previous allergic reaction to a radiocontrast agent, only 4 (4%) of 96 patients had positive tests, indicating that a majority of patients experienced IgE-independent processes.9 Some investigators attribute the anaphylactoid properties of iodinated contrast agents to the hyperosmolarity of the solution compared with blood, rather than to the iodine content of the agent itself.7 It has been proposed that this hyperosmolar solution may act as a direct stimulant to mast cells and basophils, directly causing their degranulation and subsequent release of inflammatory mediators.11 One study evaluated the adverse reaction rates of ionic radiocontrast agents compared with nonionic agents.11 A rate of 68% was found with ionic media as opposed to its nonionic counterparts, which demonstrated a much lower reaction rate of 0.2%. However, some studies do support IgE mediation.12, 13 In one study, blood samples were collected from patients immediately after an allergic reaction to contrast media.12 In vitro analysis of the samples demonstrated significantly greater levels of IgE in patients who had a reaction compared with the control population. Although literature regarding this topic is scarce, there have been reports of single cases and a small series of patients who, after experiencing a reaction to an iodinated contrast agent, were able to tolerate both oral and intravenous amiodarone without any consequences.3, 13 We could identify only one published case report describing a patient who had a previous allergic reaction to iodinated radiocontrast media and subsequently developed a reaction after receiving amiodarone.4 This report described a 55-year-old man with a history of urticaria after coronary angiography who developed atrial fibrillation after coronary artery bypass grafting and was given a loading dose of intravenous amiodarone followed by a 12hour infusion without any reaction. It was not until he was given 400 mg of oral amiodarone that he developed lip swelling and tingling within 1 hour of receiving his first dose. The symptoms resolved spontaneously after intravenous promethazine 12.5 mg, and he had no further sequelae. However, because the patient had previously tolerated intravenous amiodarone 900 mg, the author concluded that the reaction might be unrelated to the amiodarone itself and instead be due to an excipient in the oral formulation. The results seen in these small studies and case reports are consistent with our finding that a past reaction to an iodine-containing agent does not reflect how a patient will tolerate amiodarone.

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PHARMACOTHERAPY Volume 32, Number 7, 2012 review of hospital records, our study was not designed to assess the presence or absence of long-term or delayed reactions to drugs received as inpatients. Finally, our results in inpatients may not be applicable to outpatients, in whom potential allergic reactions to amiodarone cannot be quickly identified and treated. Conclusion We found an extremely low incidence (0.4%) of allergic reactions to amiodarone in hospitalized patients with a recorded allergy to iodine or iodinated contrast agents. Our results suggest that true allergic cross-reactivity between iodine or iodinated contrast agents and amiodarone is rare or nonexistent. Most hospitalized patients with arrhythmias who have a listed iodine or radiocontrast agent allergy may be given amiodarone safely. Iodine allergy may not represent a valid absolute contraindication to amiodarone. Patients with arrhythmias might benefit from a careful reevaluation of all of the evidence for and against the current labeling of amiodarone in light of our findings. References
1. Amiodarone prescribing information. Available from http:// labeling.pfizer.com/showlabeling.aspx?id=93. Accessed August 28, 2011. 2. Vassallo P, Trohman R. Prescibing amiodarone. An evidence based review of clinical indications. JAMA 2007;298:131222. 3. Brouse SD, Phillips SM. Amiodarone use in patients with documented allergy to iodine-containing compounds. Pharmacotherapy 2005;25:42934. 4. Snider M, Boyd M, Carnes CA. Amiodarone use in patients with documented hypersensitivity to intravenous contrast dye. Ann Pharmacother 2008;42:134950. 5. Stafford L. Hypersensitivity reaction to amiodarone in a patient with a previous reaction to an iodinated radiocontrast agent. Ann Pharmacother 2007;41:13104. 6. Naranjo CA, Busto U, Sellers EM, et al. A method for estimating the probability of adverse drug reactions. Clin Pharmacol Ther 1981;30:23945. 7. Maddox TG. Adverse reactions to contrast material: recognition, prevention, and treatment. Am Fam Physician 2002;66:122934. 8. Schabelman E, Witting M. The relationship of radiocontrast, iodine, and seafood allergies: a medical myth exposed. J Emerg Med 2010;39:7017. 9. Trcka J, Schmidt C, Seitz CS, Brocker EB, Gross GE, Trautmann A. Anaphylaxis to iodinated contrast material: nonallergic hypersensitivity or IgE-mediated allergy? Am J Roentgenol 2008;190:66670. 10. Katelaris CH, Smith WB. Iodine allergy label is misleading. Aust Prescr 2009;32:1258. 11. Cochran ST, Bomyea K, Sayre JW. Trends in adverse events after IV administration of contrast media. Am J Roentgenol 2001;176:13858. 12. Laroche D, Aimone-Gastin I, Dubois F, et al. Mechanisms of severe, immediate reactions to iodinated contrast material. Radiology 1998;209:18390. 13. Mita H, Tadokoro K, Akiyama K. Detection of IgE antibody to a radiocontrast medium. Allergy 1998;53:113340.

Based on the literature published to date, we hypothesized that patients with listed iodine or iodinated radiocontrast media allergies would be unlikely to exhibit signs or symptoms of an allergic reaction on administration of amiodarone. We found that most patients with a listed allergy to iodine or radiocontrast media tolerated amiodarone without experiencing any allergic symptoms. The low rate of such reactions in our population (0.4%) suggests that iodine is not the allergen when patients react to iodine-containing agents and that true cross-reactivity between amiodarone and other iodine-containing compounds is rare or nonexistent. Our findings have important clinical implications for the management of hospitalized patients with arrhythmias who have listed allergies to iodine or iodinated contrast media. Iodine and iodinated radiocontrast media allergies are relatively common, and they are probably more common in patients with cardiac arrhythmias, many of whom have been exposed to such agents during cardiac studies. Although we found that the labeling of amiodarone is not always heeded, the explicit contraindication for patients with an iodine allergy may result in many such patients being denied the benefits of the most effective antiarrhythmic agent when experiencing serious or life-threatening arrhythmias. Our results suggest that the benefits of amiodarone may outweigh the risk in most of these patients when amiodarone is given in the hospital setting and a rare potential cross-reaction can be promptly recognized and treated. Our results also suggest that patients with arrhythmias might benefit from reevaluation of all of the evidence for the labeling of amiodarone and this particular contraindication. Our study has several limitations. The retrospective nature of the study made us dependent on contemporaneous documentation by health care providers. Documentation of the nature of past reactions to iodine or iodinated radiocontrast agents in particular was sometimes limited. When entering patient allergies into the electronic medical record, practitioners generally chose from a list of possible options, and allergies that were entered outside the drop-down menu could not be captured in this retrospective review. We had to rely on the allergy list entered in the electronic record and could not independently verify the allergy or reaction. It is possible that a prospective study might capture more subtle amiodarone reactions that were not documented in our study. As a retrospective