Doi:10.1016/j.pediatrneurol.2007.03.010

Clinical Profile of
defined by recent American Academy of Neurology–American Epilepsy Society guidelines, a newer antiepilep-tic drug is one approved by the U.S. Food and Drug Oxcarbazepine-
Administration since 1990.) The oral suspension formula-tion was approved on May 25, 2001. Tablet and suspen- Related Angioneurotic
sion formulations were approved on August 7, 2003, foruse as monotherapy in the treatment of partial seizures in Edema: Case Report
children aged 4-16. Oxcarbazepine, a 10-keto analog ofcarbamazepine, is indicated for use as monotherapy oradjunctive therapy in the treatment of partial seizures in and Review
adults and children (Ն4 years of age in the United Statesand Ն6 years of age in the European Union). Data fromthe manufacturer’s clinical development program indi- James F. Knudsen, PhD, MD*,
cate that oxcarbazepine was well tolerated in children, Charlene M. Flowers, RPh†,
with 10% (57/572) withdrawing from oxcarbazepine Cindy Kortepeter, PharmD†, and
therapy due to adverse events, the most frequent being Yasser Awaad, MD‡
Angioneurotic edema (angioedema and Quincke’s edema) can be a life-threatening event. It is a vascular reactionoccurring in the skin and mucous membranes: essentially, Oxcarbazepine, a carbamazepine analog, was ap-
anaphylaxis of the skin. This asymmetrical, nonpitting proved for use as an antiepileptic agent in the United
edema may affect any part of the body but is usually States in 2000. A search of the United States Food and
confined to the head and neck. Symptoms include facial Drug Administration’s Adverse Event Reporting System
swelling (perioral and periorbital edema), dysphagia, full- identified nine cases of oxcarbazepine-associated angio-
ness in the floor of the mouth, hoarseness, and muffled edema in pediatric patients aged 16 years and younger.
voice Drooling occurs. Angioedema involving the We describe in detail the first U.S. case report, of a
tongue and throat can be fatal due to asphyxia, stridor, 4½-year-old boy who experienced angioedema during
dyspnea, laryngeal edema, and other signs of acute airway treatment with oxcarbazepine. The reporting rate for
obstruction can occur rapidly The mean duration from angioedema was calculated to be 9.8 cases per 1,000,000
the onset of symptoms and presentation to the hospital has pediatric patients. Oxcarbazepine-associated angioedema
been reported in one study of patients exposed to angio- manifested by swelling of the face, eyes, lips, or tongue or
tensin-converting enzyme inhibitors to be 9 hours (range, difficulty swallowing or breathing (or both) is a rare but
1-48 hours) Mortality may range from 25 to 30% and potentially life-threatening reaction for which early rec-
results from rapidly progressive obstruction of the upper ognition and management are vital.
2007 by Elsevier
Inc. All rights reserved.
Angioedema may be hereditary or acquired, with the overwhelming majority of cases induced by various pre- Knudsen JF, Flowers CM, Kortepeter C, Awaad Y. Clinical cipitating factors such as extreme temperature exposure, profile of oxcarbazepine-related angioneurotic edema: case trauma, food sensitivity, and exposure to such diverse report and review. Pediatr Neurol 2007;37:134-137.
drugs as aspirin, indomethacin (and other nonsteroidalanti-inflammatory drugs), penicillin, and angiotensin-con-verting enzyme inhibitors Introduction
The objectives of our study were as follows: 1) to document U.S. reports of angioedema in pediatric patients Oxcarbazepine is a newer aromatic antiepileptic agent, treated with oxcarbazepine, 2) to present an illustrative approved in the United States on January 14, 2000. (As case of angioedema in a pediatric patient, and 3) to present From the *Office of Drug Evaluation I, Division of Neurology Products, and †Office of Surveillance and Epidemiology, Food and Dr. Knudsen, Office of Drug Evaluation I; Division of Neurology Drug Administration, Silver Spring, Maryland, and ‡Pediatric Products; Food and Drug Administration, 10903 New Hampshire Ave., Neurology & Movement Disorders Program, Oakwood Healthcare Building 22 Room 4336, Silver Spring, MD 20993-0002.
E-mail: [email protected] January 29, 2007; accepted March 23, 2007.
2007 by Elsevier Inc. All rights reserved.
doi:10.1016/j.pediatrneurol.2007.03.010 ● 0887-8994/07/$—see front matter a systematic review of the medical literature for reports of angioedema associated with exposure to oxcarbazepine inthe pediatric population and to calculate the U.S. reporting Summary of Cases
rate of angioedema in pediatric patients 16 years of age Our search of the Adverse Event Reporting System database for reports of angioedema identified nine pediat-ric cases associated with oxcarbazepine use, four of which occurred in the United States. Six of the nine reportsdocumented a serious outcome. A best representative case, Patient Data Collection
that of a 4½-year-old boy, will be described in detail.
All cases of angioedema occurred in temporal relation- Through the MedWatch program, the U.S. Food and Drug Adminis- ship to oxcarbazepine therapy, although the time to onset tration compiles and maintains an adverse event reports database for of the angioedema varied considerably. In each case, the drugs and biologic products used by humans. Reports from manufactur- diagnosis of angioedema related to use of the drug was ers associated with their products are required by law, and those fromhealth care professionals and consumers are voluntary. The reports are deemed probable, possible, or not able to be excluded by collected into an electronic database, referred to as the Adverse Event the reporter. The duration from the initiation of drug use to the onset of the event ranged from 30 minutes to 7 months.
We searched the Adverse Event Reporting System for reports of Patient 1 (a 5-year-old boy with a swollen tongue and angioedema in association with oxcarbazepine use from 2000, when the pharynx) had been taking the drug for about 7 months drug was approved in the United States, through November 15, 2006. Weused a broad search strategy to identify any report potentially related to before the adverse event occurred 15 minutes after his last angioedema using the following preferred terms: hypersensitivity, ana- dose, whereas patient 4 (a 4½-year-old with dyspnea, phylaxis, angioedema or other swelling-related terms such as face edema, periorbital edema, and drooling) received only one dose eyelid edema, laryngeal edema, mouth edema, periorbital edema, tongue before he manifested symptoms 30 minutes later. He edema, circumoral edema, and C1 esterase deficiency.
required hospitalization, whereas patient 1 did not.
Patient 2 had rash, angioedema, and fever after expo- Literature Search
sure to oxcarbazepine. Patients 3 and 5-9 reported rash andangioedema only. Patients 1 and 7 mentioned a history of We performed a literature search using MEDLINE, EMBASE, angioedema and intolerance to antiepileptic drugs, respec- TOXLINE, International Pharmaceutical Abstracts (IPA), and the Co- tively. All patients recovered following cessation of ox- chrane Library for the period 1980 through carbazepine and in some instances following treatment November 2006. The following subject heading terms were used in thesearch: oxcarbazepine, angioedema, anaphylaxis, and anaphylactoid reaction. Bibliographies of review articles were searched for additionalinformation.
Representative Case Report
Reporting Rate
A 4½-year-old, 18.5-kg boy from Michigan with diag- noses of hydrocephalus and seizure disorder presented Data for this analysis included a cumulative total of unique patients with acute onset of dyspnea and stridor 30 minutes after aged 0-16 years receiving oxcarbazepine from January 2002 through swallowing his first dose of an oral suspension of oxcar- August 2006. Reporting rate calculations were made on the basis of bazepine. There was an increase in the severity of his domestic case counts divided by projected patient counts, which repre- condition accompanied by facial swelling and drooling sent the total number of unique patients who have filled a prescription ata retail pharmacy in the United States.
over the next 2 hours. His condition led to presentation to With the Adverse Event Reporting System it is not possible to calculate the absolute incidence of a drug-related side effect, because we He had no history of cough, wheezing, sore throat, know neither the actual number of patients who experienced the adverse fever, or other complaints prior to the event. There was no event (numerator) nor the actual number of patients exposed to the drug history of atopy. The patient had not taken any other new and duration of use (denominator). We can, however, estimate theincidence using a reporting rate.
drug or new food products, nor had he been exposed to To approximate the extent of oxcarbazepine use in the pediatric age insect stings, bites, or environmental triggers. He was up group, we obtained an estimate of the total number of individual patients to date on his immunizations. There was no family history in the United States prescribed oxcarbazepine. The Verispan Total Patient Tracker is a national-level projected The patient was afebrile, tachycardic, and tachypneic on audit designed to estimate the total number of unique patients by drugand therapeutic class usage in the retail outpatient setting. The Total admission to the emergency department. The general Patient Tracker derives its data from the Vector One Prescriber Extract examination revealed a boy in moderate distress with database (Medical Marketing Service, Wood Dale, IL), which integrates audible inspiratory stridor. His pharynx was not erythem- prescription activity from a variety of sources, including national retail atous, and his tonsils were not enlarged. The chest x-ray chains. mail order pharmacies, mass merchandisers, and pharmacy findings were negative. The boy’s airway on anteroposte- benefits mangers and their data systems. Vector One compiles more than2 billion prescription claims per year, which represents more than 160 rior lateral neck view showed subglottic narrowing and a million patients tracked across time.
thickened epiglottis. No foreign body was found. The Knudsen et al: Oxcarbazepine and Angioedema patient’s temperature spiked to 38.3°C in the emergency Discussion
department. Blood cultures were performed, showing nogrowth, and a complete blood count showed 22,000/mm3.
We describe the first U.S. reports of angioedema in One dose of ceftriaxone was given intravenously. He was pediatric patients treated with oxcarbazepine. Health care given one racemic epinephrine nebulization without im- practitioners should consider this potentially life-threaten-ing event as being possibly drug-induced. The case report provement. He was given one dose each of dexamethasone described in considerable detail is of a 4½-year-old boy and diphenhydramine, with improvement of his respira- who presented with sudden onset of difficult breathing, tory stridor and less drooling. He was transferred to the stridor, facial swelling, and drooling after swallowing 1 intensive care unit, where he was given dexamethasone mL of oxcarbazepine suspension. It was the only drug the intravenously every 6 hours and l-epinephrine nebuliza- patient used before the onset of the adverse event. The level of evidence, in addition to the temporal correlation The child improved over a period of 2 hours. He had between oxcarbazepine therapy and the development of some stridor, but exhibited no retractions. When his vital the adverse event, included the fact that other alternative signs stabilized, he was transferred out of the intensive causes such as food, insect stings and bites, epiglottis, and care unit. Examination revealed an alert, active, and C1 esterase inhibitor protein deficiency were excluded.
playful child with some mild periorbital puffiness, some The patient had no history of atopy. There was no family hoarseness, and no stridor. The boy continued to receive history of allergic diatheses. Angioedema and rash have dexamethasone intravenously every 6 hours and racemic been reported in the literature in a 27-year-old Indian epinephrine as needed. The boy was subsequently dis- woman following treatment with carbamazepine a charged and the parents were advised to use an epineph- drug structurally related to oxcarbazepine.
rine autoinjector at home and to continue administering Whereas the patient case we described here (patient 4) prednisolone for the next 3 days. The boy’s parents were was characterized by a rapid onset after one dose, another instructed to follow up with his primary care physician in case (patient 1) was not. This 5-year-old boy had been 3-5 days, and with his neurologist in 1-2 weeks for taking oxcarbazepine for 7 months before the abrupt and potentially life-threatening onset of symptoms of angio-edema ensued 15 minutes after dosing. These cases revealthat although adverse events may occur after the first dose, Literature Review
they can occur at any time during treatment with the drug.
It is unclear why some patients become symptomatic and Our literature search identified one foreign report of angioedema in a neonate exposed transplacentally to A similar dilemma of variable latency of drug exposure oxcarbazepine this incident was captured in our case until the development of acute angioedema has been series as patient 9. The patient’s mother was treated with reported with angiotensin-converting enzyme inhibitors, in 1050 mg/day oxcarbazepine for epilepsy for an unknown which angioedema is a well-documented but still fre- period of time. The neonate was reported to have eyelid quently unrecognized side effect occurring in 0.1-0.7% ofpatients In one report that highlighted the potential edema, a feeding problem, and disproportionate head-to- risks of angioedema in children, two children with sys- trunk size. We found no other foreign or domestic litera- temic lupus erythematosus developed acute angioedema ture reports of angioedema, anaphylaxis, anaphylactoid after months of treatment with enalapril The duration reactions in individuals of any age exposed to oxcarbaz- of angiotensin-converting enzyme inhibitor use prior to the onset of angioedema may vary from months to years,but is more commonly observed in patients whose use ofthe drug was more recent The median duration of Calculation of U.S. Reporting Rate
angiotensin-converting enzyme inhibitor therapy beforeangioedema onset was 12 months (range, 1 day to 13 According to data from the Verispan Total Patient Tracker for the period January 1, 2002, to August 31, Given the nature of the spontaneous reporting system, 2006, ϳ1,622,717 patients of any age had a prescription an exact incidence rate for angioedema-like symptoms in filled for oxcarbazepine in an outpatient retail pharmacy the pediatric population exposed to oxcarbazepine cannot setting in the United States. Approximately 25% (407,391; be calculated. Underestimates of the true incidence of 95% confidence interval, 405,944-408,839) of those pa- adverse events are widely recognized in a passive surveil- tients were between 0 and 16 years of age. Therefore, with lance program. The proportion of serious adverse events a case count of 4 and a projected patient count of 407,391 reported to the Food and Drug Administration is reported in the United States, the calculated reporting rate for to range from Ͻ1 to 10% Consequently, underre- angioedema in pediatric patients in the United States is 9.8 porting of angioedema in pediatric patients exposed to oxcarbazepine seems likely. We calculated a U.S. report- ing rate for angioedema in a pediatric population exposed Frank MM, Gelfand JA, Atkinson JP. Hereditary angioedema:
to oxcarbazepine to be 9.8 cases per 1,000,000 pediatric the clinical syndrome and its management. Ann Intern Med 1976;84: patients. To put this in some perspective, Slater et al. Chiu AG, Newkirk KA, Davidson BJ, Burningham AR, Krowiak
reported 138 cases consistent with the diagnosis of angio- EJ, Deeb ZE. Angiotensin-converting enzyme inhibitor-induced angio- edema from the overall controlled and marketed experi- edema: a multicenter review and an algorithm for airway management.
ence using enalapril in more than 1.2 million patients of Ann Otol Rhinol Laryngol 2001;110:834-40.
Sondhi D, Lippmann M, Murali G. Airway compromise due to
Angioedema associated with the use of oxcarbazepine is angiotensin-converting enzyme inhibitor-induced angioedema: clinicalexperience at a large community teaching hospital. Chest 2004;126: a rare but potentially life-threatening reaction. Angio- edema may have a considerable impact on patient safety Seidman MD, Lewandowski CA, Sarpa JR, Potesta E,
and treatment decisions. Early recognition and discontin- Schweitzer VG. Angioedema related to angiotensin-converting enzyme uation of the offending agent, in this case oxcarbazepine, inhibitors. Otolaryngol Head Neck Surg 1990;102:727-31.
remain the primary therapy Management of the Lindhout D, Omtzigt JG. Teratogenic effects of antiepileptic
drugs: implications for the management of epilepsy in women of edema should be according to its clinical presentation.
childbearing age. Epilepsia 1994;35(Suppl 4):S19-28.
Patients should be advised to immediately report signs Elias A, Madhusoodanan S, Pudukkadan D, Antony JT. Angio-
and symptoms suggesting angioedema (swelling of the edema and maculopapular eruptions associated with carbamazepine face, eyes, lips, or tongue, or difficulty swallowing or administrations. CNS Spectr 2006;11:352-4.
breathing) and to stop taking the drug until they have Israili ZH, Hall WD. Cough and angioneurotic edema associated
with angiotensin-converting enzyme inhibitor therapy: a review of the consulted their physician. It is recommended that pa- literature and pathophysiology. Ann Intern Med 1992;117:234-42.
tients presenting with angioedema be tested for C1 Sabroe RA, Black AK. Angiotensin-converting enzyme (ACE)
inhibitor function and for C4, C3, and C1q antigens, to inhibitors and angio-oedema. Br J Dermatol 1997;136:153-8.
exclude the possibility of hereditary angioedema or Assadi FK, Wang HE, Lawless S, McKay CP, Hopp L, Fattori
D. Angiotensin converting enzyme inhibitor-induced angioedema: areport of two cases. Pediatr Nephrol 1999;13:917-9.
Zingale LC, Beltrami L, Zanichelli A, et al. Angioedema
without urticaria: a large clinical survey. CMAJ 2006;175:1065-70.
The views and opinions expressed herein are those of the authors and La Grenade L, Graham DJ, Nourjah P. Underreporting of
do not represent those of the Food and Drug Administration or the hemorrhagic stroke associated with phenylpropanolamine. JAMA 2001; Slater EE, Merrill DD, Guess HA, et al. Clinical profile of
angioedema associated with angiotensin converting-enzyme inhibition.
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