Clinical/Scientific Notes Marcia L. Buck, PharmD Matthew J. Gurka, PhD Howard P. Goodkin, MD, PhD Supplemental data at www.neurology.org POSTMARKETING MODIFICATIONS IN THE SAFETY LABELING OF THE NEW ANTIEPILEPTICS The adverse effect profiles of new drugs are often incomplete at the time of approval.1,2 Rare or idiosyncratic reactions, as well as mutagenic or teratogenic effects, may only become evident with widespread use. These reactions may be identified through reports from clinicians to the manufacturer or to the US Food and Drug Administration (FDA) or through postmarketing clinical trials and database searches.1,3 One of the most striking examples occurred with felbamate. It entered the market in 1993 after having been studied in fewer than 5,000 adults. Shortly after introduction, the FDA began to receive reports of felbamate-associated aplastic anemia. In August 1994, a black box warning was added to the product labeling. In October 1994, the black box was modified to include a warning for hepatotoxicity. With an estimated incidence of 1 in 8,000 for aplastic anemia and 1 in 10,000 for hepatotoxicity, it is understandable that these reactions were not identified in small-scale premarketing clinical trials.4 Felbamate was the first of eight antiepileptic drugs (AEDs) approved by the FDA from 1993 to 2000. For many patients, these AEDs provide a major improvement over traditional agents. However, as the experience with felbamate has shown, knowledge of their adverse effects at the time of approval was limited. To examine the importance of postmarketing adverse reaction reporting for the new AEDs, we conducted an analytical review of the safety labeling modifications made by the FDA since their release. Methods. Safety labeling modifications were evaluated for felbamate, gabapentin, lamotrigine, levetiracetam, oxcarbazepine, tiagabine, topiramate, and zonisamide from approval to December 2005. Modifications were identified through a review of prescribing information, FDA safety alerts, and the MedWatch Safety Information and Adverse Event Reporting System database.5 Safety labeling changes were listed according to the section modified (in descending order of severity): Black Box 1536 Neurology 68 May 1, 2007 Warnings, Contraindications, Warnings, Precautions, and Adverse Reactions. Safety information in other sections of the prescribing information (e.g., Clinical Pharmacology) was also included if it was listed in the MedWatch database. Safety labeling modifications were tabulated by timing and content. The changes were treated as recurrent-event data and analyzed by estimating the mean cumulative function (MCF) for the number of modifications.6 The goal of this analysis was to determine whether a time after approval could be identified when the probability of new safety information markedly declined. The analysis was performed using SAS version 9.1 (SAS Institute, Cary, NC). Results. A total of 38 safety labeling modifications were made in the prescribing information during the 13 years evaluated (table E-1 on the Neurology Web site at www.neurology.org). All of the drugs had at least one safety labeling modification (median 5 labeling modifications, range 1 to 12). Three changes (8%) involved the addition or modification of a black box warning. The remaining modifications consisted of 10 changes in Warnings (26%), 10 changes in Precautions (26%), 14 changes in Adverse Reactions (37%), and 1 change in Clinical Pharmacology. Many of the changes resulted from new information gained from postmarketing clinical trials conducted by the manufacturer to support a request for an additional indication or to expand use to special populations such as children or the elderly. No changes were made in the Contraindications section. To evaluate the relationship between the years after approval of a new AED and its adverse effect profile, an MCF was derived from the 38 safety labeling changes (figure). Although the majority of modifications came within 6 years, the MCF has not yet leveled off. Thus, the analysis did not identify a definite time point during the 13-year study period after which additional changes in safety labeling were unlikely to be made. Gabapentin exemplifies this finding, undergoing its first modification 12 years after approval. Figure Estimate of the mean cumulative function and its 95% CI for the number of label modifications for a new antiepileptic drug Discussion. Postmarketing safety information is becoming increasingly important as studies conducted before approval become smaller and shorter in duration. Although additional adverse event information has traditionally come from voluntary clinician reporting, it is now often obtained from postmarketing clinical trials conducted by the manufacturer or large-scale database searches. The FDA may also request additional postmarketing studies as a contingency for drug approval. The frequency of postmarketing safety labeling modification, as well as the number of drugs withdrawn from the market, has increased over the past decade.2,3 As of 2002, 8.2% of the 548 drugs approved between 1975 and 1999 had received a black box warning after marketing, and 2.9% had been withdrawn.2 Half of the warnings came within the first 7 years after approval, and half of the withdrawals occurred within 2 years. In our analysis of safely labeling modifications of the new AEDs, more than three dozen changes were made, including three black box warnings. The majority of the changes, however, involved less severe adverse reactions. Although the majority of modifications were made within the first 6 years after approval, there was no definite time point at which adverse reaction data seemed to be complete. A limitation of this study is that the MCF analysis was performed as a function of time after FDA approval. Ideally, the safety labeling modifications should also be evaluated as a function of patient-year exposure or number of postmarketing trials, but these values were not available. Because of the increasing frequency of the postmarketing modifications and occasional need for drug withdrawal, it has been suggested that clinicians avoid new drugs when older drugs are available that provide similar efficacy. Although this may be useful for some diseases, it may not be feasible for clinicians prescribing AEDs. Traditional therapies may not provide effective seizure control and can produce adverse effects that limit dosing or lead to nonadherence. Therefore, because major changes to the drug approval system in the near future are not likely, the findings of this study reinforce the need for clinicians prescribing the new AEDs to be aware of the latest adverse reaction information. In addition, clinicians who suspect a new or unusual adverse reaction to an AED should report their findings through MedWatch to further define the adverse effect profiles of these agents.1,5 From the Departments of Pharmacy (M.L.B.), Pediatrics (M.L.B., H.P.G.), Public Health Sciences (M.J.G.), and Neurology (H.P.G.), University of Virginia Health Systems, Charlottesville, VA. H.P.G. receives support from NS-048413 and HD-001421. Disclosure: The authors report no conflicts of interest. Received September 6, 2006. Accepted in final form January 10, 2007. Address correspondence and reprint requests to Dr. Howard P. Goodkin, Department of Neurology, Box 800394, University of Virginia Health System, Charlottesville, VA 22908; hpg9v@virginia.edu Copyright © 2007 by AAN Enterprises, Inc. ACKNOWLEDGMENT The authors thank Gregory Holmes for helpful comments. 1. 2. 3. 4. 5. 6. Brewer T, Colditz GA. Postmarketing surveillance and adverse drug reactions: current perspectives and future needs. JAMA 1999;281:824–829. Lasser KE, Allen PD, Woolhandler SJ, et al. Timing of new black box warnings and withdrawals for prescription medications. JAMA 2002;287:2215–2220. Wysowski DK, Swartz L. Adverse drug event surveillance and drug withdrawals in the United States, 1969-2002: the importance of reporting suspected reactions. Arch Intern Med 2005;165:1363–1369. Pellock JM, Brodie MJ. Felbamate: 1997 update. Epilepsia 1997;38:1261–1264. U.S. Food and Drug Administration. MedWatch: The FDA Safety and Information Adverse Event Reporting Program. Available at: www.fda.gov/medwatch/index. html. Accessed May 1, 2006. Nelson WB. Recurrent events analysis for product repairs, disease recurrences, and other applications, ASASIAM series on statistics and applied probability. Philadelphia: SIAM; Alexandria, VA: ASA, 2003. Neurology 68 May 1, 2007 1537 C. Denier, MD, PhD A. Orgibet, MD F. Roffi, MD E. Jouvent, MD C. Buhl, MD F. Niel O. Boespflug-Tanguy, MD, PhD G. Said, MD D. Ducreux, MD, PhD Supplemental data at www.neurology.org ADULT-ONSET VANISHING WHITE MATTER LEUKOENCEPHALOPATHY PRESENTING AS PSYCHOSIS Childhood ataxia with CNS hypomyelination, also called leukoencephalopathy with vanishing white matter (CACH/VWM; OMIM 603896), is an autosomal recessive disease, defined by clinical and neuroradiologic features.1 After usually normal early development, patients aged between 2 and 5 years present with progressive cerebellar ataxia, spasticity, and a relatively mild mental impairment. Disease progression can be exacerbated during febrile illnesses or after head trauma, leading to death usually after 2 to 5 years of evolution. Since recent reports, disease severity seems to be correlated to age at disease onset.1 The most severe forms are the rapidly fatal congenital forms.1 In contrast, adult onset forms are recently recognized.1-6 Cerebral MRI findings in CACH/VWM are very characteristic, with a CSF-like diffuse signal of the cerebral hemispheric white matter. Neuropathologic studies reveal a cavitating orthochromatic leukodystrophy. CACH/ VWM is caused by mutations within one of the five EIF2B genes.1 We report on one patient with adultonset VWM revealed by isolated schizophrenia-like syndrome. This presentation expands the spectrum of phenotypes featuring CACH/VWM. Case report. A 32-year-old man with progressive behavioral changes was referred. He worked as a baggage handler in a hotel until last year. Five years before referral, he started to report sexual disturbances with impotency, which remains his main concern. Concomitantly, he presented a progressive social isolation and some unexplained episodes of agitation with crying with no reason. His relatives also noticed simultaneous onset of gradual flat affect and amotivational state with lack of initiative. On examination, he presented ideomotor decrease and unmotivated laughs, with no depressive mood. He had no decline in recent or ancient memory, or orientation (Mini-Mental State Examination 30/30). The psychiatric interview was dominated by positive psychotic symptoms and thought disorders with auditory hallucinations, formal thought insertion, delusions, and imperative commenting. Psychiatric symptoms were consistent with schizophrenia diagnosis, using Diagnostic and Statistical Manual of Mental Disorders, 4th edition criteria, i.e., 1) positive and negative psychotic symptoms, 2) social occupational dysfunction, and 3) continuous signs persisting for at least 6 months. The diagnosis of schizophrenia was secondarily excluded because of neurologic abnormalities. Neurologic examination revealed brisk and exaggerated tendon reflexes, 1538 Neurology 68 May 1, 2007 bilateral Babinski sign, and mild spastic gait. The patient’s parents were unrelated. MRI study. The cerebral MRI showed diffuse abnormalities of hemispheric cerebral, cerebellar, and brainstem white matter with a low signal intensity on T1-weighted images and a high signal intensity on T2-weighted images (figure and data not shown). On proton density images, deep hemispheric white matter had a low signal intensity, close to the CSF signal, suggesting cavitating white matter degeneration. Within these white matter lesions, the apparent diffusion coefficient (ADC) was increased (mean ADC values: 1.34 ⫾ 0.02 ⫻ 10⫺9 m2 䡠 second⫺1 vs 0.58 ⫾ 0.01 ⫻ 10⫺9 m2 䡠 second⫺1 in healthy controls); mean fractional anisotropy (FA) values at the same locations were 0.33 ⫾ 0.08 vs 0.39 ⫾ 0.08 in controls. FA and ADC values measured on the corticospinal tracts were normal. Chemical shift imaging spectroscopy showed a marked decrease of all usually detected brain metabolites (N-acetylaspartate, choline, creatine/phosphocreatine, myoinositol) in the centrum semiovale white matter contrasting with the normal profile observed in the subcortical area (figure E-1 on the Neurology Web site at www.neurology.org). Fiber tracking of the brain showed altered pattern of the associative white matter tracts, but only slightly altered corticospinal tracts (figure E-2). Laboratory including DNA analysis. Routine blood, CSF, and endocrinologic examination results were normal. Assessment of the very long chain fatty acids, lysosomal enzymes arylsulfatases A, ␤-hexosaminidase, ␤-glucosidase, glucocerebrosidases, and ␤ galactosidases excluded adrenoleukodystrophy, metachromatic leukodystrophy, and GM1/GM2 gangliosidosis. Nerve conduction velocity and EMG were normal. Genetic study identified a homozygous mutation in the EIF2B5 gene resulting in Arg113His amino acid substitution. Both parents were heterozygous for this mutation. CACH/ VWM diagnosis was retained. Discussion. One hundred forty-eight CACH/VWM patients have been reported to date,1 including 10 adult-onset cases with identified EIF2B mutations.2-6 Adult-onset VWM usually includes progressive cerebellar ataxia, spasticity, and mental decline or dementia (table E-1).2-6 Our patient is remarkable by the psychiatric presentation with schizophrenia-like syndrome. Two other adult-onset VWM patients have been previously reported with isolated “paranoid behavior” at the onset of their disease, both at age 25 years.4,5 These psychotic symptoms probably Figure Conventional cerebral MRI imaging point that in cases of atypical psychotic symptoms, in peculiar with signs at the neurologic examination, it is important to revisit the possibility of an underlying general medical condition causing psychiatric manifestations. From the Departments of Neurology (C.D., E.J., G.S.), Psychiatry (A.O., C.B.), and Neuroradiology (F.R., D.D.), Hôpital de Bicêtre, Assistance-Publique-Hôpitaux de Paris, Université Paris XI, Le Kremlin-Bicêtre, France; Department of Human Genetic, CHU de Clermont-Ferrand (F.N., O.B.-T.) and INSERM-Université d’Auvergne UMR 384 (O.B.-T.), Clermont-Ferrand, France. Disclosure: The authors report no conflicts of interest. Received August 31, 2006. Accepted in final form January 12, 2007. Address correspondence and reprint requests to Dr. Christian Denier, Department of Neurology, Hôpital de Bicêtre, 78 rue du Général Leclerc, 94275 Le Kremlin-Bicêtre, France; christian.denier@bct.aphp.fr Copyright © 2007 by AAN Enterprises, Inc. 1. 2. 3. Sagittal T2-weighted (A) and axial fluid-attenuated inversion recovery (FLAIR) (B) are shown. Virtually, all hemispheric white matter appeared homogeneously hyperintense on T2-weighted and hypointense on T1weighted (not shown) with atrophy of the corpus callosum. On FLAIR, large part of the white matter has a signal identical to CSF, surrounded by a rim of hyperintensity demonstrating the cavitated breakdown of the white matter. have to be included in the clinical spectrum of the adult-onset VWM. Interestingly, psychotic features have been specifically reported in another autosomal recessive leukodystrophy, the metachromatic leukodystrophy (MLD). In MLD presenting in adolescence or early adulthood, schizophrenia-like psychosis existed in 53% of 129 cases,7 numerous patients being initially considered schizophrenic and treated by psychiatrists, until unequivocal neurologic signs appear.7 Our case serves to impress the 4. 5. 6. 7. Fogli A, Boespflug-Tanguy O. The large spectrum of eIF2B-related diseases. Biochem Soc Trans 2006;34:22–29. Fogli A, Rodriguez D, Eymard-Pierre E, et al. Ovarian failure related to eukaryotic initiation factor 2B mutations. Am J Hum Genet 2003;72:1544–1550. Ohtake H, Shimohata T, Terajima K, et al. Adult-onset leukoencephalopathy with vanishing white matter with a missense mutation in EIF2B5. Neurology 2004;62:1601– 1603. Gallo A, Rocca MA, Falini A, et al. Multiparametric MRI in a patient with adult-onset leukoencephalopathy with vanishing white matter. Neurology 2004;62:323–326. Van der Knaap MS, Leegwater PA, van Berkel CG, et al. Arg113His mutation in eIF2Bepsilon as cause of leukoencephalopathy in adults. Neurology 2004;62:1598–1600. Biancheri R, Rossi A, Di Rocco M, et al. Leukoencephalopathy with vanishing white matter: an adult onset case. Neurology 2003;61:1818–1819. Hyde TM, Ziegler JC, Weinberger DR. Psychiatric disturbances in metachromatic dystrophy. Insights into the neurobiology of psychosis. Arch Neurol 1992;49:401–406. Neurology 68 May 1, 2007 1539 ADULT-ONSET VANISHING WHITE MATTER LEUKOENCEPHALOPATHY PRESENTING AS PSYCHOSIS C. Denier, A. Orgibet, F. Roffi, et al. Neurology 2007;68;1538-1539 DOI 10.1212/01.wnl.0000260701.76868.44 This information is current as of April 30, 2007 Updated Information & Services including high resolution figures, can be found at: http://www.neurology.org/content/68/18/1538.full.html Supplementary Material Supplementary material can be found at: http://www.neurology.org/content/suppl/2007/04/27/68.18.1538.DC1.h tml References This article cites 7 articles, 4 of which you can access for free at: http://www.neurology.org/content/68/18/1538.full.html##ref-list-1 Citations This article has been cited by 1 HighWire-hosted articles: http://www.neurology.org/content/68/18/1538.full.html##otherarticles Subspecialty Collections This article, along with others on similar topics, appears in the following collection(s): All Psychiatric disorders http://www.neurology.org//cgi/collection/all_psychiatric_disorders Leukodystrophies http://www.neurology.org//cgi/collection/leukodystrophies Psychosis http://www.neurology.org//cgi/collection/psychosis Permissions & Licensing Information about reproducing this article in parts (figures,tables) or in its entirety can be found online at: http://www.neurology.org/misc/about.xhtml#permissions Reprints Information about ordering reprints can be found online: http://www.neurology.org/misc/addir.xhtml#reprintsus Neurology ® is the official journal of the American Academy of Neurology. 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