Predicting possible zonisamide hypersensitivity syndrome
Manuela G. Neuman
In Vitro Drug Safety and Biotechnology Laboratory, MaRS Discovery Centre, University of Toronto, Toronto, ON, Canada
Department of Pharmacology and Institute of Drug Research, University of Toronto, Toronto, ON, Canada
Search for more papers by this authorNeil H. Shear
Department of Pharmacology and Institute of Drug Research, University of Toronto, Toronto, ON, Canada
Drug Safety Clinic, Division of Dermatology, University of Toronto, Toronto, ON, Canada
Search for more papers by this authorIzabella M. Malkiewicz
In Vitro Drug Safety and Biotechnology Laboratory, MaRS Discovery Centre, University of Toronto, Toronto, ON, Canada
Search for more papers by this authorMona Kessas
In Vitro Drug Safety and Biotechnology Laboratory, MaRS Discovery Centre, University of Toronto, Toronto, ON, Canada
Search for more papers by this authorAmy W. Lee
In Vitro Drug Safety and Biotechnology Laboratory, MaRS Discovery Centre, University of Toronto, Toronto, ON, Canada
Search for more papers by this authorLawrence Cohen
Division of Gastroenterology, Sunnybrook Sciences Centre, University of Toronto, Toronto, ON, Canada
Search for more papers by this authorManuela G. Neuman
In Vitro Drug Safety and Biotechnology Laboratory, MaRS Discovery Centre, University of Toronto, Toronto, ON, Canada
Department of Pharmacology and Institute of Drug Research, University of Toronto, Toronto, ON, Canada
Search for more papers by this authorNeil H. Shear
Department of Pharmacology and Institute of Drug Research, University of Toronto, Toronto, ON, Canada
Drug Safety Clinic, Division of Dermatology, University of Toronto, Toronto, ON, Canada
Search for more papers by this authorIzabella M. Malkiewicz
In Vitro Drug Safety and Biotechnology Laboratory, MaRS Discovery Centre, University of Toronto, Toronto, ON, Canada
Search for more papers by this authorMona Kessas
In Vitro Drug Safety and Biotechnology Laboratory, MaRS Discovery Centre, University of Toronto, Toronto, ON, Canada
Search for more papers by this authorAmy W. Lee
In Vitro Drug Safety and Biotechnology Laboratory, MaRS Discovery Centre, University of Toronto, Toronto, ON, Canada
Search for more papers by this authorLawrence Cohen
Division of Gastroenterology, Sunnybrook Sciences Centre, University of Toronto, Toronto, ON, Canada
Search for more papers by this authorAbstract
Abstract: Zonisamide (ZNS) is an anticonvulsant (AC) that contains a sulpha moiety potentially triggering hypersensitivity syndrome reactions (HSR). The lymphocyte toxicity assay (LTA) is an in vitro drug rechallenge test, which is believed to reflect a decreased capacity of the individual to detoxify reactive metabolites. The study examined whether cross-reactivity is present between ZNS and other AC and/or sulphonamides and if this HSR may be predicted using the LTA. The second aim was to determine age-related differences in ZNS-induced HSR. LTA was previously validated in patients who received sulphamethoxazole (SMX) or AC.
Methods: Forty adult patients who displayed clinical HSR to SMX (20) or AC (20) participated in the study. Each group was represented with an equal number of individuals above and below the age of 60. LTA-SMX, LTA-AC and LTA-ZNS from 20 patients who previously presented a clinical reaction to one of the drugs and who had a positive LTA result to the specific drug were compared with 20 individuals who received the same drugs but did not present reactions. Binary logistic regression was used to evaluate the statistical significance.
Results: In vitro results correlated with the clinical diagnosis. LTA presented a significant difference (P < 0.0001) between control and hypersensitive patients. In each age group, only a single patient had a severe clinical manifestation of SMX-HSR. These individuals tested positive to both SMX and ZNS.
Conclusions: Sulphamethoxazole-HSR but not AC-HSR patients may present a cross-reactivity to ZNS-HSR. The use of LTA to predict a possible ZNS reaction is recommended for SMX-sensitive individuals who prescribed ZNS.
References
- 1 Classen D C, Pestonik S L, Evans R S et al. Adverse drug events in hospitalized patients. Excess length of stay, extra costs, and attributable mortality. JAMA 1997: 277: 301–306.
- 2 Bate D W, Spell N, Cullen D J et al. The costs of adverse drug events in hospitalized patients. Adverse Drug Events Prevention Study Group. JAMA 1997: 277: 307–311.
- 3 Lazarou J, Pomeranz B H, Corey P N. Incidence of adverse drug reactions in hospitalized patients – a meta-analysis of prospective studies. JAMA 1998: 279: 1200–1205.
- 4 Zimmerman H J. The spectrum of hepatotoxicity. Prospect Biol Med 1968: 12: 135.
- 5 Neuman M G, Krivoy N, Shapiro L et al. Molecular mechanisms in hypersensitivity syndrome to sulphonamides. Trans Res 2007: 149: 243–253.
- 6 Neuman M G, Nicar M. Ibuprophen-induced Steven-Johnson Syndrome. Trans Res 2007: 149: 253–273.
- 7 Shear N, Spielberg S. Anticonvulsant hypersensitivity syndrome. J Clin Invest 1988: 82: 1826–1832.
- 8 Krivoy N, Taeri M, Neuman M G. Antiepileptic drug-induced hypersensitivity syndrome reactions. Current Drug Safety 2006: 1: 289–299.
- 9 Shear N H, Knowles S R, Shapiro L E. Cutaneous adverse drug reactions. In D C Dale, D D Federman, eds. Scientific American Medicine. Scientific American Inc. New York. 1999: 2, VI: 1–8.
- 10 Schwartz R. Toxic epidermal necrolysis. Cutis 1997: 59: 123–127.
- 11 Petkov T, Pehlivanov G, Grozdev I, Kavaklieva S, Tsankov N. Toxic epidermal necrolysis as a dermatological manifestation of drug hypersensitivity syndrome. Eur J Dermatol 2007: 17: 422–427.
- 12 Huang L Y, Liao W C, Chiou C C, Lou J P, Hu P, Ko F C. Fatal toxic epidermal necrolysis induced by carbamazepine treatment in a patient who previously had carbamazepine-induced Stevens-Johnson syndrome. J Formos Med Assoc 2007: 106: 1032–1037.
- 13 Majeres K D, Suppes T A. Cautionary note when using zonisamide in youths: a case report of association with toxic epidermal necrolysis. J Clin Psychiatry 2004: 65: 1720.
- 14 Tennis P, Stern R S. Risk of serious cutaneous disorders after initiation of use of phenytoin, carbamazepine, or sodium valproate: a record linkage study. Neurology 1997: 49: 542–546.
- 15 Allam J P, Paus T, Reichel C, Bieber T, Novak N. DRESS syndrome associated with carbamazepine and phenytoin. Eur J Dermatol 2004: 14: 339–42.
- 16 Hyson C, Sadler M. Cross sensitivity of skin rashes with antiepileptic drugs. Can J Neurol Sci 1997: 24: 245–249.
- 17 Field T S, Gurwitz J H, Avorn J et al. Risk factors for adverse drug events among nursing home residents. Arch Intern Med 2001: 161: 1629–1634.
- 18 Rosholm J U, Bjerrum L, Hallas J, Worm J, Gram L F. Polypharmacy and the risk of drug-drug interactions among Danish elderly. A prescription database study. Danish Med Bulletin 1998: 45: 210–213.
- 19 Huying F, Klimpe S, Werhahn K J. Antiepileptic drug use in nursing home residents: a cross-sectional, regional study. Seizure: J Br Epilepsy Assoc 2006: 15: 194–197.
- 20 Juurlink D N, Mamdani M, Kopp A, Laupacis A, Redelmeier D A. Drug–drug interactions among elderly patients hospitalized for drug toxicity. JAMA: J Am Med Assoc 2003: 289: 1652–1658.
- 21 Field T S, Gurwitz J H, Harrold L R et al. Risk factors for adverse drug events among older adults in the ambulatory setting. J Am Geriatrics Soc 2004: 52: 1349–1354.
- 22 Gurwitz J H, Field T S, Judge J et al. The incidence of adverse drug events in two large academic long-term care facilities. Am J Med 2005: 118: 251–258.
- 23 Neuman M G, Malkiewicz I M, Phillips E J et al. Monitoring adverse drug reactions to sulfonamide antibiotics in human immunodeficiency virus-infected individuals. Ther Drug Monit 2002: 24: 728–736.
- 24 Mauri-Hellweg D, Bettens F, Mauri D, Brander C, Hunziker T, Pichler W J. Activation of drug-specific CD4 super(+) and CD8 super(+) T cells in individuals allergic to sulfonamides, phenytoin, and carbamazepine. J Immunol 1995: 155: 462–472.
- 25 Willmore L J. Antiepileptic drug therapy in the elderly. Pharmacol Ther 1998: 78: 9–16.
- 26 Kim C W, Choi G S, Yun C H, Kim D I. Drug hypersensitivity to previously tolerated phenytoin by carbamazepine-induced DRESS syndrome. J Korean Med Sci 2006: 21: 768–772.
- 27 Kwong K L, Lam S Y, Lui Y S, Wong S N, So K T. Cross-sensitivity in a child with anticonvulsant hypersensitivity syndrome. J Paediatr Child Health 2006: 42: 474–476.
- 28 Mendiratta V, Bhushan P. Phenytoin-induced DRESS with cross-reactivity to carbamazepine in a 10-year-old Indian child. Clin Exp Dermatol 2006: 31: 720–721.
- 29 Moss D M, Rudis M, Henderson S O. Cross-sensitivity and the anticonvulsant hypersensitivity syndrome. J Emerg Med 1999: 17: 503–506.
- 30 Romano A, Pettinato R, Andriolo M et al. Hypersensitivity to aromatic anticonvulsants: In vivo and in vitro cross-reactivity studies. Curr Pharm Des 2006: 12: 3373–3381.
- 31 Seitz C S, Pfeuffer P, Raith P, Brocker E B, Trautmann A. Anticonvulsant hypersensitivity syndrome: cross-reactivity with tricyclic antidepressant agents. Ann Allergy Asthma Immunol: Official Publ Am College of Allergy Asthma Immunol 2006: 97: 698–702.
- 32 Sierra N M, Garcia B, Marco J, Plaza S, Hidalgo F, Bermejo T. Cross hypersensitivity syndrome between phenytoin and carbamazepine. Pharm World Sci: PWS 2005: 27: 170–174.
- 33 Shimizu M, Uno H, Ito T, Masuda Y, Kurokawa M. Research and development of zonisamide, a new type of antiepileptic drug. Yakugaku Zasshi. J Pharm Soc Japan 1996: 116: 533–547.
- 34 Kanba S, Yagi G, Kamijima K et al. The first open study of zonisamide, a novel anticonvulsant, shows efficacy in mania. Prog Neuropsychopharmacol Biol Psychiatry 1994: 18: 707–715.
- 35 Yagi K. Overview of Japanese experience-controlled and uncontrolled trials. Seizure: J Br Epilepsy Assoc 2004: 13 (Suppl 1): S11–S15.
- 36 Tosches W A, Tisdell J. Long-term efficacy and safety of monotherapy and adjunctive therapy with zonisamide. Epilepsy Behav 2006: 8: 522–526.
- 37 Kochak G M, Page J G, Buchanan R A, Peters R, Padgett C S. Steady-state pharmacokinetics of zonisamide, an antiepileptic agent for treatment of refractory complex partial seizures. J Clin Pharmacol 1998: 38: 166–171.
- 38 Nakasa H, Nakamura H, Ono S et al. Prediction of drug-drug interactions of zonisamide metabolism in humans from in vitro data. Eur J Clin Pharmacol 1998: 54: 177–183.
- 39 Tasaki K, Minami T, Ieiri I et al. Drug interactions of zonisamide with phenytoin and sodium valproate: serum concentrations and protein binding. Brain Dev 1995: 17: 182–185.
- 40 Ragueneau-Majlessi I, Levy R H, Bergen D et al. Carbamazepine pharmacokinetics are not affected by zonisamide: in vitro mechanistic study and in vivo clinical study in epileptic patients. Epilepsy Res 2004: 62: 1–11.
- 41 Levy R H, Ragueneau-Majlessi I, Brodie M J, Smith D F, Shah J, Pan W J. Lack of clinically significant pharmacokinetic interactions between zonisamide and lamotrigine at steady state in patients with epilepsy. Ther Drug Monit 2005: 27: 193–198.
- 42 Levy R H, Ragueneau-Majlessi I, Garnett W R et al. Lack of a clinically significant effect of zonisamide on phenytoin steady-state pharmacokinetics in patients with epilepsy. J Clin Pharmacol 2004: 44: 1230–1234.
- 43 Shinoda M, Akita M, Hasegawa M, Hasegawa T, Nabeshima T. The necessity of adjusting the dosage of zonisamide when co-administered with other anti-epileptic drugs. Biol Pharm Bull 1996: 19: 1090–1092.
- 44 Masuda Y, Karasawa T, Shiraishi Y, Hori M, Shimizu M. 3-Sulfamoylmethyl-1,2-benzisoxazole, a new type of anticonvulsant drug. Pharmacological profile. Arzneimittelforschung 1980: 30: 477–483.
- 45 Hori M, Ito T, Oka M, Noda Y, Kadokawa T. General pharmacology of the novel antiepileptic compound zonisamide. Part 1. Effects on central nervous system. Arzneimittelforschung 1987: 37: 1124–1130.
- 46 Sakamoto T, Mizutani K, Shinohara Y, Iwatsuki K, Takigawa M. Drug eruption due to zonisamide: Flow cytometric analysis of lymphocyte blastogenesis in vivo. Eur J Dermatol 1994: 4: 69.
- 47 Leppik I E, Willmore L J, Homan R W et al. Efficacy and safety of zonisamide: results of a multicenter study. Epilepsy Res 1993: 14: 165–173.
- 48 Neuman M G, Malkiewicz I M, Shear N H. A novel lymphocyte toxicity assay to assess drug hypersensitivity syndromes. Clin Biochem 2000: 33: 517–524.
- 49 Neuman M G. Personalized medicine, preventing and treating adverse drug reactions. Biotechnol Focus 2006: 4: 13–16, 41.
- 50 Schmidt D, Jacob R, Loiseau P et al. Zonisamide for add-on treatment of refractory partial epilepsy: a European double-blind trial. Epilepsy Res 1993: 15: 67–73.
- 51 Maldonado N R, Tello J S, Garcia-Baquero E R, Castano A H. Anticonvulsant hypersensitivity syndrome with fatal outcome. Eur J Dermatol 2002: 12: 503–505.
Citing Literature
