title: Changing incidence of hyperammonemia in Japan from 2006 to 2013: expansion of new antiepileptic drugs reduces the risk of hyperammonemia.
abstract: OBJECTIVE
  The purpose of the present study was to examine the relationship between the incidence of hyperammonemia and changes in the prescribing of concomitant antiepileptic drugs (AEDs) in patients receiving valproic acid.
  
  
  METHODS
  We evaluated 40,363 plasma samples from 6009 epilepsy patients obtained from 2006 to 2013. Hyperammonemia was defined as a plasma ammonia level exceeding 100 μg/dL.
  
  
  RESULTS
  In 2006, 32.6 % of the plasma samples were from patients with concomitant use of phenytoin but this decreased to 16.0 % in 2013. Lamotrigine and levetiracetam were approved in 2008 and 2010, respectively, and were prescribed for patients who provided 27.8 and 14.9 % of the plasma samples in 2013. The incidence rate of hyperammonemia (per 100 person years) decreased markedly from 40.8 (95 % confidence interval (CI), 37.7-43.9) in 2006 to 14.2 (95 % CI, 12.5-15.9) in 2013. In any year reviewed, concomitant use of phenytoin, phenobarbital, carbamazepine, or carbonic anhydrase inhibitors was a risk factor for hyperammonemia. Among enzyme-inducing AEDs, concomitant use of phenytoin was associated with the highest risk of hyperammonemia.
  
  
  CONCLUSIONS
  Drug interactions caused by enzyme-inducing AEDs, especially phenytoin, are closely related to the development of hyperammonemia. This study demonstrated that introduction of new AEDs changed the co-prescribing pattern in patients receiving valproic acid, resulting in a marked decrease of hyperammonemia. Although their higher cost may be problematic, new AEDs are beneficial for reducing the risk of drug interactions.
authors.affiliation: Department of Clinical Research, National Epilepsy Center, Shizuoka Institute of Epilepsy and Neurological Disorders, 886, Urushiyama, Shizuoka, 420-8688, Japan. yamamoty-3@hosp.go.jp.|Department of Clinical Pharmaceutics, Graduate School of Pharmaceutical Sciences, University of Shizuoka, 52-1, Yada, Shizuoka, 422-8526, Japan. yamamoty-3@hosp.go.jp.
authors.forename: Yoshiaki
authors.initials: Y
authors.lastname: Yamamoto
authors.affiliation: Department of Clinical Research, National Epilepsy Center, Shizuoka Institute of Epilepsy and Neurological Disorders, 886, Urushiyama, Shizuoka, 420-8688, Japan.|Department of Clinical Pharmaceutics, Graduate School of Pharmaceutical Sciences, University of Shizuoka, 52-1, Yada, Shizuoka, 422-8526, Japan.
authors.forename: Yukitoshi
authors.initials: Y
authors.lastname: Takahashi
authors.affiliation: Department of Clinical Research, National Epilepsy Center, Shizuoka Institute of Epilepsy and Neurological Disorders, 886, Urushiyama, Shizuoka, 420-8688, Japan.
authors.forename: Katsumi
authors.initials: K
authors.lastname: Imai
authors.affiliation: Department of Clinical Research, National Epilepsy Center, Shizuoka Institute of Epilepsy and Neurological Disorders, 886, Urushiyama, Shizuoka, 420-8688, Japan.
authors.forename: Nobuyuki
authors.initials: N
authors.lastname: Mishima
authors.affiliation: Department of Clinical Pharmaceutics, Graduate School of Pharmaceutical Sciences, University of Shizuoka, 52-1, Yada, Shizuoka, 422-8526, Japan.|Laboratory of Clinical Pharmacokinetics and Drug Safety, Shizuoka General Hospital, 4-27-1 Kita Ando, Shizuoka, 420-8527, Japan.
authors.forename: Yoshiyuki
authors.initials: Y
authors.lastname: Kagawa
authors.affiliation: Department of Clinical Research, National Epilepsy Center, Shizuoka Institute of Epilepsy and Neurological Disorders, 886, Urushiyama, Shizuoka, 420-8688, Japan.
authors.forename: Yushi
authors.initials: Y
authors.lastname: Inoue
mesh_terms: D000293:Adolescent; D000328:Adult; D000927:Anticonvulsants / Q000008:administration & dosage / Q000009:adverse effects* / Q000627:therapeutic use; D002648:Child; D004347:Drug Interactions; D004359:Drug Therapy, Combination; D004827:Epilepsy / Q000188:drug therapy*; D005260:Female; D006801:Humans; D022124:Hyperammonemia / Q000139:chemically induced* / Q000453:epidemiology; D015994:Incidence; D007564:Japan / Q000453:epidemiology; D008297:Male; D012189:Retrospective Studies; D012307:Risk Factors; D014635:Valproic Acid / Q000008:administration & dosage / Q000009:adverse effects* / Q000627:therapeutic use
chemical_list: D000927:Anticonvulsants; D014635:Valproic Acid
keywords: Drug utilization; Hyperammonemia; Pharmacoepidemiology; Pharmacovigilance; Valproic acid