Eur J Clin Pharmacol (2013) 69:1193–1194
`DOI 10.1007/s00228-012-1450-z
`
`LETTER TO THE EDITORS
`
`Gamma-hydroxybutyrate (GHB) and topiramate—clinically
`relevant drug interaction suggested by a case of coma
`and increased plasma GHB concentration
`
`Tobias Weiss & Daniel Müller & Isabelle Marti &
`Caroline Happold & Stefan Russmann
`
`Received: 19 September 2012 / Accepted: 1 November 2012 / Published online: 17 November 2012
`# Springer-Verlag Berlin Heidelberg 2012
`
`To the Editor:
`A 52-year-old woman was hospitalized for worsening
`chronic cluster headache refractory to all guideline-based
`medical and invasive treatments. Based on class IV evi-
`dence [1] she had regularly taken high-dose gamma-
`hydroxybutyrate GHB = sodium oxybate (Xyrem®;
`UCB-Pharma AG, Bulle, Switzerland) 4.5 g twice-nightly
`at 2300 and 0300 hours for the last 6 years. This was the
`only drug that markedly improved her nocturnal headache
`episodes and insomnia. As an additional therapeutic effort,
`topiramate (Topamax®; Janssen-Cilag AG, Baar, Switzer-
`land) was added to the therapeutic regime, with the patient
`taking a single dose of topiramate 25 mg at 1800 hours,
`followed by the usual two daily doses of GHB. The next
`morning the patient had developed confusion, followed by
`intermittent myoclonic jerks, miosis, and a rapid onset of
`coma [Glasgow Coma Scale (GCS) score was 3 at 0800
`hours]. Pulse, blood pressure, respiratory rate, pulse oxi-
`metry, electrocardiogram, and laboratory values, including
`electrolytes and blood glucose, were unremarkable. The
`plasma GHB concentration, determined by gas chromatog-
`raphy–mass spectrometry (GC-MS) of a blood sample
`collected at 0800 hours, was 259 mg/L. One hour later
`
`T. Weiss : I. Marti : C. Happold
`Department of Neurology, University Hospital Zurich,
`Zurich, Switzerland
`
`D. Müller
`Department of Clinical Chemistry, University Hospital Zurich,
`Zurich, Switzerland
`
`S. Russmann (*)
`Department of Clinical Pharmacology and Toxicology,
`University Hospital Zurich, Rämistrasse 100,
`8091 Zurich, Switzerland
`e-mail: stefan.russmann@usz.ch
`
`electroencephalography (EEG) showed intermittent bifron-
`tal theta activity, a pattern described during sedation with
`GHB [2]. At 1300 hours the patient awoke from coma and
`rapidly recovered within a few hours. Topiramate was
`stopped, but GHB was continued as before. Two days later
`the plasma GHB concentration was 91 mg/L based on GC-
`MS analysis of a blood sample collected at 0800 hours.
`In this patient, who was given topiramate concomitant
`with GHB, the GHB concentration 5 h after the second daily
`dose of GHB was 2.8-fold higher than without topiramate,
`and 1.8-fold higher than the peak concentration of 142 mg/L
`that would be expected 0.5–2 h after the daily second dose
`according to Xyrem®’s product information. The patient
`had taken topiramate without concomitant GHB in the past
`without problems. Based on the rapid onset but short dura-
`tion of the otherwise unexplained coma and the EEG find-
`ings, we suggest that the coma was drug induced due to a
`pharmacokinetic interaction between GHB and topiramate.
`GHB has a short half-life of about 30 min [3], and metab-
`olism via GHB-dehydrogenase is its main route of elimina-
`tion [4]. In vitro studies have demonstrated that GHB-
`dehydrogenase is inhibited by the antiepileptic drugs val-
`proate and ethosuximide [4], but according to Xyrem®’s
`product information no interaction studies with antiepilep-
`tics have been performed in humans. Alternatively, changes
`in the bioavailability of GHB or other unknown mechanisms
`of interaction are theoretically possible. In addition, topir-
`amate increases GABA activity at its neuroreceptors, and an
`additional pharmacodynamic interaction must therefore also
`be considered.
`In light of the increasing therapeutic as well as illicit use
`of GHB, as well as of newer antiepileptic drugs, possible
`interactions should be evaluated in formal pharmacokinetic
`studies. In the mean time, we suggest using such combina-
`tions only with great care.
`
`Ranbaxy Ex. 1023
`IPR Petition - USP 9,050,302
`
`

`

`1194
`
`Conflicts of Interest None.
`
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`Eur J Clin Pharmacol (2013) 69:1193–1194
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