Safety of newer generation anti-epileptic drugs in non-accidental overdose: an Irish population study

      Abstract

      Seven new anti-epileptic drugs (AEDs) have become available in Ireland over the last 10 years; data from animal models and clinical trials suggest that they have a superior safety profile to older AEDs. A specific relationship between epilepsy and psychiatric co-morbidity has long been recognised, including the relationship between epilepsy and suicide.
      AEDs are common agents taken in intentional drug overdoses.
      We undertook a study to review the frequency and outcome of non-accidental overdose with seven new AEDS in an Irish population from 1996 to 2000. Method: All reported cases of drug overdoses with AEDs from 1996 to 2000 were reviewed. Data was provided by the National Poisons Information Centre, Beaumont Hospital and the Central Statistics Office. Medical records from Beaumont Hospital were reviewed in specific cases of serious drug toxicities. An extensive review of published literature reviewing the safety profile of these AEDs was performed and medical literature retrieved from the databases of the pharmaceutical industry was similarly reviewed. Results: Of the 164 reported cases of newer AEDs, there were no fatalities among the cases followed up. Conclusion: The absence of mortalities and serious consequences from deliberate self-poisoning with the newer agents is supportive evidence for the superior safety profile of the newer AEDs.

      Keywords

      Introduction

      Over the last 10 years, seven new anti-epileptic drugs (AEDs) have become available in Ireland. These newer agents have a number of advantages over older AEDs.
      • Wilmore L.J.
      Clinical pharmacology of new antiepileptic drugs.
      Many have longer half lives, enabling once or twice daily dosing. They have a reduced potential for drug interactions, and although most of them undergo extensive hepatic metabolism (with the exception of levetiracetam, gabapentin and vigabatrin), they are less likely to cause hepatic enzyme induction, facilitating their use as add-on agents and making polypharmacy safer.
      • Faught E.
      Pharmacokinetic considerations in prescribing antiepileptic drugs.
      • Ferrendelli J.A.
      Concerns with antiepileptic drug initiation: safety, tolerability and efficacy.
      Data from animal models and clinical trials suggest that they have a safety profile which is superior to the older AEDs.
      There are estimated to be up to 40,000 people with epilepsy in Ireland, affecting 1 in 200 adults and 1 in 100 children. This is comparable to the prevalence figures world-wide, estimated at 5–10 per 1000.
      • Bell G.S.
      • Sander J.W.
      The epidemiology of epilepsy: the size of the problem.
      Epilepsy carries with it a mortality rate which is two to three times that of the general population.
      • Barraclough B.M.
      The suicide rate of epilepsy.
      • Camfield C.S.
      • Camfield P.R.
      • Veugelers P.J.
      Death in children with epilepsy: a population-based study.
      While this excess is made up partly by seizure-related accidental deaths
      • Sperling M.R.
      • Feldman H.
      • Kinman J.
      • Liporace J.D.
      • O’Connor M.J.
      Seizure control and mortality in epilepsy.
      (trauma, drowning), sudden unexpected deaths in epilepsy
      • Ficker D.M.
      • So E.L.
      • Shen W.K.
      • Annegers J.F.
      • O’Brien P.C.
      • Cascino G.D.
      • et al.
      Population-based study of the incidence of sudden unexpected death in epilepsy.
      (SUDEP) and death from underlying diseases (e.g. strokes, infections of the central nervous system), a recognised contribution comes from drug intoxication.
      • Goodwin F.K.
      Anticonvulsant therapy and suicide risk in affective disorders.
      • Greenwood R.S.
      Adverse effects of antiepileptic drugs.
      • Morrow J.L.
      • Routledge P.A.
      Poisoning by anticonvulsants.
      Gowers in 1901 was the first to recognise and document a specific association between epilepsy and suicide.

      Robertson MM. Suicide, parasuicide and epilepsy. In: Engel J, Pedley TA, editors. Epilepsy: a comprehensive textbook [chapter 202].

      The association between epilepsy and psychiatric co-morbidity is well recognised. AEDs are relatively common agents taken in intentional drug overdose.
      • Nordentoft M.
      • Breum L.
      • Munck L.K.
      • Nordestgaard A.G.
      • Hunding A.
      • Bjaeldager P.A.L.
      High mortality by natural and unnatural cases: a 10 year follow up study of patients admitted to a poisoning treatment centre after suicide attempts.
      Hawton et al.
      • Hawton K.
      • Fagg J.
      • Marsack P.
      Association between epilepsy and attempted suicide.
      looked at the association between suicide and epilepsy over a 2-year period (1976–1977). Eighty-four percent of suicide attempts among patients with epilepsy in this study involved self-poisoning, and in 65% of these cases, AEDs were consumed. A 6-year retrospective study by Manon-Espaillat et al.
      • Manon-Espaillat R.
      • Burnstine T.H.
      • Remler B.
      • Reed R.C.
      • Osorio I.
      Antiepileptic drug intoxication: factors and their significance.
      found that suicide occurred in 18% of reported drug intoxications with AEDs between 1979 and 1985. The incidence of suicide in patients with epilepsy as a percentage of deaths in the same population was averaged over 17 studies at 13.2%. More recent figures suggest an incidence of 5–7%
      • Shackleton D.P.
      • Westendorp R.G.J.
      • Trenite D.G.A.K.N.
      • Vandenbroucke J.P.
      Mortality in patients with epilepsy: 40 years of follow up in a Dutch cohort study.
      and male patients with epilepsy are a particularly vulnerable group.
      • Leppik I.E.
      Issues in the treatment of epilepsy.
      The prevalence of depression has been reported as 60% in certain epilepsy populations.
      • Piazzinni A.
      • Canger R.
      Depression and anxiety in patients with suicide.
      • Mendez M.F.
      • Cummings J.
      • Benson F.
      Depression in epilepsy.
      Mendez et al.
      • Mendez M.F.
      • Lanska D.J.
      • Manon-Espaillat R.
      • Burnstine T.H.
      Causative factors for suicide attempts by overdose in epileptics.
      reviewed the possible causative factors for deliberate self-poisoning in epilepsy. Across the cohort of patients who were hospitalised for suicide attempts by drug overdose, when matched by age, sex and race, patients with epilepsy had more borderline personality disorders with multiple impulsive suicide attempts and psychosis compared with patients without epilepsy.
      • Mendez M.F.
      • Doss R.C.
      Ictal and psychiatric aspects of suicide in epileptic patients.
      Patients with complex partial seizures were especially felt to be at high risk from attempted suicide. A case control study evaluating a large cohort of patients in Sweden, found a high incidence of psychiatric disease amongst the patients with epilepsy who attempted suicide, with depression being the most common diagnosis.
      • Nilson L.
      • Tomson T.
      • Farahmand B.Y.
      • Diwan V.
      • Persson P.G.
      Cause-specific mortality in epilepsy: a cohort of more than 9000 patients once hospitalised for epilepsy.
      • Nilsson L.
      • Ahlbom A.
      • Farahmand B.Y.
      • Asberg M.
      • Tomson T.
      Risk factors for suicide in epilepsy: a case control study.
      In excess of 81% of this group carried a diagnosis of intercurrent psychiatric disease. Hence, the safety of anti-convulsants has significant implications for the management and prevention of mortality in situations of non-accidental overdose.
      In acute toxicity studies with gabapentin in mice and rats, at maximum doses of 2000–8000 mg/kg, ataxia and laboured breathing were reported but no deaths. With gabapentin, at doses exceeding 600 mg, saturation of the carrier-mediated absorption pathway results in reduced bioavailability with increasing doses.
      • Fischer J.H.
      • Barr A.N.
      • Rogers S.L.
      • Fischer P.A.
      • Trudeau V.L.
      Lack of serious toxicity following gabapentin overdose.
      The mean lethal doses of lamotrigine in mice and rats have been established.
      • Richens A.
      Safety of lamotrigine.
      Acute median oral lethal doses for mice were 202–245 and 163–205 mg/kg for rats. Animal studies with levetiracetam demonstrated selective protection against induced seizures with a very high safety margin for the drug in rodents.
      • Klitgaard H.
      • Matagne A.
      • Gobert J.
      • Wulfert E.
      Evidence for a unique profile of levetiracetam in rodent models of seizures and epilepsy.
      With oxcarbazepine, there is a low level of hepatic induction of cytochrome P450 microsomal system.
      • Tecoma E.S.
      Oxcarbazeine.
      In acute toxicity studies across multiple species, extremely high doses of oral oxcarbazepine were tolerated and there were no compound-related deaths. Animal studies with topiramate demonstrated, there was no accumulation of the drug at higher doses and there was no autoinduction or inhibition of enzymes that metabolise topiramate.
      • Streeter A.J.
      • Stahle P.L.
      • Holland M.L.
      • Pritchard J.F.
      • Takacs A.R.
      Pharmacokinetics and bioavailability of topiramate in the beagle dog.
      The clinical development of vigabatrin was delayed by the finding of microvacuolation in the white matter of rodents and dogs.
      • Mumford J.P.
      • Cannon D.J.
      Vigabtrin.
      Since then however, extensive studies have confirmed that microvacuolation is species specific and does not occur in humans.

      Methods

      We undertook a study to examine the frequency and outcome of non-accidental overdose with seven newer AEDs in an Irish population during the 5-year period 1996–2000. A study of this nature has not been undertaken in Ireland previously. This retrospective study was performed in the Department of Neurology, Beaumont Hospital in collaboration with the National Poisons Information Centre (NPIC), Beaumont Hospital.
      We reviewed data provided by the NPIC and the Central Statistics Office (CSO). The NPIC are contacted by hospitals all around the country when patients present to Accident and Emergency (A&E) departments with deliberate self-poisoning. The type of agent(s) and severity of the overdose reported is noted by the NPIC and any potentially fatal overdoses are followed up by the NPIC through telephone contact with the relevant medical team in Beaumont Hospital. The CSO keep a register of all reported deaths due to AEDs. Deaths from anti-convulsant agents other than phenytoin and succinimides are represented within a single category by the CSO, therefore it is not possible to distinguish mortalities from data between individual AEDs.
      In addition, we undertook an extensive literature review of established case reports of overdose with the newer AEDs and the published literature reviewing the general safety profile of these drugs. We were assisted by medical information from the pharmaceutical industry retrieved from their databases, specifically addressing the safety profile of these agents in situations of overdose. The pharmaceutical industry had comprehensive data for any potential fatalities from poisoning with the newer AEDs from 1996 to 2000.
      A comparative review was undertaken with the older agents for the same time period.

      Results

      The total number of reported overdoses using any of the seven newer AEDs over the 5-year period 1996–2000 inclusive was 164. In addition there were three reports from the United Kingdom and seven others requesting information.
      The majority of overdoses involved more than one agent (115 of 164 cases). There were no reported mortalities among the cases reported from 1996 to 2000 (see Table 1). It was possible to confirm this through follow up information from both the NPIC and the pharmaceutical industry data.
      Table 1Figures for non-accidental cases of overdose with the newer AEDs based on reports to the NPIC, Beaumont Hospital.
      DrugYearNo. of reportsSingle/multiple
      Gabapentin19962Both > 1 drug
      19971>1 drug
      1998117 cases > 1 drug
      199974 cases > 1 drug
      20001210 cases > 1 drug
      Lamotrigine199686 cases > 1 drug
      19971811 cases > 1 drug
      19981713 cases > 1 drug
      19992817 cases > 1 drug
      20002616 cases > 1 drug
      Levetiracetam1996–19990
      20001>1 drug
      Oxcarbazepine1996–20000
      Tiagabine1996–19980
      19992>1 drug
      20003>1 drug
      Topiramate1996–19980
      19991>1 drug
      200064 cases > 1 drug
      Vigabatrin199663 cases > 1 drug
      19973All > drug
      199865 cases > 1 drug
      19993All > 1 drug
      20003All > 1 drug
      From 1996 to 2000, eight of the cases of deliberate self-poisoning recorded above were admitted and treated at Beaumont Hospital. Three patients overdosed with lamotrigine, three patients with gabapentin and two patients with vigabatrin. Representative brief case histories of their brief admissions are as follows.

       Case 1

      An 18-year-old girl, with a background of epilepsy, presented to the A&E department with convulsions. Through collateral history, it was discovered that she has ingested 45 tablets of lamotrigine and 20 tablets of penicillin in the previous 2 h. The precise doses ingested are not known. She was treated with activated charcoal and underwent cardiac monitoring. She recovered on supportive therapy without complication.

       Case 2

      A 21-year-old man presented to the A&E department with drowsiness having taken an overdose of his medications which consisted of sodium valproate, carbamazepine, thioridazine and gabapentin. It was uncertain how many tablets he ingested in total. He was too drowsy for gastric lavage or charcoal administration. He was monitored closely and treated symptomatically and subsequently made a complete recovery.

       Case 3

      A 22-year-old woman with a background history of epilepsy, presented to the A&E department, admitting to consuming unknown quantities of vigabatrin and carbamazepine. She was asymptomatic at presentation and was treated with activated charcoal. She remained asymptomatic and was discharged after overnight observation and psychiatric review.

      Discussion

      From review of published literature and medical information provided from the pharmaceutical industry database, deliberate overdoses with the seven newer agents are infrequent (see Table 2). Acute life-threatening toxicity has not been observed to date with gabapentin. Reduced absorption of the drug at higher doses may limit drug bioavailability at the time of overdosing, therefore reducing toxicity. Overdose with up to 49 g of gabapentin has resulted in no serious consequences.
      • Fischer J.H.
      • Barr A.N.
      • Rogers S.L.
      • Fischer P.A.
      • Trudeau V.L.
      Lack of serious toxicity following gabapentin overdose.
      With lamotrigine, numerous case reports show recovery without serious sequel for doses up to 4.5 g.
      • Briassoulis G.
      • Kalabalikis P.
      • Tamiolaki M.
      • Hatzis T.
      Lamotrigine childhood overdose.
      • Buckley N.A.
      • Whyte I.M.
      • Dawson A.H.
      Self-poisoning with Lamotrigine.
      • O’Donnell J.
      • Batemen N.
      Lamotrigine overdose in an adult.
      However, fatalities have been reported in cases of lamotrigine poisoning. In a post-mortem case, where the distribution of lamotrigine was determined, the blood concentration of lamotrigine was 52 mg/l (therapeutic range of up to 14 mg/l) with no other AEDs detected. The precise cause of death in this case was undetermined.
      • Levine B.
      • Jufer R.A.
      • Smialek J.E.
      Lamotrigine distribution in two postmortem cases.
      Both gabapentin and lamotrigine confer an additional advantage in prescribing that they have both been reported to have mood stabilising effects in patients.
      Table 2Case reports retrieved from pharmaceutical industry databases based on information submitted to the AED manufacturers.
      DrugPharmaceutical industry data
      GabapentinUnpublished case reports submitted to manufacturer. Single published case report of ingestion of 49 g with complete recovery following supportive treatment.
      • Fischer J.H.
      • Barr A.N.
      • Rogers S.L.
      • Fischer P.A.
      • Trudeau V.L.
      Lack of serious toxicity following gabapentin overdose.
      LamotrigineOverdoses up to 15 g have been reported. Numerous case reports published and unpublished available. Fatalities reported from CNS and cardiovascular toxicity.
      LevetiracetamNo case reports.
      OxcarbazepineNo case reports.
      TiagabineNumerous case reports including 23 cases published in a single study.
      • Damgaard B.
      • Friis S.
      Overdose experience with Tiagabine.
      No serious sequel reported.
      TopiramateFive cases of overdoses with doses ranging from 1.8 to 100 g. One unpublished case report submitted to the manufacturer. All cases recovered without complication.
      VigabatrinSingle published case report of overdosage.
      There have been no case reports relating to acute intoxication with either levetiracetam or oxcarbazepine to date. There have been unpublished reports of overdoses with topiramate, with overdoses of up to 100 g of topiramate, without any resulting fatality. A study reviewing 23 cases of overdose with tiagabine reported complete recovery in all patients.
      • Leach J.P.
      • Stolarek I.
      • Brodie M.J.
      Deliberate overdose with the novel anticonvulsant tiagabine.
      • Damgaard B.
      • Friis S.
      Overdose experience with Tiagabine.
      There have been no case reports relating to acute intoxication with either levetiracetam or oxcarbazepine and no reported fatalities with vigabatrin in the published literature to date.
      In our study, we found that despite the number of patients who took overdoses of the newer AEDs, whether in isolation or in combination with other drugs, there were no fatalities seen amongst the 164 reported cases. The only other comparable population study in the literature was a Polish study, which was conducted between 1990 and 1992 by Miller et al., looking at suicide attempts reported through their Poisons Control Centre.
      • Miller K.
      • Kloptowski T.
      • Rosciszewska D.
      Suicide attempts in epileptic patients during the years 1990–92. Analysis of patients in the Regional Poison Control Center in Sosnowiec.
      In the above study, 9% of all patients treated for attempted suicide carried a diagnosis of epilepsy.
      The number of cases of non-accidental overdose with the older anti-convulsants reported to the NPIC between 1996 and 2000 is represented in Table 3. The outcome of cases that were admitted solely to Beaumont Hospital is represented in Table 4. There were no fatalities amongst the 26 cases admitted. Five of these admissions, however were prolonged hospital admissions lasting a minimum of 1 week, signifying more serious consequences from drug toxicity.
      Table 3Total number of anti-convulsant overdoses involving older agents reported to the NPIC between 1996 and 2000, excluding any cases involving the seven newer anti-convulsants.
      Name of drugNumber of reports to NPIC 1996–2000Number of cases with >1 drug involved
      Carbamazepine14987
      Clobazam107
      Ethosuximide00
      Phenobarbitone3516
      Phenytoin4327
      Sodium valproate8354
      Table 4Number of overdoses with older AEDs admitted to Beaumont Hospital from 1996 to 2000.
      YearNumber of overdoses with older AEDs admitted to Beaumont HospitalOutcome of admissions
      19961Overnight admission.
      19973No fatalities. One overnight admission. Two cases requiring hospitalisation for >1 week and prolonged monitoring.
      19983No fatalities. One prolonged admission (>1 week).
      199912No fatalities. One prolonged admission (1 week).
      20007No fatalities. One prolonged admission (>1 week).
      There were 320 cases of poisoning with older AEDs reported to the NPIC. The number of fatalities outside admissions to Beaumont Hospital cannot be determined for the same time period. There are, however, numerous case reports citing non-accidental overdoses and case reports of fatalities with most of the older AEDs.
      • Costello J.B.
      • Poklis A.
      Treatment of massive phenobarbital overdose with dopamine diuresis.
      • Connacher A.A.
      • Macnab M.S.
      • Moody J.P.
      • Jung R.T.
      Fatality due to massive overdose of sodium valproate.
      • Mellick L.B.
      • Morgan J.A.
      • Mellick G.A.
      Presentations of acute phenytoin overdose.
      Acute, life threatening fatalities have been reported with phenobarbitone,
      • Costello J.B.
      • Poklis A.
      Treatment of massive phenobarbital overdose with dopamine diuresis.
      sodium valproate,
      • Connacher A.A.
      • Macnab M.S.
      • Moody J.P.
      • Jung R.T.
      Fatality due to massive overdose of sodium valproate.
      phenytoin
      • Mellick L.B.
      • Morgan J.A.
      • Mellick G.A.
      Presentations of acute phenytoin overdose.
      and carbamazepine.
      • Bush D.M.
      • Levine B.S.
      • Smyth B.F.
      • Caplan V.H.
      A fatal intoxication involving carbamazepine, desimipramine and ethylene glycol.
      This contrasts with the paucity of fatalities from the newer AEDs.
      Given the high incidence of impulsive suicidal gestures reported among patients with epilepsy, especially partial epilepsy, as well as the high prevalence of depression, the newer generation AEDs may confer an additional advantage in prescribing. The absence of serious consequences from deliberate self-poisoning of these agents in our study is supportive evidence for their superior safety profile in normal prescribing but also in the management and prevention of fatality from the significant risk of non-accidental overdose of AEDs in individuals with epilepsy.

      Acknowledgements

      We would like to acknowledge the assistance of the Central Statistics Office, Dublin and the following pharmaceutical companies for medical information provided: Aventis Pharma, GlaxoSmithKline, Janssen-Cilag, Novartis Ireland, Pfizer, Sanofi-Winthrop Ireland, UCB Pharma, United Drug House.

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