Article
Review of toxicity and trends in the use of tiagabine as reported to US poison centers from 2000 to 2012
Human and Experimental Toxicology 1–5 ª The Author(s) 2015 Reprints and permission: sagepub.co.uk/journalsPermissions.nav DOI: 10.1177/0960327115579206 het.sagepub.com
HA Spiller1,2, D Wiles1, JL Russell1 and MJ Casavant1,2
Abstract Background: Tiagabine is a novel antiepileptic that acts by increasing synaptic and extracellular gammaaminobutyric acid concentrations. Information concerning overdose of tiagabine is limited. After introduction, an increasing number of off-label uses suggested that tiagabine use would increase. However in 2005 and 2008, warnings from the Food and Drug Administration (FDA) were issued on the risk of seizures in non-epileptic and increased suicide ideation. We evaluated the temporal trends associated with these two warnings as well as clinical outcomes from tiagabine overdose. Method: A retrospective review of all single substance tiagabine exposures in National Poison Data System (NPDS) from 2000 to 2012. Results: A total of 2147 patients had ingested tiagabine, with a mean of 165 year1. This was disproportionally distributed, with a steep rise leading up to 2004 (max 559 year1) and then a significant decline (p < 0.05) between 2005 and 2006. The number of cases reported to NPDS mirrored the sales of tiagabine. Clinical effects were predominantly neurological, with the most commonly reported effects being drowsiness (27%), agitation (19%), confusion (12%), seizures (11%), and tachycardia (10%). In all, 758 patients (35%) showed a major or moderate medical outcome, with no deaths reported. A disproportionate share of the major outcomes was in the suicide attempt group (73%). The majority of patients (75%) were treated in a health-care facility (HCF). Conclusions: The HCF usage is likely due to high rate of symptomatic patients (59%) and the large proportion of suicide attempt cases. The frequency of tiagabine cases in NPDS mirrored pharmaceutical sales, with steep declines temporally related to the 2005 FDA warning. Keywords Tiagabine, FDA warning, toxicity
Introduction Tiagabine is a novel antiepileptic that acts by binding to the gamma-aminobutyric acid (GABA) uptake transporter in presynaptic neurons and glial cells resulting in increased synaptic and extracellular GABA concentrations. The increased concentration of the inhibitory neurotransmitter GABA is believed to be responsible for the antiepileptic effects. Information concerning overdose of tiagabine is limited to case reports and a single case series.1–9 These reports suggest the effects in supratherapeutic doses and overdoses that follow the GABA neurological mechanism, with lethargy, confusion, and coma. Seizures, convulsive, and nonconvulsive status
epilepticus have also been reported. The epileptogenic mechanism for tiagabine is not known but suggestions have included possible mediation via GABA receptors in the thalamus and stimulation of dopamine, serotonin, or glycine receptors.9,10 An atypical 1
Central Ohio Poison Center, Nationwide Children’s Hospital, Columbus, OH, USA 2 Department of Pediatrics, The Ohio State University College of Medicine, Columbus, OH, USA Corresponding author: HA Spiller, Central Ohio Poison Center, Nationwide Children’s Hospital, 700 Children’s Dr, Columbus, OH 43205, USA. Email: [email protected]
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Human and Experimental Toxicology
presentation has been reported with profuse vomiting, hypersalivation, bradycardia, and hypertension.4 Tiagabine was approved by the Food and Drug Administration (FDA) in 1997 for use in the United States for adjunctive treatment of partial seizures in adults and children 12 years and older. Since its introduction, additional off-label uses have included posttraumatic stress disorder, neuropathic pain, generalized anxiety disorder, cocaine dependence, and rage.11–15 Initially, these wider uses suggested that tiagabine use would continue to increase. However, in February 2005, the US FDA announced that a bolded warning would be added to the labeling for tiagabine to warn prescribers of the risk of seizures in patients without epilepsy being treated with this drug. Although tiagabine has been shown to reduce the frequency of seizures in patients with epilepsy, paradoxically tiagabine’s use has been associated with the occurrence of seizures in patients without epilepsy. In 2008, the FDA notified health-care professionals that tiagabine was 1 of 11 drugs used to treat epilepsy as well as psychiatric disorders and other conditions that may cause increased risk of suicidal thoughts or behavior. We examined National Poison Data System (NPDS) data and compared rate trends in tiagabine exposures reported to poison control centers (PCCs) before and after the issuance of the FDA warnings. We believe that there would be a decrease in overdose/adverse reaction events occurring concomitantly with the warnings due to decreased prescribing and concern for negative effects. While other studies have established a decrease in prescribing following FDA safety warnings, this situation is unusual in that we are able to examine changes in exposure rates following the issuance of multiple FDA warnings and are looking at adverse effects related to exposure to the medication in addition to amount prescribed.16 Additionally, we sought to describe the clinical picture with tiagabine overdose from a large national database.
Methods This was a retrospective review of all human tiagabine patients reported to the NPDS of the American Association of Poison Control Centers (AAPCC) from 2000 through 2012. Inclusion criteria included single substance ingestion of tiagabine in a human. Exclusion criteria were polysubstance ingestion, information calls, animal exposures, and confirmed nonexposure. Additionally, annual sales volume for tiagabine was obtained as a measure of use of
Figure 1. Annual number of patients reported to NPDS with tiagabine poisoning and sales of tiagabine by year. NPDS: National Poison Data System.
tiagabine. Data for tiagabine sales were only available from 2000 through 2010. Year to year means were compared using a Student’s t-test, and monthly trend lines (R2) between 2005 and 2008 were compared. The definitions for medical outcome were the standard definitions used by NPDS as follows: no effect (no signs or symptoms as a result of the exposure), minor effect (signs or symptoms were minimally bothersome and resolved rapidly; e.g. self-limited gastrointestinal symptoms, drowsiness, and sinus tachycardia without hypotension), moderate effect (signs or symptoms were more pronounced, more prolonged, or more systemic in nature, usually requiring treatment but not life threatening; e.g. acid–base disturbances, hypotension rapidly responsive to treatment, and isolated brief seizures), major effect (signs or symptoms were life threatening or resulted in significant residual disability; e.g. repeated seizures or status epilepticus, respiratory compromise requiring intubation, and ventricular dysrhythmias), or death (death resulted from the exposure or direct complication of the exposure). A serious outcome was defined as combining moderate outcome, major outcome, and death.
Results There were 2147 patients with a single substance ingestion of tiagabine. There was a mean of 165 patients/ year, but this was disproportionally distributed with a steep rise leading up to 2004 (max 559 year1) and then a significant decline (p < 0.05) between 2005 and 2006 (Figure 1). A decline in exposures was also noted between 2008 and 2009, but this was found to be nonsignificant. We observed a significant downtrend (R2 ¼ 0.789) in 2005 following the month of February. We did not see a downtrend change throughout the year of 2008 (R2 ¼ 0.0056). The number of cases reported to NPDS mirrored sales reported of tiagabine (Figure 1).
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Spiller et al.
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Table 1. Reported clinical effects with single substance ingestion of tiagabine. Clinical effect Drowsiness/lethargy Agitated Confusion Total with SZ SZ—single SZ—multiple SZ—status epilepticus Tachycardia Dizziness Coma Hypertension Vomiting Mydriasis Slurred speech Dystonia Hypotension Hallucinations/delusions Bradycardia Muscle rigidity Respiratory depression Muscle weakness Headache Fasciculation Fever Acidosis Tachypnea Chest pain
N
Percent of total (%)
570 405 260 226 89 81 56 213 106 99 84 55 45 39 35 23 23 16 15 26 11 10 8 8 7 6 3
26.5 18.9 12.1 10.5 4.1 3.8 2.6 9.9 4.9 4.6 3.9 2.6 2.1 1.8 1.6 1.1 1.1 0.7 0.7 1.2 0.5 0.5 0.4 0.4 0.3 0.3 0.1
Figure 2. Percentages of reason for tiagabine ingestion in all patients and those patients with serious (major of moderate) medical outcome.
SZ: seizures.
Demographically, the mean age of patients was 30.7 years, with 1267 females (59%). The patients were predominantly adults (72%), with 239 young children
Review of toxicity and trends in the use of tiagabine as reported to US poison centers from 2000 to 2012
Human and Experimental Toxicology 1–5 ª The Author(s) 2015 Reprints and permission: sagepub.co.uk/journalsPermissions.nav DOI: 10.1177/0960327115579206 het.sagepub.com
HA Spiller1,2, D Wiles1, JL Russell1 and MJ Casavant1,2
Abstract Background: Tiagabine is a novel antiepileptic that acts by increasing synaptic and extracellular gammaaminobutyric acid concentrations. Information concerning overdose of tiagabine is limited. After introduction, an increasing number of off-label uses suggested that tiagabine use would increase. However in 2005 and 2008, warnings from the Food and Drug Administration (FDA) were issued on the risk of seizures in non-epileptic and increased suicide ideation. We evaluated the temporal trends associated with these two warnings as well as clinical outcomes from tiagabine overdose. Method: A retrospective review of all single substance tiagabine exposures in National Poison Data System (NPDS) from 2000 to 2012. Results: A total of 2147 patients had ingested tiagabine, with a mean of 165 year1. This was disproportionally distributed, with a steep rise leading up to 2004 (max 559 year1) and then a significant decline (p < 0.05) between 2005 and 2006. The number of cases reported to NPDS mirrored the sales of tiagabine. Clinical effects were predominantly neurological, with the most commonly reported effects being drowsiness (27%), agitation (19%), confusion (12%), seizures (11%), and tachycardia (10%). In all, 758 patients (35%) showed a major or moderate medical outcome, with no deaths reported. A disproportionate share of the major outcomes was in the suicide attempt group (73%). The majority of patients (75%) were treated in a health-care facility (HCF). Conclusions: The HCF usage is likely due to high rate of symptomatic patients (59%) and the large proportion of suicide attempt cases. The frequency of tiagabine cases in NPDS mirrored pharmaceutical sales, with steep declines temporally related to the 2005 FDA warning. Keywords Tiagabine, FDA warning, toxicity
Introduction Tiagabine is a novel antiepileptic that acts by binding to the gamma-aminobutyric acid (GABA) uptake transporter in presynaptic neurons and glial cells resulting in increased synaptic and extracellular GABA concentrations. The increased concentration of the inhibitory neurotransmitter GABA is believed to be responsible for the antiepileptic effects. Information concerning overdose of tiagabine is limited to case reports and a single case series.1–9 These reports suggest the effects in supratherapeutic doses and overdoses that follow the GABA neurological mechanism, with lethargy, confusion, and coma. Seizures, convulsive, and nonconvulsive status
epilepticus have also been reported. The epileptogenic mechanism for tiagabine is not known but suggestions have included possible mediation via GABA receptors in the thalamus and stimulation of dopamine, serotonin, or glycine receptors.9,10 An atypical 1
Central Ohio Poison Center, Nationwide Children’s Hospital, Columbus, OH, USA 2 Department of Pediatrics, The Ohio State University College of Medicine, Columbus, OH, USA Corresponding author: HA Spiller, Central Ohio Poison Center, Nationwide Children’s Hospital, 700 Children’s Dr, Columbus, OH 43205, USA. Email: [email protected]
Downloaded from het.sagepub.com by guest on November 16, 2015
2
Human and Experimental Toxicology
presentation has been reported with profuse vomiting, hypersalivation, bradycardia, and hypertension.4 Tiagabine was approved by the Food and Drug Administration (FDA) in 1997 for use in the United States for adjunctive treatment of partial seizures in adults and children 12 years and older. Since its introduction, additional off-label uses have included posttraumatic stress disorder, neuropathic pain, generalized anxiety disorder, cocaine dependence, and rage.11–15 Initially, these wider uses suggested that tiagabine use would continue to increase. However, in February 2005, the US FDA announced that a bolded warning would be added to the labeling for tiagabine to warn prescribers of the risk of seizures in patients without epilepsy being treated with this drug. Although tiagabine has been shown to reduce the frequency of seizures in patients with epilepsy, paradoxically tiagabine’s use has been associated with the occurrence of seizures in patients without epilepsy. In 2008, the FDA notified health-care professionals that tiagabine was 1 of 11 drugs used to treat epilepsy as well as psychiatric disorders and other conditions that may cause increased risk of suicidal thoughts or behavior. We examined National Poison Data System (NPDS) data and compared rate trends in tiagabine exposures reported to poison control centers (PCCs) before and after the issuance of the FDA warnings. We believe that there would be a decrease in overdose/adverse reaction events occurring concomitantly with the warnings due to decreased prescribing and concern for negative effects. While other studies have established a decrease in prescribing following FDA safety warnings, this situation is unusual in that we are able to examine changes in exposure rates following the issuance of multiple FDA warnings and are looking at adverse effects related to exposure to the medication in addition to amount prescribed.16 Additionally, we sought to describe the clinical picture with tiagabine overdose from a large national database.
Methods This was a retrospective review of all human tiagabine patients reported to the NPDS of the American Association of Poison Control Centers (AAPCC) from 2000 through 2012. Inclusion criteria included single substance ingestion of tiagabine in a human. Exclusion criteria were polysubstance ingestion, information calls, animal exposures, and confirmed nonexposure. Additionally, annual sales volume for tiagabine was obtained as a measure of use of
Figure 1. Annual number of patients reported to NPDS with tiagabine poisoning and sales of tiagabine by year. NPDS: National Poison Data System.
tiagabine. Data for tiagabine sales were only available from 2000 through 2010. Year to year means were compared using a Student’s t-test, and monthly trend lines (R2) between 2005 and 2008 were compared. The definitions for medical outcome were the standard definitions used by NPDS as follows: no effect (no signs or symptoms as a result of the exposure), minor effect (signs or symptoms were minimally bothersome and resolved rapidly; e.g. self-limited gastrointestinal symptoms, drowsiness, and sinus tachycardia without hypotension), moderate effect (signs or symptoms were more pronounced, more prolonged, or more systemic in nature, usually requiring treatment but not life threatening; e.g. acid–base disturbances, hypotension rapidly responsive to treatment, and isolated brief seizures), major effect (signs or symptoms were life threatening or resulted in significant residual disability; e.g. repeated seizures or status epilepticus, respiratory compromise requiring intubation, and ventricular dysrhythmias), or death (death resulted from the exposure or direct complication of the exposure). A serious outcome was defined as combining moderate outcome, major outcome, and death.
Results There were 2147 patients with a single substance ingestion of tiagabine. There was a mean of 165 patients/ year, but this was disproportionally distributed with a steep rise leading up to 2004 (max 559 year1) and then a significant decline (p < 0.05) between 2005 and 2006 (Figure 1). A decline in exposures was also noted between 2008 and 2009, but this was found to be nonsignificant. We observed a significant downtrend (R2 ¼ 0.789) in 2005 following the month of February. We did not see a downtrend change throughout the year of 2008 (R2 ¼ 0.0056). The number of cases reported to NPDS mirrored sales reported of tiagabine (Figure 1).
Downloaded from het.sagepub.com by guest on November 16, 2015
Spiller et al.
3
Table 1. Reported clinical effects with single substance ingestion of tiagabine. Clinical effect Drowsiness/lethargy Agitated Confusion Total with SZ SZ—single SZ—multiple SZ—status epilepticus Tachycardia Dizziness Coma Hypertension Vomiting Mydriasis Slurred speech Dystonia Hypotension Hallucinations/delusions Bradycardia Muscle rigidity Respiratory depression Muscle weakness Headache Fasciculation Fever Acidosis Tachypnea Chest pain
N
Percent of total (%)
570 405 260 226 89 81 56 213 106 99 84 55 45 39 35 23 23 16 15 26 11 10 8 8 7 6 3
26.5 18.9 12.1 10.5 4.1 3.8 2.6 9.9 4.9 4.6 3.9 2.6 2.1 1.8 1.6 1.1 1.1 0.7 0.7 1.2 0.5 0.5 0.4 0.4 0.3 0.3 0.1
Figure 2. Percentages of reason for tiagabine ingestion in all patients and those patients with serious (major of moderate) medical outcome.
SZ: seizures.
Demographically, the mean age of patients was 30.7 years, with 1267 females (59%). The patients were predominantly adults (72%), with 239 young children
