a) Hypertension has been reported as occurring in at least 1 of 100 patients participating in tiagabine clinical trials (Prod Info GABITRIL(R) oral tablets, 2010).

a) Hypertension was reported in a 44-year-old woman who intentionally ingested 1500 mg of tiagabine. At presentation, her blood pressure was 205/60 mmHg (Forbes et al, 2007).

a) Palpitations and tachycardia were reported as frequent occurrences following therapeutic administration of tiagabine during stage 2 and stage 3 of clinical trials (Prod Info GABITRIL(R) oral tablets, 2005).

a) A 44-year-old woman who intentionally ingested 1500 mg of tiagabine presented bradycardic, with pulses ranging between 40 to 60 beats/min(Forbes et al, 2007).

a) Bronchitis, dyspnea, and pneumonia have been reported as frequent occurrences in 2,531 patients who participated in phase 2 and phase 3 tiagabine clinical trials (Prod Info GABITRIL(R) oral tablets, 2005).

a) Respiratory depression has been reported following tiagabine overdose (Bauer & Cooper-Mahkorn, 2008).
b) RETROSPECTIVE CASE SERIES: Data reported over a two year period from 6 poison control centers and one statewide poison control system were reviewed for tiagabine only ingestions. Fifty-seven cases met inclusion criteria. Respiratory depression was reported in 21% (12/57) of the cases. The mean dose for patients developing respiratory depression was 270 mg (range: 96 to 680 mg) (Spiller et al, 2005).

a) During tiagabine clinical trials, CNS depression occurred in 5% to 7% of patients treated with tiagabine (Prod Info GABITRIL(R) oral tablets, 2010; Leppik, 1995; Shorvon & Stefan, 1997).

a) CNS depression was a common occurrence among eleven patients who ingested up to 800 mg of tiagabine, in single doses, during clinical trials (Prod Info GABITRIL(R) oral tablets, 2010).

a) SUMMARY: Coma has been reported following tiagabine overdose (Bauer & Cooper-Mahkorn, 2008).
b) CASE REPORT: A 44-year-old woman was found unresponsive after intentionally ingesting 1500 mg of tiagabine and declined into a coma that lasted 10 hours post ingestion. After awaking spontaneously with profound agitation, the patient was given supportive care and made a full recovery within 26 hours (Forbes et al, 2007).
c) CASE REPORT: A 30-year-old man intentionally ingested 320 mg tiagabine and 400 mg phenytoin and subsequently deteriorated into a grade III coma. The patient completely recovered without any active intervention, and there was no evidence of a neurological deficit 12 hours later (Leach et al, 1995).
d) RETROSPECTIVE CASE SERIES: Data reported over a two year period from six poison control centers and one statewide poison control system were reviewed for tiagabine only ingestions. Fifty-seven cases met inclusion criteria. Coma was reported in 28% (16/57) of the cases. The mean dose for patients developing coma was 270 mg (range: 96 to 680 mg) (Spiller et al, 2005).

a) In postmarketing experience, new onset seizures and status epilepticus have occurred in patients without epilepsy (Prod Info GABITRIL(R) oral tablets, 2010).
b) During controlled and uncontrolled epilepsy studies, 5% of patients receiving tiagabine experienced some form of status epilepticus. Approximately 33% of patients with a history of status epilepticus had a recurrence during tiagabine treatment, indicating that a previous history of status epilepticus is a critical risk factor in patients receiving tiagabine (Sabers & Gram, 2000; Prod Info GABITRIL(R) oral tablets, 2005).
c) Following a 4 week tiagabine withdrawal period, more patients experienced an increase in seizure frequency, indicating that tiagabine should be withdrawn gradually to minimize the potential for an increase in the occurrence of seizures (Prod Info GABITRIL(R) oral tablets, 2010).
d) Three patients, on tiagabine therapy to control seizures, experienced increasing unresponsiveness and trance-like states, that lasted from 30 minutes to three hours, after the tiagabine dose was increased to 48 milligrams/day, in one patient, and 60 milligrams/day in the other two patients. These episodes were clinically consistent with the diagnosis of non-convulsive status epilepticus. The patients' behavior resolved following the reduction of the tiagabine dose in one patient and the discontinuation of tiagabine in the other two patients (Schapel & Chadwick, 1996).
e) CASE REPORT: A 27-year-old woman who was treated with tiagabine for documented pseudoseizure developed non-convulsive status epilepticus after 3 weeks at a dose of tiagabine 56 milligrams/day. After 2 days of intermittent confusion, she was lethargic, disoriented, slow in speech and showed generalized sharp and slow discharges on her electroencephalogram (EEG). Tiagabine was discontinued and she was treated with lorazepam 2 milligrams twice within 10 minutes. Her mental status and EEG returned to normal. Subsequent episodes of pseudoseizure occurred and were confirmed again to be nonepileptic. Thus, tiagabine may induce seizures in patients without epilepsy (zhu & Vaughn, 2002).
f) CASE REPORT: A 30-year-old man (110 kg) developed nonconvulsive status epilepticus when tiagabine was added to his stable antiepileptic medication of lamotrigine 400 mg daily and valproate 300 mg daily. The initial tiagabine dose of 5 milligrams/day was increased weekly by 5 milligrams/day. When the dose reached 20 milligrams/day, he was hospitalized in a confused state, with slowed reactions and speech, and with inability to finish a sentence or to recall 3 previously shown items after 5 minutes. An EEG revealed complex-partial status with bilateral spike-wave activity. Discontinuation of tiagabine resulted in normalization of the EEG and behavior. The authors noted that most previously reported cases occurred at doses of 40 milligrams/day or more (Fitzek et al, 2001).

a) CASE REPORT: A patient experienced status epilepticus after ingesting a 400 mg single dose of tiagabine. The patient recovered following administration of intravenous phenobarbital (Prod Info GABITRIL(R) oral tablets, 2005).
b) CASE REPORT: Status epilepticus was reported in a patient without an underlying seizure disorder approximately 1 hour after ingesting an unknown amount of tiagabine. Clinically, the seizures subsided following intubation with 20 milligrams diazepam and 200 mg succinylcholine, with a total seizure time of 2.5 hours. A subsequent EEG revealed further subclinical seizure activity. Administration of a continuous midazolam infusion completely stopped all seizures (Viner et al, 1999). Using pharmacokinetic calculations, the authors estimated that the patient may have ingested 52 to 84 mg of tiagabine.
c) CASE REPORT: Following a suicide attempt, a 39-year-old man developed convulsive status epilepticus after ingesting an unknown amount of tiagabine (tiagabine level 1,870 nanograms/milliliter). Prolonged video-EEG revealed sustained myoclonic jerks and continuous generalized bursts of spike-and-wave activity. Following supportive care, his mental status returned to normal. A week later, he was readmitted for recurrent convulsive status epilepticus after ingesting approximately 1 gram of tiagabine (tiagabine level 2,620 nanograms/milliliter). He was admitted to psychiatric care following recovery (Ostrovskiy et al, 2002).
d) CASE REPORT: Non-convulsive status epilepticus was reported in a 14-year-old girl with no prior history of seizure who ingested an unknown amount of tiagabine (estimated amount 180 milligrams). A tiagabine plasma level obtained on arrival to the emergency department was 420 nanograms/milliliter. Attempted anitconvulsant therapy included diazepam, lorazepam, and pyridoxine. EEG monitoring showed seizure activity which was suppressed with a continuous midazolam infusion. Approximately 96 hours after admission, the midazolam infusion was weaned. The patient was discharged to psychiatry with no neurologic sequelae (Fulton et al, 2005; Jette et al, 2006). The patient remained seizure-free one year after discharge.
e) CASE REPORT: A 2-year-old girl (13 kg), developed generalized tonic-clonic seizure activity after ingesting 90 milligrams of tiagabine. Serum concentrations were 530 and 130 nanograms/milliliter at 5 and 11 hours post ingestion, respectively. With supportive care, the patient made a full recovery within 27 hours of presentation (Kazzi et al, 2006).

a) Seizures and status epilepticus have occurred in overdose (Prod Info GABITRIL(R) oral tablets, 2010).
b) RETROSPECTIVE CASE SERIES: Data reported over a two year period from six poison control centers and one statewide poison control system were reviewed for tiagabine only ingestions. Fifty-seven cases met inclusion criteria. Multiple discrete seizures were reported in 28% (16/57) of the cases. Status epilepticus was reported in 5% (3/57) of the cases. Single episode seizure was reported in 4% (2/57) cases. The mean dose associated with seizures was 224 mg (range: 96 to 680 mg) (Spiller et al, 2005).

a) Dizziness occurred in 27% to 31% of patients during tiagabine clinical trials (Sabers & Gram, 2000; Prod Info GABITRIL(R) oral tablets, 2010; Leppik, 1995; Shorvon & Stefan, 1997).
b) During a study to evaluate the pharmacokinetics and safety of tiagabine administration in patients with various degrees of hepatic function, dizziness was reported as an adverse effect in four of the six healthy volunteers. Dizziness was reported in all of the patients (n=4) with mild hepatic impairment and in 25% of the patients (n=4) with moderate hepatic impairment (Lau et al, 1997).

a) RETROSPECTIVE CASE SERIES: Data reported over a two year period from six poison control centers and one statewide poison control system were reviewed for tiagabine only ingestions. Fifty-seven cases met inclusion criteria. Dizziness was reported in 11% (6/57) of the cases (Spiller et al, 2005).

a) During tiagabine clinical trials, 20% to 24% of patients experienced asthenia, and during dose-response tiagabine studies, asthenia was reported in 23% and 18% of patients who ingested 56 mg and 32 mg, respectively (Sabers & Gram, 2000; Prod Info GABITRIL(R) oral tablets, 2005; Leppik, 1995; Shorvon & Stefan, 1997).

a) Fatigue, lethargy, and drowsiness have been reported following tiagabine overdoses of up to 800 milligrams (Prod Info GABITRIL(R) oral tablets, 2010).
b) RETROSPECTIVE CASE SERIES: Data reported over a two year period from six poison control centers and one statewide poison control system were reviewed for tiagabine only ingestions. Fifty-seven cases met inclusion criteria. Lethargy was reported in 56% (32/57) of the cases (Spiller et al, 2005).

a) Agitation occurred following ingestions of tiagabine up to 800 mg as single doses (Prod Info GABITRIL(R) oral tablets, 2010).
b) RETROSPECTIVE CASE SERIES: Data reported over a two year period from six poison control centers and one statewide poison control system were reviewed for tiagabine only ingestions. Fifty-seven cases met inclusion criteria. Agitation was reported in 32% (18/57) of the cases (Spiller et al, 2005).
c) CASE REPORT: A 44-year-old woman intentionally ingested 1500 mg of tiagabine and deteriorated into a coma. The patient awoke from the coma 10 hours later, but recovery was complicated by a profound agitated delirium that resembled a central anticholinergic delirium with paranoia and visual hallucinations. This behavior persisted for 12 hours, and a full recovery was made within 26 hours of ingestion with supportive care (Forbes et al, 2007).

a) Nervousness occurred in 10% to 14% of patients involved in placebo-controlled tiagabine clinical trials, and in 14% and 11% of patients who ingested 56 mg or 32 mg, respectively, during tiagabine dose-response clinical trials (Sabers & Gram, 2000; Prod Info GABITRIL(R) oral tablets, 2005; Leppik, 1995; Shorvon & Stefan, 1997; Anon, 1995).

a) Dysphasia occurred in 4% of patients during tiagabine clinical trials and following overdose ingestions up to 800 mg as single doses (Prod Info GABITRIL(R) oral tablets, 2010).

a) Confusion was reported in 5% of patients involved in tiagabine clinical trials and was due to discontinuation of tiagabine therapy in 1.1% of patients (Prod Info GABITRIL(R) oral tablets, 2010).

a) RETROSPECTIVE CASE SERIES: Data reported over a two year period from six poison control centers and one statewide poison control system were reviewed for tiagabine only ingestions. Fifty-seven cases met inclusion criteria. Confusion was reported in 30% (17/57) of the cases (Spiller et al, 2005).

a) Tremor occurred in 9% to 21% of patients involved in tiagabine clinical trials (Prod Info GABITRIL(R) oral tablets, 2010; Leppik, 1995; Shorvon & Stefan, 1997).
b) Tremor was reported in 50% of the patients (n=4) who had mild or moderate hepatic impairment while on tiagabine therapy (Lau et al, 1997).

a) RETROSPECTIVE CASE SERIES: Data reported over a two year period from six poison control centers and one statewide poison control system were reviewed for tiagabine only ingestions. Fifty-seven cases met inclusion criteria. Tremor was reported in 19% (11/57) of the cases (Spiller et al, 2005).

a) Amnesia was reported as a frequent adverse effect during a tiagabine efficacy study. It was reported that the patients experienced only mild memory problems and no patient was dropped from the study for that reason (Sabers & Gram, 2000; Anon, 1995).

a) CASE REPORT: A 46-year-old woman with a history of anxiety and depression developed an extrapyramidal reaction after ingesting 18 tiagabine tablets (72 mg). She was found confused and nonverbal while wandering in a field. The physical examination revealed abnormal facial grimacing, rigid flexure posturing of both upper extremities, and 7 mm reactive pupils. She was able to track visually but was non-verbal and unable to follow commands. She was treated with diphenhydramine 50 mg without effect. She was then given lorazepam 2 mg with improvement; all her symptoms resolved within 12 hours of admission. Tiagabine blood concentrations were not drawn (Cantrell et al, 2004).
b) RETROSPECTIVE CASE SERIES: Data reported over a two year period from 6 poison control centers and one statewide poison control system were reviewed for tiagabine only ingestions. Fifty-seven cases met inclusion criteria. Dystonia and abnormal posturing were reported in 11% (6/57) of the cases (Spiller et al, 2005).

a) Nausea and vomiting occurred in 11% and 7%, respectively, of patients during placebo-controlled clinical trials of tiagabine. Approximately 9% of patients experienced nausea and 3% of patients experienced vomiting after administration of the placebo (Prod Info GABITRIL(R) oral tablets, 2010).
b) During tiagabine studies, 2% to 10% of patients developed diarrhea (Prod Info GABITRIL(R) oral tablets, 2010; Leppik, 1995; Shorvon & Stefan, 1997).
c) Nausea was reported in 1 of 6 healthy volunteers who were involved in a pharmacokinetic and safety study of tiagabine in patients with various degrees of hepatic function. Approximately 25% of patients (n=4) with mild hepatic impairment and 50% of patients (n=4) with moderate hepatic impairment also experienced nausea (Lau et al, 1997).

a) Profuse vomiting was reported in a an adult following an intentional ingestion of 1500 mg of tiagabine (Forbes et al, 2007).

a) Abdominal pain occurred in 5% to 7% of patients taking tiagabine, during clinical trials (Sabers & Gram, 2000; Prod Info GABITRIL(R) oral tablets, 2010; Anon, 1995).

a) Hypersalivation was reported in one adult after an intentional ingestion of 1500 mg of tiagabine (Forbes et al, 2007).

a) Two patients developed maculopapular rashes following tiagabine treatment during premarketing clinical trials (Prod Info GABITRIL(R) oral tablets, 2010).
b) One patient, involved in a pharmacokinetic and safety tiagabine study, developed a maculopapular rash and itching on her arms, back, and chest, possibly associated with tiagabine administration. The rash resolved in 19 days (Lau et al, 1997).

a) One patient developed a vesiculobullous rash after receiving tiagabine therapy during premarketing clinical trials (Prod Info GABITRIL(R) oral tablets, 2010).

a) Stevens-Johnson syndrome was reported by one patient following tiagabine therapy during premarketing clinical trials (Prod Info GABITRIL(R) oral tablets, 2010).

a) Myalgias occurred in 5% and 2% of patients following tiagabine ingestions of 56 mg and 32 mg, respectively, during dose-response studies (Prod Info GABITRIL(R) oral tablets, 2005).

a) Obtain and ECG in patients with tachycardia or bradycardia.
b) Monitor blood pressure for possible hypertension.

a) Consider administration of activated charcoal after a potentially toxic ingestion (Chyka et al, 2005). Administer charcoal as an aqueous slurry; most effective when administered within one hour of ingestion.

a) Use a minimum of 240 milliliters of water per 30 grams charcoal (FDA, 1985). Optimum dose not established; usual dose is 25 to 100 grams in adults and adolescents; 25 to 50 grams in children aged 1 to 12 years (or 0.5 to 1 gram/kilogram body weight) ; and 0.5 to 1 gram/kilogram in infants up to 1 year old (Chyka et al, 2005).
b) ADVERSE EFFECTS/CONTRAINDICATIONS

a) Attempt initial control with a benzodiazepine (eg, diazepam, lorazepam). If seizures persist or recur, administer phenobarbital or propofol.
b) Monitor for respiratory depression, hypotension, and dysrhythmias. Endotracheal intubation should be performed in patients with persistent seizures.
c) Evaluate for hypoxia, electrolyte disturbances, and hypoglycemia (or, if immediate bedside glucose testing is not available, treat with intravenous dextrose).

a) ADULT DOSE: Initially 5 to 10 mg IV, OR 0.15 mg/kg IV up to 10 mg per dose up to a rate of 5 mg/minute; may be repeated every 5 to 20 minutes as needed (Brophy et al, 2012; Prod Info diazepam IM, IV injection, 2008; Manno, 2003).
b) PEDIATRIC DOSE: 0.1 to 0.5 mg/kg IV over 2 to 5 minutes; up to a maximum of 10 mg/dose. May repeat dose every 5 to 10 minutes as needed (Loddenkemper & Goodkin, 2011; Hegenbarth & American Academy of Pediatrics Committee on Drugs, 2008).
c) Monitor for hypotension, respiratory depression, and the need for endotracheal intubation. Consider a second agent if seizures persist or recur after repeated doses of diazepam .

a) DIAZEPAM may be given rectally or intramuscularly (Manno, 2003). RECTAL DOSE: CHILD: Greater than 12 years: 0.2 mg/kg; 6 to 11 years: 0.3 mg/kg; 2 to 5 years: 0.5 mg/kg (Brophy et al, 2012).
b) MIDAZOLAM has been used intramuscularly and intranasally, particularly in children when intravenous access has not been established. ADULT DOSE: 0.2 mg/kg IM, up to a maximum dose of 10 mg (Brophy et al, 2012). PEDIATRIC DOSE: INTRAMUSCULAR: 0.2 mg/kg IM, up to a maximum dose of 7 mg (Chamberlain et al, 1997) OR 10 mg IM (weight greater than 40 kg); 5 mg IM (weight 13 to 40 kg); INTRANASAL: 0.2 to 0.5 mg/kg up to a maximum of 10 mg/dose (Loddenkemper & Goodkin, 2011; Brophy et al, 2012). BUCCAL midazolam, 10 mg, has been used in adolescents and older children (5-years-old or more) to control seizures when intravenous access was not established (Scott et al, 1999).

a) MAXIMUM RATE: The rate of intravenous administration of lorazepam should not exceed 2 mg/min (Brophy et al, 2012; Prod Info lorazepam IM, IV injection, 2008).
b) ADULT DOSE: 2 to 4 mg IV initially; repeat every 5 to 10 minutes as needed, if seizures persist (Manno, 2003; Brophy et al, 2012).
c) PEDIATRIC DOSE: 0.05 to 0.1 mg/kg IV over 2 to 5 minutes, up to a maximum of 4 mg/dose; may repeat in 5 to 15 minutes as needed, if seizures continue (Brophy et al, 2012; Loddenkemper & Goodkin, 2011; Hegenbarth & American Academy of Pediatrics Committee on Drugs, 2008; Sreenath et al, 2009; Chin et al, 2008).

a) ADULT LOADING DOSE: 20 mg/kg IV at an infusion rate of 50 to 100 mg/minute IV. An additional 5 to 10 mg/kg dose may be given 10 minutes after loading infusion if seizures persist or recur (Brophy et al, 2012).
b) Patients receiving high doses will require endotracheal intubation and may require vasopressor support (Brophy et al, 2012).
c) PEDIATRIC LOADING DOSE: 20 mg/kg may be given as single or divided application (2 mg/kg/minute in children weighing less than 40 kg up to 100 mg/min in children weighing greater than 40 kg). A plasma concentration of about 20 mg/L will be achieved by this dose (Loddenkemper & Goodkin, 2011).
d) REPEAT PEDIATRIC DOSE: Repeat doses of 5 to 20 mg/kg may be given every 15 to 20 minutes if seizures persist, with cardiorespiratory monitoring (Loddenkemper & Goodkin, 2011).
e) MONITOR: For hypotension, respiratory depression, and the need for endotracheal intubation (Loddenkemper & Goodkin, 2011; Manno, 2003).
f) SERUM CONCENTRATION MONITORING: Monitor serum concentrations over the next 12 to 24 hours. Therapeutic serum concentrations of phenobarbital range from 10 to 40 mcg/mL, although the optimal plasma concentration for some individuals may vary outside this range (Hvidberg & Dam, 1976; Choonara & Rane, 1990; AMA Department of Drugs, 1992).

a) If seizures persist after phenobarbital, propofol or pentobarbital infusion, or neuromuscular paralysis with general anesthesia (isoflurane) and continuous EEG monitoring should be considered (Manno, 2003). Other anticonvulsants can be considered (eg, valproate sodium, levetiracetam, lacosamide, topiramate) if seizures persist or recur; however, there is very little data regarding their use in toxin induced seizures, controlled trials are not available to define the optimal dosage ranges for these agents in status epilepticus (Brophy et al, 2012):

a) If seizures are not controlled by the above measures, patients will require endotracheal intubation, mechanical ventilation, continuous EEG monitoring, a continuous infusion of an anticonvulsant, and may require neuromuscular paralysis and vasopressor support. Consider continuous infusions of the following agents:
b) Endotracheal intubation, mechanical ventilation, and vasopressors will be required (Brophy et al, 2012) and consultation with a neurologist is strongly advised.
c) Neuromuscular paralysis (eg, rocuronium bromide, a short-acting nondepolarizing agent) may be required to avoid hyperthermia, severe acidosis, and rhabdomyolysis. If rhabdomyolysis is possible, avoid succinylcholine chloride, because of the risk of hyperkalemic-induced cardiac dysrhythmias. Continuous EEG monitoring is mandatory if neuromuscular paralysis is used (Manno, 2003).

a) A patient was found unresponsive with generalized twitching after an intentional ingestion of 1500 milligrams of tiagabine. Approximately two hours after ingestion, the tiagabine serum concentration was 4600 micrograms/liter, as measured by HPLC (Forbes et al, 2007).
b) A tiagabine plasma level of 3.1 micrograms/milliliter was reported 4 hours after an overdose ingestion of 320 mg tiagabine. This plasma level was 30 times higher than the typical steady state plasma level during therapeutic dosing (Leach et al, 1995).
c) A patient developed status epilepticus after ingesting an unknown amount of tiagabine and had a serum level of 710 nanograms/milliliter (measured by HPLC) reported 4.5 hours post-ingestion (Viner et al, 1999).

a) A 2-year-old girl, weighing 13 kilograms, ingested 90 mg of tiagabine and developed generalized tonic-clonic seizure activity. Serum concentrations at approximately 5 and 11 hours post-ingestion were 530 ng/mL and 130 ng/mL, respectively (Kazzi et al, 2006).
b) A tiagabine plasma level of 420 ng/mL was reported in a 14-year-old girl after an ingestion of an unknown amount of tiagabine. The patient had no prior history of seizures but developed status epilepticus (Fulton et al, 2005).