Tiagabine

375.55

375.55

Z80I64HMNP

DTXSID5023663

N03AG06|N - Nervous system

log Kow = 2.04 (est)|2.6

1.208±0.06 g/cm3(Predicted)

192oC dec.

568.0±50.0 °C(Predicted)

≥ 13.5mg/mL in Water

7.2X10-14 mm Hg at 25 °C (est)

3.86±0.20(Predicted)

Henry's Law constant = 3.5X10-13 atm-cu m/mol at 25 °C (est)

pKa1 = 3.56 (carboxylic acid); pKa2 = 9.49 (secondary amine) (est)

184.5 Ų [M+H]+ [CCS Type: TW, Method: Major Mix IMS/Tof Calibration Kit (Waters)]

Mol wt: 215.71. White to off-white, odorless crystalline powder, mp 192 °C (decomposes) (Mengel). Specific optical rotation: -11 deg at 20 °C/D. pKa2 = 9.4. log Kow = 39.3 (pH 7.4). Solubility in water: 3%. Practically insoluble in hexane. /Hydrochloride/|Soluble in aqueous base /Hydrochloride/|Hydroxyl radical reaction rate constant = 2.9X10-10 cu cm/molec-sec at 25 °C (est)

under inert gas (nitrogen or Argon) at 2-8°C

Xi

26-37/39

36/37/38

SRP: At the time of review, criteria for land treatment or burial (sanitary landfill) disposal practices are subject to significant revision. Prior to implementing land disposal of waste residue (including waste sludge), consult with environmental regulatory agencies for guidance on acceptable disposal practices.

The Approved Drug Products with Therapeutic Equivalence Evaluations List identifies currently marketed prescription drug products, incl tiagabine, approved on the basis of safety and effectiveness by FDA under sections 505 of the Federal Food, Drug, and Cosmetic Act.

mptoms most often accompanying tiagabine overdose, alone or in combination with other drugs, have included: seizures including status epilepticus in patients with and without underlying seizure disorders, nonconvulsive status epilepticus, coma, ataxia, confusion, somnolence, drowsiness, impaired speech, agitation, lethargy, myoclonus, spike wave stupor, tremors, disorientation, vomiting, hostility, and temporary paralysis. Respiratory depression was seen in a number of patients, including children, in the context of seizures.

Limited data are available on the hepatotoxicity of tiagabine. In clinical trials, therapy with tiagabine was not associated with an increased frequency of serum aminotransferase elevations or liver toxicity. No individual case reports of liver injury from tiagabine have been published and its use has not been associated with hypersensitivity syndromes or autoimmunity. However, its overall use has been limited.

/Concomitant administration of tiagabine with/ alcohol or central nervous system depression-producing medications may increase CNS depression.|Tiagabine clearance is increased by 60% in patients taking carbamazepine, phenobarbital, phenytoin, or primidone.|Tiagabine causes a slight decrease (about 10%) in steady-state valproate concentrations; in vitro studies have shown that valproate decreases the protein binding of tiagabine from 96.3 to 94.8, resulting in an increase of approximately 40% in the free tiagabine concentration; clinical relevance of this finding is unknown.|Co-administration of cimetidine (800 mg/day) to patients taking tiagabine chronically had no effect on tiagabine pharmacokinetics.|For more Interactions (Complete) data for TIAGABINE (13 total), please visit the HSDB record page.

96%

While data specific to tiagabine were not located(SRC, 2007), the literature suggests that some pharmaceutically active compounds originating from human and veterinary therapy are not eliminated completely in municipal sewage treatment plants and are therefore discharged into receiving waters(1). Wastewater treatment processes often were not designed to remove them from the effluent(2). Selected organic waste compounds may be degrading to new and more persistent compounds that may be released instead of or in addition to the parent compound(2).

For the treatment of partial seizures|FDA Label

Tiagabine is a unique anticonvulsant used largely as an adjunctive agent in therapy of partial seizures in adults or children. Therapy with tiagabine is not associated with serum aminotransferase elevations, and clinically apparent liver injury from tiagabine has not been reported and must be rare if it occurs at all.

Anticonvulsants

Tiagabine is indicated as an adjunct to other anticonvulsant medications in the treatment of partial seizures in adults and children 12 years of age and older. /Included in US product label/

Although tiagabine reduces the frequency of seizures in patients with epilepsy, use of the drug has been associated with a paradoxical occurrence of seizures in patients without a history of epilepsy.|Post-marketing reports have shown that /tiagabine/ use has been associated with new onset seizures and status epilepticus in patients without epilepsy. Dose may be an important predisposing factor in the development of seizures, although seizures have been reported in patients taking daily doses of /tiagabine/ as low as 4 mg/day. In most cases, patients were using concomitant medications (antidepressants, antipsychotics, stimulants, narcotics) that are thought to lower the seizure threshold. Some seizures occurred near the time of a dose increase, even after periods of prior stable dosing.|The /tiagabine/ dosing recommendations in current labeling for treatment of epilepsy were based on use in patients with partial seizures 12 years of age and older, most of whom were taking enzyme-inducing antiepileptic drugs (AEDs; e.g., carbamazepine, phenytoin, primidone and phenobarbital) which lower plasma levels of /tiagabine/ by inducing its metabolism. Use of /tiagabine/ without enzyme-inducing antiepileptic drugs results in blood levels about twice those attained in the studies on which current dosing recommendations are based|Safety and effectiveness of /tiagabine/ have not been established for any indication other than as adjunctive therapy for partial seizures in adults and children 12 years and older.|For more Drug Warnings (Complete) data for TIAGABINE (19 total), please visit the HSDB record page.

Tiagabine is used primarily as an anticonvulsant for the adjunctive treatment of epilepsy. The precise mechanism by which Tiagabine exerts its antiseizure effect is unknown, although it is believed to be related to its ability to enhance the activity of gamma aminobutyric acid (GABA), the major inhibitory neurotransmitter in the central nervous system. Tiagabine binds to recognition sites associated with the GABA uptake carrier. It is thought that, by this action, Tiagabine blocks GABA uptake into presynaptic neurons, permitting more GABA to be available for receptor binding on the surfaces of post-synaptic cells.

Drugs used to prevent SEIZURES or reduce their severity. (See all compounds classified as Anticonvulsants.)|Compounds that suppress or block the plasma membrane transport of GAMMA-AMINOBUTYRIC ACID by GABA PLASMA MEMBRANE TRANSPORT PROTEINS. (See all compounds classified as GABA Uptake Inhibitors.)

Tiagabine is nearly completely absorbed (>95%).|Approximately 2% of an oral dose of tiagabine is excreted unchanged, with 25% and 63% of the remaining dose excreted into the urine and feces, respectively, primarily as metabolites.|109 mL/min [Healthy subjects]|Absorption of tiagabine is rapid, with peak plasma concentrations occurring at approximately 45 minutes following an oral dose in the fasting state. Tiagabine is nearly completely absorbed (>95%), with an absolute oral bioavailability of about 90%. A high fat meal decreases the rate (mean T max was prolonged to 2.5 hours, and mean C max was reduced by about 40%) but not the extent (AUC) of tiagabine absorption.|The pharmacokinetics of tiagabine are linear over the single dose range of 2 to 24 mg. Following multiple dosing, steady state is achieved within 2 days.|Tiagabine is 96% bound to human plasma proteins, mainly to serum albumin and alpha1-acid glycoprotein over the concentration range of 10 ng/mL to 10,000 ng/mL. While the relationship between tiagabine plasma concentrations and clinical response is not currently understood, trough plasma concentrations observed in controlled clinical trials at doses from 30 to 56 mg/day ranged from <1 ng/mL to 234 ng/mL.|A diurnal effect on the pharmacokinetics of tiagabine was observed. Mean steady-state C min values were 40% lower in the evening than in the morning. Tiagabine steady-state AUC values were also found to be 15% lower following the evening tiagabine dose compared to the AUC following the morning dose.|For more Absorption, Distribution and Excretion (Complete) data for TIAGABINE (9 total), please visit the HSDB record page.

Tiagabine is likely metabolized primarily by the 3A isoform subfamily of hepatic cytochrome P450.|Although the metabolism of tiagabine has not been fully elucidated, in vivo and in vitro studies suggest that at least two metabolic pathways for tiagabine have been identified in humans: 1) thiophene ring oxidation leading to the formation of 5-oxo-tiagabine; and 2) glucuronidation. The 5-oxo-tiagabine metabolite does not contribute to the pharmacologic activity of tiagabine.|Based on in vitro data, tiagabine is likely to be metabolized primarily by the 3A isoform subfamily of hepatic cytochrome P450 (CYP 3A), although contributions to the metabolism of tiagabine from CYP 1A2, CYP 2D6 or CYP 2C19 have not been excluded.

7-9 hours|... The average elimination half-life for tiagabine in healthy subjects ranged from 7 to 9 hours. The elimination half-life decreased by 50 to 65% in hepatic enzyme-induced patients with epilepsy compared to uninduced patients with epilepsy.|Its half-life is about 8 hrs but is shortened by 2 to 3 hrs when coadministered with hepatic enzyme-inducing drugs such as phenobarbital, phenytoin, or carbamazepine.

Though the exact mechanism by which Tiagabine exerts its effect on the human body is unknown, it does appear to operate as a selective GABA reuptake inhibitor.|Although the precise mechanism of action of tiagabine is unknown, the drug enhances inhibitory neurotransmission mediated by gamma-aminobutyric acid (GABA). Tiagabine increases the amount of GABA available in extracellular spaces of the globus pallidus, ventral pallidum, and substantia nigra, suggesting a GABA-mediated anticonvulsant mechanism of action (i.e., inhibition of neural impulse propagations that contribute to seizures). Tiagabine inhibits presynaptic neuronal and glial GABA reuptake, and increases the amount of GABA available for postsynaptic receptor binding. The drug does not stimulate GABA release, and does not have activity at other receptor binding and uptake sites at concentrations that inhibit the uptake of GABA. Tiagabine selectively blocks presynaptic GABA uptake by binding reversibly and saturably to recognition sites associated with GABA transporter protein in neuronal and glial membranes.|In vitro binding studies indicate that tiagabine does not inhibit substantially the uptake of dopamine, norepinephrine, serotonin, glutamate, or choline, and does not bind substantially to dopamine D1 or D2; cholinergic muscarinic; serotonergic type 1A, type 2, or type 3 (5HT1A, 5HT2, or 5HT3, respectively); alpha1- or alpha2-adrenergic; beta1- or beta2-adrenergic; histamine H2 or H3; adenosine A1 or A2; opiate mu or kappa1; glutamate N-methyl-d- aspartate (NMDA); or GABAA receptors. Also, tiagabine has little or no affinity for sodium or calcium channels. Tiagabine binds to histamine H1, serotonergic type 1B (5HT1B), benzodiazepine, and chloride channel receptors at concentrations 20-400 times those that inhibit the uptake of GABA.

Maintain an open airway and assist ventilation if necessary. Administer supplemental oxygen. Treat stupor and coma if they occur. Protect the patient from self-injury caused by ataxia. Treat agitation and delirium if they occur. Monitor asymptomatic patients for a minimum of 4-6 hours. Admit symptomatic patients for at least 24 hours lamotrigine, felbamate, topiramate, or zonisamide ingestions. ... Administer activated charcoal orally if conditions are appropriate. Gastric lavage is not necessary after small to moderate ingestions if activated charcoal can be given promptly. ... /Anticonvulsants, Newer/|... Usual precautions to maintain the airway should be taken. To enhance elimination- Since tiagabine is primarily metabolized by the liver and highly protein-bound, dialysis is not likely to be beneficial. Monitoring- Monitor vital signs. Supportive care- General supportive care including observation of clinical status.|/SRP:/ Basic treatment: Establish a patent airway (oropharyngeal or nasopharyngeal airway, if needed). Suction if necessary. Watch for signs of respiratory insufficiency and assist ventilations if needed. Administer oxygen by nonrebreather mask at 10 to 15 L/min. Monitor for pulmonary edema and treat if necessary ... . Monitor for shock and treat if necessary ... . Anticipate seizures and treat if necessary ... . For eye contamination, flush eyes immediately with water. Irrigate each eye continuously with 0.9% saline (NS) during transport ... . Do not use emetics. For ingestion, rinse mouth and administer 5 ml/kg up to 200 ml of water for dilution if the patient can swallow, has a strong gag reflex, and does not drool ... . Cover skin burns with dry sterile dressings after decontamination ... . /Poisons A and B/|/SRP:/ Advanced treatment: Consider orotracheal or nasotracheal intubation for airway control in the patient who is unconscious, has severe pulmonary edema, or is in severe respiratory distress. Positive-pressure ventilation techniques with a bag valve mask device may be beneficial. Consider drug therapy for pulmonary edema ... . Consider administering a beta agonist such as albuterol for severe bronchospasm ... . Monitor cardiac rhythm and treat arrhythmias as necessary ... . Start IV administration of D5W /SRP: "To keep open", minimal flow rate/. Use 0.9% saline (NS) or lactated Ringer's if signs of hypovolemia are present. For hypotension with signs of hypovolemia, administer fluid cautiously. Watch for signs of fluid overload ... . Treat seizures with diazepam or lorazepam ... . Use proparacaine hydrochloride to assist eye irrigation ... . /Poisons A and B/

/HUMAN EXPOSURE STUDIES/ The long-term effects of tiagabine monotherapy on cognition and mood were evaluated in adult patients with chronic partial epilepsy in a 48-week, open-label extension period that followed an 8-week, double-blind, titration study. Cognitive function was evaluated using neuropsychological evaluations that measured learning and memory, general intellectual ability, attention and mental speed, and reaction speed. Mood was assessed using a Finnish modification of the Profile of Mood States. Of the 34 patients who entered the open-label extension period, 18 successfully continued long-term monotherapy and underwent neuropsychological evaluation at 48 weeks of tiagabine monotherapy. The mean daily dose of tiagabine monotherapy at the end of open-label treatment was 19.7 mg/day (range, 5-35 mg/day). Tiagabine monotherapy did not adversely affect cognitive function. No significant changes in mood were observed. The median number of seizures was 2 (range, 0-71), and 8 patients (44%) were seizure-free during the 48 weeks of open-label tiagabine treatment. The results of this small open-label extension study indicate that patients with chronic partial epilepsy who were successfully converted to long-term tiagabine monotherapy demonstrated no adverse effects on cognitive function or mood.|/SIGNS AND SYMPTOMS/ Symptoms most often accompanying /tiagabine/ overdose alone or in combination with other drugs have included: seizures including status epilepticus in patients with and without underlying seizure disorders, nonconvulsive status epilepticus, coma, ataxia, confusion, somnolence, drowsiness, impaired speech, agitation, lethargy, myoclonus, spike wave stupor, tremors, disorientation, vomiting, hostility, and temporary paralysis. Respiratory depression was seen in a number of patients, including children, in the context of seizures.|/SIGNS AND SYMPTOMS/ /Acute intoxication/: Agitation, severe; ataxia, severe (clumsiness or unsteadiness); confusion, severe; hostility; impaired consciousness (coma); lethargy (sluggishness; mental depression; myoclonus (severe muscle twitching or jerking); precipatation of a tonic-clonic seizure (increased seizures); somnolence, severe (drowsiness); speech problems, severe; weakness.|/CASE REPORTS/ There have been as many as 10 cases of sudden unexpected deaths during the clinical development of tiagabine among 2531 patients with epilepsy (3831 patient-years of exposure). This represents an estimated incidence of 0.0026 deaths per patient-year. This rate is within the range of estimates for the incidence of sudden and unexpected deaths in patients with epilepsy not receiving /tiagabine/ (ranging from 0.0005 for the general population with epilepsy, 0.003 to 0.004 for clinical trial populations similar to that in the clinical development program for /tiagabine/, to 0.005 for patients with refractory epilepsy). The estimated SUDEP rates in patients receiving /tiagabine/ are also similar to those observed in patients receiving other antiepilepsy drugs, chemically unrelated to /tiagabine/, that underwent clinical testing in similar populations at about the same time.|For more Human Toxicity Excerpts (Complete) data for TIAGABINE (9 total), please visit the HSDB record page.

(R)-(4,4-bis(3-methyl-2-thienyl)-3-butenyl)-3-piperidinecarboxylic acid, hydrochloride

Oral Tablets: 2 mg Gabitril, Cephalon; 4 mg Gabitril, Cephalon; 6 mg Gabitril, Cephalon; 8 mg Gabitril, Cephalon; 10 mg Gabitril, Cephalon; 12 mg Gabitril, Cephalon; 16 mg Gabitril, Cephalon.

Analyte: tiagabine hydrochloride; matrix: chemical identification; procedure: infrared absorption spectrophotometry with comparison to standards /tiagabine hydrochloride/|Analyte: tiagabine hydrochloride; matrix: chemical identification; procedure: retention time of the major peak of the liquid chromatogram with comparison to standards /tiagabine hydrochloride/|Analyte: tiagabine hydrochloride; matrix: chemical purity; procedure: liquid chromatography with detection at 254 nm and comparison to standards /tiagabine hydrochloride/

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