Tiagabine (DB00906): A Comprehensive Pharmacological and Clinical Monograph

Section 1: Executive Summary & Drug Identification

1.1 Overview of Tiagabine: Key Characteristics and Clinical Role

Tiagabine is an anti-epileptic drug (AED) distinguished by its unique and highly specific mechanism of action: the selective inhibition of the gamma-aminobutyric acid (GABA) transporter 1 (GAT-1).[1] This mechanism enhances GABAergic neurotransmission, positioning Tiagabine as a targeted therapy for controlling neuronal hyperexcitability. Its primary, United States Food and Drug Administration (FDA)-approved clinical indication is as an adjunctive therapy for the treatment of partial-onset seizures in adults and adolescents aged 12 years and older.[3]

The clinical application of Tiagabine is fundamentally governed by a critical pharmacokinetic dichotomy: its metabolism is significantly influenced by the presence of hepatic enzyme-inducing concomitant medications. Patients co-administered enzyme-inducing AEDs (e.g., carbamazepine, phenytoin) exhibit markedly accelerated clearance of Tiagabine compared to "non-induced" patients. This metabolic variability necessitates distinct dosing and titration strategies for these two populations to ensure both efficacy and safety. While the drug has been explored for off-label uses, such as in anxiety disorders and neuropathic pain, its use in non-epileptic populations has been associated with significant safety concerns, including the paradoxical development of new-onset seizures, which has led to prominent regulatory warnings.[5] This report provides a comprehensive monograph on Tiagabine, detailing its chemical properties, pharmacological profile, clinical applications, safety considerations, and regulatory history.

1.2 Comprehensive Identification and Nomenclature

A precise and unambiguous identification of Tiagabine is essential for research, clinical, and regulatory purposes. The drug is most commonly administered as a hydrochloride salt, a distinction that is critical for understanding its physicochemical properties and formulation. The following table consolidates its nomenclature and cross-references from major chemical and pharmacological databases.

Identifier Type	Value	Source(s)
Generic Name	Tiagabine	7
International Names	Tiagabina (Spanish), Tiagabinum (Latin)	8
Brand Name	Gabitril	3
DrugBank Accession No.	DB00906	7
CAS Registry Number	115103-54-3 (free base)	10
	145821-59-6 (hydrochloride salt)	12
Drug Type/Modality	Small Molecule	7
Systematic (IUPAC) Name	(3R)-1-[4,4-bis(3-methylthiophen-2-yl)but-3-enyl]piperidine-3-carboxylic acid	10
Chemical Name (HCl Salt)	(-)-(R)-1-nipecotic acid hydrochloride	15
Synonyms/Dev. Codes	TGB, NO-05-0328, NNC-05-0328, Abbott-70569, ABT-569, NO-328	14
FDA UNII	Z80I64HMNP	10
ChEBI ID	CHEBI:9586	10
ChEMBL ID	CHEMBL1027	10
KEGG ID	D08588, C07503	10
PubChem CID	60648	14
ATC Code	N03AG06	3

Section 2: Physicochemical Properties and Formulation

2.1 Chemical Structure and Properties

Tiagabine is a synthetic organic compound derived from (R)-nipecotic acid, a piperidinemonocarboxylic acid.[10] Its structure incorporates a lipophilic 1,1-bis(3-methyl-2-thienyl)but-1-en-4-yl group attached to the nitrogen of the nipecotic acid ring, which is crucial for its ability to cross the blood-brain barrier.[3]

• Molecular Formula: The free base has a molecular formula of $C_{20}H_{25}NO_{2}S_{2}$.[3] The clinically used hydrochloride salt has the formula $C_{20}H_{25}NO_{2}S_{2} \cdot HCl$.[15]
• Molecular Weight: The average molecular weight of the free base is approximately 375.55 g/mol.[7] The molecular weight of the hydrochloride salt is 412.0 g/mol.[15]
• Chemical Descriptors:
• SMILES: CC1=C(SC=C1)C(=CCCN2CCC[C@H](C2)C(=O)O)C3=C(C=CS3)C [10]
• InChIKey: PBJUNZJWGZTSKL-MRXNPFEDSA-N [10]
• Physical Description: Tiagabine hydrochloride is a white to off-white, odorless, crystalline solid.[15]
• Solubility Profile: It is characterized as being insoluble in heptane, sparingly soluble in water, and soluble in aqueous base.[15] This pH-dependent solubility suggests more favorable dissolution and absorption in the neutral to alkaline environment of the small intestine compared to the highly acidic stomach.
• Melting Point: The compound melts at 192°C with decomposition.[17]

2.2 Pharmaceutical Formulation and Excipients

Tiagabine is formulated for oral administration as immediate-release tablets under the brand name Gabitril.[15]

• Dosage Form and Strengths: It is available as tablets in strengths of 2 mg, 4 mg, 12 mg, and 16 mg.[15]
• Inactive Ingredients (Excipients): The tablet formulation contains a range of standard pharmaceutical excipients, including: Ascorbic acid, colloidal silicon dioxide, crospovidone, hydrogenated vegetable oil wax, hydroxypropyl cellulose, hypromellose, lactose, magnesium stearate, microcrystalline cellulose, pregelatinized starch, stearic acid, and titanium dioxide.[15]
• Coloring Agents: The different tablet strengths are distinguished by specific coloring agents:
• 2 mg tablets: FD&C Yellow No. 6
• 4 mg tablets: D&C Yellow No. 10
• 12 mg tablets: D&C Yellow No. 10 and FD&C Blue No. 1
• 16 mg tablets: FD&C Blue No. 2 [16]

The formulation and administration guidelines for Tiagabine are closely linked to its physicochemical and pharmacokinetic properties. The drug exhibits high overall absorption (>95%), but its rate of absorption is significantly affected by food.[7] Administration with a high-fat meal can delay the time to reach peak plasma concentration (Tmax) from approximately 45 minutes to 2.5 hours.[3] This slowing of the absorption rate, without altering the total amount of drug absorbed, serves a critical clinical purpose. The most common adverse effects of Tiagabine, such as dizziness and somnolence, are dose-related and linked to peak plasma concentrations.[1] By recommending that the drug be taken with food, the resulting blunted peak concentration helps to improve patient tolerability, particularly during the initial dose-titration period when the central nervous system is adapting to the medication's effects. This administration guideline is therefore a key strategy for mitigating predictable, concentration-dependent side effects.

Section 3: Pharmacological Profile

3.1 Pharmacodynamics: A Deep Dive into GAT-1 Inhibition

3.1.1 Primary Mechanism of Action at the Synapse

The anticonvulsant effect of Tiagabine is attributed to its potent and selective action as a GABA reuptake inhibitor.[7] While some clinical literature refers to the "precise mechanism" of its antiseizure effect as unknown, this reflects the complexity of translating a molecular action into a network-level clinical outcome in epilepsy; the primary pharmacological mechanism is well-characterized.[7]

Tiagabine's primary molecular target is the Sodium- and chloride-dependent GABA transporter 1 (GAT-1).[2] GAT-1 is a key presynaptic and glial membrane protein responsible for the rapid removal of GABA from the synaptic cleft following its release, thereby terminating its inhibitory signal.[17] By binding to recognition sites on the GAT-1 carrier, Tiagabine potently blocks this reuptake process.[10] This inhibition leads to an increased concentration of GABA in the synapse and prolongs its duration of action on postsynaptic GABAA and GABAB receptors.[3] This enhancement of the brain's primary inhibitory neurotransmitter system is believed to counteract the neuronal hyperexcitability that underlies seizure generation and propagation.[15] In vitro and in vivo studies have confirmed this mechanism, demonstrating that Tiagabine prolongs GABA-mediated inhibitory post-synaptic potentials (IPSPs) and increases extracellular GABA levels in key brain regions such as the hippocampus, globus pallidus, and substantia nigra.[3]

3.1.2 Receptor Binding Profile and Selectivity

A defining feature of Tiagabine is its high selectivity for the GAT-1 transporter, which contributes to a relatively clean neurological side-effect profile compared to less selective agents.[17] It has minimal activity at other neurotransmitter transporters or receptors at clinically relevant concentrations.

• Transporter Selectivity: Tiagabine selectively blocks GAT-1 over other GABA transporters (GAT-2, GAT-3) and does not significantly inhibit the reuptake of other major neurotransmitters, including dopamine, norepinephrine, serotonin, glutamate, or choline.[22]
• Receptor Affinity: At concentrations up to 100 µM, Tiagabine shows little to no significant affinity for a wide array of receptors, including dopamine (D1, D2), muscarinic, serotonin (5HT1A, 5HT2, 5HT3), adrenergic (α1, α2, β1, β2), histamine (H2, H3), adenosine (A1, A2), NMDA-glutamate, and opiate (µ, K1) receptors.[16] It also lacks significant affinity for voltage-gated sodium or calcium channels, distinguishing its mechanism from many other AEDs.[15]

3.1.3 Downstream Effects on GABAergic Neurotransmission

The interaction of Tiagabine with GAT-1 is structurally specific. The nipecotic acid portion of the molecule occupies the primary GABA binding site, while the lipophilic bis-thienyl side chains interact with an allosteric site, effectively locking the transporter in an outward-facing, non-transporting conformation.[3] This lipophilicity is a key design feature that allows the molecule to effectively penetrate the blood-brain barrier, unlike its parent compound, nipecotic acid.[3] Furthermore, preclinical evidence suggests that Tiagabine may indirectly potentiate the effects of other GABAergic drugs, as it has been shown to increase the affinity of benzodiazepines for the GABAA receptor complex.[3]

3.2 Pharmacokinetics: Absorption, Distribution, Metabolism, and Excretion (ADME)

The pharmacokinetics of Tiagabine are well-characterized and linear within the therapeutic dose range. However, its clinical use is dominated by its susceptibility to metabolic induction by concomitant medications, creating two distinct patient phenotypes: "induced" and "non-induced."

3.2.1 Absorption and Bioavailability

Tiagabine is rapidly and almost completely absorbed following oral administration, with an absolute bioavailability exceeding 95%.[3] Under fasting conditions, peak plasma concentrations (Tmax) are reached within approximately 45 minutes.[3] As previously noted, co-administration with food slows the rate of absorption but does not impact the overall extent.[16] Steady-state plasma concentrations are typically achieved within two days of initiating a stable dosing regimen.[15]

3.2.2 Distribution

Tiagabine is extensively bound to plasma proteins (approximately 96%), primarily to serum albumin and α1-acid glycoprotein.[7] This high degree of protein binding suggests a potential for displacement interactions with other highly protein-bound drugs, although the clinical significance of this is managed through careful dosing.

3.2.3 Metabolic Pathways and the Central Role of CYP3A4

Tiagabine is extensively metabolized by the liver, with less than 2% of the dose excreted unchanged.[15] The primary metabolic pathway involves oxidation of the thiophene rings, a reaction mediated predominantly by the cytochrome P450 3A4 (CYP3A4) isoenzyme.[3] This process yields pharmacologically inactive metabolites, such as 5-oxo-tiagabine.[3] A secondary metabolic route is glucuronidation.[3] While minor contributions from other CYP isoforms (CYP1A2, CYP2D6, CYP2C19) cannot be entirely ruled out, CYP3A4 is the principal enzyme responsible for Tiagabine clearance.[15]

3.2.4 Elimination Half-Life and Excretion

The elimination of Tiagabine is highly dependent on the patient's enzyme-induction status.

• In healthy subjects or "non-induced" patients (those not taking enzyme-inducing drugs), the elimination half-life of Tiagabine is approximately 7 to 9 hours.[7]
• In "induced" patients (those taking potent CYP3A4 inducers like carbamazepine, phenytoin, phenobarbital, or primidone), the systemic clearance of Tiagabine is increased by approximately 60%.[16] This results in a dramatically shortened elimination half-life of only 2 to 5 hours.[16]

This profound difference in metabolic rate is the single most important pharmacokinetic consideration in the clinical use of Tiagabine. It means that for a given dose, plasma concentrations in non-induced patients can be more than double those seen in induced patients.[15] This reality underpins the need for separate dosing guidelines and explains the heightened risk of adverse events when the drug is used in non-induced populations, particularly for off-label indications. Following metabolism, the byproducts are primarily excreted in the feces (approximately 63%) and urine (approximately 25%).[7]

The following table summarizes and contrasts the key pharmacokinetic parameters of Tiagabine in these two distinct patient populations.

PK Parameter	Value in Non-Induced Patients	Value in Induced Patients	Key Notes	Source(s)
Bioavailability	>95%	>95%	High and complete absorption, unaffected by induction status.	3
Tmax (Fasting)	~45 minutes	~45 minutes	Rate of absorption is not affected by induction status.	3
Protein Binding	~96%	~96%	Primarily to albumin and α1-acid glycoprotein.	7
Primary Metabolism	Hepatic (CYP3A4)	Hepatic (CYP3A4)	Metabolism is dramatically accelerated by CYP3A4 inducers.	7
Elimination Half-Life	7–9 hours	2–5 hours	Reduced by 50-65% due to enzyme induction. This is the critical difference.	3
Excretion	25% renal, 63% fecal (as metabolites)	25% renal, 63% fecal (as metabolites)	Excretion route is unchanged, but rate of metabolite formation is faster.	3

Section 4: Clinical Applications and Efficacy

4.1 FDA-Approved Indication: Adjunctive Therapy for Partial Seizures

The sole FDA-approved indication for Tiagabine is for use as an adjunctive therapy in the treatment of partial-onset seizures in adults and adolescents aged 12 years and older.[3] This includes seizure types classified as focal aware (formerly simple partial), focal impaired awareness (formerly complex partial), and focal to bilateral tonic-clonic (formerly secondarily generalized) seizures.[1] It is specifically intended as an "add-on" medication for patients whose seizures are not satisfactorily controlled with other AEDs.[9]

The efficacy of Tiagabine for this indication was established in three pivotal multicenter, double-blind, placebo-controlled clinical trials. These studies enrolled a total of 769 patients with refractory partial seizures who, critically, were already being treated with at least one hepatic enzyme-inducing AED.[15] The results demonstrated that Tiagabine, at maintenance doses between 30 and 56 mg/day, was significantly more effective than placebo in reducing seizure frequency across all subtypes of partial seizures.[1] Furthermore, long-term safety studies have shown that the efficacy of Tiagabine is sustained over time, with no evidence of pharmacological tolerance developing.[1] Some open-label extension studies have also suggested that a subset of patients may be successfully converted from polytherapy to Tiagabine monotherapy, although it is not formally approved for this use.[1]

4.2 Off-Label and Investigational Uses

The mechanism of Tiagabine—enhancing central GABAergic inhibition—has made it an attractive candidate for conditions beyond epilepsy that are hypothesized to involve GABAergic dysregulation. However, its off-label use is accompanied by a significant and specific safety risk.

• Anxiety Disorders: Tiagabine has been used off-label in the treatment of anxiety disorders, including panic disorder and Generalized Anxiety Disorder (GAD).[3] It is typically employed as an augmenting agent for primary treatments like selective serotonin reuptake inhibitors (SSRIs) or benzodiazepines.[25] A Phase 3 clinical trial investigating its efficacy for GAD has been completed.[27]
• Neuropathic Pain: Another off-label application is in the management of neuropathic pain conditions, such as fibromyalgia.[3]
• Other Investigational Uses: Reports also describe its off-label use for infantile spasms (West syndrome), spasticity, and migraine headaches.[1]

The history of Tiagabine's off-label use serves as a critical case study in clinical pharmacology. The drug's initial safety and dosing profile was established in a population of epilepsy patients who were concurrently taking enzyme-inducing AEDs. When clinicians began prescribing Tiagabine for psychiatric or pain conditions in patients who were not taking these inducers, they were inadvertently treating a "non-induced" population. As established, these individuals metabolize Tiagabine much more slowly, leading to plasma concentrations more than twice as high as those observed in the original trial population for the same dose.[15] This unexpectedly high drug exposure in individuals without an underlying epileptic focus led to a paradoxical pro-convulsant effect, resulting in reports of new-onset seizures and status epilepticus.[5] This prompted the FDA to issue a prominent, bolded warning in 2005, cautioning against the use of Tiagabine in patients without epilepsy due to this risk.[5] This warning fundamentally limits the off-label utility of the drug and underscores the necessity of understanding its pharmacokinetic profile before prescribing.

Section 5: Dosage, Administration, and Patient Management

The safe and effective use of Tiagabine is highly dependent on strict adherence to established dosing and administration protocols, which are designed to mitigate its dose-related adverse effects and account for its variable metabolism.

5.1 General Dosing and Administration Protocols

The following guidelines apply to all patients receiving Tiagabine:

• Route of Administration: Tiagabine is administered orally.[15]
• Administration with Food: It is essential that Tiagabine tablets be taken with food. This slows the rate of drug absorption, blunting peak plasma concentrations and thereby improving tolerability of CNS side effects.[15]
• Dose Titration: A loading dose should never be used. The dose must be escalated slowly and gradually according to a recommended schedule. Rapid dose increases are strictly contraindicated as they increase the risk of adverse events.[15]
• Management of Missed Doses: Patients should be instructed not to compensate for a missed dose by taking extra medication at the next scheduled time. If multiple doses are missed, re-titration under a physician's guidance may be necessary.[15]

5.2 Titration Strategies: Induced vs. Non-Induced Patients

Dosage and titration schedules for Tiagabine must be tailored based on the patient's concomitant medications, specifically whether they are taking hepatic enzyme-inducing AEDs.

For Patients on Enzyme-Inducing AEDs ("Induced Patients")

This population includes patients taking medications such as carbamazepine, phenytoin, phenobarbital, and primidone. They require higher maintenance doses due to accelerated drug clearance.

• Adults (18 years and older):
• Initial Dose: 4 mg once daily.
• Titration: The total daily dose may be increased by 4 to 8 mg at weekly intervals.
• Maintenance Dose: The usual effective maintenance dosage is 32 to 56 mg per day, administered in two to four divided doses.
• Maximum Dose: Doses exceeding 56 mg per day have not been systematically evaluated in controlled trials.[15]
• Adolescents (12 to 18 years):
• Initial Dose: 4 mg once daily.
• Titration: The dose may be increased by 4 mg at the beginning of the second week, and thereafter by 4 to 8 mg at weekly intervals.
• Maximum Dose: The total daily dose should not typically exceed 32 mg per day, given in two to four divided doses.[15]

The following table provides a typical titration regimen for induced patients.

Week of Therapy	Action	Total Daily Dose	Dosing Frequency
Week 1	Initiate at 4 mg once daily	4 mg/day	Once daily
Week 2	Increase total daily dose by 4 mg	8 mg/day	Two divided doses
Week 3	Increase total daily dose by 4 mg	12 mg/day	Three divided doses
Week 4	Increase total daily dose by 4 mg	16 mg/day	Two to four divided doses
Week 5	Increase total daily dose by 4 to 8 mg	20 to 24 mg/day	Two to four divided doses
Week 6	Increase total daily dose by 4 to 8 mg	24 to 32 mg/day	Two to four divided doses
Maintenance	Titrate to clinical response	32 to 56 mg/day	Two to four divided doses

For Patients NOT on Enzyme-Inducing AEDs ("Non-Induced Patients")

This population experiences more than double the plasma concentration for a given dose compared to induced patients. Consequently, treatment requires significantly lower doses and a much slower rate of titration.[15] While a specific, universally accepted titration schedule for this group is not as rigorously defined as for induced patients, the guiding principle is extreme caution, with smaller initial doses and longer intervals between dose increases.

5.3 Management in Special Populations

• Hepatic Impairment: Tiagabine is extensively metabolized by the liver. In patients with moderate hepatic impairment (Child-Pugh Class B), unbound drug clearance is reduced by approximately 60%.[16] These patients require reduced initial and maintenance doses and/or extended dosing intervals.[30] The drug is contraindicated in patients with severe hepatic impairment.[30]
• Renal Impairment: The pharmacokinetics of Tiagabine are not significantly affected by renal function. No dosage adjustments are necessary for patients with mild, moderate, or severe renal impairment, including those requiring hemodialysis.[23]
• Pediatric Use: The safety and efficacy of Tiagabine have not been established in children younger than 12 years of age.[23]
• Geriatric Use: While specific studies in the elderly are limited, no major differences in safety or efficacy are expected compared to younger adults. However, caution is advised, particularly regarding potential for increased CNS side effects like dizziness and somnolence.[28]
• Pregnancy and Lactation:
• Pregnancy: Tiagabine is classified as Pregnancy Category C. There is a lack of adequate and well-controlled studies in pregnant women. It should be used during pregnancy only if the potential benefit to the mother justifies the potential risk to the fetus.[17]
• Lactation: Very limited data are available on the presence of Tiagabine in human breast milk. Due to the potential for adverse effects in the nursing infant, a decision should be made whether to discontinue nursing or discontinue the drug. If used, the infant should be closely monitored for sedation and poor feeding.[26]

Section 6: Safety, Tolerability, and Risk Management

The safety profile of Tiagabine is characterized primarily by dose-related central nervous system effects and a significant risk of paradoxical seizures when used inappropriately, particularly in non-epileptic individuals.

6.1 Adverse Drug Reactions: From Common to Severe

The following table summarizes the adverse effects associated with Tiagabine, categorized by system organ class.

System Organ Class	Adverse Effect	Typical Severity/Frequency	Source(s)
Nervous System	Dizziness, Somnolence/Drowsiness	Very Common; dose-related, often during titration	1
	Asthenia (Weakness/Lack of Energy)	Common; can be incapacitating in some cases	1
	Tremor	Common	21
	Difficulty with Concentration/Attention	Common	21
	Speech/Language Problems, Confusion	Less Common; may be associated with EEG changes	29
	New-onset Seizures / Status Epilepticus	Rare but Serious; primarily in off-label use in non-epileptics	5
	Non-convulsive Status Epilepticus	Rare but Serious; can occur in patients with epilepsy	4
Psychiatric	Nervousness/Irritability	Common	1
	Depression	Less Common; reported in ~4% of epilepsy patients	17
	Suicidal Ideation and Behavior	Rare but Serious; class effect for all AEDs	9
Gastrointestinal	Nausea	Common	1
	Abdominal Pain, Diarrhea	Less Common	15
Skin and Subcutaneous Tissue	Rash	Less Common	30
	Stevens-Johnson Syndrome (SJS), Toxic Epidermal Necrolysis (TEN)	Very Rare but Life-Threatening	32

Notably, unlike some other AEDs, Tiagabine therapy has not been associated with clinically significant serum aminotransferase elevations or hepatotoxicity.[21]

6.2 Warnings and Precautions

• Risk of Seizures in Non-Epileptic Patients: As detailed previously, there is a significant risk of provoking seizures or status epilepticus when Tiagabine is used for off-label indications in individuals without an underlying seizure disorder. This is the most critical warning associated with the drug.[6]
• Suicidal Behavior and Ideation: As with all AEDs, patients treated with Tiagabine should be monitored for the emergence or worsening of depression, suicidal thoughts or behavior, or any unusual changes in mood.[9]
• Abrupt Discontinuation: Tiagabine should not be discontinued abruptly, as this may lead to an increased frequency of seizures. A gradual dose reduction is required.[4]
• Use in Generalized Epilepsy: Caution is advised in patients with generalized epilepsy, as Tiagabine may exacerbate absence seizures or generalized spike-and-wave discharges on EEG.[6]
• CNS Effects: Patients should be warned that Tiagabine can impair judgment, thinking, and motor skills. They should exercise caution when driving or operating heavy machinery until they are familiar with the drug's effects.[28]

6.3 Contraindications

Tiagabine is contraindicated in the following situations:

• Patients with a known hypersensitivity to Tiagabine or any of the inactive ingredients in the tablet formulation.[30]
• Patients with severely impaired liver function.[30]

6.4 Comprehensive Analysis of Drug-Drug Interactions

The potential for drug-drug interactions with Tiagabine is primarily driven by its metabolism via CYP3A4 and its intrinsic CNS depressant effects. The following table outlines the most clinically significant interactions.

Interacting Drug/Class	Mechanism of Interaction	Effect on Tiagabine	Effect on Other Drug	Clinical Recommendation	Source(s)
Enzyme-Inducing AEDs (Carbamazepine, Phenytoin, Phenobarbital, Primidone)	CYP3A4 Induction	Decreased plasma concentration and half-life (~50-65%)	None (Tiagabine does not alter their levels)	Higher doses of Tiagabine are required. Follow "Induced Patient" dosing guidelines.	23
Other CYP3A4 Inducers (e.g., Rifampin, St. John's Wort, Bosentan)	CYP3A4 Induction	Decreased plasma concentration	Variable	Monitor for reduced Tiagabine efficacy; dose increase may be needed.	20
CYP3A4 Inhibitors (e.g., Ketoconazole, Clarithromycin, Ritonavir, Nefazodone)	CYP3A4 Inhibition	Increased plasma concentration	Variable	Monitor for Tiagabine toxicity; dose reduction may be necessary.	7
CNS Depressants (Alcohol, Benzodiazepines, Opioids, Antihistamines, Antipsychotics)	Additive Pharmacodynamic Effect	None	Increased sedation, dizziness, cognitive and motor impairment	Counsel patient on the risk of additive CNS depression. Avoid co-use with alcohol.	7
Valproate	Protein Binding Displacement	May increase free (unbound) Tiagabine levels	None	Monitor for increased Tiagabine side effects.	32
Drugs that Lower Seizure Threshold (e.g., Amphetamine, Chloroquine, Mefloquine)	Pharmacodynamic Antagonism	Decreased therapeutic efficacy	Variable	Co-administration may reduce anticonvulsant effect. Use with caution.	7

An important clinical consideration is the largely unidirectional nature of its pharmacokinetic interactions with other major AEDs. While enzyme inducers like carbamazepine and phenytoin profoundly reduce Tiagabine levels, studies have shown that the addition of Tiagabine to a stable regimen of these drugs does not significantly alter their steady-state concentrations.[36] This simplifies therapeutic drug management, as clinicians can focus on adjusting the Tiagabine dose without needing to preemptively modify the dose of the concomitant inducer.

Section 7: Regulatory and Commercial Landscape

7.1 Regulatory History and Key FDA Actions

• Initial FDA Approval: Tiagabine, under the brand name Gabitril, was granted marketing approval by the US FDA on September 30, 1997. The original New Drug Application (NDA 20646) was sponsored by Abbott Laboratories.[39]
• Post-Marketing Safety Actions: The post-approval period for Tiagabine has been marked by significant safety-related labeling changes.
• February 2005: In response to post-marketing reports of new-onset seizures in patients without epilepsy, the FDA required the manufacturer, Cephalon Inc., to add a bolded warning to the prescribing information. This warning specifically highlighted the risk of seizures and status epilepticus associated with the drug's off-label use.[5]
• 2008–2010: Following a class-wide FDA review of AEDs that identified an increased risk of suicidal thoughts and behavior, Tiagabine became subject to a Risk Evaluation and Mitigation Strategy (REMS). This REMS, approved in 2010, mandated the provision of a Medication Guide to all patients to ensure they were aware of this serious risk.[41]

7.2 Brand Information, Patent Status, and Generic Availability

• Brand Name and Availability: The original brand name for Tiagabine is Gabitril, marketed by Cephalon Inc..[6] It is available in the United States, the United Kingdom, and Australia, but is not marketed in Canada.[6]
• Generic Status: Lower-cost generic versions of Tiagabine hydrochloride are now available.[9] The first Abbreviated New Drug Application (ANDA) for generic Tiagabine was approved by the FDA in 2011.[42]
• Patent Information: The drug was originally developed by Novo Nordisk.[17] The primary patents covering the Tiagabine molecule and its use (e.g., U.S. Patents 5,354,760; 5,866,590; 5,958,951) have since expired, paving the way for generic competition.[42]

Section 8: Synthesis and Concluding Remarks

8.1 Integrated Profile of Tiagabine: Balancing Efficacy and Risk

Tiagabine represents a mechanistically targeted therapeutic agent in the field of epileptology. Its high selectivity as an inhibitor of the GAT-1 GABA transporter offers a precise method for enhancing synaptic inhibition, a fundamental strategy for seizure control. Its efficacy as an add-on therapy for refractory partial-onset seizures is supported by robust clinical trial data.

However, the clinical utility of Tiagabine is sharply defined and constrained by its pharmacokinetic profile. The drug's heavy reliance on the CYP3A4 metabolic pathway makes its clearance exceptionally sensitive to the presence of enzyme-inducing or -inhibiting drugs. This creates a stark dichotomy between "induced" and "non-induced" patient populations, demanding fundamentally different clinical management approaches. The history of its off-label use, which led to paradoxical seizures in non-induced individuals, serves as a powerful illustration of how a failure to appreciate these pharmacokinetic principles can transform a therapeutic agent into a source of significant risk. The resulting regulatory warnings have appropriately narrowed its clinical application, reinforcing its role as a specialized tool rather than a broad-spectrum agent.

8.2 Key Considerations for Clinical Practice and Future Research

The paramount consideration for any clinician prescribing Tiagabine is the patient's co-medication profile. A thorough assessment of a patient's enzyme induction status is not merely advisable but essential for safe and effective dosing. The principles of slow, careful dose titration and administration with food must be strictly followed to enhance tolerability.

Tiagabine's journey from development to post-marketing surveillance offers valuable lessons for clinical pharmacology. It underscores that a drug's safety profile is not an intrinsic property alone but an emergent one, arising from the complex interplay between its mechanism, its pharmacokinetics, and the specific patient population in which it is used. While its broader application has been limited, Tiagabine remains a viable option for appropriately selected patients with refractory partial epilepsy. Future research could explore novel drug delivery systems that might provide more consistent plasma levels, potentially mitigating the risks associated with its variable metabolism and widening its therapeutic index.

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