AHFS Class:

• GABA-mediated Anticonvulsants 28:12.28

Generic Name(s):

• tiaGABine Hydrochloride

Tiagabine, a nipecotic acid derivative, is an anticonvulsant.1,2,7

Seizure Disorders

Partial Seizures

Tiagabine hydrochloride is used as adjunctive therapy (i.e., in combination with other anticonvulsants) in the management of partial seizures in adults and pediatric patients 12 years of age or older.1,5,10,12,13,24,25,26,27

In controlled clinical studies, adjunctive therapy with tiagabine was effective in reducing seizure frequency in patients with simple and/or complex partial seizures refractory to therapy with one or more conventional anticonvulsant drugs (e.g., carbamazepine, phenytoin, valproate).1,10,12,13,24,25,26,27 In 2 multicenter, parallel-group studies conducted in the US, patients received tiagabine or placebo in addition to their existing anticonvulsant regimen, and efficacy of the drug was evaluated principally in terms of the median decrease (from baseline) in the frequency of complex partial seizures per 4-week period during adjunctive treatment; the median frequency of all partial seizures per 4-week period also was recorded in these studies.1 In the first US study, patients were randomized to receive adjunctive therapy with placebo or 16, 32, or 56 mg of tiagabine hydrochloride administered in 4 divided doses daily for 12 weeks (after a 4-week titration period to achieve the assigned daily dosage).1 In patients receiving adjunctive tiagabine therapy, a reduction from baseline of 2.2 or 2.9 in the median 4-week frequency of complex partial seizures occurred with tiagabine hydrochloride dosages of 32 or 56 mg daily, respectively, while the median reduction in the 4-week frequency of all partial seizures in patients receiving adjunctive tiagabine was 2.7 or 3.5, respectively.1 Seizure frequency did not decrease substantially in patients receiving adjunctive therapy with placebo or tiagabine hydrochloride 16 mg daily.1

In the second US study, patients were randomized to receive tiagabine hydrochloride 16 mg twice daily, 8 mg 4 times daily, or placebo for 8 weeks as an adjunct to existing anticonvulsant therapy after a 4-week dosage titration period.1,10 Patients receiving tiagabine hydrochloride 8 mg 4 times daily experienced a median reduction of 1.3 in the 4-week frequencies of both complex partial and all partial seizures, although the difference in seizure frequency reduction for all partial seizures was not statistically significant.1,10 Patients receiving tiagabine hydrochloride 16 mg twice daily or placebo did not experience a substantial reduction in 4-week seizure frequency for either complex partial1,10 or all partial seizures.1

In a multicenter, parallel-group study conducted in Europe, patients were randomized to receive adjunctive therapy with 10 mg of tiagabine hydrochloride or placebo 3 times daily for 12 weeks after a 6-week dosage titration period.1,24 Efficacy of tiagabine was evaluated principally in terms of the proportion of patients achieving at least a 50% reduction from baseline in partial seizure frequency (i.e., responder rate).1,24 Secondary analyses were performed using evaluation criteria similar to those used in the US studies (i.e., median decrease from baseline in the 4-week frequency of complex partial or all partial seizures).1,24 Although the responder rate was numerically greater in patients receiving tiagabine (14%) compared with those receiving placebo (6%), the difference was not statistically significant.1,24 In additional analyses, patients receiving tiagabine experienced a substantial median decrease from baseline of 1.3 or 1.1 in the 4-week frequency of complex partial or all partial seizures, respectively,1 but patients receiving placebo tended to have a median increase in the 4-week frequency of complex partial or all partial seizures.1

In 2 other small, placebo-controlled crossover studies, which consisted of a dosage titration period followed by two 7-week treatment periods with a 3-week washout period between treatments (tiagabine followed by placebo, or placebo followed by tiagabine), median within-patient reductions in the frequency of complex partial and all partial seizures per 4-week period during administration of tiagabine were greater than those reported during placebo administration.1,25,26

Other Uses

Tiagabine has been studied in a limited number of patients for the management of psychiatric disorders† and other conditions (e.g., chronic pain†);14,15,16,17,18 however, safety and efficacy of the drug for any indication other than the management of partial seizures have not been established,1 and unlabeled (off-label) use of tiagabine has been associated with new-onset seizures, including status epilepticus.1,14 (See Seizures in Nonepileptic Patients under Warnings/Precautions: Warnings, in Cautions.) Therefore, use of tiagabine for unlabeled indications is strongly discouraged.14

Administration

Tiagabine hydrochloride is administered orally with food.1 Food delays, but does not decrease the extent of tiagabine absorption.1,5,13 The initial tiagabine dosage is given once daily; following dosage increases after the initial period, the dosage should be administered in 2-4 divided doses daily.1

Patients currently receiving or beginning therapy with tiagabine and/or any other anticonvulsant should be closely monitored for notable changes in behavior that could indicate the emergence or worsening of suicidal thoughts or behavior or depression.1,20 (See Suicidality Risk under Warnings/Precautions: Warnings, in Cautions.)

The manufacturer states that a therapeutic range of plasma tiagabine concentrations has not been established; however, because of the potential for altered tiagabine clearance during concurrent administration of hepatic microsomal enzyme-inducing or -inhibiting drugs, it may be useful to determine plasma tiagabine concentrations before and after changes are made to the patient's drug regimen.1

Because of the possibility of increasing seizure frequency, anticonvulsant drugs, including tiagabine, should not be discontinued abruptly.1,13 (See Discontinuance of Therapy under Warnings/Precautions: Warnings, in Cautions.)

Dosage

Partial Seizures

A loading dose of tiagabine should not be administered.1 Dosage should be increased slowly; rapid and/or large increases in dosage should be avoided.1 If a patient misses a dose, the next dose should not be increased to compensate for the missed dose.1 If a patient misses multiple doses, dosage retitration should be considered.1

The dosage regimen of tiagabine depends on whether a hepatic enzyme-inducing anticonvulsant drug is administered concomitantly.1 Tiagabine undergoes extensive hepatic metabolism,1,5,6 and the plasma half-life of the drug is decreased from 7-9 hours in healthy individuals to 2-5 hours in patients concomitantly receiving an anticonvulsant drug that induces hepatic microsomal enzymes (e.g., carbamazepine, phenobarbital, phenytoin, primidone).1,5,6,11,13 Administration of tiagabine with an anticonvulsant drug that induces hepatic microsomal enzymes increases the clearance (i.e., reduces plasma concentrations) of tiagabine; conversely, discontinuance of such a concomitantly administered anticonvulsant drug may result in decreased clearance (i.e., increased plasma concentrations) of tiagabine.1 Patients receiving a combination of enzyme-inducing and non-enzyme-inducing anticonvulsant drugs (e.g., carbamazepine and valproate) should be considered to have induced hepatic microsomal enzymes.1

When initiating therapy with tiagabine, the clinician must take into account whether the patient is receiving a hepatic enzyme-inducing drug when selecting the initial dose of tiagabine and a dosage titration schedule.1 Clinicians should be aware that addition of hepatic enzyme-inducing anticonvulsant drugs, dosage change of these drugs, or their discontinuance from an anticonvulsant regimen including tiagabine may require modification of the dosage of tiagabine.1 Tiagabine does not appear to induce or inhibit hepatic microsomal enzymes nor does it appear to have any clinically important effects on the pharmacokinetics of other anticonvulsants.1,6 Therefore, unless clinically indicated, modification of concomitant anticonvulsant therapy is not necessary when tiagabine is added to an existing anticonvulsant regimen.1

Patients Receiving Hepatic Enzyme-inducing Anticonvulsants

For adjunctive therapy in the management of partial seizures in adults who are receiving a hepatic enzyme-inducing anticonvulsant (e.g., carbamazepine, phenytoin, primidone, phenobarbital), the initial dosage of tiagabine hydrochloride is 4 mg once daily for the first week of therapy.1 Beginning with the second week of treatment, the total daily dosage of tiagabine (administered as 2-4 divided doses) may be increased by 4-8 mg at weekly intervals until a clinical response is achieved or a total daily dosage of 56 mg is reached.1 The manufacturer's prescribing information should be consulted for a typical dosage titration regimen.1 The usual maintenance dosage of tiagabine hydrochloride in adults is 32-56 mg daily.1 The manufacturer states that dosages exceeding 56 mg daily have not been evaluated systematically in controlled clinical studies and that limited experience exists in adults receiving tiagabine hydrochloride twice daily at daily dosages exceeding 32 mg.1

The usual initial dosage of tiagabine hydrochloride in adolescents 12 years of age or older who are receiving a hepatic enzyme-inducing anticonvulsant drug is 4 mg once daily for the first week of therapy.1 Daily dosage may be increased to 4 mg twice daily beginning with the second week of treatment; thereafter, the total daily dosage (administered in 2-4 divided doses) may be increased by 4-8 mg at weekly intervals until a clinical response is achieved or a total daily dosage of 32 mg is reached.1 The manufacturer states that daily dosages exceeding 32 mg have been tolerated in a limited number of adolescents for a relatively short duration.1

Patients Not Receiving Hepatic Enzyme-inducing Anticonvulsants

Adults and adolescents 12 years of age or older not receiving concomitant therapy with a hepatic enzyme-inducing anticonvulsant drug require a lower dosage of tiagabine hydrochloride and a slower dosage titration schedule than patients receiving such concomitant therapy.1 Systemic exposure following administration of a 32- or 56-mg dose of tiagabine hydrochloride in an individual receiving a hepatic enzyme-inducing drug concomitantly is expected to be comparable to that of a 12- or 22-mg dose, respectively, in a patient not receiving a hepatic enzyme-inducing drug.1

Special Populations

Tiagabine clearance is decreased in patients with hepatic impairment, and the manufacturer states that such patients may require decreased initial and maintenance dosages of tiagabine and/or longer dosing intervals than patients who have normal hepatic function.1

The manufacturer makes no specific dosage recommendations in patients with renal impairment or in geriatric patients.1

Contraindications

Known hypersensitivity to tiagabine or any ingredient in the formulation.1

Warnings/Precautions

Warnings

Seizures in Nonepileptic Patients

Tiagabine may cause new-onset seizures and status epilepticus in patients without epilepsy.1

More than 30 cases of seizure activity have been reported in patients without a history of epilepsy receiving tiagabine for unlabeled uses.14 Most of these patients were receiving tiagabine for psychiatric disorders and were receiving concomitant drugs (antidepressants, antipsychotic agents, CNS stimulants, opiate analgesics) that are thought to lower the seizure threshold.1,14 Dosage of tiagabine may be an important predisposing factor in the development of seizures.1,14 Dosage recommendations for tiagabine have been based principally on experience in patients receiving concomitant therapy with hepatic enzyme-inducing anticonvulsants (e.g., carbamazepine, phenytoin, primidone, phenobarbital), which lower plasma concentrations of tiagabine.1,14 (See Dosage and Administration: Dosage.)

Tiagabine should be discontinued if seizures occur in patients without epilepsy, and such patients should be evaluated for seizure disorders.1 The manufacturer states that use of the drug is not recommended for any indication other than adjunctive therapy of partial seizures in adults and adolescents 12 years of age or older.1

Suicidality Risk

An increased risk of suicidality (suicidal behavior or ideation) was observed in an analysis of 199 placebo-controlled studies evaluating 11 anticonvulsants (carbamazepine, felbamate, gabapentin, lamotrigine, levetiracetam, oxcarbazepine, pregabalin, tiagabine, topiramate, valproate, and zonisamide) in patients with epilepsy, psychiatric disorders (e.g., bipolar disorder, depression, anxiety), and other conditions (e.g., migraine, neuropathic pain).1,20 The analysis revealed that patients receiving these anticonvulsants had approximately twice the risk of suicidal behavior or ideation (0.43%) compared with patients receiving placebo (0.24%); the increased risk was observed as early as one week after beginning therapy and continued through 24 weeks.1,20 Although patients treated with an anticonvulsant for epilepsy, psychiatric disorders, and other conditions were all found to have an increased suicidality risk compared with those receiving placebo, the relative suicidality risk was higher for patients with epilepsy compared with those receiving anticonvulsants for other conditions.20

Clinicians should inform patients, their families, and caregivers of the potential for an increased suicidality risk with anticonvulsant therapy; all patients currently receiving or beginning therapy with any anticonvulsant for any indication should be closely monitored for the emergence or worsening of depression, suicidal thoughts or behavior (suicidality), and/or any unusual changes in mood or behavior.1,20

Clinicians who prescribe tiagabine or any other anticonvulsant should balance the risk for suicidality with the risk of untreated illness.1,20 Epilepsy and many other illnesses for which anticonvulsants are prescribed are themselves associated with an increased risk of morbidity and mortality and an increased risk of suicidal thoughts and behavior.1,23 If suicidal thoughts and behavior emerge during anticonvulsant therapy, the clinician must consider whether the emergence of these symptoms in any given patient may be related to the illness being treated.1,23

Discontinuance of Therapy

Because of the possibility of increasing seizure frequency, anticonvulsant drugs, including tiagabine, should not be discontinued abruptly.1 The manufacturer states that tiagabine should be withdrawn gradually unless more rapid withdrawal is required for safety reasons.1

In a placebo-controlled study, dosage of tiagabine hydrochloride was gradually reduced after 16 weeks of treatment and discontinued over a 4-week period.1,11 An increased frequency of seizures (compared with baseline) was observed during the withdrawal period for each type of partial seizure, for all types of partial seizures combined, and for secondarily generalized tonic-clonic seizures in patients receiving tiagabine compared with those receiving placebo; the increase in seizure frequency was similar regardless of the dosage of tiagabine hydrochloride administered.1

Cognitive and Neuropsychiatric Effects

Neuropsychiatric effects reported during tiagabine therapy are classified into 2 categories: impaired cognitive or psychomotor performance, including difficulties in concentrating, language, and speech, or confusion; and somnolence or fatigue.1 Such effects were usually mild to moderate in severity and observed during the initial dose-titration phase; some of the events were dose related.1 In controlled clinical trials, cognitive/neuropsychiatric events led to discontinuance of therapy in 6% of patients receiving tiagabine compared with 2% of placebo-treated patients.1

Cognitive/neuropsychiatric events have been accompanied by EEG abnormalities (e.g., generalized spike and wave activity), which indicate that these effects may be a manifestation of underlying seizure activity.1 In the reported cases, dosage adjustment of tiagabine usually was required.1

Status Epilepticus

It is not known whether the incidence of status epilepticus with tiagabine (5% in controlled and uncontrolled trials) is higher or lower than would be expected in patients with epilepsy not treated with the drug.1 Seizures and status epilepticus may occur with tiagabine overdosage.1 In clinical studies, approximately one-third of patients with a history of status epilepticus experienced a recurrence while receiving tiagabine therapy.1

Sudden Unexpected Death In Epilepsy

A higher incidence of sudden and unexplained deaths than would be expected in a healthy (nonepileptic) population has been reported with tiagabine; however, the incidence is within the range of estimates for epileptic patients who are not receiving tiagabine or other anticonvulsant agents.1 This evidence suggests that the sudden and unexplained death rates reflect population rates, and is not a drug effect.1

Sensitivity Reactions

Dermatologic Reactions

At least 4 cases of serious rash (i.e., Stevens-Johnson syndrome, maculopapular rash, vesiculobullous rash) have been reported in patients receiving tiagabine in clinical trials.1 In none of the cases is it certain that tiagabine was the primary, or even a contributory, cause of the rash; however, serious drug-associated rash can cause irreversible morbidity, even death.1

Other Warnings and Precautions

Use in Patients not Receiving Concomitant Enzyme-inducing Anticonvulsants

Virtually all experience with tiagabine has been in the population of patients receiving concomitant enzyme-inducing anticonvulsants.1 Plasma concentrations of tiagabine in patients not receiving such concomitant therapy may be substantially increased, requiring a reduction in dosage.1 (See Dosage and Administration: Dosage.)

Generalized Weakness

Generalized weakness (moderately severe to incapacitating) has been reported following tiagabine administration in approximately 1% of patients with epilepsy; in all cases, weakness resolved after a reduction in dosage or discontinuance of therapy.1

Binding to Melanin-rich Tissues

Results of animal toxicology studies suggest that tiagabine may bind to melanin-containing tissues, including parts of the eye.1 Following administration of a single dose of tiagabine in dogs, residual binding of the drug in the retina and uvea was observed after 3 weeks; however, ophthalmic changes were not noted following longer-term (up to one year) exposure.1 Although the potential clinical consequences and relevance to humans is unknown, clinicians should be aware of the possibility that tiagabine may cause long-term ophthalmic effects.1

Specific Populations

Pregnancy

There are no adequate and well-controlled studies of tiagabine in pregnant women; adverse effects on embryofetal development, including teratogenic effects, have been observed in animals.1 Tiagabine should be used during pregnancy only if clearly indicated.1

Women who are pregnant while receiving tiagabine should be encouraged to enroll in the North American Antiepileptic Drug (NAAED) Pregnancy Registry at 888-233-2334 (for patients); registry information also is available on the website [Web].1

Lactation

Tiagabine and/or its metabolites are distributed into milk in rats; it is not known whether the drug is distributed into human milk.1 The effects of tiagabine on the nursing infant also are unknown.1 Tiagabine should be used in nursing women only if the benefits clearly outweigh the risks.1

Pediatric Use

Safety and efficacy of tiagabine in children younger than 12 years of age have not been established.1

Pharmacokinetic analysis indicates that clearance and volume of distribution of tiagabine are similar in pediatric patients (3-10 years of age) and adults receiving concomitant enzyme-inducing anticonvulsant drugs; however, in the non-induced population (e.g., those receiving non-inducing anticonvulsants such as valproate), clearance is increased in pediatric patients compared with adults.1

Geriatric Use

Clinical trials have not included sufficient numbers of patients older than 65 years of age to determine whether they respond differently than younger patients; safety and efficacy of tiagabine in geriatric patients have not been established.1 However, the pharmacokinetic profile of tiagabine in healthy geriatric adults was similar to that in younger adults.1,11

Hepatic Impairment

Clearance of tiagabine (unbound portion) is decreased by about 60% in patients with moderate hepatic impairment (Child-Pugh class B).1

Renal Impairment

The pharmacokinetics of total and unbound tiagabine in patients with mild (creatinine clearance 40-80 mL/minute), moderate (creatinine clearance 20-39 mL/minute), or severe (creatinine clearance 5-19 mL/minute) renal impairment are similar to those in patients with normal renal function (creatinine clearance greater than 80 mL/minute).1 Pharmacokinetics of total and unbound tiagabine also appear to be unchanged in patients with renal failure undergoing hemodialysis.1

Common Adverse Effects

Adverse effects occurring in 5% or more of patients receiving tiagabine in combination with other anticonvulsant drugs and more frequently than with placebo in clinical trials include dizziness/lightheadedness, asthenia/lack of energy, somnolence, nausea, vomiting, diarrhea, nervousness/irritability, tremor, abdominal pain, generalized pain, insomnia, ataxia, confusion, rash, pharyngitis, and difficulty with concentration or attention.1

Drugs Affecting or Metabolized by Hepatic Microsomal Enzymes

In vitro data indicate that tiagabine is likely metabolized by cytochrome P-450 (CYP) isoenzymes, principally CYP3A.1 The drug also may be metabolized by CYP1A2, CYP2D6, or CYP2C19.1 Pharmacokinetic interactions are possible when tiagabine is administered concomitantly with drugs that inhibit or induce these hepatic microsomal enzymes.1

Tiagabine does not appear to induce or inhibit hepatic microsomal enzymes based on pharmacokinetic studies using antipyrine.1,6

Protein-bound Drugs

Tiagabine is highly (96%) bound to plasma proteins and has the potential to interact with other highly protein-bound drugs; the interaction can potentially lead to higher free fractions of either tiagabine or the competing drug.1,6

Alcohol

In healthy individuals receiving tiagabine and alcohol concomitantly, no apparent changes in the pharmacodynamics (e.g., vigilance, cognitive abilities, reaction time, visual tracking) of alcohol were observed; the pharmacokinetics of both alcohol and tiagabine were unchanged.1,21 However, because of possible additive depressive effects, alcohol should be used with caution in patients receiving tiagabine.1

Anticonvulsants

Tiagabine is considered a non-enzyme inducing anticonvulsant and does not appear to have clinically important effects on the pharmacokinetics of other anticonvulsants when administered concomitantly.1,6 However, CYP enzyme-inducing anticonvulsants (e.g., carbamazepine, phenytoin, phenobarbital, primidone) can increase tiagabine clearance and substantially reduce plasma concentrations of the drug.1

Tiagabine had no effect on the steady-state plasma concentrations of carbamazepine or its epoxide metabolite in patients with epilepsy; however, population pharmacokinetic analyses indicate that tiagabine clearance is increased by 60% when administered concomitantly with carbamazepine with or without other enzyme-inducing anticonvulsants.1

Tiagabine had no effect on the steady-state plasma concentrations of phenytoin in patients with epilepsy; however, population pharmacokinetic analyses indicate that tiagabine clearance is increased by 60% when administered concomitantly with phenytoin with or without other enzyme-inducing anticonvulsants.1

Limited data in patients receiving concomitant therapy with tiagabine and phenobarbital or primidone in clinical studies indicate that systemic exposure of phenobarbital or primidone was not altered.1 Population pharmacokinetic analyses indicate that tiagabine clearance is increased by 60% when administered concomitantly with phenobarbital or primidone with or without other enzyme-inducing anticonvulsants.1

In vitro findings indicate that valproate reduces tiagabine plasma protein binding from 96.3 to 94.8%, which results in a 40% increase in free plasma tiagabine concentrations; however, the clinical relevance of this interaction is not known.1 Tiagabine causes a slight (about 10%) decrease in steady-state valproate concentrations.1

Antipyrine

Antipyrine pharmacokinetics were not substantially altered prior to and after multiple-dose administration of tiagabine.1

Cimetidine

Administration of cimetidine (800 mg/day) in patients receiving long-term tiagabine therapy had no effect on tiagabine pharmacokinetics.1

CNS Depressants

Concomitant use of tiagabine with CNS depressants (e.g., alcohol, benzodiazepines) may cause additive depressive effects.1,19 Caution is advised.1

Digoxin

Concomitant administration of tiagabine and digoxin did not affect steady-state pharmacokinetics or trough serum concentrations of digoxin.1

Oral Contraceptives

Tiagabine does not alter the pharmacokinetics of oral contraceptives.1 When tiagabine hydrochloride was administered at a dosage of 8 mg daily in healthy women receiving oral contraceptives, pharmacokinetics of the oral contraceptive were not altered.1

St. John's Wort (Hypericum perforatum)

Concomitant use of tiagabine and St. John's wort may enhance the metabolism of tiagabine.1

Theophylline

A single 10-mg dose of tiagabine hydrochloride did not alter the pharmacokinetics of theophylline at steady state.1

Triazolam

In healthy individuals, no substantial differences in the pharmacokinetics or pharmacodynamics (e.g., sedative or cognitive effects) of triazolam were observed when a single 0.125-mg dose of the drug was administered concomitantly with tiagabine hydrochloride (single dose of 10 mg).1,19 The pharmacokinetics of tiagabine were not altered by triazolam.19 However, because of possible additive depressive effects, triazolam should be used with caution in patients receiving tiagabine.1

Warfarin

No substantial differences were observed in the steady-state pharmacokinetics of R -warfarin or S -warfarin when a single dose of tiagabine was administered concomitantly; prothrombin time (PT) also was not affected.1

Description

Tiagabine, a nipecotic acid derivative, is an anticonvulsant agent.1,2,7 The drug is commercially available as the hydrochloride salt and differs structurally from other currently available anticonvulsant agents.2

Although the precise mechanism of action of tiagabine is unknown, the drug enhances inhibitory neurotransmission mediated by γ-aminobutyric acid (GABA).1,3,5,6,7,9,13 Tiagabine increases the amount of GABA available in extracellular spaces of the globus pallidus, ventral pallidum, and substantia nigra,1 suggesting a GABA-mediated anticonvulsant mechanism of action (i.e., inhibition of neural impulse propagations that contribute to seizures).1 Tiagabine inhibits presynaptic neuronal and glial GABA reuptake,1,3,5,6,7,9,13 and increases the amount of GABA available for postsynaptic receptor binding.1,6,7,9 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.1,2,7,9 Tiagabine selectively blocks presynaptic GABA uptake by binding reversibly and saturably to recognition sites associated with GABA transporter protein in neuronal and glial membranes.1,2,3,6,7,9

Tiagabine exhibits anticonvulsant activity in several animal seizure models.1,2,7,9 Although the drug is effective against tonic seizures induced in some animals by subcutaneous administration of pentylenetetrazole (PTZ),1,7,9 tiagabine is only partially effective against PTZ-induced clonic seizures in some animals,1,2,7,9 indicating that it may not have substantial activity against absence seizures in humans.9 Tiagabine decreases seizure severity and aftercharge duration in animals with amygdala-kindled seizures,1,2,7,9 indicating potential anticonvulsant activity against partial seizures in humans.1,2,8,9 Tiagabine exhibits a dose-dependent effect against clonic seizures induced by proconvulsant methyl-6,7-dimethyoxy-4-ethyl-β-carboline-3-carboxylate (DMCM), with diminished effectiveness at higher dosages,1,7,9 and is effective against audiogenic seizures in genetically epilepsy-prone animals.1,2,7,9 Tiagabine is partially effective against picrotoxin-induced seizures,1 bicuculline-induced seizures,1,7 and photic seizures,1,2,7 and is minimally effective against maximal electroshock seizures (MES) in animals.1,2,7,9

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.14

In vitro binding studies indicate that tiagabine does not inhibit substantially the uptake of dopamine, norepinephrine, serotonin, glutamate, or choline,1,7 and does not bind substantially to dopamine D₁ or D₂;1,7 cholinergic muscarinic;1,7 serotonergic type 1A, type 2, or type 3 (5HT_1A, 5HT₂, or 5HT₃, respectively);1,7α₁- or α₂-adrenergic; β₁- or β₂-adrenergic;1,7 histamine H₂ or H₃;1,7 adenosine A₁ or A₂;1,7 opiate µ or κ₁;1,7 glutamate N -methyl-d-aspartate (NMDA);1,7,9 or GABA_A receptors.1,7 Also, tiagabine has little or no affinity for sodium or calcium channels.1,7,9 Tiagabine binds to histamine H₁, serotonergic type 1B (5HT_1B), benzodiazepine, and chloride channel receptors at concentrations 20-400 times those that inhibit the uptake of GABA.1,7

Advice to Patients

Importance of patients reading the manufacturer's patient information (medication guide) prior to initiating therapy.1

Importance of taking tiagabine exactly as prescribed.1 Importance of not abruptly discontinuing therapy.1

Risk of dizziness or drowsiness; avoid driving or operating machinery until effects on individual are known.1

Risk of suicidality (anticonvulsants may increase risk of suicidal thoughts or actions in about 1 in 500 people).1,20 Importance of patients, family members, and caregivers being aware that anticonvulsants, including tiagabine, may increase the risk of having suicidal thoughts or actions in a very small number of people (about 1 in 500).1,20 Advise patients, family members, and caregivers to pay close attention to any day-to-day changes in mood, behavior, and actions; these changes can happen very quickly.1,20 They should also be aware of common warning signs that may signal suicide risk (e.g., talking or thinking about wanting to hurt oneself or end one's life, withdrawing from friends and family, becoming depressed or experiencing worsening of existing depression, becoming preoccupied with death and dying, giving away prized possessions).1,20 Advise patients, family members, and caregivers to contact the responsible clinician immediately if these or any new and worrisome behaviors occur.1,20

Importance of women informing clinicians if they are or plan to become pregnant or plan to breast-feed.1

Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs, as well as concomitant illnesses.1

Importance of advising patients of other important precautionary information.1 (See Cautions.)

Additional Information

The American Society of Health-System Pharmacists, Inc. represents that the information provided in the accompanying monograph was formulated with a reasonable standard of care, and in conformity with professional standards in the field. Readers are advised that decisions regarding use of drugs are complex medical decisions requiring the independent, informed decision of an appropriate health care professional, and that the information contained in the monograph is provided for informational purposes only. The manufacturer's labeling should be consulted for more detailed information. The American Society of Health-System Pharmacists, Inc. does not endorse or recommend the use of any drug. The information contained in the monograph is not a substitute for medical care.

1. Cephalon, a subsidiary of Teva Pharmaceuticals. Gabitril^® (tiagabine hydrochloride) tablets prescribing information. North Wales, PA; 2016 Aug.

2. Rogawski MA, Porter RJ. Antiepileptic drugs: Pharmacological mechanisms and clinical efficacy with consideration of promising developmental stage compounds. Pharmacol Rev . 1990; 42:223-86. [PubMed 2217531]

3. Taylor CP. Mechanism of action of new anti-epileptic drugs. In: Chadwick D, ed. New trends in epilepsy management: the role of gabapentin. London, UK. Royal Society of Medicine Services Limited. 1993:13-40.

4. Hosfard DA, Wang Y. Utility of the lethargic (lh/lh) mouse model of absence seizures in predicting the effects of lamotrigine, vigabatrin, tiagabine and topiramate against human absence seizures. Epilepsia . 1997; 38:4408-14.

5. Natsch S, Hekster YA, Keyser A et al. Newer anticonvulsant drugs: role of pharmacology, drug interactions and adverse reactions in drug choice. Drug Saf . 1997; 17:228-40. [PubMed 9352959]

6. Walker MC, Patsalos PN. Clinical pharmacokinetics of new antiepileptic drugs. Pharmacol Ther . 1995; 67:351-84. [PubMed 8577822]

7. Suzdak PD, Jansen JA. A review of the preclinical pharmacology of tiagabine: a potent and selective anticonvulsant GABA uptake inhibitor. Epilepsia . 1995; 36:612-26. [PubMed 7555976]

8. McNamara JO. Drugs effective in the treatment of the epilepsies. In: Hardman JG, Limbird LE, Molinoff PB et al, eds. Goodman and Gilman's the pharmacological basis of therapeutics. 9th ed. New York: Macmillan Publishing Company; 1996:461-86.

9. White HS. Clinical significance of animal seizure models and mechanism of action studies of potential antiepileptic drugs. Epilepsia . 1997; 38(Suppl 1):S9-17. [PubMed 9092952]

10. Sachdeo RC, Leroy RF, Krauss GL et al et al. Tiagabine therapy for complex partial seizures: a dose-frequency study. Arch Neurol . 1997; 54:595-601. [PubMed 9152116]

11. Abbott Laboratories, North Chicago, IL: Personal communication.

12. Ben-Menachem E. International experience with tiagabine add-on therapy. Epilepsia . 1995; 36(Suppl 6):S14-21. [PubMedCentral]

13. Anon. Tiagabine for epilepsy. Med Lett Drug Ther . 1998; 40:45-6.

14. FDA Alert. Tiagabine hydrochloride (marketed as Gabitril): seizures in patients without epilepsy. 2005 Feb 18. From FDA website ([Web]).

15. Stahl SM. Anticonvulsants as anxiolytics, part 1; Tiagabine and other anticonvulsants with actions on GABA. J Clin Psychiatry . 2004; 65:291-2. [PubMed 15096065]

16. Todorov AA, Kolchev CB, Todorov AB. Tiagabine and gabapentin for the management of chronic pain. Clin J Pain . 2005; 21:358-61 [PubMed 15951655]

17. Taylor FB. Tiagabine for posttraumatic stress disorder: a case series of 7 women. J Clin Psychiatry . 2003; 64:1421-5. [PubMed 14728102]

18. Rosenthal M. Tiagabine for the treatment of generalized anxiety disorder; a randomized, open-label, clinical trial with paroxetine as a positive control. J Clin Psychiatry . 2003; 64:1245-9. [PubMed 14658975]

19. Richens A, Marshall RW, Dirach J et al. Absence of interaction between tiagabine, a new antiepileptic drug, and the benzodiazepine triazolam. Drug Metabol Drug Interact . 1998; 14:159-77. [PubMed 10366992]

20. Food and Drug Administration. FDA Alert: Information for health care professionals: Suicidality and antiepileptic drugs. Rockville, MD; 2008 Jan 31. From the FDA website.

21. Kastberg H, Jansen JA, Cole G et al. Tiagabine: absence of kinetic or dynamic interactions with ethanol. Drug Metabol Drug Interact . 1998; 14:259-73. [PubMed 10694933]

23. Food and Drug Administration. Suicidal behavior and ideation and antiepileptic drugs: update 5/5/2009. Rockville, MD; 2009 May 5. From the FDA website.

24. Kälviäinen R, Brodie MJ, Duncan J et al. A double-blind, placebo-controlled trial of tiagabine given three-times daily as add-on therapy for refractory partial seizures. Northern European Tiagabine Study Group. Epilepsy Res . 1998; 30:31-40. [PubMed 9551842]

25. Richens A, Chadwick DW, Duncan JS et al. Adjunctive treatment of partial seizures with tiagabine: a placebo-controlled trial. Epilepsy Res . 1995; 21:37-42. [PubMed 7641674]

26. Crawford P, Meinardi H, Brown S et al. Tiagabine: efficacy and safety in adjunctive treatment of partial seizures. Epilepsia . 2001; 42:531-8. [PubMed 11440349]

27. Pulman J, Hutton JL, Marson AG. Tiagabine add-on for drug-resistant partial epilepsy. Cochrane Database Syst Rev . 2014; :CD001908. [PubMed 24500879]