Gabitril

Pronunciation

Generic Name: Tiagabine Hydrochloride
Class: Anticonvulsants, Miscellaneous
VA Class: CN400
Chemical Name: (R)-1-[4,4-bis(3-Methyl-2-thienyl)-3-butenyl]-3-piperidinecarboxylic acid hydrochloride
Molecular Formula: C20H25NO2S2•HCl
CAS Number: 145821-59-6

Warning(s)

Special Alerts:

[UPDATE 05/05/2009] FDA notified healthcare professionals that it approved updated labeling for antiepileptic drugs used to treat epilepsy, psychiatric disorders, and other conditions (e.g., migraine and neuropathic pain syndromes). FDA also required development of a medication guide, to be issued to patients each time the product is dispensed. Since issuing safety alerts on December 16, 2008 and January 31, 2008, FDA has been working with the manufacturers of drugs in this class to better understand the suicidality risk. Eleven antiepileptic drugs were included in a pooled analysis of placebo-controlled clinical studies in which these drugs were used to treat epilepsy as well as psychiatric disorders and other conditions. The increased risk of suicidal thoughts or behavior was generally consistent among the eleven drugs, with varying mechanisms of action and across a range of indications. This observation suggests that the risk applies to all antiepileptic drugs used for any indication.

The drugs included in the analyses include (some of these drugs are also available in generic form):

  • Carbamazepine (marketed as Carbatrol, Equetro, Tegretol, Tegretol XR)

  • Felbamate (marketed as Felbatol)

  • Gabapentin (marketed as Neurontin)

  • Lamotrigine (marketed as Lamictal)

  • Levetiracetam (marketed as Keppra)

  • Oxcarbazepine (marketed as Trileptal)

  • Pregabalin (marketed as Lyrica)

  • Tiagabine (marketed as Gabitril)

  • Topiramate (marketed as Topamax)

  • Valproate (marketed as Depakote, Depakote ER, Depakene, Depacon)

  • Zonisamide (marketed as Zonegran)

For more information visit the FDA website at: and .

[UPDATE 12/16/2008] The FDA has completed its analysis of reports of suicidality (suicidal behavior or ideation [thoughts]) from placebo-controlled clinical trials of drugs used to treat epilepsy, psychiatric disorders, and other conditions. Based on the outcome of this review, FDA is requiring that all manufacturers of drugs in this class include a Warning in their labeling and develop a Medication Guide to be provided to patients prescribed these drugs to inform them of the risks of suicidal thoughts or actions.

For more information visit the FDA website at: and .

[Posted 01/31/2008] FDA informed healthcare professionals that the Agency has analyzed reports of suicidality (suicidal behavior or ideation) from placebo-controlled clinical studies of eleven drugs used to treat epilepsy as well as psychiatric disorders, and other conditions. In the FDA’s analysis, patients receiving antiepileptic drugs had approximately twice the risk of suicidal behavior or ideation (0.43%) compared to patients receiving placebo (0.22%). The increased risk of suicidal behavior and suicidal ideation was observed as early as one week after starting the antiepileptic drug and continued through 24 weeks. The results were generally consistent among the eleven drugs. The relative risk for suicidality was higher in patients with epilepsy compared to patients who were given one of the drugs in the class for psychiatric or other conditions.

Healthcare professionals should closely monitor all patients currently taking or starting any antiepileptic drug for notable changes in behavior that could indicate the emergence or worsening of suicidal thoughts or behavior or depression.

The drugs included in the analyses include (some of these drugs are also available in generic form):

  • Carbamazepine (marketed as Carbatrol, Equetro, Tegretol, Tegretol XR)

  • Felbamate (marketed as Felbatol)

  • Gabapentin (marketed as Neurontin)

  • Lamotrigine (marketed as Lamictal)

  • Levetiracetam (marketed as Keppra)

  • Oxcarbazepine (marketed as Trileptal)

  • Pregabalin (marketed as Lyrica)

  • Tiagabine (marketed as Gabitril)

  • Topiramate (marketed as Topamax)

  • Valproate (marketed as Depakote, Depakote ER, Depakene, Depacon)

  • Zonisamide (marketed as Zonegran)

Although the 11 drugs listed above were the ones included in the analysis, FDA expects that the increased risk of suicidality is shared by all antiepileptic drugs and anticipates that the class labeling changes will be applied broadly. For more information visit the FDA website at: and .

REMS:

FDA approved a REMS for tiagabine to ensure that the benefits of a drug outweigh the risks. The REMS may apply to one or more preparations of tiagabine and consists of the following: medication guide. See the FDA REMS page () or the ASHP REMS Resource Center ().

Introduction

Anticonvulsant; a nipecotic acid derivative.1 2 7

Uses for Gabitril

Pending revision, the material in this section should be considered in light of more recently available information in the MedWatch notification at the beginning of this monograph.

Seizure Disorders

Management (in combination with other anticonvulsants) of partial seizures in adults and children ≥12 years of age.1 5 10 12 13

Slideshow: Flashback: FDA Drug Approvals 2013

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

Other Uses

Safety and efficacy for any indication other than the management of partial seizures have not been established;1 unlabeled (off-label) use has been associated with new-onset seizures, including status epilepticus.1 14 Use of tiagabine for unlabeled indications is strongly discouraged.14 (See Seizures in Nonepileptic Patients under Cautions.)

Gabitril Dosage and Administration

General

  • Abrupt withdrawal may result in increased seizure frequency; withdraw gradually and reduce dosage slowly unless safety concerns require more rapid withdrawal.1 13

  • Therapeutic plasma concentration range has not been established; determination of plasma concentrations may be useful before and after changes to drug regimen.1

Administration

Oral Administration

Administer orally with food.1

Administer initial dosage (4 mg) once daily; following dosage increases, administer in 2–4 divided doses daily.1 Limited experience exists for dosages >32 mg daily given in a twice-daily regimen.1

Dosage

Pending revision, the material in this section should be considered in light of more recently available information in the MedWatch notification at the beginning of this monograph.

Available as tiagabine hydrochloride; dosage expressed in terms of the salt.1

Dosage is based on whether a hepatic enzyme-inducing anticonvulsant drug (e.g., carbamazepine, phenobarbital, phenytoin, primidone) is administered concomitantly.1 5 6 13 11 (See Specific Drugs under Interactions.)

Patients receiving a combination of enzyme-inducing and non-enzyme-inducing anticonvulsants (e.g., carbamazepine and valproate) should be considered to have induced hepatic microsomal enzymes.1

Modification of tiagabine dosage may be required with the addition of a hepatic enzyme-inducing anticonvulsant, dosage change of these drugs, or their discontinuance from the regimen.1

Unless clinically indicated, modification of concomitant anticonvulsant therapy is not necessary when tiagabine is added to an anticonvulsant regimen.1 (See Specific Drugs under Interactions.)

Administration of a loading dose is not recommended.1 Increase dosage slowly; avoid rapid increases in dosage and/or large dosage increments.1

Consider dosage retitration if a patient misses multiple doses.1

Pediatric Patients

Partial Seizures
Patients Receiving Hepatic Enzyme-inducing Anticonvulsants
Oral

Adolescents 12–18 years of age: Initially, 4 mg once daily for the first week.1 Daily dosage may be increased to 4 mg twice daily beginning with the second week; 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

See manufacturer’s prescribing information for typical dosing titration regimen.1

Patients Not Receiving Hepatic Enzyme-inducing Anticonvulsants
Oral

Adolescents 12–18 years of age: Use lower dosage and a slower dosage titration schedule than that used in those receiving an enzyme-inducing anticonvulsant.1

Systemic exposure following administration of a 12-mg dose in a patient not receiving a hepatic enzyme-inducing drug is expected to be comparable to that of a 32-mg dose in a patient receiving a hepatic enzyme-inducing drug.1

Adults

Partial Seizures
Patients Receiving Hepatic Enzyme-inducing Anticonvulsants
Oral

Initially, 4 mg once daily for the first week.1 Beginning with the second week, the total daily dosage (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

Usual maintenance dosage: 32–56 mg daily administered as 2–4 divided doses.1

See manufacturer’s prescribing information for typical dosing titration regimen.1

Patients Not Receiving Hepatic Enzyme-inducing Anticonvulsants
Oral

Use lower dosage and a slower dosage titration schedule than that used in those receiving an enzyme-inducing anticonvulsant.1

Systemic exposure following administration of a 12- or 22-mg dose in a patient not receiving a hepatic enzyme-inducing drug is expected to be comparable to that of a 32- or 56-mg dose in a patient receiving a hepatic enzyme-inducing drug.1

Prescribing Limits

Pediatric Patients

Partial Seizures
Oral

Daily dosages >32 mg have been tolerated in a limited number of adolescents for a relatively short duration.1

Adults

Partial Seizures
Oral

Dosages >56 mg daily have not been systemically evaluated.1

Special Populations

Hepatic Impairment

Decreased initial and maintenance dosages and/or longer dosing intervals may be required.1 (See Special Populations under Pharmacokinetics.)

Renal Impairment

No special population dosage recommendations at this time.1

Geriatric Patients

No special population dosage recommendations at this time.1

Cautions for Gabitril

Contraindications

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

Warnings/Precautions

Warnings

Pending revision, the material in this section should be considered in light of more recently available information in the MedWatch notification at the beginning of this monograph.

Seizures in Nonepileptic Patients

New-onset seizures and status epilepticus reported in patients without epilepsy; may be dose-related and may occur in patients using concomitant drugs that lower seizure threshold (e.g., antidepressants, antipsychotics, stimulants, narcotics).1 14

Safety and efficacy not established for any indication other than the management of partial seizures.1 Use of tiagabine for unlabeled indications is strongly discouraged.14

Discontinue therapy if seizures develop in nonepileptic patients and evaluate patient for underlying seizure disorder.1

Withdrawal Seizures

Abrupt withdrawal may result in increased seizure frequency; withdraw gradually and reduce dosage slowly unless safety concerns require a more rapid withdrawal.1 13

Cognitive/Neuropsychiatric Effects

Possible somnolence and fatigue, impaired concentration, speech or language problems, and confusion; usually mild to moderate in severity, may be dose-related, and usually begins during initial dosage titration.1

Cognitive/neuropsychiatric events may be accompanied by EEG abnormalities (e.g., generalized spike and wave activity). 1 May be a manifestation of underlying seizure activity; dosage adjustment may be required.1

Status Epilepticus

Not established whether incidence of status epilepticus (5% in controlled and uncontrolled trials of tiagabine) is higher or lower than would be expected to occur in patients with epilepsy not treated with the drug.1

Seizures and status epilepticus may occur with tiagabine overdosage.1

Sudden, Unexpected Death In Epilepsy

Higher incidence of sudden and unexplained deaths than would be expected in a healthy (nonepileptic) population; however, incidence is within range of estimates for patients with epilepsy or refractory epilepsy.1

Sensitivity Reactions

Dermatologic Reactions

Serious rash (i.e., Stevens-Johnson syndrome, maculopapular rash, vesiculobullous rash), potentially fatal, reported rarely.1

General Precautions

Pending revision, the material in this section should be considered in light of more recently available information in the MedWatch notification at the beginning of this monograph.

Generalized Weakness

Generalized weakness (moderately severe to incapacitating) reported; resolves after a reduction in dose or discontinuance of tiagabine.1

Binding to Melanin-rich Tissues

Possible long-term ophthalmologic effects.1 Accumulation of tiagabine in melanin-containing cells in the eye observed in dogs; however ophthalmologic changes were not noted in long-term studies in these animals.1

Manufacturer makes no specific recommendations for periodic ophthalmologic monitoring.1

Specific Populations

Pregnancy

Category C.1

Lactation

Distributed into milk in rats; not known whether distributed into human milk.1 Use only if potential benefits outweigh the risks.1

Pediatric Use

Safety and efficacy not established in children <12 years of age.1 Pharmacokinetics evaluated in a limited number of children 3–10 years of age.1 (See Special Populations under Pharmacokinetics.)

Geriatric Use

Insufficient experience in patients ≥65 years of age to determine whether safety and efficacy of tiagabine in geriatric patients differ from safety and efficacy in younger adults.1 The pharmacokinetic profile in healthy geriatric adults does not appear to differ from that in younger adults.1 11

Hepatic Impairment

Decreased clearance in patients with moderate hepatic impairment (Child-Pugh class B); dosage adjustments recommended.1 (See Hepatic Impairment under Dosage and Administration.)

Renal Impairment

Pharmacokinetics not altered in patients with mild, moderate, or severe renal impairment or in those undergoing hemodialysis.1

Common Adverse Effects

Dizziness/light-headedness, asthenia, somnolence, nausea, nervousness/irritability, tremor, abdominal pain, abnormal thinking/difficulty with concentration or attention.1

Interactions for Gabitril

Metabolized by CYP isoenzymes, principally CYP3A.1 May also be metabolized by CYP1A2, CYP2D6, or CYP2C19.1

Does not appear to induce or inhibit hepatic microsomal enzymes.1 6

Does not appear to have clinically important effects on the pharmacokinetics of other anticonvulsants.1 6

Drugs Affecting Hepatic Microsomal Enzymes

Inducers of CYP3A4: Potential pharmacokinetic interaction (decreased plasma tiagabine concentrations).1

Tiagabine does not induce or inhibit hepatic microsomal enzymes responsible for metabolizing antipyrine.1

Protein-bound Drugs

Potential for tiagabine to displace or to be displaced by other protein-bound drugs.1 6

Specific Drugs

Drug

Interaction

Comments

Carbamazepine

Increased tiagabine clearance1

Carbamazepine pharmacokinetics not altered1

Adjust dosage of tiagabine accordingly (see Dosage under Dosage and Administration)1

Cimetidine

Pharmacokinetics of tiagabine not altered1

Digoxin

Pharmacokinetics of digoxin not altered1

Ethanol

Possible additive CNS depressant effects1

Use concomitantly with caution1

Hormonal contraceptives, oral

Pharmacokinetics of the oral contraceptive not altered1

Phenobarbital

Increased tiagabine clearance1

Phenobarbital pharmacokinetics not altered1

Adjust dosage of tiagabine accordingly (see Dosage under Dosage and Administration)1

Phenytoin

Increased tiagabine clearance1

Phenytoin pharmacokinetics not altered1

Adjust dosage of tiagabine accordingly (see Dosage under Dosage and Administration)1

Primidone

Increased tiagabine clearance1

Primidone pharmacokinetics not altered1

Adjust dosage of tiagabine accordingly (see Dosage under Dosage and Administration)1

Theophylline

Pharmacokinetics of theophylline not altered1

Triazolam

Possible additive CNS depressant effects1

Use concomitantly with caution1

Valproate

Decreased serum valproate concentrations (approximately 10%); no effects on tiagabine pharmacokinetics1

Decreased tiagabine plasma protein binding in vitro from 96.3 to 94.8%; such a change could result in a 40% increase in free tiagabine concentrations1

Clinical significance of in vitro finding unknown1

Warfarin

Pharmacokinetics of warfarin not altered; PT not affected1

Gabitril Pharmacokinetics

Absorption

Bioavailability

Well absorbed; absolute bioavailability is about 90%.1

Rapidly absorbed following oral administration, with peak plasma concentration usually occurring in approximately 45 minutes.1

Food

Food does not affect extent of absorption but delays time to peak plasma concentrations to 2.5 hours.1 5 13

Distribution

Plasma Protein Binding

96% (mainly albumin and α1-acid glycoprotein).1

Elimination

Metabolism

Undergoes extensive hepatic metabolism, principally via CYP3A4.1 5 6

Elimination Route

Excreted in feces (63%) and in urine (25%) mainly as metabolites; approximately 2% is excreted unchanged.1

Half-life

7–9 hours.1 5 6 13 11

Decreases to 2–5 hours in patients receiving an anticonvulsant that induces hepatic microsomal enzymes (e.g., carbamazepine, phenobarbital, phenytoin, primidone).1 5 6 13 11

Special Populations

In patients with moderate hepatic impairment (Child-Pugh class B), clearance of unbound tiagabine was reduced by about 60%. 1 Dosage adjustment may be needed.1 (See Hepatic Impairment under Dosage and Administration.)

Pharmacokinetics similar in those with normal renal function (Clcr >80 mL/minute), mild, moderate, or severe renal impairment (Clcr 40–80, 20–39, or 5–19 mL/minute, respectively), and those undergoing dialysis.1

In children 3–10 years of age receiving hepatic enzyme-inducing anticonvulsants, clearance is similar to that found in adults receiving these anticonvulsants (e.g., carbamazepine, phenytoin).1 In children receiving non-inducing anticonvulsants (e.g., valproate), clearance is increased compared with adults not receiving a hepatic enzyme-inducing agent.1

Stability

Storage

Oral

Tablets

20–25°C.1 Protect from light and moisture.1

Actions and Spectrum

  • Exact mechanism of action is unknown; however, enhances inhibitory neurotransmission mediated by γ-aminobutyric acid (GABA).1 3 5 6 7 9 13

  • Increases the amount of GABA available in extracellular spaces of the globus pallidus, ventral pallidum, and substantia nigra, which suggests a GABA-mediated anticonvulsant mechanism of action (i.e., inhibition of neural impulse propagations that contribute to seizures).1

  • Inhibits presynaptic neuronal and glial GABA reuptake1 3 5 6 7 9 13 and increases the amount of GABA available for postsynaptic receptor binding.1 6 7 9

  • 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

  • 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

Advice to Patients

Pending revision, the material in this section should be considered in light of more recently available information in the MedWatch notification at the beginning of this monograph.

  • 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

  • Importance of taking a missed dose as soon as possible, unless it is almost time for the next dose.19 However, a double dose of tiagabine should not be taken to make up for the missed dose.1 19

  • Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs, especially other CNS depressants, as well as any concomitant illnesses.1

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

  • Importance of informing patients of other important precautionary information. (See Cautions.)

Preparations

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Tiagabine Hydrochloride

Routes

Dosage Forms

Strengths

Brand Names

Manufacturer

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

Comparative Pricing

This pricing information is subject to change at the sole discretion of DS Pharmacy. This pricing information was updated 02/2014. Actual costs to patients will vary depending on the use of specific retail or mail-order locations and health insurance copays.

Gabitril 12MG Tablets (CEPHALON): 30/$210.00 or 90/$599.94

Gabitril 16MG Tablets (CEPHALON): 30/$300.26 or 90/$855.78

Gabitril 2MG Tablets (CEPHALON): 30/$192.01 or 90/$542.49

Gabitril 4MG Tablets (CEPHALON): 30/$185.48 or 90/$520.84

AHFS DI Essentials. © Copyright, 2004-2014, Selected Revisions October 27, 2011. American Society of Health-System Pharmacists, Inc., 7272 Wisconsin Avenue, Bethesda, Maryland 20814.

References

1. Abbott Laboratories. Gabitril (tiagabine hydrochloride) tablets prescribing information. West Chester, PA; 2005 Feb.

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. [IDIS 273932] [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.

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 ().

15. Stahl SM. Anticonvulsants as anxiolytics, part 1; Tiagabine and other anticonvulsants with actions on GABA. J Clin Psychiatry. 2004; 65:291-2. [IDIS 513951] [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. [IDIS 509255] [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. [IDIS 510414] [PubMed 14658975]

19. Cephalon, Inc. Gabitril FAQs. Available at: . Accessed 2005 Aug 15.

a. Cephalon, Inc. Gabitril (tiagabine hydrochloride) tablets prescribing information. Frazer, PA; 2005 Jun.

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