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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

Introduction

Anticonvulsant; a nipecotic acid derivative.1 2 7

Uses for Gabitril

Seizure Disorders

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

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

  • Withdraw gradually to minimize potential for increased seizure frequency.1 13 (See Discontinuance of Therapy under Cautions.)

  • Closely monitor for notable changes in behavior that could indicate emergence or worsening of suicidal thoughts or behavior or depression.20 21 24 (See Suicidality Risk under Cautions.)

  • 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

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

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

Discontinuance of Therapy

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

Suicidality Risk

Increased risk of suicidality (suicidal behavior or ideation) observed in an analysis of studies using various anticonvulsants in patients with epilepsy, psychiatric disorders (e.g., bipolar disorder, depression, anxiety), and other conditions (e.g., migraine, neuropathic pain); risk in patients receiving anticonvulsants (0.43%) was approximately twice that in patients receiving placebo (0.24%).20 21 24 Increased suicidality risk was observed ≥1 week after initiation of anticonvulsant therapy and continued through 24 weeks.20 21 24 Relative risk was higher for patients with epilepsy compared with those receiving anticonvulsants for other conditions.20

Closely monitor all patients currently receiving or beginning anticonvulsant therapy for changes in behavior that may indicate emergence or worsening of suicidal thoughts or behavior or depression.20 21 24 Anxiety, agitation, hostility, insomnia, and mania may be precursors to emerging suicidality.20

Balance risk of suicidality with risk of untreated illness.20 24 Epilepsy and other illnesses treated with anticonvulsants are themselves associated with morbidity and mortality and an increased risk of suicidality.23 24 If suicidal thoughts or behavior emerges during anticonvulsant therapy, consider whether these symptoms may be related to the illness itself.23 24 (See Advice to Patients.)

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

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

  • 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).20 21 24 Importance of patients, family members, and caregivers being alert to day-to-day changes in mood, behavior, and actions and immediately informing clinician of any new or worrisome behaviors (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).20 24

  • 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.

Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.

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

AHFS DI Essentials. © Copyright 2017, Selected Revisions April 10, 2017. American Society of Health-System Pharmacists, Inc., 4500 East-West Highway, Suite 900, Bethesda, Maryland 20814.

References

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

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. Food and Drug Administration. FDA News: FDA alerts health care providers to risk of suicidal thoughts and behavior with antiepileptic medications. Rockville, MD; 2008 Jan 31. From the FDA website.

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. Cephalon, Inc. Gabitril (tiagabine hydrochloride) tablets prescribing information. Frazer, PA; 2009 Apr 27.

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