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Gabitril

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

Medically reviewed by Drugs.com. Last updated on Dec 17, 2018.

Introduction

Anticonvulsant; a nipecotic acid derivative.1 2 7

Uses for Gabitril

Seizure Disorders

Adjunctive therapy (i.e., in combination with other anticonvulsants) of partial seizures in adults and children ≥12 years of age.1 5 10 12 13 24 25 26 27

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

Other Uses

Safety and efficacy for any indication other than the management of partial seizures not 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.1 20 (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 after the initial period, 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 (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 hydrochloride 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

If a dose is missed, do not increase next dose to compensate.1 Consider dosage retitration if a patient misses multiple doses.1

Pediatric Patients

Partial Seizures
Patients Receiving Hepatic Enzyme-inducing Anticonvulsants
Oral

Adolescents ≥12 years of age: Initially, 4 mg once daily for the first week.1 May increase to 4 mg twice daily beginning with the second week; thereafter, may increase the total daily dosage (administered in 2–4 divided doses) by 4–8 mg at weekly intervals until a clinical response is achieved or a total daily dosage of 32 mg is reached.1

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

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

Patients Not Receiving Hepatic Enzyme-inducing Anticonvulsants
Oral

Adolescents ≥12 years of age: Use lower dosage and slower dosage titration schedule than those recommended in patients 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 Dosages >56 mg daily have not been systematically evaluated.1

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

Patients Not Receiving Hepatic Enzyme-inducing Anticonvulsants
Oral

Use lower dosage and slower dosage titration schedule than those recommended in patients 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

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%).1 20 Increased suicidality risk was observed ≥1 week after initiation of anticonvulsant therapy and continued through 24 weeks.1 20 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.1 20

Balance risk of suicidality with risk of untreated illness.1 20 Epilepsy and other illnesses treated with anticonvulsants are themselves associated with morbidity and mortality and an increased risk of suicidality.1 23 If suicidal thoughts or behavior emerges during anticonvulsant therapy, consider whether these symptoms may be related to the illness itself.1 23 (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 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) reported rarely; drug-associated rash can cause irreversible morbidity, and even death.1

General Precautions

Use in Patients not Receiving Concomitant Enzyme-inducing Anticonvulsants

Virtually all experience with tiagabine has been in patients receiving concomitant enzyme-inducing anticonvulsant drugs.1 Plasma concentrations of tiagabine in patients not receiving such concomitant therapy may be substantially increased.1 (See Dosage under Dosage and Administration.)

Generalized Weakness

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

Binding to Melanin-rich Tissues

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

Specific Populations

Pregnancy

No adequate and well-controlled studies in pregnant women; adverse embryofetal effects, including teratogenicity, demonstrated in animals.1 Use during pregnancy only if clearly indicated.1

North American Antiepileptic Drug (NAAED) Pregnancy Registry at 888-233-2334 (for patients) or http://www.aedpregnancyregistry.org.1

Lactation

Distributed into milk in rats; not known whether distributed into human milk.1 Effects of the drug on the nursing infant not known.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/lightheadedness, asthenia/lack of energy, somnolence, nausea, vomiting, diarrhea, nervousness/irritability, tremor, abdominal pain, generalized pain, insomnia, ataxia, confusion, rash, pharyngitis, difficulty with concentration or attention.1

Interactions for Gabitril

Metabolized by CYP isoenzymes, principally CYP3A.1 Also may 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 or Metabolized by Hepatic Microsomal Enzymes

Potential pharmacokinetic interaction with drugs that inhibit or induce CYP isoenzymes.1

Pharmacokinetic interaction with drugs metabolized by CYP isoenzymes not expected.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

Alcohol

Possible additive CNS depressant effects1

Changes in pharmacokinetics or pharmacodynamics (e.g., vigilance, cognitive abilities, reaction time, visual tracking) of alcohol not observed; pharmacokinetics of tiagabine also not altered1 21

Use concomitantly with caution1

Carbamazepine

Tiagabine clearance increased by 60% 1

No effect on steady-state plasma concentrations of carbamazepine or its epoxide metabolite1

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

Cimetidine

Pharmacokinetics of tiagabine not altered1

CNS depressants

Possible additive CNS depressant effects1 19

Use concomitantly with caution1

Digoxin

Pharmacokinetics of digoxin not altered1

Hormonal contraceptives, oral

Pharmacokinetics of the oral contraceptive not altered1

Phenobarbital

Tiagabine clearance increased by 60%1 1

Phenobarbital pharmacokinetics not altered1

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

Phenytoin

Tiagabine clearance increased by 60%1

Phenytoin pharmacokinetics not altered1

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

Primidone

Tiagabine clearance increased by 60%1

Primidone pharmacokinetics not altered1

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

St. John's wort

May enhance tiagabine metabolism1

Theophylline

Pharmacokinetics of theophylline not altered1

Triazolam

Possible additive CNS depressant effects1

Changes in pharmacokinetics or pharmacodynamics (e.g., sedative or cognitive effects) of triazolam not observed; pharmacokinetics of tiagabine not altered1 19

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 importance 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 concomitant hepatic enzyme-inducing anticonvulsants, clearance was similar to that in adults receiving these anticonvulsants (e.g., carbamazepine, phenytoin).1 In the non-induced population (e.g., those concomitantly receiving non-inducing anticonvulsants such as valproate), clearance in children was increased compared with that observed in adults.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 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 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).1 20

  • 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.

* available from one or more manufacturer, distributor, and/or repackager by generic (nonproprietary) name

tiaGABine Hydrochloride

Routes

Dosage Forms

Strengths

Brand Names

Manufacturer

Oral

Tablets, film-coated

2 mg*

tiaGABine Hydrochloride Tablets

Gabitril

Cephalon

4 mg*

tiaGABine Hydrochloride Tablets

Gabitril

Cephalon

12 mg*

tiaGABine Hydrochloride Tablets

Gabitril

Cephalon

16 mg*

tiaGABine Hydrochloride Tablets

Gabitril

Cephalon

AHFS DI Essentials™. © Copyright 2019, Selected Revisions December 17, 2018. American Society of Health-System Pharmacists, Inc., 4500 East-West Highway, Suite 900, Bethesda, Maryland 20814.

References

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. http://www.ncbi.nlm.nih.gov/pubmed/2217531?dopt=AbstractPlus

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. http://www.ncbi.nlm.nih.gov/pubmed/9352959?dopt=AbstractPlus

6. Walker MC, Patsalos PN. Clinical pharmacokinetics of new antiepileptic drugs. Pharmacol Ther. 1995; 67:351-84. http://www.ncbi.nlm.nih.gov/pubmed/8577822?dopt=AbstractPlus

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. http://www.ncbi.nlm.nih.gov/pubmed/7555976?dopt=AbstractPlus

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. http://www.ncbi.nlm.nih.gov/pubmed/9092952?dopt=AbstractPlus

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. http://www.ncbi.nlm.nih.gov/pubmed/9152116?dopt=AbstractPlus

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. http://www.pubmedcentral.nih.gov/picrender.fcgi?tool=pmcentrez&artid=3498458&blobtype=pdf

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 (http://www.fda.gov/Safety/MedWatch/SafetyInformation/SafetyAlertsforHumanMedicalProducts/ucm151502.htm).

15. Stahl SM. Anticonvulsants as anxiolytics, part 1; Tiagabine and other anticonvulsants with actions on GABA. J Clin Psychiatry. 2004; 65:291-2. http://www.ncbi.nlm.nih.gov/pubmed/15096065?dopt=AbstractPlus

16. Todorov AA, Kolchev CB, Todorov AB. Tiagabine and gabapentin for the management of chronic pain. Clin J Pain. 2005; 21:358-61 http://www.ncbi.nlm.nih.gov/pubmed/15951655?dopt=AbstractPlus

17. Taylor FB. Tiagabine for posttraumatic stress disorder: a case series of 7 women. J Clin Psychiatry. 2003; 64:1421-5. http://www.ncbi.nlm.nih.gov/pubmed/14728102?dopt=AbstractPlus

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. http://www.ncbi.nlm.nih.gov/pubmed/14658975?dopt=AbstractPlus

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. http://www.ncbi.nlm.nih.gov/pubmed/10366992?dopt=AbstractPlus

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. http://www.ncbi.nlm.nih.gov/pubmed/10694933?dopt=AbstractPlus

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. http://www.ncbi.nlm.nih.gov/pubmed/9551842?dopt=AbstractPlus

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. http://www.ncbi.nlm.nih.gov/pubmed/7641674?dopt=AbstractPlus

26. Crawford P, Meinardi H, Brown S et al. Tiagabine: efficacy and safety in adjunctive treatment of partial seizures. Epilepsia. 2001; 42:531-8. http://www.ncbi.nlm.nih.gov/pubmed/11440349?dopt=AbstractPlus

27. Pulman J, Hutton JL, Marson AG. Tiagabine add-on for drug-resistant partial epilepsy. Cochrane Database Syst Rev. 2014; :CD001908. http://www.ncbi.nlm.nih.gov/pubmed/24500879?dopt=AbstractPlus

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