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Pronunciation
(tye AG a been)
Generic Available (U.S.)
No
Index Terms
Medication Guide
An FDA-approved patient medication guide, which is available with the product information and at http://www.fda.gov/downloads/Drugs/DrugSafety/UCM229203.pdf, must be dispensed with this medication.
REMS Components
Gabitril®: Released from REMS requirement 1/25/2012
Brand Names: U.S.
Pharmacologic Category
Pharmacologic Category Synonyms
Use: Labeled Indications
Adjunctive therapy in adults and children ≥12 years of age in the treatment of partial seizures
Pregnancy Risk Factor
C
Pregnancy Considerations
Patients exposed to tiagabine during pregnancy are encouraged to enroll themselves into the AED Pregnancy Registry by calling 1-888-233-2334. Additional information is available at www.aedpregnancyregistry.org.
Lactation
Enters breast milk/not recommended
Contraindications
Hypersensitivity to tiagabine or any component of the formulation
Warnings/Precautions
Concerns related to adverse effects:
• CNS depression: May cause CNS depression, which may impair physical or mental abilities; patients must be cautioned about performing tasks which require mental alertness (eg, operating machinery or driving).
• Dermatologic reactions: Severe reactions, including toxic epidermal necrolysis and Stevens-Johnson syndromes, although rarely reported, have resulted in fatalities; drug should be discontinued if there are any signs of hypersensitivity.
• Suicidal ideation: Pooled analysis of trials involving various antiepileptics (regardless of indication) showed an increased risk of suicidal thoughts/behavior (incidence rate: 0.43% treated patients compared to 0.24% of patients receiving placebo); risk observed as early as 1 week after initiation and continued through duration of trials (most trials ≤24 weeks). Monitor all patients for notable changes in behavior that might indicate suicidal thoughts or depression; notify healthcare provider immediately if symptoms occur.
Disease-related concerns:
• Hepatic impairment: Use with caution in patients with hepatic impairment.
Concurrent drug therapy issues:
• Enzyme-inducing drugs: Experience in patients not receiving enzyme-inducing drugs has been limited; caution should be used in treating any patient who is not receiving one of these medications (decreased dose and slower titration may be required).
• Sedatives: Effects with other sedative drugs or ethanol may be potentiated.
Other warnings/precautions:
• Unlabeled use: New-onset seizures and status epilepticus have been associated with tiagabine use when taken for unlabeled indications; often these seizures have occurred shortly after the initiation of treatment or shortly after a dosage increase. Seizures have also occurred with very low doses or after several months of therapy. In most cases, patients were using concomitant medications (eg, antidepressants, antipsychotics, stimulants, narcotics). In these instances, the discontinuation of tiagabine, followed by an evaluation for an underlying seizure disorder, is suggested. Use for unapproved indications, however, has not been proven to be safe or effective and is not recommended.
• Withdrawal: Anticonvulsants should not be discontinued abruptly because of the possibility of increasing seizure frequency; therapy should be withdrawn gradually to minimize the potential of increased seizure frequency, unless safety concerns require a more rapid withdrawal.
Adverse Reactions
>10%:
Central nervous system: Concentration decreased, dizziness, nervousness, somnolence
Gastrointestinal: Nausea
Neuromuscular & skeletal: Tremor, weakness
1% to 10%:
Cardiovascular: Chest pain, edema, hypertension, palpitation, peripheral edema, syncope, tachycardia, vasodilation
Central nervous system: Agitation, ataxia, chills, confusion, depersonalization, depression, difficulty with memory, euphoria, hallucination, hostility, insomnia, malaise, migraine, paranoid reaction, personality disorder, speech disorder
Dermatologic: Alopecia, bruising, dry skin, pruritus, rash
Gastrointestinal: Abdominal pain, appetite increased, diarrhea, gingivitis, mouth ulceration, stomatitis, vomiting, weight gain/loss
Neuromuscular & skeletal: Abnormal gait, arthralgia, dysarthria, hyper-/hypokinesia, hyper-/hypotonia, myasthenia, myalgia, myoclonus, neck pain, paresthesia, reflexes decreased, stupor, twitching, vertigo
Ocular: Abnormal vision, amblyopia, nystagmus
Otic: Ear pain, hearing impairment, otitis media, tinnitus
Respiratory: Bronchitis, cough, dyspnea, epistaxis, pneumonia
Miscellaneous: Allergic reaction, cyst, diaphoresis, flu-like syndrome, lymphadenopathy
<1% (Limited to important or life-threatening): Abortion, abscess, amenorrhea, anemia, angina, apnea, arthrosis, asthma, blepharitis, blindness, cellulitis, cerebral ischemia, cholycystitis, cholelithiasis, CNS neoplasm, coma, deafness, dehydration, dysphagia, dystonia, electrocardiogram abnormal, encephalopathy, facial hemorrhage, erythrocytes abnormal, fecal incontinence, glossitis, goiter, herpes simplex/zoster, hirsutism, hematuria, hemiplegia, hemoptysis, hepatomegaly, hyperacusis, hypercholesteremia, hyper-/hypoglycemia, hyperlipemia, hyperventilation, hypokalemia, hyponatremia, hypotension, hypothyroidism, impotence, kidney failure, leukopenia, liver function tests abnormal, MI, neoplasm, peripheral vascular disorder, paralysis, photophobia, psychosis, petechia, photosensitivity, seizure (when used for unlabeled uses), sepsis, skin benign neoplasm, skin discoloration, spasm, suicide attempt, taste perversion, thrombocytopenia, thrombophlebitis, urinary retention, urinary urgency, urticaria, visual field defect
Metabolism/Transport Effects
Substrate of CYP3A4 (major); Note: Assignment of Major/Minor substrate status based on clinically relevant drug interaction potential
Drug Interactions
Alcohol (Ethyl): CNS Depressants may enhance the CNS depressant effect of Alcohol (Ethyl). Risk C: Monitor therapy
CNS Depressants: May enhance the adverse/toxic effect of other CNS Depressants. Exceptions: Levocabastine (Nasal). Risk C: Monitor therapy
Conivaptan: May increase the serum concentration of CYP3A4 Substrates. Risk X: Avoid combination
CYP3A4 Inducers (Strong): May increase the metabolism of CYP3A4 Substrates. Risk C: Monitor therapy
CYP3A4 Inhibitors (Moderate): May decrease the metabolism of CYP3A4 Substrates. Risk C: Monitor therapy
CYP3A4 Inhibitors (Strong): May decrease the metabolism of CYP3A4 Substrates. Risk D: Consider therapy modification
Dasatinib: May increase the serum concentration of CYP3A4 Substrates. Risk C: Monitor therapy
Deferasirox: May decrease the serum concentration of CYP3A4 Substrates. Risk C: Monitor therapy
Droperidol: May enhance the CNS depressant effect of CNS Depressants. Management: Consider dose reductions of droperidol or of other CNS agents (e.g., opioids, barbiturates) with concomitant use. Risk D: Consider therapy modification
Herbs (CYP3A4 Inducers): May increase the metabolism of CYP3A4 Substrates. Risk C: Monitor therapy
HydrOXYzine: May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapy
Ketorolac: May diminish the therapeutic effect of Anticonvulsants. Risk C: Monitor therapy
Ketorolac (Nasal): May diminish the therapeutic effect of Anticonvulsants. Risk C: Monitor therapy
Ketorolac (Systemic): May diminish the therapeutic effect of Anticonvulsants. Risk C: Monitor therapy
Mefloquine: May diminish the therapeutic effect of Anticonvulsants. Mefloquine may decrease the serum concentration of Anticonvulsants. Management: Mefloquine is contraindicated for malaria prophylaxis in persons with a history of convulsions. Monitor anticonvulsant concentrations and treatment response closely with concurrent use. Risk D: Consider therapy modification
Methotrimeprazine: CNS Depressants may enhance the CNS depressant effect of Methotrimeprazine. Methotrimeprazine may enhance the CNS depressant effect of CNS Depressants. Management: Reduce adult dose of CNS depressant agents by 50% with initiation of concomitant methotrimeprazine therapy. Further CNS depressant dosage adjustments should be initiated only after clinically effective methotrimeprazine dose is established. Risk D: Consider therapy modification
Selective Serotonin Reuptake Inhibitors: CNS Depressants may enhance the adverse/toxic effect of Selective Serotonin Reuptake Inhibitors. Specifically, the risk of psychomotor impairment may be enhanced. Risk C: Monitor therapy
Tocilizumab: May decrease the serum concentration of CYP3A4 Substrates. Risk C: Monitor therapy
Ethanol/Nutrition/Herb Interactions
Ethanol: May increase CNS depression; monitor for increased effects with coadministration. Caution patients about effects.
Food: Food reduces the rate but not the extent of absorption.
Herb/Nutraceutical: St John's wort may decrease tiagabine levels. Avoid valerian, St John's wort, kava kava, gotu kola (may increase CNS depression).
Mechanism of Action
The exact mechanism by which tiagabine exerts antiseizure activity is not definitively known; however, in vitro experiments demonstrate that it enhances the activity of gamma aminobutyric acid (GABA), the major neuroinhibitory transmitter in the nervous system; it is thought that binding to the GABA uptake carrier inhibits the uptake of GABA into presynaptic neurons, allowing an increased amount of GABA to be available to postsynaptic neurons; based on in vitro studies, tiagabine does not inhibit the uptake of dopamine, norepinephrine, serotonin, glutamate, or choline
Pharmacodynamics/Kinetics
Absorption: Rapid (45 minutes); prolonged with food
Protein binding: 96%, primarily to albumin and α1-acid glycoprotein
Metabolism: Hepatic via CYP (primarily 3A4)
Bioavailability: Oral: Absolute: 90%
Half-life elimination: 2-5 hours when administered with enzyme inducers; 7-9 hours when administered without enzyme inducers
Time to peak, plasma: 45 minutes
Excretion: Feces (63%); urine (25%); 2% as unchanged drug; primarily as metabolites
Dosage
Oral (administer with food):
Patients receiving enzyme-inducing AED regimens:
Children 12-18 years: 4 mg once daily for 1 week; may increase to 8 mg daily in 2 divided doses for 1 week; then may increase by 4-8 mg weekly to response or up to 32 mg daily in 2-4 divided doses
Adults: 4 mg once daily for 1 week; may increase by 4-8 mg weekly to response or up to 56 mg daily in 2-4 divided doses; usual maintenance: 32-56 mg/day
Patients not receiving enzyme-inducing AED regimens: The estimated plasma concentrations of tiagabine in patients not taking enzyme-inducing medications is twice that of patients receiving enzyme-inducing AEDs. Lower doses are required; slower titration may be necessary.
Monitoring Parameters
A reduction in seizure frequency is indicative of therapeutic response to tiagabine in patients with partial seizures; complete blood counts, renal function tests, liver function tests, and routine blood chemistry should be monitored periodically during therapy; suicidality (eg, suicidal thoughts, depression, behavioral changes)
Reference Range
Maximal plasma level after a 24 mg/dose: 552 ng/mL
Dietary Considerations
Take with food.
Patient Education
While using this medication, do not use alcohol. Maintain adequate hydration unless instructed to restrict fluid intake. You may experience drowsiness, dizziness, disturbed concentration, blurred vision, nausea, vomiting, or loss of appetite. Wear identification of epileptic status and medications. Report behavioral or CNS changes, suicide ideation, or depression; skin rash; muscle cramping, weakness, tremors, changes in gait; vision difficulties; persistent GI distress (cramping, pain, vomiting); chest pain, irregular heartbeat, or palpitations; cough or respiratory difficulty; or worsening of seizure activity or loss of seizure control.
Geriatric Considerations
No special recommendations are made for the elderly; dose according to response.
Additional Information
Animal studies suggest that tiagabine may bind to retina and uvea; however, no treatment-related ophthalmoscopic changes were seen long-term; periodic monitoring may be considered.
Dental Health: Effects on Dental Treatment
Key adverse event(s) related to dental treatment: Stomatitis, gingivitis, and mouth ulceration.
Dental Health: Vasoconstrictor/Local Anesthetic Precautions
No information available to require special precautions
Nursing: Physical Assessment/Monitoring
Monitor therapeutic effectiveness (seizure activity, type, duration) at beginning of therapy and throughout. Taper dosage slowly when discontinuing. Teach patient seizure safety precautions.
Dosage Forms
Excipient information presented when available (limited, particularly for generics); consult specific product labeling.
Tablet, oral, as hydrochloride:
Gabitril®: 2 mg, 4 mg, 12 mg, 16 mg
Pricing: U.S. (www.drugstore.com)
Tablets (Gabitril)
2 mg (30): $192.01
4 mg (30): $185.48
12 mg (30): $207.85
16 mg (30): $300.26
Extemporaneously Prepared
A 1 mg/mL tiagabine hydrochloride oral suspension may be made with tablets and a 1:1 mixture of Ora-Sweet® and Ora-Plus®. Crush ten 12 mg tablets in a mortar and reduce to a fine powder. Add small portions of the vehicle and mix to a uniform paste; mix while adding the vehicle in incremental proportions to almost 120 mL; transfer to a graduated cylinder; rinse mortar with vehicle, and add quantity of vehicle sufficient to make 120 mL. Label "shake well" and "refrigerate". Store in amber plastic prescription bottles; stable for 70 days at room temperature or 91 days refrigerated (preferred).
A 1 mg/mL oral suspension may be made with tablets and a 6:1 mixture of simple syrup, NF and methylcellulose 1%. Crush ten 12 mg tablets in a mortar and reduce to a fine powder. Add 17 mL of methylcellulose 1% gel and mix to a uniform paste; mix while adding simple syrup, NF in incremental proportions to almost 120 mL; transfer to a graduated cylinder, rinse mortar with syrup, and add quantity of syrup sufficient to make 120 mL. Label "shake well" and "refrigerate". Store in amber plastic prescription bottles; stable for 42 days at room temperature or 91 days refrigerated (preferred).
Nahata MC, Pai VB, and Hipple TF, Pediatric Drug Formulations, 5th ed, Cincinnati, OH: Harvey Whitney Books Co, 2004.
References
Adkins JC and Noble S, “Tiagabine. A Review of Its Pharmacodynamic and Pharmacokinetic Properties and Therapeutic Potential in the Management of Epilepsy,” Drugs, 1998, 55(3):437-60.
Dodrill CB, Arnett JL, Sommerville KW, et al, “Cognitive and Quality of Life Effects of Differing Dosages of Tiagabine in Epilepsy,” Neurology, 1997, 48(4):1025-31.
Gustavson LE, Boellner SW, Granneman GR, et al, “A Single-Dose Study to Define Tiagabine Pharmacokinetics in Pediatric Patients With Complex Partial Seizures,” Neurology, 1997, 48(4):1032-7.
Kalviainen 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(1):31-40.
Leach JP and Brodie MJ, “Tiagabine,” Lancet, 1998, 351(9097):203-7.
Patsalos PN and Sander JW, “Newer Antiepileptic Drugs: Towards an Improved Risk-Benefit Ratio,” Drug Saf, 1994, 11(1):37-67.
Samara EE, Gustavson LE, El-Shourbagy T, et al, “Population Analysis of the Pharmacokinetics of Tiagabine in Patients With Epilepsy,” Epilepsia, 1998, 39(8):868-73.
Uthman BM, Rowan AJ, Ahmann PA, et al, “Tiagabine for Complex Partial Seizures: A Randomized, Add-On, Dose-Response Trial,” Arch Neurol, 1998, 55(1):56-62.
International Brand Names
Lexi-Comp.com
Last full review/revision January 2012
Content last modified January 2012
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