Usage
Tiagabine is an anticonvulsant medication primarily prescribed for the adjunctive treatment of partial-onset seizures in adults and children 12 years of age and older. It is used in patients whose seizures are not adequately controlled by other antiepileptic drugs. The drug’s mechanism of action involves inhibiting the reuptake of gamma-aminobutyric acid (GABA), a major inhibitory neurotransmitter in the central nervous system. By increasing GABA availability in the synaptic cleft, tiagabine reduces neuronal excitability and thus suppresses seizure activity.
Alternate Names
Gabitril (brand name)
How It Works
Pharmacodynamics: Tiagabine enhances GABAergic inhibition in the brain. It selectively binds to the GABA transporter GAT-1, preventing the reuptake of GABA from the synaptic cleft. This increased GABA concentration leads to enhanced inhibitory neurotransmission.
Pharmacokinetics:
- Absorption: Tiagabine is well-absorbed orally, although food may delay absorption. It is recommended to take tiagabine with food to improve tolerability.
- Metabolism: Tiagabine is extensively metabolized in the liver, primarily by the CYP3A4 enzyme. Concomitant administration with drugs that induce or inhibit CYP3A4 can significantly alter tiagabine plasma concentrations.
- Elimination: Tiagabine and its metabolites are primarily excreted in the urine. The elimination half-life ranges from 7-9 hours in patients not taking enzyme-inducing antiepileptic drugs and can be reduced to 2-3 hours in patients taking enzyme-inducing antiepileptic drugs.
Mode of Action: Tiagabine’s primary mode of action is the selective inhibition of GAT-1, increasing the extracellular concentration of GABA and prolonging its inhibitory effects.
Receptor Binding/Enzyme Inhibition: Tiagabine selectively binds to and inhibits the GABA transporter GAT-1. It does not appear to interact directly with GABA receptors or other neurotransmitter systems.
Elimination Pathways: Tiagabine is predominantly eliminated through hepatic metabolism (CYP3A4) followed by renal excretion of metabolites.
Dosage
Standard Dosage
Adults:
- Initial: 4 mg orally once daily with food for one week.
- Titration: Increase the total daily dose by 4-8 mg at weekly intervals, administered in 2 to 4 divided doses. The maximum recommended dose is 56 mg/day. For patients not receiving enzyme-inducing antiepileptic drugs, lower doses and slower titration are necessary as plasma concentrations are higher in this group.
Children (12-18 years):
- Initial: 4 mg orally once daily with food for one week.
- Titration: Increase by 4 mg at the beginning of week 2, then increase the total daily dose by 4-8 mg at weekly intervals, administered in 2 to 4 divided doses. The maximum recommended dose is 32 mg/day. Doses above 32 mg/day have been tolerated in a small number of adolescents for short periods. For patients not receiving enzyme-inducing antiepileptic drugs, lower doses and slower titration are necessary.
Special Cases:
- Elderly Patients: Use with caution; similar pharmacokinetics as younger adults but consider lower starting doses and slower titration.
- Patients with Renal Impairment: No dose adjustment necessary.
- Patients with Hepatic Dysfunction: Reduce initial and maintenance doses and/or prolong dosing intervals.
- Patients with Comorbid Conditions: Consider comorbidities and potential drug interactions when determining appropriate dosage.
Clinical Use Cases
Tiagabine is indicated for the adjunctive treatment of partial-onset seizures. It is not indicated for use in settings like intubation, surgical procedures, mechanical ventilation, ICU use, or emergency situations such as status epilepticus or cardiac arrest.
Dosage Adjustments
Dosage adjustments should be made for patients with hepatic impairment and those taking concomitant CYP3A4-inducing or -inhibiting drugs. Lower doses are typically needed for patients not taking enzyme-inducing antiepileptic drugs.
Side Effects
Common Side Effects:
Dizziness, fatigue, nervousness, tremor, somnolence, nausea, diarrhea, abdominal pain, difficulty concentrating, insomnia, confusion, pharyngitis, rash, depressed mood.
Rare but Serious Side Effects:
New-onset seizures, status epilepticus (even in patients without a prior history of epilepsy), suicidal ideation, visual field defects, spontaneous bruising, serious rash (including Stevens-Johnson syndrome).
Long-Term Effects:
The potential long-term effects of tiagabine are not fully established. Regular monitoring for any emergence or worsening of psychiatric symptoms is essential.
Adverse Drug Reactions (ADR):
Severe skin reactions (Stevens-Johnson Syndrome, toxic epidermal necrolysis), neuropsychiatric events (suicidal behavior, psychosis), status epilepticus.
Contraindications
Hypersensitivity to tiagabine, severe hepatic impairment.
Drug Interactions
Enzyme-inducing antiepileptic drugs (e.g., phenytoin, carbamazepine, phenobarbital) decrease tiagabine concentrations. CYP3A4 inhibitors (e.g., ketoconazole, erythromycin) increase tiagabine concentrations. Other CNS depressants can exacerbate the sedative effects of tiagabine.
Pregnancy and Breastfeeding
Pregnancy Category C. There are no adequate and well-controlled studies in pregnant women. Use during pregnancy only if the potential benefit justifies the potential risk to the fetus. Tiagabine is excreted in breast milk; caution is advised when administering to nursing mothers.
Drug Profile Summary
- Mechanism of Action: Inhibits GABA reuptake, increasing GABAergic neurotransmission.
- Side Effects: Dizziness, fatigue, nervousness, tremor, somnolence, nausea, diarrhea, new onset seizures, status epilepticus, suicidal ideation, visual disturbances.
- Contraindications: Hypersensitivity, severe hepatic impairment.
- Drug Interactions: Enzyme-inducing AEDs, CYP3A4 inhibitors, CNS depressants.
- Pregnancy & Breastfeeding: Category C; use with caution.
- Dosage: Adults: 4-56 mg/day; Children (12-18 years): 4-32 mg/day; Adjust for hepatic impairment and concomitant medications.
- Monitoring Parameters: Seizure frequency, liver function tests, mood and behavior.
Popular Combinations
Tiagabine is often used in combination with other antiepileptic drugs like valproate, lamotrigine, or levetiracetam.
Precautions
- General Precautions: Monitor for suicidality, depression, new-onset seizures, skin reactions, visual changes, and hepatic dysfunction. Taper dose gradually upon discontinuation.
- Specific Populations: Use with caution in patients with hepatic impairment, elderly, pregnancy, and breastfeeding. Not established for children under 12.
FAQs (Frequently Asked Questions)
Q1: What is the recommended dosage for Tiagabine?
A: Adults: 4-56 mg/day; Children (12-18 years): 4-32 mg/day. The initial dose is 4 mg once daily, titrated weekly based on response and tolerability.
Q2: How should Tiagabine be administered?
A: Orally with food, usually in two to four divided doses per day.
Q3: What are the common side effects of Tiagabine?
A: Dizziness, fatigue, nervousness, tremor, somnolence, nausea, and diarrhea.
Q4: Is Tiagabine safe to use during pregnancy?
A: Pregnancy Category C; use only if the potential benefit justifies the potential risk to the fetus.
Q5: Does Tiagabine interact with other medications?
A: Yes, it interacts with enzyme-inducing AEDs, CYP3A4 inhibitors, and other CNS depressants.
Q6: What should be monitored in patients taking Tiagabine?
A: Seizure frequency, liver function, mood changes, and any signs of new or worsening seizures.
Q7: Can Tiagabine be used in children?
A: Yes, in children 12 years and older. The safety and efficacy have not been established in children younger than 12 years.
Q8: What should be done if a dose is missed?
A: Take the missed dose as soon as possible. If it is near the time of the next dose, skip the missed dose and continue the regular dosing schedule. Do not double the dose.
Q9: How should Tiagabine be discontinued?
A: Gradually taper the dose to minimize the risk of withdrawal seizures.
Q10: What are the signs of Tiagabine overdose?
A: Somnolence, confusion, seizures, respiratory depression, coma.
