Tiagabine Hydrochloride

Pronunciation: tye-AG-a-been HYE-droe-KLOR-ide
Class: Anticonvulsant

Trade Names

Gabitril
- Tablets 2 mg
- Tablets 4 mg
- Tablets 12 mg
- Tablets 16 mg

Pharmacology

Mechanism unknown; may block GABA uptake into presynaptic neurons, allowing more GABA to be available for binding with the GABA receptor of postsynaptic cells.

Slideshow: Flashback: FDA Drug Approvals 2013

Pharmacokinetics

Absorption

Tiagabine is rapidly and well absorbed, with food slowing the absorption rate but not altering the extent of absorption. T max is 45 min following oral dosing in the fasting state. Bioavailability is 90%. Steady state is achieved within 2 days following multiple dosing.

Distribution

Tiagabine is 96% bound to plasma proteins.

Metabolism

At least 2 metabolic pathways have been identified in humans: 1) thiophene ring oxidation leading to the formation of 5-oxo-tiagabine, and 2) glucuronidation. Tiagabine is metabolized primarily by the 3A isoform subfamily of hepatic CYP-450 (CYP3A4), although contributions to the metabolism from CYP1A2, 2D6, or 2C19 have not been excluded.

Elimination

The half-life is 7 to 9 h in healthy volunteers, and 2 to 5 h in patients receiving hepatic enzyme-inducing drugs (eg, carbamazepine, phenobarbital, phenytoin, primidone). Approximately 2% of oral dose is excreted unchanged, with 25% and 63% of remaining dose excreted into the urine and feces, respectively.

Peak

Mean steady-state values were 40% lower in the evening than in the morning. Steady-state AUC values were 15% lower following the evening dose compared with AUC following the morning dose.

Special Populations

Renal Function Impairment

The pharmacokinetics of total and unbound tiagabine were similar in patients with healthy renal function (CrCl more than 80 mL/min) and in subjects with mild (CrCl 40 to 80 mL/min), moderate (CrCl 20 to 39 mL/min), or severe (CrCl 5 to 19 mL/min) renal impairment. The pharmacokinetics of total and unbound tiagabine were also unaffected in patients with renal failure requiring hemodialysis.

Hepatic Function Impairment

Moderate hepatic impairment (Child-Pugh class B) caused a 60% decrease in the Cl of unbound tiagabine.

Elderly

The pharmacokinetic profile was similar in healthy elderly and healthy younger adults.

Children

The apparent Cl and Vd of tiagabine per unit BSA or per kg were fairly similar in 25 children (range, 3 to 10 years of age) and in adults taking enzyme-inducing antiepileptic drugs (AEDs) (eg, carbamazepine, phenytoin). In children who were taking a noninducing AED (eg, valproate), the Cl of tiagabine based upon body weight and BSA was 2- and 1.5-fold higher, respectively, than in noninduced adults with epilepsy.

Gender

Retrospective pharmacokinetic analyses suggest that there is no clinically important difference between the Cl of tiagabine in men and women when adjusted for body weight.

Race

Population pharmacokinetic analyses indicate that tiagabine Cl values were not significantly different in white, black, or Hispanic patients with epilepsy.

Cigarette smoking

Tiagabine Cl values were not significantly affected by tobacco use.

Indications and Usage

Adjunctive therapy in treatment of partial seizures.

Unlabeled Uses

Bipolar disorders, posttraumatic stress disorders, refractory seizures in children.

Contraindications

Standard considerations.

Dosage and Administration

Induced Adults

PO Initial dose: 4 mg once daily. Increase by 4 to 8 mg at weekly intervals until clinical response achieved. Maintenance dosage: 32 to 56 mg/day in 2 to 4 divided doses (max, 56 mg/day).

Induced Adolescents 12 to 18 y of Age

PO Initial dose: 4 mg once daily. Increase dose by 4 mg/day at beginning of wk 2. Thereafter, total daily dose may be increased by 4 to 8 mg at weekly intervals until clinical response is achieved (max, 32 mg/day).

Noninduced Adults and Adolescents 12 to 18 y of Age

PO Following a given dose of tiagabine, the estimated plasma concentration is more than twice that in patients receiving enzyme-inducing agents. Tiagabine use in noninduced patients requires lower doses and slower titration.

General Advice

  • Administer total daily dose in divided doses 2 to 3 times per day with food.
  • Avoid rapid escalation and/or large dose increments.
  • If a dose is missed, skip that dose and administer the next dose at the regularly scheduled time. Do not double the dose to catch up. If multiple doses have been missed, possible retitration may be required.
  • Consider dosage adjustment whenever a change in patient's enzyme-inducing status occurs as a result of the addition, discontinuation, or dose change of the enzyme-inducing agent.
  • Do not abruptly discontinue; withdrawal gradually to minimize the potential for increased seizure frequency, unless safety concerns require a more rapid withdrawal.

Storage/Stability

Store at 68° to 77°F. Protect from light and moisture.

Drug Interactions

Bupropion, gemfibrozil

Tiagabine plasma concentrations may be increased, resulting in increased toxicity (eg, confusion, seizures, and coma). Closely monitor the patient and adjust the tiagabine dose as needed.

Enzyme-inducing antiepileptic drugs (eg, carbamazepine, phenobarbital, phenytoin, primidone)

Tiagabine clearance may be increased. Monitor the patient and adjust the tiagabine dose accordingly.

Food

A high-fat meal decreases the rate (mean T max is prolonged to 2.5 hours and mean C max is reduced approximately 40%), but not the extent (AUC) of tiagabine absorption.

Highly protein bound drugs

Because tiagabine is 96% protein bound, higher concentrations of tiagabine or the competing drug may occur. Such an interaction can potentially lead to higher free fractions of either drug. Monitor the response of the patient. If an interaction is suspected, adjust the dose of either drug as needed.

Valproate

Slight increases (approximately 10%) in valproate concentrations may occur. Valproate decreases tiagabine binding in vitro (from 96.3% to 94.8%), which may result in an increase of approximately 40% in the free tiagabine. The clinical relevance is unknown.

Adverse Reactions

Cardiovascular

Vasodilation (2%); hypertension, palpitation, syncope, tachycardia (at least 1%).

CNS

Dizziness (31%); asthenia (23%); somnolence, tremor (21%); attention/concentration difficulty, nervousness (14%); ataxia, tremor (9%); depression (7%); insomnia (6%); abnormal gait, confusion, hostility (5%); difficulty with memory, paresthesia, speech disorder (4%); emotional liability (3%); language problems, nystagmus (2%); anxiety, depersonalization, dysarthria, euphoria, hallucination, headache, hyperkinesia, hypertonia, hypesthesia, hypokinesia, hypotonia, incoordination, malaise, migraine, myoclonus, paranoid reaction, personality disorder, reflexes decreased, stupor, twitching, vertigo (at least 1%); agitation (1%).

Dermatologic

Rash (5%); pruritus (2%); acne, alopecia, dry skin, sweating (at least 1%).

EENT

Amblyopia (9%); abnormal vision, conjunctivitis, diplopia, ear pain, otitis media, rhinitis, sinusitis, tinnitus (at least 1%).

GI

Nausea (11%); diarrhea (10%); abdominal pain, vomiting (7%); increased appetite (2%); anorexia, constipation, dyspepsia, dry mouth, gingivitis, stomatitis (at least 1%); mouth ulceration (1%).

Genitourinary

UTI (5%); dysmenorrhea, dysuria, flatulence, gastroenteritis, metrorrhagia, urinary frequency, urinary incontinence, vaginitis (at least 1%).

Hematologic-Lymphatic

Ecchymosis (6%); lymphadenopathy (at least 1%).

Metabolic-Nutritional

Edema, peripheral edema, weight gain or loss (at least 1%).

Musculoskeletal

Myalgia (5%); arthralgia, back pain, neck pain (at least 1%); myasthenia (1%).

Respiratory

Pharyngitis (8%); cough increased (4%); bronchitis, dyspnea, epistaxis, pneumonia (at least 1%).

Miscellaneous

Infection (19%); flu syndrome (9%); pain (7%); allergic reaction, chest pain, chills, cyst, fever (at least 1%).

Precautions

Monitor

Therapeutic tiagabine plasma levels have not been established. Because of potential for pharmacokinetic interactions between tiagabine and drugs that induce or inhibit hepatic metabolizing enzymes, it may be useful to obtain plasma levels of tiagabine before and after changes are made in the therapeutic regimen. Monitor patients for the emergence or worsening of depression, suicidal thoughts or behavior, and/or any unusual changes in mood or behavior.


Pregnancy

Category C .

Lactation

Undetermined.

Children

Safety and efficacy in children younger than 12 y of age not established.

Hepatic Function

Dosage reduction or longer dosing interval may be necessary.

Hazardous Tasks

May cause dizziness, somnolence, and other symptoms and signs of CNS depression.

CNS effects

Confusion, fatigue, impaired concentration, somnolence, and speech or language problems can occur. Some of these reactions were dose-related and usually began during initial titration. In addition, some patients with a history of spike and wave discharges on EEG may have exacerbations of EEG abnormalities associated with cognitive/neuropsychiatric reactions, which may be a manifestation of underlying seizure activity. Dosage reduction of tiagabine may be necessary.

EEG abnormalities

Patients with a history of spike and wave discharges on EEG have been reported to have exacerbations of their EEG abnormalities associated with cognitive/neuropsychiatric events. Patients usually continued tiagabine, but required dosage adjustment.

Generalized weakness

Moderately severe to incapacitating generalized weakness has been reported following administration of tiagabine. Weakness resolved in all cases after the dose was reduced or therapy was discontinued.

Melanin-containing tissues

Tiagabine may bind to melanin-containing tissues. Long-term use may cause toxicity and ophthalmologic changes.

Seizures in patients without epilepsy

Tiagabine use has been associated with new-onset seizures and status epilepticus in patients without epilepsy. Discontinue use in nonepileptic patient who develops seizures and evaluate patient for underlying seizure disorder.

Serious rash

Four patients treated with tiagabine during the product's premarketing clinical testing developed what were considered to be serious rashes (maculopapular, vesiculobullous, and Stevens-Johnson syndrome). Drug-associated rash can, if extensive and serious, cause irreversible morbidity, even death.

Sudden unexpected death in epilepsy

During clinical trials, some patients experienced status epilepticus, and 10 sudden unexpected deaths occurred. Evidence suggested that this reflected population rates and was not caused by tiagabine.

Suicidal behavior and ideation

Antiepileptic drugs, including tiagabine, increase the risk of suicidal thoughts or behavior in patients taking these drugs for any indication. Balance the risk of suicidal thoughts or behaviors with the risk of untreated illness.

Withdrawal seizures

Do not discontinue antiepileptic drugs abruptly because of possible increased seizure frequency upon drug withdrawal.

Overdosage

Symptoms

Agitation, ataxia, confusion, depression, drowsiness, hostility, impaired consciousness, lethargy, myoclonus, somnolence, speech difficulty, weakness.

Patient Information

  • Advise patient, family, or caregiver to read the patient information leaflet before starting therapy and with each refill.
  • Counsel patients and their caregivers and families that antiepileptic drugs, including tiagabine, may increase the risk of suicidal thoughts and behavior, and advise them of the need to be alert for the emergence or worsening of symptoms of depression; any unusual changes in mood or behavior; or the emergence of suicidal thoughts, behavior, or thoughts about self-harm. Instruct them to report behaviors of concern immediately to a health care provider.
  • Instruct patient, family, or caregiver to continue other medications for seizures unless advised by health care provider.
  • Advise patient, family, or caregiver that medication will be started at a low dose and then gradually increased as tolerated until max benefit is obtained.
  • Instruct patient, family, or caregiver to take exactly as prescribed and not to change the dose or discontinue therapy unless advised by health care provider.
  • Advise patient to take each dose with food.
  • Instruct patient, family, or caregiver that if a dose is missed to skip that dose and not double up on the next dose.
  • Advise patient, family, or caregiver that if medication needs to be discontinued, it will be slowly withdrawn unless safety concerns (eg, rash) require a more rapid withdrawal.
  • Caution patient that drug may cause dizziness, drowsiness, and other signs and symptoms of CNS depression, and to use caution while driving or performing other tasks requiring mental alertness until tolerance is determined.
  • Caution patient that alcohol and other CNS depressants (eg, sedatives) will have additional sedative effects if used with tiagabine.
  • Instruct patient, family, or caregiver to contact health care provider if seizures worsen, if new types of seizures occur, or if bothersome side effects develop.

Copyright © 2009 Wolters Kluwer Health.

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