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Drugs reference index «Tiagabine Hydrochloride»

Tiagabine Hydrochloride

Pronunciation: (TIE-egg-un-bine)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.

Pharmacokinetics

Absorption

Tiagabine is rapidly and well absorbed, with food slowing 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 t ½ is 7 to 9 h in healthy volunteers, and 2 to 5 h in patients receiving hepatic enzyme-inducing drugs (eg, carbamazepine, phenytoin, primidone, phenobarbital). 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

Hepatic Function Impairment

Moderate hepatic impairment (Child-Pugh class B) is caused by a 60% decrease in the Cl of unbound tiagabine. Patients with impaired liver function may require reduced initial and maintenance doses or longer dosing intervals.

Indications and Usage

Adjunctive therapy in treatment of partial seizures.

Contraindications

Standard considerations.

Dosage and Administration

Induced adults

PO Initial dose: 4 mg once daily. Increase by 4 to 8 mg at wk intervals until clinical response achieved (max, 56 mg/day).

Induced adolescents 12 to 18 yr 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 wk intervals until clinical response achieved (max, 32 mg/day).

Non-induced adults and adolescents 12 to 18 yr 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 non-induced patients requires lower doses and slower titration.

General Advice

  • Administer total daily dose in divided doses bid to qid 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.
  • 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.

Storage/Stability

Store at controlled room temperature (68° to 77°F). Protect from light and moisture.

Drug Interactions

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

Increased tiagabine Cl.

Highly protein bound drugs

Because tiagabine is 96% protein bound, higher concentrations of tiagabine or the competing drug may occur.

Valproate

Slight increases (about 10%) in valproate concentrations may occur.

Laboratory Test Interactions

None well documented.

Adverse Reactions

Cardiovascular

Hypertension, palpitation, syncope, tachycardia, vasodilation (at least 1%).

CNS

Abnormal gait, asthenia, ataxia, attention/concentration difficulty, depression, dizziness, hostility, insomnia, nervousness, somnolence, tremor (at least 5%); agitation, confusion, decreased reflexes, depersonalization, dysarthria, emotional lability, euphoria, hallucinations, hyperkinesias, hypertonia, hypesthesia, hypotonia, language problems, malaise, memory difficulty, migraine, myoclonus, nystagmus, paranoid reaction, paresthesia, personality disorder, speech disorder, stupor, twitching, vertigo (at least 1%).

Dermatologic

Alopecia, dry skin, pruritus, rash, sweating (at least 1%).

EENT

Amblyopia, pharyngitis, (at least 5%); abnormal vision, ear pain, epistaxis, otitis media, tinnitus (at least 1%).

GI

Abdominal pain, diarrhea (at least 5%); increased appetite, gingivitis, mouth ulceration, nausea, stomatitis, vomiting (at least 1%).

Genitourinary

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

Hematologic-Lymphatic

Ecchymosis (at least 5%); lymphadenopathy (at least 1%).

Metabolic-Nutritional

Myalgia (at least 5%); edema, peripheral edema, weight gain or loss (at least 1%).

Musculoskeletal

Arthralgia, myasthenia, neck pain (at least 1%).

Respiratory

Bronchitis, dyspnea, increased cough, pneumonia (at least 1%).

Miscellaneous

Accidental injury, flu syndrome, infection, pain (at least 5%); allergic reactions, chest pain, chills, cyst (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.

Pregnancy

Category C .

Lactation

Undetermined.

Children

Safety and efficacy in children younger than 12 yr 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.

Cognitive/Neuropsychiatric adverse reactions

Impaired concentration, speech or language problems, confusion, somnolence, and fatigue 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.

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.

Sudden unexpected death in epilepsy (SUDEP)

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.

Use in non-induced patients

Use of tiagabine in non-induced patients requires lower doses and slower dosage titration.

Withdrawal seizures

Do not discontinue anti-epileptic 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.
  • 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 taken 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.