Tiagabine (Systemic)


VA CLASSIFICATION
Primary: CN400

Commonly used brand name(s): Gabitril.

Note: For a listing of dosage forms and brand names by country availability, see Dosage Forms section(s).



Category:


Anticonvulsant—

Indications

Accepted

Epilepsy (treatment adjunct)—Tiagabine is indicated as an adjunct to other anticonvulsant medications in the treatment of partial seizures in adults and children 12 years of age and older {01}.


Pharmacology/Pharmacokinetics

Physicochemical characteristics:
Molecular weight—
    Tiagabine hydrochloride: 412 {01}

Mechanism of action/Effect:

The precise mechanism of tiagabine's antiseizure effects is unknown {01}. In vitro experiments have documented tiagabine's ability to enhance the activity of gamma-aminobutyric acid (GABA), the major inhibitory neurotransmitter in the central nervous system (CNS) {01}. These experiments have shown that tiagabine binds to recognition sites associated with the GABA uptake carrier {01}. It is thought that this binding enables tiagabine to block GABA uptake into presynaptic neurons, permitting more GABA to be available for receptor binding on the surfaces of post-synaptic cells {01}. Inhibition of GABA uptake has been shown for synaptosomes, neuronal cell cultures, and glial cell cultures {01}.

In vitro binding studies have shown that tiagabine does not significantly inhibit the uptake of dopamine, norepinephrine, serotonin, glutamate, or choline, and shows little or no binding to dopamine D 1 and D 2; muscarinic; serotonin 5HT 1A, 5HT 2, and 5HT 3; beta 1- and beta 2-adrenergic; alpha 1- and alpha 2-adrenergic; histamine H 2 and H 3; adenosine A 1 and A 2; opiate mu and K 1; N-methyl- D-aspartate (NMDA) glutamate; and GABA A receptors {01}. Tiagabine also lacks significant affinity for sodium or calcium channels {01}. At concentrations 20 to 400 times those inhibiting the uptake of GABA, tiagabine binds to histamine H 1, serotonin 5HT 1B, benzodiazepine, and chloride channel receptors {01}.

Absorption:

Tiagabine is rapidly and nearly completely absorbed (> 95%), with an absolute bioavailability of about 90% {01}. Food slows the rate but not the extent of absorption {01}.

Protein binding:

Very high (96%), mainly to serum albumin and alpha-1–acid glycoprotein {01}.

Biotransformation:

Hepatic; not fully elucidated {01}. At least two metabolic pathways have been identified: thiophene ring oxidation, leading to an inactive metabolite, and glucuronidation {01}. Tiagabine is most likely metabolized primarily by the 3A isoform subfamily of hepatic cytochrome P450 (CYP3A); contributions to the metabolism of tiagabine from isoenzymes CYP1A2, CYP2D6, or CYP2C19 have not been excluded {01}.

In patients with moderate hepatic impairment (Child-Pugh Class B), clearance of unbound tiagabine was reduced by about 60% {01}. Patients with impaired liver function may require lower initial and maintenance doses of tiagabine and/or longer dosing intervals than patients with normal hepatic function {01}.

Half-life:


Elimination:

Normal volunteers: 7 to 9 hours {01}.

Epileptic patients taking hepatic enzyme-inducing drugs: 4 to 7 hours {01}.

Note: In clinical trials, most patients were induced {01}.



Time to peak concentration:

Approximately 45 minutes following an oral dose administered in the fasting state {01}. The presence of food (i.e., a high fat meal) may prolong the time to reach maximum concentration to 2.5 hours {01}.

Other pharmacokinetic parameters

A diurnal effect was observed on the pharmacokinetics of tiagabine {01}. Mean steady-state minimum plasma concentration (C min) values were 40% lower in the evening than in the morning {01}. The area under the plasma concentration–time curve (AUC) values at steady-state were 15% lower following the evening dose as compared to the AUC values following the morning dose {01}.

Elimination:
    Approximately 2% of an oral dose of tiagabine is excreted unchanged {01}. Of the remaining dose, 25% and 63% are excreted into the urine and feces, respectively, primarily as metabolites {01}.


Precautions to Consider

Carcinogenicity/Tumorigenicity

A carcinogenicity study in rats receiving 200 mg of tiagabine per kg of body weight (mg/kg) a day (36 to 100 times the maximum recommended human dosage [MRHD] of 56 mg a day) for 2 years resulted in small but statistically significant increases in the incidences of hepatocellular adenomas in female rats and Leydig cell tumors of the testis in male rats {01}. The significance of these findings relative to the use of tiagabine in humans is not known {01}. The no effect dosage for induction of tumors in this study was 100 mg/kg a day (17 to 50 times the MRHD) {01}. No statistically significant increases in tumor formation were noted in mice at dosages of up to 250 mg/kg a day (20 times the MRHD on a mg per square meter of body surface area [mg/m 2] basis) {01}.

Mutagenicity

Tiagabine produced an increase in structural chromosome aberration frequency in human lymphocytes in vitro in the absence of metabolic activation {01}; no increase in chromosomal aberration frequencies was demonstrated in this assay in the presence of metabolic activation {01}. No evidence of genetic toxicity was found in the in vitro bacterial gene mutation assays, the in vitro HGPRT forward mutation assay in Chinese hamster lung cells, the in vivo mouse micronucleus test, or an unscheduled DNA synthesis assay {01}.

Pregnancy/Reproduction
Fertility—
Studies in male and female rats receiving tiagabine prior to and during mating, gestation, and lactation have shown no impairment of fertility at doses of up to 100 mg/kg a day (approximately 16 times the MRHD on a mg/m 2 basis) {01}. Lowered maternal weight gain and decreased viability and growth in the rat pups did occur at this dose {01}.

Pregnancy—
Adequate and well-controlled studies in humans have not been done {01}.

Tiagabine has been shown to have adverse effects on embryo-fetal development, including teratogenic effects, when administered to pregnant rats and rabbits at doses greater than the human therapeutic dose {01}.

An increased incidence of malformed fetuses (various craniofacial, appendicular, and visceral defects) and decreased fetal weights were observed following oral administration of 100 mg/kg a day to pregnant rats during the period of organogenesis {01}. This dose is approximately 16 times the MRHD on a mg/m 2 basis {01}. Maternal toxicity (transient weight loss and reduced maternal weight gain during gestation) was associated with this dose, but there was no evidence to suggest that the teratogenic effects were secondary to the maternal effects {01}. No adverse maternal or embryo-fetal effects were seen at a dose of 20 mg/kg a day (3 times the MRHD on a mg/m 2 basis) {01}.

Decreased maternal weight gain, increased resorption of embryos, and increased incidence of fetal variations, but not malformations, were observed when pregnant rabbits were administered 25 mg of tiagabine per kg a day (8 times the MRHD on a mg/m 2 basis) during organogenesis. The no effect level for maternal and embryo-fetal toxicity in rabbits was 5 mg/kg a day (equivalent to the MRHD on a mg/m 2 basis) {01}.

Decreased maternal weight gain during gestation, an increase in stillbirths, and decreased postnatal offspring viability and growth were observed in female rats that received tiagabine 100 mg/kg a day during late gestation and throughout parturition and lactation {01}.

FDA Pregnancy Category C {01}.

Breast-feeding

It is not known whether tiagabine and/or its metabolites are distributed into human milk or what effects it may have on the nursing infant {01}. Animal studies have shown that tiagabine and/or its metabolites appear in the milk of rats {01}. Risk-benefit must be considered {01}.

Pediatrics

Adequate and well-controlled studies have not been conducted in children up to 12 years of age {01}. However, pharmacokinetic studies in a small number of children 3 to 10 years of age showed that apparent clearance (per unit of body surface area) and volume of distribution (per kg) of tiagabine were similar to those in adults when both groups were receiving enzyme-inducing anticonvulsants (e.g., carbamazepine or phenytoin) {01}. In children taking a non–enzyme-inducing anticonvulsant (e.g., valproate), the clearance of tiagabine based upon body weight and body surface area was 2- and 1.5-fold higher, respectively, than in uninduced adults with epilepsy {01}. Safety and efficacy in children up to 12 years of age have not been established {01}.


Geriatrics


The pharmacokinetic profile of tiagabine in healthy elderly adults was similar to that in healthy young adults {01}. However, only a small number of patients over 65 years of age were exposed to tiagabine during clinical evaluation; therefore, safety and efficacy in this age group have not been established {01}.


Pharmacogenetics

Population pharmacokinetic analyses indicated that tiagabine clearance values were not significantly different in white, black, or Hispanic patients with epilepsy {01}.

Drug interactions and/or related problems
The following drug interactions and/or related problems have been selected on the basis of their potential clinical significance (possible mechanism in parentheses where appropriate)—not necessarily inclusive (» = major clinical significance):


Note: Administration of hepatic enzyme-inducing medications will increase the clearance of tiagabine {01}.
Combinations containing any of the following medications, depending on the amount present, may also interact with this medication.

Alcohol{01} or
Central nervous system (CNS) depression–producing medications{01} , other (see Appendix II )    (increased CNS depression may occur)


» Carbamazepine{01}    (tiagabine clearance is increased by 60% in patients taking carbamazepine)


» Phenobarbital{01}    (tiagabine clearance is increased by 60% in patients taking phenobarbital)


» Phenytoin{01}    (tiagabine clearance is increased by 60% in patients taking phenytoin)


» Primidone{01}    (tiagabine clearance is increased by 60% in patients taking primidone)


Valproic acid{01}    (tiagabine causes a slight decrease [about 10%] in steady-state valproate concentrations; in vitro studies have shown that valproate decreased the protein binding of tiagabine from 96.3 to 94.8%, resulting in an increase of approximately 40% in the free tiagabine concentration; clinical relevance of this finding is unknown)


Medical considerations/Contraindications
The medical considerations/contraindications included have been selected on the basis of their potential clinical significance (reasons given in parentheses where appropriate)— not necessarily inclusive (» = major clinical significance).


Risk-benefit should be considered when the following medical problems exist
Electroencephalogram (EEG) abnormalities    (patients with a history of spike and wave discharges on EEG have been reported to have exacerbations of EEG abnormalities associated with cognitive/neuropsychiatric events; these clinical events may, in some cases, be a manifestation of underlying seizure activity; dosage adjustments may be required)


Hepatic function impairment    (dosage reductions or longer dosing intervals may be required)

{01}
Sensitivity to tiagabine{01}
Status epilepticus, history of    (condition may be precipitated)

{01}

Patient monitoring
The following may be especially important in patient monitoring (other tests may be warranted in some patients, depending on condition; » = major clinical significance):

Therapeutic monitoring of plasma concentrations    (a therapeutic range for tiagabine plasma concentrations has not been established; in controlled trials, trough plasma concentrations observed in patients randomized to tiagabine doses that were statistically significantly more effective than placebo ranged from < 1 nanogram/mL to 234 nanograms/mL; because of the potential for interactions between tiagabine and drugs that induce or inhibit hepatic metabolizing enzymes, obtaining tiagabine plasma concentrations before and after changes are made in the patient's medication regimen may be useful)

{01}


Side/Adverse Effects

Note: In studies in dogs receiving a single dose of radiolabeled tiagabine, residual binding in the retina and uvea after 3 weeks was apparent. Binding to melanin is likely. The ability of available tests to detect potentially adverse consequences of the binding of tiagabine to melanin-containing tissue is unknown, and no systematic monitoring for relevant ophthalmologic changes during the clinical development of tiagabine was conducted. However, long-term (up to 1 year) toxicological studies of tiagabine in dogs showed no treatment-related ophthalmoscopic changes, and macro- and microscopic examinations of the eye were unremarkable. Although there are no specific recommendations for periodic ophthalmologic monitoring, the possibility of long-term ophthalmologic effects exists.

The following side/adverse effects have been selected on the basis of their potential clinical significance (possible signs and symptoms in parentheses where appropriate)—not necessarily inclusive:

Those indicating need for medical attention
Incidence more frequent
    
Difficulty in concentrating or paying attention —may be dose-related
    
ecchymosis (blue or purple spots on skin)

Incidence less frequent
    
Ataxia (clumsiness or unsteadiness)
    
confusion
    
mental depression
    
paresthesias (burning, numbness, or tingling sensations)
    
pruritus (itching)
    
speech and/or language problems

Incidence rare
    
Abnormal gait (walking in unusual manner)
    
agitation
    
emotional lability (quick to react or overreact emotionally)
    
generalized weakness
    
hostility
    
memory problems
    
nystagmus (uncontrolled back-and-forth and/or rolling eye movements)
    
rash
    
urinary tract infection (bloody or cloudy urine; burning, pain, or difficulty in urinating; frequent urge to urinate)

Note: Moderately severe to incapacitating generalized weakness has been reported in about 1% of patients with epilepsy following administration of tiagabine {01}. Weakness resolved in all cases following a reduction in dose or discontinuation of tiagabine {01}.
Four patients treated with tiagabine during premarketing clinical testing developed serious rashes; two cases were described as maculopapular, one case was described as vesiculobullous, and one case was diagnosed as Stevens-Johnson syndrome {01}. A causal relationship to tiagabine has not been established {01}. However, drug-associated rash can, if extensive and serious, cause irreversible morbidity, even death {01}.




Those indicating need for medical attention only if they continue or are bothersome
Incidence more frequent
    
Asthenia (unusual tiredness or weakness)—may be dose-related
    
diarrhea
    
dizziness
    
influenza-like syndrome (chills; fever; headache; muscle aches or pain)
    
nervousness
    
pharyngitis (sore throat)
    
somnolence (drowsiness)
    
tremor —may be dose-related
    
vomiting

Incidence less frequent
    
Abdominal pain{01}
    
amblyopia (impaired vision)
    
cough, increased
    
increased appetite
    
insomnia (trouble in sleeping)
    
mouth ulcers
    
muscle weakness
    
myalgia (muscle ache or pain)
    
nausea{01}
    
pain (unspecified)
    
vasodilation (flushing)





Overdose
For information on the management of overdose or unintentional ingestion of tiagabine, contact a Poison Control Center (see Poison Control Center Listing ).

Clinical effects of overdose
The following effects have been selected on the basis of their potential clinical significance (possible signs and symptoms in parentheses where appropriate)—not necessarily inclusive:
Acute
    
Agitation, severe
    
ataxia, severe (clumsiness or unsteadiness)
    
confusion, severe
    
hostility
    
impaired consciousness (coma)
    
lethargy (sluggishness)
    
mental depression
    
myoclonus (severe muscle twitching or jerking)
    
precipitation of a tonic-clonic seizure (increase in seizures)
    
somnolence, severe (drowsiness)
    
speech problems, severe
    
weakness


Treatment of overdose
There is no specific antidote for overdose with tiagabine {01}.

To decrease absorption—Elimination of unabsorbed drug by inducing emesis or by gastric lavage, if indicated; usual precautions to maintain the airway should be taken {01}.

To enhance elimination—Since tiagabine is primarily metabolized by the liver and highly protein-bound, dialysis is not likely to be beneficial {01}.

Monitoring—Monitoring of vital signs {01}.

Supportive care—General supportive care, including observation of clinical status {01}. Patients in whom intentional overdose is confirmed or suspected should be referred for psychiatric consultation.


Patient Consultation
As an aid to patient consultation, refer to Advice for the Patient, Tiagabine (Systemic).
In providing consultation, consider emphasizing the following selected information (» = major clinical significance):

Before using this medication
»   Conditions affecting use, especially:
Sensitivity to tiagabine

Pregnancy—Teratogenicity and maternal toxicity have been demonstrated in animal studies
Other medications, especially carbamazepine, phenobarbital, phenytoin, or primidone

Proper use of this medication
Compliance with therapy; not taking more or less medicine than prescribed

Taking with food

» Proper dosing
Missed dose: Taking as soon as possible; if almost time for next dose, skipping missed dose and returning to regular dosing schedule; not doubling doses

» Proper storage

Precautions while using this medication
» Possible dizziness, drowsiness, impairment of thinking or motor skills; caution when driving or doing jobs requiring alertness or coordination

Discussing alcohol use or use of other CNS depressants with physician

» Not discontinuing tiagabine abruptly; consulting physician about gradually reducing dosage


Side/adverse effects
Signs of potential side effects, especially difficulty in concentrating or paying attention, ecchymosis, ataxia, confusion, mental depression, paresthesias, pruritus, speech and/or language problems, abnormal gait, agitation, emotional lability, generalized weakness, hostility, memory problems, nystagmus, rash, and urinary tract infection


General Dosing Information
Anticonvulsants should not be abruptly discontinued because of the possibility of increasing seizure frequency {01}. Unless safety concerns require a more rapid withdrawal, tiagabine should be withdrawn gradually {01}.

Diet/Nutrition
Tiagabine should be taken with food {01}.


Oral Dosage Forms

TIAGABINE HYDROCHLORIDE TABLETS

Note: Clinical trials of adjunctive use of tiagabine were conducted in patients taking enzyme-inducing anticonvulsants (e.g., barbiturates, carbamazepine, phenytoin) {01}. Patients taking only non–enzyme-inducing anticonvulsants (e.g., gabapentin, lamotrigine, valproate) may require a lower dose or slower titration of tiagabine {01}. Patients taking a combination of inducing and non-inducing anticonvulsants should be considered to be induced {01}.


Usual adult dose
Anticonvulsant
Oral, initially 4 mg once a day {01}. The total daily dose may be increased by 4 to 8 mg at weekly intervals until clinical response is achieved or a dose of 56 mg a day is reached {01}. The total daily dose should be given in divided doses two to four times a day {01}.

Note: Dosage modification of concomitant anticonvulsants is not necessary, unless clinically indicated {01}.


A typical dosing titration regimen for patients taking enzyme-inducing anticonvulsants follows:

Week  Initiation and titration schedule  Total daily dose 
Initiate at 4 mg once a day  4 mg/day 
Increase total daily dose by 4 mg  8 mg/day (in two divided doses) 
Increase total daily dose by 4 mg  12 mg/day (in three divided doses)  
Increase total daily dose by 4 mg   16 mg/day (in two to four divided doses)  
Increase total daily dose by 4 to 8 mg   20 to 24 mg/day (in two to four divided doses)  
Increase total daily dose by 4 to 8 mg  24 to 32 mg/day (in two to four divided doses) 
Usual adult maintenance dose  32 to 56 mg/day in two to four divided doses 


Note: Dosage reduction may be necessary in patients with liver disease due to reduced clearance of tiagabine {01}.



Usual adult prescribing limits
56 mg a day {01}.

Note: Doses above 56 mg a day have not been evaluated in adequate and well-controlled studies {01}.


Usual pediatric dose
Anticonvulsant
Children 12 to 18 years of age: Oral, initially 4 mg once a day {01}. The total daily dose may be increased by 4 mg at the beginning of the second week of therapy {01}. Thereafter, the total daily dose may be further increased by 4 to 8 mg at weekly intervals until clinical response is achieved or a dose of 32 mg a day is reached {01}. The total daily dose should be given in divided doses two to four times a day {01}.

Note:  Dosage modification of concomitant anticonvulsants is not necessary, unless clinically indicated {01}.


Children up to 12 years of age: Safety and efficacy have not been established {01}.


Usual adolescent prescribing limits
32 mg a day {01}.

Note: Doses above 32 mg a day have been tolerated in a small number of adolescent patients for a relatively short time {01}.


Usual geriatric dose
See Usual adult dose {01}.

Strength(s) usually available
U.S.—


4 mg (Rx) [Gabitril (film-sealed) (ascorbic acid) (colloidal silicon dioxide) (crospovidone) ( hydrogenated vegetable oil wax) (hydroxypropyl cellulose ) (hydroxypropyl methylcellulose) (lactose) (magnesium stearate) (microcrystalline cellulose) (pregelatinized starch) (stearic acid) ( titanium dioxide) (D&C Yellow No. 10)]


12 mg (Rx) [Gabitril (film-sealed) (ascorbic acid) (colloidal silicon dioxide) (crospovidone) ( hydrogenated vegetable oil wax) (hydroxypropyl cellulose ) (hydroxypropyl methylcellulose) (lactose) (magnesium stearate) (microcrystalline cellulose) (pregelatinized starch) (stearic acid) ( titanium dioxide) (D&C Yellow No. 10) (FD&C Blue No. 1)]


16 mg (Rx) [Gabitril (film-sealed) (ascorbic acid) (colloidal silicon dioxide) (crospovidone) ( hydrogenated vegetable oil wax) (hydroxypropyl cellulose ) (hydroxypropyl methylcellulose) (lactose) (magnesium stearate) (microcrystalline cellulose) (pregelatinized starch) (stearic acid) ( titanium dioxide) (D&C Blue No. 2)]


20 mg (Rx) [Gabitril (film-sealed) (ascorbic acid) (colloidal silicon dioxide) (crospovidone) ( hydrogenated vegetable oil wax) (hydroxypropyl cellulose ) (hydroxypropyl methylcellulose) (lactose) (magnesium stearate) (microcrystalline cellulose) (pregelatinized starch) (stearic acid) ( titanium dioxide) (D&C Red No. 30)]

Packaging and storage:
Store between 20 and 25 ºC (68 and 77 ºF) {01}. Protect from light and moisture {01}.

Auxiliary labeling:
   • Take with food.
   • May cause drowsiness.
   • May cause dizziness.



Revised: 09/07/2001



References
  1. Gabitril package insert (Abbott—US) Rev 9/97, Rec 11/97.
  1. Product Information: Gabitril, tiagabine hydrochloride Cephalon, West Chester, PA (PI revised 01/2001) PI reviewed 09/2001
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