Drugs Details

Drugs Info of Gabitril
Drugs Details
  • Drugs Type  : Multum
  • Date : 26th Jan 2015 03:31 am
  • Brand Name : Gabitril
  • Generic Name : tiagabine (Pronunciation: tye AG a been)
Descriptions

GABITRIL® (tiagabine hydrochloride) (tiagabine HC1) is an antiepilepsy drug available as 2 mg, 4 mg, 12 mg, and 16 mg tablets for oral administration. Its chemical name is (-)-(R)-l-[4,4-Bis(3-methyl-2-thienyl)-3-butenyljnipecotic acid hydrochloride, its molecular formula is C20H25NO2S2, and its molecular weight is 412.0. Tiagabine HC1 is a white to off-white, odorless, crystalline powder. It is insoluble in heptane, sparingly soluble in water, and soluble in aqueous base. The structural formula is:

 

GABITRIL®
  (tiagabine hydrochloride) Structural Formula Illustration

Inactive Ingredients

GABITRIL (tiagabine hydrochloride) tablets contain the following inactive ingredients: Ascorbic acid, colloidal silicon dioxide, crospovidone, hydrogenated vegetable oil wax, hydroxypropyl cellulose, hypromellose, lactose, magnesium stearate, microcrystalline cellulose, pregelatinized starch, stearic acid, and titanium dioxide.

In addition, individual tablets contain:

2 mg tablets: FD&C Yellow No. 6.
4 mg tablets: D&C Yellow No. 10.
12 mg tablets: D&C Yellow No. 10 and FD&C Blue No. 1.
16 mg tablets: FD&C Blue No. 2.

What are the possible side effects of tiagabine (Gabitril)?

Get emergency medical help if you have any of these signs of an allergic reaction: hives; fever; swollen glands; painful sores in or around your eyes or mouth; difficulty breathing; swelling of your face, lips, tongue, or throat.

Call your doctor at once if you have any new or worsening symptoms such as: mood or behavior changes, depression, anxiety, or if you feel agitated, hostile, restless, hyperactive (mentally or physically), or have thoughts about suicide or hurting yourself.

Call your doctor at once if you have any of these serious side effects:

  • new or...

Read All Potential Side Effects and See Pictures of Gabitril »

What are the precautions when taking tiagabine hydrochloride (Gabitril)?

Before taking tiagabine, tell your doctor or pharmacist if you are allergic to it; or if you have any other allergies. This product may contain inactive ingredients, which can cause allergic reactions or other problems. Talk to your pharmacist for more details.

Before using this medication, tell your doctor or pharmacist your medical history, especially of: liver disease, depression/other mental condition, status epilepticus.

This drug may make you dizzy or drowsy. Do not drive, use machinery, or do any activity that requires alertness until you are sure you can perform such activities safely. Avoid alcoholic beverages.

Older adults may be more sensitive to the side effects of this drug, especially dizziness, or confusion. These effects can increase the risk of...

Read All Potential Precautions of Gabitril »


This monograph has been modified to include the generic and brand name in many instances.

Indications

GABITRIL (tiagabine hydrochloride) is indicated as adjunctive therapy in adults and children 12 years and older in the treatment of partial seizures.

Dosage Administration

General

The blood level of tiagabine obtained after a given dose depends on whether the patient also is receiving a drug that induces the metabolism of tiagabine. The presence of an inducer means that the attained blood level will be substantially reduced. Dosing should take the presence of concomitant medications into account.

  • GABITRIL (tiagabine hydrochloride) (tiagabine HC1) is recommended as adjunctive therapy for the treatment of partial seizures in patients 12 years and older.
  • The following dosing recommendations apply to all patients taking GABITRIL (tiagabine hydrochloride) :
  • GABITRIL (tiagabine hydrochloride) is given orally and should be taken with food.
  • Do not use a loading dose of GABITRIL (tiagabine hydrochloride) .
  • Dose titration: Rapid escalation and/or large dose increments of GABITRIL (tiagabine hydrochloride) should not be used.
  • Missed dose(s): If the patient forgets to take the prescribed dose of GABITRIL (tiagabine hydrochloride) at the scheduled time, the patient should not attempt to make up for the missed dose by increasing the next dose. If a patient has missed multiple doses, patient should refer back to his or her physician for possible re-titration as clinically indicated.
  • Dosage adjustment of GABITRIL (tiagabine hydrochloride) should be considered 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.

Induced Adults and Adolescents 12 Years or Older: The following dosing recommendations apply to patients who are already taking enzyme-inducing antiepilepsy drugs (AEDs) (e.g., carbamazepine, phenytoin, primidone, and phenobarbital). Such patients are considered induced patients when administering GABITRIL (tiagabine hydrochloride) .

In adolescents 12 to 18 years old, GABITRIL (tiagabine hydrochloride) should be initiated at 4 mg once daily. Modification of concomitant antiepilepsy drugs is not necessary, unless clinically indicated. The total daily dose of GABITRIL (tiagabine hydrochloride) may be increased by 4 mg at the beginning of Week 2. Thereafter, the total daily dose may be increased by 4 to 8 mg at weekly intervals until clinical response is achieved or up to 32 mg/day. The total daily dose should be given in divided doses two to four times daily. Doses above 32 mg/day have been tolerated in a small number of adolescent patients for a relatively short duration.

In adults, GABITRIL (tiagabine hydrochloride) should be initiated at 4 mg once daily. Modification of concomitant antiepilepsy drugs is not necessary, unless clinically indicated. The total daily dose of GABITRIL (tiagabine hydrochloride) may be increased by 4 to 8 mg at weekly intervals until clinical response is achieved or, up to 56 mg/day. The total daily dose should be given in divided doses two to four times daily. Doses above 56 mg/day have not been systematically evaluated in adequate and well-controlled clinical trials.

Experience is limited in patients taking total daily doses above 32 mg/day using twice daily dosing. A typical dosing titration regimen for patients taking enzyme-inducing AEDs (induced patients) is provided in Table 7.

Table 7: Typical Dosing Titration Regimen for Patients Already Taking Enzyme-Inducing AEDs

  Initiation and Titration Schedule Total Daily Dose
Week l Initiate at 4 mg once daily 4 mg/day
Week 2 Increase total daily dose by 4 mg 8 mg/day (in two divided doses)
WeekS Increase total daily dose by 4 mg 12 mg/day (in three divided doses)
Week 4 Increase total daily dose by 4 mg 16 mg/day (in two to four divided doses)
WeekS Increase total daily dose by 4 to 8 mg 20 to 24 mg/day (in two to four divided doses)
Week 6 Increase total daily dose by 4 to 8 mg 24 to 32 mg/day (in two to four divided doses)
Usual Adult Maintenance Dose in Induced Patients: 32 to 56 mg/day in two to four divided doses

Non-Induced Adults and Adolescents 12 Years or Older: The following dosing recommendations apply to patients who are taking only non-enzyme-inducing AEDs. Such patients are considered non-induced patients:

Following a given dose of GABITRIL (tiagabine hydrochloride) , the estimated plasma concentration in the non-induced patients is more than twice that in patients receiving enzyme-inducing agents. Use in non-induced patients requires lower doses of GABITRIL (tiagabine hydrochloride) . These patients may also require a slower titration of GABITRIL (tiagabine hydrochloride) compared to that of induced patients (see CLINICAL PHARMACOLOGY, Pharmacokinetics and PRECAUTIONS, General, Use in Non-Induced Patients).

How Supplied

GABITRIL (tiagabine hydrochloride) tablets are available in four dosage strengths.

2 mg orange-peach, round tablets, debossed with liSl on one side and 402 on the opposite side, are available in bottles of 30 (NDC 63459-402-30).

4 mg yellow, round tablets, debossed with liSl on one side and 404 on the opposite side, are available in bottles of 30 (NDC 63459-404-30).

12 mg green, ovaloid tablets, debossed with li£zl on one side and 412 on the opposite side, are available in bottles of 30 (NDC 63459-412-30).

16 mg blue, ovaloid tablets, debossed with liSl on one side and 416 on the opposite side, are available in bottles of 30 (NDC 63459-416-30).

Recommended Storage: Store tablets at controlled room temperature, between 20-25°C (68-77°F). See USP. Protect from light and moisture.

Distributed by: Cephalon, Inc. Frazer, PA 19355. Revised: September 2010.

>This Medication Guide has been approved by the U.S. Food and Drug Administration.


This monograph has been modified to include the generic and brand name in many instances.

Side Effects

The most commonly observed adverse events in placebo-controlled, parallel-group, add-on epilepsy trials associated with the use of GABITRIL (tiagabine hydrochloride) in combination with other antiepilepsy drugs not seen at an equivalent frequency among placebo-treated patients were dizziness/light-headedness, asthenia/lack of energy, somnolence, nausea, nervousness/irritability, tremor, abdominal pain, and thinking abnormal/difficulty with concentration or attention.

Approximately 21% of the 2531 patients who received GABITRIL (tiagabine hydrochloride) in clinical trials of epilepsy discontinued treatment because of an adverse event. The adverse events most commonly associated with discontinuation were dizziness (1.7%), somnolence (1.6%), depression (1.3%), confusion (1.1%), and asthenia (1.1%).

In Studies 1 and 2 (U.S. studies), the double-blind, placebo-controlled, parallel-group, add-on studies, the proportion of patients who discontinued treatment because of adverse events was 11% for the group treated with GABITRIL (tiagabine hydrochloride) and 6% for the placebo group. The most common adverse events considered the primary reason for discontinuation were confusion (1.2%), somnolence (1.0%), and ataxia (1.0%).

Adverse Event Incidence in Controlled Clinical Trials: Table 5 lists treatment-emergent signs and symptoms that occurred in at least 1% of patients treated with GABITRIL (tiagabine hydrochloride) for epilepsy participating in parallel-group, placebo-controlled trials and were numerically more common in the GABITRIL (tiagabine hydrochloride) group. In these studies, either GABITRIL (tiagabine hydrochloride) or placebo was added to the patient's current antiepilepsy drug therapy. Adverse events were usually mild or moderate in intensity.

The prescriber should be aware that these figures, obtained when GABITRIL (tiagabine hydrochloride) was added to concurrent antiepilepsy drug therapy, cannot be used to predict the frequency of adverse events in the course of usual medical practice when patient characteristics and other factors may differ from those prevailing during clinical studies. Similarly, the cited frequencies cannot be directly compared with figures obtained from other clinical investigations involving different treatments, uses, or investigators. An inspection of these frequencies, however, does provide the prescribing physician with one basis to estimate the relative contribution of drug and non-drug factors to the adverse event incidences in the population studied.

Table 5: Treatment-Emergent Adverse Event1 Incidence in Parallel-Group, Placebo-Controlled, Add-On Trials (events in at least 1% of patients treated with GABITRIL (tiagabine hydrochloride) and numerically more frequent than in the placebo group)

Body System/COSTART GABITRIL (tiagabine hydrochloride)
N=494
%
Placebo
N=275
%
Body as a Whole
  Abdominal Pain 7 3
  Pain (unspecified) 5 3
Cardiovascular
  Vasodilation 2 1
Digestive
  Nausea 11 9
  Diarrhea 7 3
  Vomiting 7 4
  Increased Appetite 2 0
  Mouth Ulceration 1 0
Musculoskeletal
  Myasthenia 1 0
Nervous System
  Dizziness 27 15
  Asthenia 20 14
  Somnolence 18 15
  Nervousness 10 3
  Tremor 9 3
  Difficulty with Concentration/Attention* 6 2
  Insomnia 6 4
  Ataxia 5 3
  Confusion 5 3
  Speech Disorder 4 2
  Difficulty with Memory* 4 3
  Paresthesia 4 2
  Depression 3 1
  Emotional Lability 3 2
  Abnormal Gait 3 2
  Hostility 2 1
  Nystagmus 2 1
  Language Problems* 2 0
  Agitation 1 0
Respiratory System
  Pharyngitis 7 4
  Cough Increased 4 3
Skin and Appendages
  Rash 5 4
  Pruritus 2 0
1 Patients in these add-on studies were receiving one to three concomitant enzyme-inducing antiepilepsy drugs in addition to GABITRIL (tiagabine hydrochloride) or placebo. Patients may have reported multiple adverse experiences; thus, patients may be included in more than one category.
*COSTART term substituted with a more clinically descriptive term.

Other events reported by 1% or more of patients treated with GABITRIL (tiagabine hydrochloride) but equally or more frequent in the placebo group were: accidental injury, chest pain, constipation, flu syndrome, rhinitis, anorexia, back pain, dry mouth, flatulence, ecchymosis, twitching, fever, amblyopia, conjunctivitis, urinary tract infection, urinary frequency, infection, dyspepsia, gastroenteritis, nausea and vomiting, myalgia, diplopia, headache, anxiety, acne, sinusitis, and incoordination.

Study 1 was a dose-response study including doses of 32 mg and 56 mg. Table 6 shows adverse events reported at a rate of ≥ 5% in at least one GABITRIL (tiagabine hydrochloride) group and more frequent than in the placebo group. Among these events, depression, tremor, nervousness, difficulty with concentration/attention, and perhaps asthenia exhibited a positive relationship to dose.

Table 6: Treatment-Emergent Adverse Event Incidence in Study l† (events in at least 5% of patients treated with GABITRIL (tiagabine hydrochloride) 32 or 56 mg and numerically more frequent than in the Dlacebo group)

Body System/COSTART Term GABITRIL (tiagabine hydrochloride)
56 mg
(N=57)
%
GABITRIL (tiagabine hydrochloride)
32 mg
(N=88)
%
Placebo
(N=91)
%
Body as a Whole
  Accidental Injury 21 15 20
  Infection 19 10 12
  Flu Syndrome 9 6 3
  Pain 7 2 3
  Abdominal Pain 5 7 4
Digestive System
  Diarrhea 2 10 6
Hemic and Lymphatic System
  Ecchymosis 0 6 1
Musculoskeletal System
  Myalgia 5 2 3
Nervous System
  Dizziness 28 31 12
  Asthenia 23 18 15
  Tremor 21 14 1
  Somnolence 19 21 17
  Nervousness 14 11 6
Difficulty with
  Concentration/Attention* 14 7 3
  Ataxia 9 6 6
  Depression 7 1 0
  Insomnia 5 6 3
  Abnormal Gait 5 5 3
  Hostility 5 5 2
Respiratory System
  Pharyngitis 7 8 6
Special Senses
  Amblyopia 4 9 8
Urogenital System
  Urinary Tract Infection 5 0 2
† Patients in this study were receiving one to three concomitant enzyme-inducing antiepilepsy drugs in addition to GABITRIL (tiagabine hydrochloride) or placebo. Patients may have reported multiple adverse experiences; thus, patients may be included in more than one category.
* COSTART term substituted with a more clinically descriptive term.

The effects of GABITRIL (tiagabine hydrochloride) in relation to those of placebo on the incidence of adverse events and the types of adverse events reported were independent of age, weight, and gender. Because only 10% of patients were non-Caucasian in parallel-group, placebo-controlled trials, there is insufficient data to support a statement regarding the distribution of adverse experience reports by race.

Other Adverse Events Observed During All Clinical Trials: GABITRIL (tiagabine hydrochloride) has been administered to 2531 patients during all phase 2/3 clinical trials, only some of which were placebo-controlled. During these trials, all adverse events were recorded by the clinical investigators using terminology of their own choosing. To provide a meaningful estimate of the proportion of individuals having adverse events, similar types of events were grouped into a smaller number of standardized categories using modified COSTART dictionary terminology. These categories are used in the listing below. The frequencies presented represent the proportion of the 2531 patients exposed to GABITRIL (tiagabine hydrochloride) who experienced events of the type cited on at least one occasion while receiving GABITRIL (tiagabine hydrochloride) . All reported events are included except those already listed above, events seen only three times or fewer (unless potentially important), events very unlikely to be drug-related, and those too general to be informative. Events are included without regard to determination of a causal relationship to tiagabine.

Events are further classified within body system categories and enumerated in order of decreasing frequency using the following definitions: frequent adverse events are defined as those occurring in at least 1/100 patients; infrequent adverse events are those occurring in 1/100 to 1/1000 patients; rare events are those occurring in fewer than 1/1000 patients.

Body as a Whole: Frequent: Allergic reaction,  pain, chills, cyst, neck pain, and malaise. Infrequent: Abscess, cellulitis, facial edema, halitosis, hernia, neck rigidity, neoplasm, pelvic pain, photosensitivity reaction, sepsis, sudden death, and suicide attempt.

Cardiovascular System: Frequent: Hypertension, palpitation, syncope, and tachycardia. Infrequent: Angina pectoris, cerebral ischemia, electrocardiogram abnormal, hemorrhage, hypotension, myocardial infarct, pallor, peripheral vascular disorder, phlebitis, postural hypotension, and thrombophlebitis.

Digestive System: Frequent: Gingivitis and stomatitis. Infrequent: Abnormal stools, cholecystitis, cholelithiasis, dysphagia, eructation, esophagitis, fecal incontinence, gastritis, gastrointestinal hemorrhage, glossitis, gum hyperplasia, hepatomegaly, increased salivation, liver function tests abnormal, melena, periodontal abscess, rectal hemorrhage, thirst, tooth caries, and ulcerative stomatitis.

Endocrine System: Infrequent: Goiter and hypothyroidism.

Hemic and Lymphatic System: Frequent: Lymphadenopathy. Infrequent: Anemia, erythrocytes abnormal, leukopenia, petechia, and thrombocytopenia.

Metabolic and Nutritional: Frequent: Edema, peripheral edema, weight gain, and weight loss. Infrequent: Dehydration, hypercholesteremia, hyperglycemia, hyperlipemia, hypoglycemia, hypokalemia, and hyponatremia.

Musculoskeletal System: Frequent: Arthralgia. Infrequent: Arthritis, arthrosis, bursitis, generalized spasm, and tendinous contracture.

Nervous System: Frequent: Depersonalization, dysarthria, euphoria, hallucination, hyperkinesia, hypertonia, hypesthesia, hypokinesia, hypotonia, migraine, myoclonus, paranoid reaction, personality disorder, reflexes decreased, stupor, twitching, and vertigo. Infrequent: Abnormal dreams, apathy, choreoathetosis, circumoral paresthesia, CNS neoplasm, coma, delusions, dry mouth, dystonia, encephalopathy, hemiplegia, leg cramps, libido increased, libido decreased, movement disorder, neuritis, neurosis, paralysis, peripheral neuritis, psychosis, reflexes increased, and urinary retention.

Respiratory System: Frequent: Bronchitis, dyspnea, epistaxis, and pneumonia. Infrequent: Apnea, asthma, hemoptysis, hiccups, hyperventilation, laryngitis, respiratory disorder, and voice alteration.

Skin and Appendages: Frequent: Alopecia, dry skin, and sweating. Infrequent: Contact dermatitis, eczema, exfoliative dermatitis, furunculosis, herpes simplex, herpes zoster, hirsutism, maculopapular rash, psoriasis, skin benign neoplasm, skin carcinoma, skin discolorations, skin nodules, skin ulcer, subcutaneous nodule, urticaria, and vesiculobullous rash.

Special Senses: Frequent: Abnormal vision, ear pain, otitis media, and tinnitus. Infrequent: Blepharitis, blindness, deafness, eye pain, hyperacusis, keratoconjunctivitis, otitis externa, parosmia, photophobia, taste loss, taste perversion, and visual field defect.

Urogenital System: Frequent: Dysmenorrhea, dysuria, metrorrhagia, urinary incontinence, and vaginitis. Infrequent: Abortion, amenorrhea, breast enlargement, breast pain, cystitis, fibrocystic breast, hematuria, impotence, kidney failure, menorrhagia, nocturia, papanicolaou smear suspicious, polyuria, pyelonephritis, salpingitis, urethritis, urinary urgency, and vaginal hemorrhage.

Drug Abuse And Dependence

The abuse and dependence potential of GABITRIL (tiagabine hydrochloride) have not been evaluated in human studies.

Read the Gabitril (tiagabine hydrochloride) Side Effects Center for a complete guide to possible side effects

Interactions

In evaluating the potential for interactions among co-administered antiepilepsy drugs (AEDs), whether or not an AED induces or does not induce metabolic enzymes is an important consideration. Carbamazepine, phenytoin, primidone, and phenobarbital are generally classified as enzyme inducers; valproate and gabapentin are not. GABITRIL (tiagabine hydrochloride) is considered to be a non-enzyme inducing AED (see PRECAUTIONS, General, Use in Non-Induced Patients).

The drug interaction data described in this section were obtained from studies involving either healthy subjects or patients with epilepsy.

Effects of GABITRIL (tiagabine hydrochloride) on other Antiepilepsy Drugs (AEDs)

Phenvtoin: Tiagabine had no effect on the steady-state plasma concentrations of phenytoin in patients with epilepsy.

Carbamazepine: Tiagabine had no effect on the steady-state plasma concentrations of carbamazepine or its epoxide metabolite in patients with epilepsy.

Valproate: Tiagabine causes a slight decrease (about 10%) in steady-state valproate concentrations.

Phenobarbital or Primidone: No formal pharmacokinetic studies have been performed examining the addition of tiagabine to regimens containing phenobarbital or primidone. The addition of tiagabine in a limited number of patients in three well-controlled studies caused no systematic changes in phenobarbital or primidone concentrations when compared to placebo.

Effects of other Antiepilepsy Drugs (AEDs) on GABITRIL (tiagabine hydrochloride)

Carbamazepine: Population pharmacokinetic analyses indicate that tiagabine clearance is 60% greater in patients taking carbamazepine with or without other enzyme-inducing AEDs.

Phenytoin: Population pharmacokinetic analyses indicate that tiagabine clearance is 60% greater in patients taking phenytoin with or without other enzyme-inducing AEDs.

Phenobarbital (Primidone): Population pharmacokinetic analyses indicate that tiagabine clearance is 60% greater in patients taking phenobarbital (primidone) with or without other enzyme-inducing AEDs.

Valproate: The addition of tiagabine to patients taking valproate chronically had no effect on tiagabine pharmacokinetics, but valproate significantly decreased tiagabine binding in vitro from 96.3 to 94.8%, which resulted in an increase of approximately 40% in the free tiagabine concentration. The clinical relevance of this in vitro finding is unknown.

Interaction of GABITRIL (tiagabine hydrochloride) with Other Drugs

Cimetidine: Co-administration of cimetidine (800 mg/day) to patients taking tiagabine chronically had no effect on tiagabine pharmacokinetics.

Theophylline: A single 10 mg dose of tiagabine did not affect the pharmacokinetics of theophylline at steady state.

Warfarin: No significant differences were observed in the steady-state pharmacokinetics of R-warfarin or S-warfarin with the addition of tiagabine given as a single dose. Prothrombin times were not affected by tiagabine.

Digoxin: Concomitant administration of tiagabine did not affect the steady-state pharmacokinetics of digoxin or the mean daily trough serum level of digoxin.

Ethanol or Triazolam: No significant differences were observed in the pharmacokinetics of triazolam (0.125 mg) and tiagabine (10 mg) when given together as a single dose. The pharmacokinetics of ethanol were not affected by multiple-dose administration of tiagabine. Tiagabine has shown no clinically important potentiation of the pharmacodynamic effects of triazolam or alcohol. Because of the possible additive effects of drugs that may depress the nervous system, ethanol or triazolam should be used cautiously in combination with tiagabine.

Oral Contraceptives: Multiple dose administration of tiagabine (8 mg/day monotherapy) did not alter the pharmacokinetics of oral contraceptives in healthy women of child-bearing age.

Antipyrine: Antipyrine pharmacokinetics were not significantly different before and after tiagabine multiple-dose regimens. This indicates that tiagabine does not cause induction or inhibition of the hepatic microsomal enzyme systems responsible for the metabolism of antipyrine.

Interaction of GABITRIL (tiagabine hydrochloride) with Highly Protein Bound Drugs:

In vitro data showed that tiagabine is 96% bound to human plasma protein and therefore has the potential to interact with other highly protein bound compounds. Such an interaction can potentially lead to higher free fractions of either tiagabine or the competing drug.

Read the Gabitril Drug Interactions Center for a complete guide to possible interactions

Learn More »


This monograph has been modified to include the generic and brand name in many instances.

Warnings

Seizures in Patients Without Epilepsy

Post-marketing reports have shown that GABITRIL (tiagabine hydrochloride) use has been associated with new onset seizures and status epilepticus in patients without epilepsy. Dose may be an important predisposing factor in the development of seizures, although seizures have been reported in patients taking daily doses of GABITRIL (tiagabine hydrochloride) as low as 4 mg/day. In most cases, patients were using concomitant medications (antidepressants, antipsychotics, stimulants, narcotics) that are thought to lower the seizure threshold. Some seizures occurred near the time of a dose increase, even after periods of prior stable dosing.

The GABITRIL (tiagabine hydrochloride) dosing recommendations in current labeling for treatment of epilepsy were based on use in patients with partial seizures 12 years of age and older, most of whom were taking enzyme-inducing antiepileptic drugs (AEDs; e.g., carbamazepine, phenytoin, primidone and phenobarbital) which lower plasma levels of GABITRIL (tiagabine hydrochloride) by inducing its metabolism. Use of GABITRIL (tiagabine hydrochloride) without enzyme-inducing antiepileptic drugs results in blood levels about twice those attained in the studies on which current dosing recommendations are based (see DOSAGE AND ADMINISTRATION).

Safety and effectiveness of GABITRIL (tiagabine hydrochloride) have not been established for any indication other than as adjunctive therapy for partial seizures in adults and children 12 years and older.

In nonepileptic patients who develop seizures while on GABITRIL (tiagabine hydrochloride) treatment, GABITRIL (tiagabine hydrochloride) should be discontinued and patients should be evaluated for an underlying seizure disorder.

Seizures and status epilepticus are known to occur with GABITRIL overdosage (see OVERDOSAGE).

Suicidal Behavior and Ideation

Antiepileptic drugs (AEDs), including GABITRIL (tiagabine hydrochloride) , increase the risk of suicidal thoughts or behavior in patients taking these drugs for any indication. Patients treated with any AED for any indication should be monitored for the emergence or worsening of depression, suicidal thoughts or behavior, and/or any unusual changes in mood or behavior.

Pooled analyses of 199 placebo-controlled clinical trials (mono- and adjunctive therapy) of 11 different AEDs showed that patients randomized to one of the AEDs had approximately twice the risk (adjusted Relative Risk 1.8, 95% CI:1.2, 2.7) of suicidal thinking or behavior compared to patients randomized to placebo. In these trials, which had a median treatment duration of 12 weeks, the estimated incidence rate of suicidal behavior or ideation among 27,863 AED-treated patients was 0.43%, compared to 0.24% among 16,029 placebo-treated patients, representing an increase of approximately one case of suicidal thinking or behavior for every 530 patients treated. There were four suicides in drug-treated patients in the trials and none in placebo-treated patients, but the number is too small to allow any conclusion about drug effect on suicide.

The increased risk of suicidal thoughts or behavior with AEDs was observed as early as one week after starting drug treatment with AEDs and persisted for the duration of treatment assessed. Because most trials included in the analysis did not extend beyond 24 weeks, the risk of suicidal thoughts or behavior beyond 24 weeks could not be assessed.

The risk of suicidal thoughts or behavior was generally consistent among drugs in the data analyzed. The finding of increased risk with AEDs of varying mechanisms of action and across a range of indications suggests that the risk applies to all AEDs used for any indication. The risk did not vary substantially by age (5-100 years) in the clinical trials analyzed.

Table 4 shows absolute and relative risk by indication for all evaluated AEDs.

Table 4: Risk by Indication for Anticpilcptic Drugs in the Pooled Analysis

Indication Placebo Patients with Events per 1000 Patients Drug Patients with Events per 1000 Patients Relative Risk: Incidence of Events in Drug Patients/Incidence in Placebo Patients Risk Difference: Additional Drug Patients with Events per 1000 Patients
Epilepsy 1.0 3.4 3.5 2.4
Psychiatric 5.7 8.5 1.5 2.9
Other 1.0 1.8 1.9 0.9
Total 2.4 4.3 1.8 1.9

The relative risk for suicidal thoughts or behavior was higher in clinical trials for epilepsy than in clinical trials for psychiatric or other conditions, but the absolute risk differences were similar for the epilepsy and psychiatric indications.

Anyone considering prescribing GABITRIL (tiagabine hydrochloride) or any other AED must balance the risk of suicidal thoughts or behavior with the risk of untreated illness. Epilepsy and many other illnesses for which AEDs are prescribed are themselves associated with morbidity and mortality and an increased risk of suicidal thoughts and behavior. Should suicidal thoughts and behavior emerge during treatment, the prescriber needs to consider whether the emergence of these symptoms in any given patient may be related to the illness being treated.

Patients, their caregivers, and families should be informed that AEDs increase the risk of suicidal thoughts and behavior and should be advised of the need to be alert for the emergence or worsening of the signs and symptoms of depression, any unusual changes in mood or behavior, or the emergence of suicidal thoughts, behavior, or thoughts about self-harm. Behaviors of concern should be reported immediately to healthcare providers.

Withdrawal Seizures

As a rule, antiepilepsy drugs should not be abruptly discontinued because of the possibility of increasing seizure frequency. In a placebo-controlled, double-blind, dose-response study (Study 1 described in Clinical Studies) designed, in part, to investigate the capacity of GABITRIL (tiagabine hydrochloride) to induce withdrawal seizures, study drug was tapered over a 4-week period after 16 weeks of treatment. Patients' seizure frequency during this 4-week withdrawal period was compared to their baseline seizure frequency (before study drug). For each partial seizure type, for all partial seizure types combined, and for secondarily generalized tonic-clonic seizures, more patients experienced increases in their seizure frequencies during the withdrawal period in the three GABITRIL (tiagabine hydrochloride) groups than in the placebo group. The increase in seizure frequency was not affected by dose. GABITRIL (tiagabine hydrochloride) should be withdrawn gradually to minimize the potential of increased seizure frequency, unless safety concerns require a more rapid withdrawal.

Cognitive/Neuropsychiatric Adverse Events

Adverse events most often associated with the use of GABITRIL (tiagabine hydrochloride) were related to the central nervous system. The most significant of these can be classified into 2 general categories: 1) impaired concentration, speech or language problems, and confusion (effects on thought processes); and 2) somnolence and fatigue (effects on level of consciousness). The majority of these events were mild to moderate. In controlled clinical trials, these events led to discontinuation of treatment with GABITRIL (tiagabine hydrochloride) in 6% (31 of 494) of patients compared to 2% (5 of 275) of the placebo-treated patients. A total of 1.6% (8 of 494) of the GABITRIL (tiagabine hydrochloride) treated patients in the controlled trials were hospitalized secondary to the occurrence of these events compared to 0% of the placebo treated patients. Some of these events were dose related and usually began during initial titration.

Patients with a history of spike and wave discharges on EEG have been reported to have exacerbations of their EEG abnormalities associated with these cognitive/neuropsychiatric events. This raises the possibility that these clinical events may, in some cases, be a manifestation of underlying seizure activity (see PRECAUTIONS, Laboratory Tests, EEG). In the documented cases of spike and wave discharges on EEG with cognitive/neuropsychiatric events, patients usually continued tiagabine, but required dosage adjustment.

Additionally, there have been postmarketing reports of patients who have experienced cognitive/neuropsychiatric symptoms, some accompanied by EEG abnormalities such as generalized spike and wave activity, that have been reported as nonconvulsant status epilepticus. Some reports describe recovery following reduction of dose or discontinuation of GABITRIL (tiagabine hydrochloride) .

Status Epilepticus

In the three double-blind, placebo-controlled, parallel-group studies (Studies 1, 2, and 3), the incidence of any type of status epilepticus (simple, complex, or generalized tonic-clonic) in patients receiving GABITRIL (tiagabine hydrochloride) was 0.8% (4 of 494 patients) versus 0.7% (2 of 275 patients) receiving placebo. Among the patients treated with GABITRIL (tiagabine hydrochloride) across all epilepsy studies (controlled and uncontrolled), 5% had some form of status epilepticus. Of the 5%, 57% of patients experienced complex partial status epilepticus. A critical risk factor for status epilepticus was the presence of a previous history; 33% of patients with a history of status epilepticus had recurrence during GABITRIL (tiagabine hydrochloride) treatment. Because adequate information about the incidence of status epilepticus in a similar population of patients with epilepsy who have not received treatment with GABITRIL (tiagabine hydrochloride) is not available, it is impossible to state whether or not treatment with GABITRIL (tiagabine hydrochloride) is associated with a higher or lower rate of status epilepticus than would be expected to occur in a similar population not treated with GABITRIL (tiagabine hydrochloride) .

Sudden Unexpected Death In Epilepsy (SUDEP)

There have been as many as 10 cases of sudden unexpected deaths during the clinical development of tiagabine among 2531 patients with epilepsy (3831 patient-years of exposure).

This represents an estimated incidence of 0.0026 deaths per patient-year. This rate is within the range of estimates for the incidence of sudden and unexpected deaths in patients with epilepsy not receiving GABITRIL (tiagabine hydrochloride) (ranging from 0.0005 for the general population with epilepsy, 0.003 to 0.004 for clinical trial populations similar to that in the clinical development program for GABITRIL (tiagabine hydrochloride) , to 0.005 for patients with refractory epilepsy). The estimated SUDEP rates in patients receiving GABITRIL (tiagabine hydrochloride) are also similar to those observed in patients receiving other antiepilepsy drugs, chemically unrelated to GABITRIL (tiagabine hydrochloride) , that underwent clinical testing in similar populations at about the same time. This evidence suggests that the SUDEP rates reflect population rates, not a drug effect.

Precautions

General

Use in Non-Induced Patients: Virtually all experience with GABITRIL (tiagabine hydrochloride) has been obtained in patients with epilepsy receiving at least one concomitant enzyme-inducing antiepilepsy drug (AED), which lowers the plasma levels of tiagabine. Use in non-induced patients requires lower doses of GABITRIL (tiagabine hydrochloride) . These patients may also require a slower titration of GABITRIL compared to that of induced patients (see DOSAGE AND ADMINISTRATION). Patients taking a combination of inducing and non-inducing agents (e.g., carbamazepine and valproate) should be considered to be induced. Patients not receiving hepatic enzyme-inducing agents are referred to as non-induced patients.

Generalized Weakness: Moderately severe to incapacitating generalized weakness has been reported following administration of GABITRIL (tiagabine hydrochloride) in 28 of 2531 (approximately 1%) patients with epilepsy. The weakness resolved in all cases after a reduction in dose or discontinuation of GABITRIL (tiagabine hydrochloride) .

Binding in the Eye and Other Melanin-Containing Tissues: When dogs received a single dose of radiolabeled tiagabine, there was evidence of residual binding in the retina and uvea after 3 weeks (the latest time point measured). Although not directly measured, melanin binding is suggested. The ability of available tests to detect potentially adverse consequences, if any, of the binding of tiagabine to melanin-containing tissue is unknown and there was no systematic monitoring for relevant ophthalmological changes during the clinical development of GABITRIL (tiagabine hydrochloride) . However, long term (up to one year) toxicological studies of tiagabine in dogs showed no treatment-related ophthalmoscopic changes and macro- and microscopic examinations of the eye were unremarkable. Accordingly, although there are no specific recommendations for periodic ophthalmologic monitoring, prescribers should be aware of the possibility of long-term ophthalmologic effects.

Use in Hepatically-Impaired Patients: Because the clearance of tiagabine is reduced in patients with liver disease, dosage reduction may be necessary in these patients.

Serious Rash: Four patients treated with tiagabine during the product's premarketing clinical testing developed what were considered to be serious rashes. In two patients, the rash was described as maculopapular; in one it was described as vesiculobullous; and in the 4th case, a diagnosis of Stevens Johnson Syndrome was made. In none of the 4 cases is it certain that tiagabine was the primary, or even a contributory, cause of the rash. Nevertheless, drug associated rash can, if extensive and serious, cause irreversible morbidity, even death.

Information for Patients

Patients should be informed of the availability of a Medication Guide, and they should be instructed to read it prior to taking GABITRIL. The complete text of the Medication Guide is provided at the end of this labeling.

Suicidal Thinking and Behavior

Patients, their caregivers, and families should be counseled that AEDs, including GABITRIL (tiagabine hydrochloride) , may increase the risk of suicidal thoughts and behavior and should be advised 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. Behaviors of concern should be reported immediately to healthcare providers.

Patients should be advised that GABITRIL (tiagabine hydrochloride) may cause dizziness, somnolence, and other symptoms and signs of CNS depression. Accordingly, patients should be advised neither to drive nor to operate other complex machinery until they have gained sufficient experience on GABITRIL (tiagabine hydrochloride) to gauge whether or not it affects their mental and/or motor performance adversely. Because of the possible additive depressive effects, caution should also be used when patients are taking other CNS depressants in combination with GABITRIL (tiagabine hydrochloride) .

Because teratogenic effects were seen in the offspring of rats exposed to maternally toxic doses of tiagabine and because experience in humans is limited, patients should be advised to notify their physicians if they become pregnant or intend to become pregnant during therapy.

Because of the possibility that tiagabine may be excreted in breast milk, patients should be advised to notify those providing care to themselves and their children if they intend to breastfeed or are breast-feeding an infant.

Patients should be encouraged to enroll in the North American Antiepileptic Drug (NAAED) Pregnancy Registry if they become pregnant. This registry is collecting information about the safety of antiepileptic drugs during pregnancy. To enroll, patients can call the toll free number 1-888-233-2334 (see PRECAUTIONS, Pregnancy).

Laboratory Tests

Therapeutic Monitoring of Plasma Concentrations of Tiagabine: A therapeutic range for tiagabine plasma concentrations has not been established. In controlled trials, trough plasma concentrations observed among patients randomized to doses of tiagabine that were statistically significantly more effective than placebo ranged from < 1 ng/mL to 234 ng/mL (median, 10th and 90th percentiles are 23.7 ng/mL, 5.4 ng/mL, and 69.8 ng/mL, respectively). Because of the potential for pharmacokinetic interactions between GABITRIL (tiagabine hydrochloride) 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.

Clinical Chemistry and Hematology: During the development of GABITRIL (tiagabine hydrochloride) , no systematic abnormalities on routine laboratory testing were noted. Therefore, no specific guidance is offered regarding routine monitoring; the practitioner retains responsibility for determining how best to monitor the patient in his/her care.

EEG: 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. This raises the possibility that these clinical events may, in some cases, be a manifestation of underlying seizure activity (see WARNINGS, Cognitive/Neuropsychiatric Adverse Events). In the documented cases of spike and wave discharges on EEG with cognitive/neuropsychiatric events, patients usually continued tiagabine, but required dosage adjustment.

Carcinogenesis, Mutagenesis, Impairment of Fertility

Carcinogenesis: In rats, a study of the potential carcinogenicity associated with tiagabine HC1 administration showed that 200 mg/kg/day (plasma exposure [AUC] 36 to 100 times that at the maximum recommended human dosage [MRHD] of 56 mg/day) for 2 years resulted in small, but statistically significant increases in the incidences of hepatocellular adenomas in females and Leydig cell tumors of the testis in males. The significance of these findings relative to the use of GABITRIL (tiagabine hydrochloride) in humans is unknown. The no effect dosage for induction of tumors in this study was 100 mg/kg/day (17 to 50 times the exposure at the MRHD). No statistically significant increases in tumor formation were noted in mice at dosages up to 250 mg/kg/day (20 times the MRHD on a mg/m2 basis).

Mutagenesis: Tiagabine produced an increase in structural chromosome aberration frequency in human lymphocytes in vitro in the absence of metabolic activation. No increase in chromosomal aberration frequencies was demonstrated in this assay in the presence of metabolic activation. 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.

Impairment of Fertility: Studies of male and female rats administered dosages of tiagabine HC1 prior to and during mating, gestation, and lactation have shown no impairment of fertility at doses up to 100 mg/kg/day. This dose represents approximately 16 times the maximum recommended human dose (MRHD) of 56 mg/day, based on body surface area (mg/m2). Lowered maternal weight gain and decreased viability and growth in the rat pups were found at 100 mg/kg, but not at 20 mg/kg/day (3 times the MRHD on a mg/m2 basis).

Pregnancy

Pregnancy Category C: 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.

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/day to pregnant rats during the period of organogenesis. This dose is approximately 16 times the maximum recommended human dose (MRHD) of 56 mg/day, based on body surface area (mg/m2). Maternal toxicity (transient weight loss/reduced maternal weight gain during gestation) was associated with this dose, but there is no evidence to suggest that the teratogenic effects were secondary to the maternal effects. No adverse maternal or embryo-fetal effects were seen at a dose of 20 mg/kg/day (3 times the MRHD on a mg/m2 basis).

Decreased maternal weight gain, increased resorption of embryos and increased incidences of fetal variations, but not malformations, were observed when pregnant rabbits were given 25 mg/kg/day (8 times the MRHD on a mg/m2 basis) during organogenesis. The no effect level for maternal and embryo-fetal toxicity in rabbits was 5 mg/kg/day (equivalent to the MRHD on a mg/m2 basis).

When female rats were given tiagabine 100 mg/kg/day during late gestation and throughout parturition and lactation, decreased maternal weight gain during gestation, an increase in stillbirths, and decreased postnatal offspring viability and growth were found. There are no adequate and well-controlled studies in pregnant women. Tiagabine should be used during pregnancy only if clearly needed.

To provide additional information regarding the effects of in utero exposure to GABITRIL (tiagabine hydrochloride) , physicians are advised to recommend that pregnant patients taking GABITRIL (tiagabine hydrochloride) enroll in the NAAED Pregnancy Registry. This can be done by calling the toll free number 1-888-233-2334, and must be done by patients themselves. Information on the registry can also be found at the website http://www. aedpregnancvregistry. org/.

Use in Nursing Mothers

Studies in rats have shown that tiagabine HC1 and/or its metabolites are excreted in the milk of that species. Levels of excretion of tiagabine and/or its metabolites in human milk have not been determined and effects on the nursing infant are unknown. GABITRIL (tiagabine hydrochloride) should be used in women who are nursing only if the benefits clearly outweigh the risks.

Pediatric Use

Safety and effectiveness in pediatric patients below the age of 12 have not been established. The pharmacokinetics of tiagabine were evaluated in pediatric patients age 3 to 10 years (see CLINICAL PHARMACOLOGY, Special Populations, Pediatric).

Geriatric Use

Because few patients over the age of 65 (approximately 20) were exposed to GABITRIL (tiagabine hydrochloride) during its clinical evaluation, no specific statements about the safety or effectiveness of GABITRIL (tiagabine hydrochloride) in this age group could be made.


This monograph has been modified to include the generic and brand name in many instances.

OverDose

Human Overdose Experience

Human experience of acute overdose with GABITRIL (tiagabine hydrochloride) is limited. Eleven patients in clinical trials took single doses of GABITRIL (tiagabine hydrochloride) up to 800 mg. All patients fully recovered, usually within one day. The most common symptoms reported after overdose included somnolence, impaired consciousness, agitation, confusion, speech difficulty, hostility, depression, weakness, and myoclonus. One patient who ingested a single dose of 400 mg experienced generalized tonic-clonic status epilepticus, which responded to intravenous phenobarbital.

From post-marketing experience, there have been no reports of fatal overdoses involving GABITRIL (tiagabine hydrochloride) alone (doses up to 720 mg), although a number of patients required intubation and ventilatory support as part of the management of their status epilepticus. Overdoses involving multiple drugs, including GABITRIL (tiagabine hydrochloride) , have resulted in fatal outcomes. Symptoms most often accompanying GABITRIL (tiagabine hydrochloride) overdose, alone or in combination with other drugs, have included: seizures including status epilepticus in patients with and without underlying seizure disorders, nonconvulsive status epilepticus, coma, ataxia, confusion, somnolence, drowsiness, impaired speech, agitation, lethargy, myoclonus, spike wave stupor, tremors, disorientation, vomiting, hostility, and temporary paralysis. Respiratory depression was seen in a number of patients, including children, in the context of seizures.

Management of Overdose

There is no specific antidote for overdose with GABITRIL (tiagabine hydrochloride) . If indicated, elimination of unabsorbed drug should be achieved by emesis or gastric lavage; usual precautions should be observed to maintain the airway. General supportive care of the patient is indicated including monitoring of vital signs and observation of clinical status of the patient. Since tiagabine is mostly metabolized by the liver and is highly protein bound, dialysis is unlikely to be beneficial. A Certified Poison Control Center should be consulted for up to date information on the management of overdose with GABITRIL (tiagabine hydrochloride) .

ContrainDications

GABITRIL (tiagabine hydrochloride) is contraindicated in patients who have demonstrated hypersensitivity to the drug or its ingredients.


This monograph has been modified to include the generic and brand name in many instances.

Clinical Pharamacology

Mechanism of Action

The precise mechanism by which tiagabine exerts its antiseizure effect is unknown, although it is believed to be related to its ability, documented in in vitro experiments, to enhance the activity of gamma aminobutyric acid (GABA), the major inhibitory neurotransmitter in the central nervous system. These experiments have shown that tiagabine binds to recognition sites associated with the GABA uptake carrier. It is thought that, by this action, tiagabine blocks GABA uptake into presynaptic neurons, permitting more GABA to be available for receptor binding on the surfaces of post-synaptic cells. Inhibition of GABA uptake has been shown for synaptosomes, neuronal cell cultures, and glial cell cultures. In rat-derived hippocampal slices, tiagabine has been shown to prolong GABA-mediated inhibitory post-synaptic potentials. Tiagabine increases the amount of GABA available in the extracellular space of the globus pallidus, ventral palladum, and substantia nigra in rats at the ED50 and ED85 doses for inhibition of pentylenetetrazol (PTZ)- induced tonic seizures. This suggests that tiagabine prevents the propagation of neural impulses that contribute to seizures by a GABA-ergic action.

Tiagabine has shown efficacy in several animal models of seizures. It is effective against the tonic phase of subcutaneous PTZ-induced seizures in mice and rats, seizures induced by the proconvulsant DMCM in mice, audiogenic seizures in genetically epilepsy-prone rats (GEPR), and amygdala-kindled seizures in rats. Tiagabine has little efficacy against maximal electroshock seizures in rats and is only partially effective against subcutaneous PTZ-induced clonic seizures in mice, picrotoxin-induced tonic seizures in the mouse, bicuculline-induced seizures in the rat, and photic seizures in photosensitive baboons. Tiagabine produces a biphasic dose-response curve against PTZ- and DMCM-induced convulsions, with attenuated effectiveness at higher doses.

Based on in vitro binding studies, tiagabine does not significantly inhibit the uptake of dopamine, norepinephrine, serotonin, glutamate, or choline and shows little or no binding to dopamine Dl and D2, muscarinic, serotonin 5HT1A,5HT2, and 5HT3, beta-1 and 2 adrenergic, alpha-1 and alpha-2 adrenergic, histamine H2 and H3, adenosine A1 and A2, opiate µ and K1, NMDA glutamate, and GABAA receptors at 100 µM. It also lacks significant affinity for sodium or calcium channels. Tiagabine binds to histamine H1, serotonin 5HT1B, benzodiazepine, and chloride channel receptors at concentrations 20 to 400 times those inhibiting the uptake of GABA.

Pharmacokinctics

Tiagabine is well absorbed, with food slowing absorption rate but not altering the extent of absorption. The elimination half-life of tiagabine is 7 to 9 hours in normal volunteers. In epilepsy clinical trials, most patients were receiving hepatic enzyme-inducing agents (e.g., carbamazepine, phenytoin, primidone, and phenobarbital). The pharmacokinetic profile in induced patients is significantly different from the non-induced population (see PRECAUTIONS, General, Use in Non-Induced Patients). The systemic clearance of tiagabine in induced patients is approximately 60% greater resulting in considerably lower plasma concentrations and an elimination half-life of 2 to 5 hours. Given this difference in clearance, the systemic exposure after a dose of 32 mg/day in an induced population is expected to be comparable to the systemic exposure after a dose of 12 mg/day in a non-induced population. Similarly, the systemic exposure after a dose of 56 mg/day in an induced population is expected to be comparable to the systemic exposure after a dose of 22 mg/day in a non-induced population.

Absorption and Distribution: Absorption of tiagabine is rapid, with peak plasma concentrations occurring at approximately 45 minutes following an oral dose in the fasting state. Tiagabine is nearly completely absorbed ( > 95%), with an absolute oral bioavailability of about 90%. A high fat meal decreases the rate (mean Tmax was prolonged to 2.5 hours, and mean Cmax was reduced by about 40%) but not the extent (AUC) of tiagabine absorption. In all clinical trials, tiagabine was given with meals.

The pharmacokinetics of tiagabine are linear over the single dose range of 2 to 24 mg. Following multiple dosing, steady state is achieved within 2 days.

Tiagabine is 96% bound to human plasma proteins, mainly to serum albumin and al-acid glycoprotein over the concentration range of 10 ng/mL to 10,000 ng/mL. While the relationship between tiagabine plasma concentrations and clinical response is not currently understood, trough plasma concentrations observed in controlled clinical trials at doses from 30 to 56 mg/day ranged from < 1 ng/mL to 234 ng/mL.

Metabolism and Elimination: Although the metabolism of tiagabine has not been fully elucidated, in vivo and in vitro studies suggest that at least two metabolic pathways for tiagabine have been identified in humans: 1) thiophene ring oxidation leading to the formation of 5-oxo-tiagabine; and 2) glucuronidation. The 5-oxo-tiagabine metabolite does not contribute to the pharmacologic activity of tiagabine.

Based on in vitro data, tiagabine is likely to be metabolized primarily by the 3 A isoform subfamily of hepatic cytochrome P450 (CYP 3 A), although contributions to the metabolism of tiagabine from CYP 1A2, CYP 2D6 or CYP 2C19 have not been excluded.

Approximately 2% of an oral dose of tiagabine is excreted unchanged, with 25% and 63% of the remaining dose excreted into the urine and feces, respectively, primarily as metabolites, at least 2 of which have not been identified. The mean systemic plasma clearance is 109 mL/min (CV = 23%) and the average elimination half-life for tiagabine in healthy subjects ranged from 7 to 9 hours. The elimination half-life decreased by 50 to 65% in hepatic enzyme-induced patients with epilepsy compared to uninduced patients with epilepsy.

A diurnal effect on the pharmacokinetics of tiagabine was observed. Mean steady-state Cmin values were 40% lower in the evening than in the morning. Tiagabine steady-state AUC values were also found to be 15% lower following the evening tiagabine dose compared to the AUC following the morning dose.

Special Populations

Renal Insufficiency: The pharmacokinetics of total and unbound tiagabine were similar in subjects with normal renal function (creatinine clearance > 80 mL/min) and in subjects with mild (creatinine clearance 40 to 80 mL/min), moderate (creatinine clearance 20 to 39 mL/min), or severe (creatinine clearance 5 to 19 mL/min) renal impairment. The pharmacokinetics of total and unbound tiagabine were also unaffected in subjects with renal failure requiring hemodialysis.

Hepatic Insufficiency: In patients with moderate hepatic impairment (Child-Pugh Class B), clearance of unbound tiagabine was reduced by about 60%. Patients with impaired liver function may require reduced initial and maintenance doses of tiagabine and/or longer dosing intervals compared to patients with normal hepatic function (see PRECAUTIONS).

Geriatric: The pharmacokinetic profile of tiagabine was similar in healthy elderly and healthy young adults.

Pediatric: Tiagabine has not been investigated in adequate and well-controlled clinical trials in patients below the age of 12. The apparent clearance and volume of distribution of tiagabine per unit body surface area or per kg were fairly similar in 25 children (age: 3 to 10 years) and in adults taking enzyme-inducing antiepilepsy drugs ([AEDs] e.g., carbamazepine or phenytoin). In children who were taking a non-inducing AED (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 non-induced adults with epilepsy.

Gender, Race and Cigarette Smoking: No specific pharmacokinetic studies were conducted to investigate the effect of gender, race and cigarette smoking on the disposition of tiagabine. Retrospective pharmacokinetic analyses, however, suggest that there is no clinically important difference between the clearance of tiagabine in males and females, when adjusted for body weight. Population pharmacokinetic analyses indicated that tiagabine clearance values were not significantly different in Caucasian (N=463), Black (N=23), or Hispanic (N=17) patients with epilepsy, and that tiagabine clearance values were not significantly affected by tobacco use.

Interactions with other Antiepilepsy Drugs: The clearance of tiagabine is affected by the co-administration of hepatic enzyme-inducing antiepilepsy drugs. Tiagabine is eliminated more rapidly in patients who have been taking hepatic enzyme-inducing drugs, e.g., carbamazepine, phenytoin, primidone and phenobarbital than in patients not receiving such treatment (see PRECAUTIONS: DRUG INTERACTIONS).

Interactions with Other Drugs: See PRECAUTIONS: DRUG INTERACTIONS.

Clinical Studies

The effectiveness of GABITRIL (tiagabine hydrochloride) as adjunctive therapy (added to other antiepilepsy drugs) was examined in three multi-center, double-blind, placebo-controlled, parallel-group, clinical trials in 769 patients with refractory partial seizures who were taking at least one hepatic enzyme-inducing antiepilepsy drug (AED), and two placebo-controlled cross-over studies in 90 patients. In the parallel-group trials, patients had a history of at least six complex partial seizures (Study 1 and Study 2, U.S. studies), or six partial seizures of any type (Study 3, European study), occurring alone or in combination with any other seizure type within the 8-week period preceding the first study visit in spite of receiving one or more AEDs at therapeutic concentrations.

In the first two studies, the primary protocol-specified outcome measure was the median reduction from baseline in the 4-week complex partial seizure (CPS) rates during treatment. In the third study, the protocol-specified primary outcome measure was the proportion of patients achieving a 50% or greater reduction from baseline in the 4-week seizure rate of all partial seizures during treatment. The results given below include data for complex partial seizures and all partial seizures for the intent-to-treat population (all patients who received at least one dose of treatment and at least one seizure evaluation) in each study.

Study 1 was a double-blind, placebo-controlled, parallel-group trial comparing GABITRIL (tiagabine hydrochloride) 16 mg/day, GABITRIL (tiagabine hydrochloride) 32 mg/day, GABITRIL (tiagabine hydrochloride) 56 mg/day, and placebo. Study drug was given as a four times a day regimen. After a prospective Baseline Phase of 12 weeks, patients were randomized to one of the four treatment groups described above. The 16-week Treatment Phase consisted of a 4-week Titration Period, followed by a 12-week Fixed-Dose Period, during which concomitant AED doses were held constant. The primary outcome was assessed for the combined 32 and 56 mg/day groups compared to placebo.

Study 2 was a double-blind, placebo-controlled, parallel-group trial consisting of an 8-week Baseline Phase and a 12-week Treatment Phase, the first 4 weeks of which constituted a Titration Period and the last 8 weeks a Fixed-Dose Period. This study compared GABITRIL (tiagabine hydrochloride) 16 mg BID and 8 mg QID to placebo. The protocol-specified primary outcome measure was assessed separately for each group treated with GABITRIL (tiagabine hydrochloride) .

The following tables display the results of the analyses of these two trials.

Table 1: Median Reduction and Median Percent Reduction from Baseline in 4-Week Seizure Rates in Study 1

View Enlarged Table

Table 2: Median Reduction and Median Percent Reduction from Baseline in 4-Week Seizure Rates in Study 2

    Placebo
(N=107)
GABITRIL (tiagabine hydrochloride)
16 mg BID
(N=106)
GABITRIL (tiagabine hydrochloride)
8 mg QID
(N=104)
Complex Partial Median Reduction 0.3 1.6 1.3*
Median % Reduction† 4% 22% 15%
All Partial Median Reduction 0.5 1.6 1.3
Median % Reduction† 5% 19% 13%
* p < 0.027, necessary for statistical significance due to multiple comparisons.
† Statistical significance was not assessed for median % reduction.

Figures 1 to 4 present the proportion of patients (X-axis) whose percent reduction from baseline in the all partial seizure rate was at least as great as that indicated on the Y axis in the three placebo-controlled adjunctive studies (Studies 1, 2, and 3). A positive value on the Y axis indicates an improvement from baseline (i.e., a decrease in seizure rate), while a negative value indicates a worsening from baseline (i.e., an increase in seizure rate). Thus, in a display of this type, the curve for an effective treatment is shifted to the left of the curve for placebo.

Figure 1 indicates that the proportion of patients achieving any particular level of reduction in seizure rate was consistently higher for the combined GABITRIL (tiagabine hydrochloride) 32 mg and 56 mg groups compared to the placebo group in Study 1. For example, Figure 1 indicates that approximately 24% of patients treated with GABITRIL (tiagabine hydrochloride) experienced a 50% or greater reduction, compared to 4% in the placebo group.

Figure 1: Study 1

View Enlarged Table

Figure 2 also displays the results for Study 1, which was a dose-response study, by treatment group, without combining GABITRIL (tiagabine hydrochloride) dosage groups. Figure 2 indicates a dose-response relationship across the three GABITRIL (tiagabine hydrochloride) groups. The proportion of patients achieving any particular level of reduction in all partial seizure rates was consistently higher as the dose of GABITRIL (tiagabine hydrochloride) was increased. For example, Figure 2 indicates that approximately 4% of patients in the placebo group experienced a 50% or greater reduction in all partial seizure rate, compared to approximately 10% of the GABITRIL (tiagabine hydrochloride) 16 mg/day group, 21% of the GABITRIL (tiagabine hydrochloride) 32 mg/day group, and 30% of the GABITRIL (tiagabine hydrochloride) 56 mg/day group.

Figure 2: Study l

View Enlarged Table

Figure 3 indicates that the proportion of patients achieving any particular level of reduction in partial seizure rate was consistently greater in patients taking GABITRIL (tiagabine hydrochloride) than in those taking placebo in Study 2. (Study 2 compared placebo to GABITRIL (tiagabine hydrochloride) 32 mg/day; one of the GABITRIL (tiagabine hydrochloride) groups received 8 mg QID, while the other GABITRIL (tiagabine hydrochloride) group received 16 mg BID). For example, Figure 3 indicates that approximately 7% of patients in the placebo group experienced a 50% or greater reduction in their partial seizure rate, compared to approximately 23% of patients in the GABITRIL (tiagabine hydrochloride) 8 mg QID group and 28% of patients in the GABITRIL (tiagabine hydrochloride) 16 mg BID group.

Figure 3: Study 2

View Enlarged Table

Study 3 was a double-blind, placebo-controlled, parallel-group trial that compared GABITRIL (tiagabine hydrochloride) 10 mg TID (N=77) with placebo (N=77). In this trial, patients were followed prospectively during a 12-week Baseline Phase and then randomized to receive study drug during an 18-week Treatment Phase. During the first 6 weeks of treatment (Titration Period), patients were titrated to 30 mg/day, after which they were maintained on this dose during the 12-week Fixed-Dose Period. The protocol-specified primary outcome measure (proportion of patients who achieved at least a 50% reduction from baseline in partial seizure rate) did not reach statistical significance. However, analyses of the median reduction from baseline in 4-week partial seizure rate (the analyses presented above for Study 1 and Study 2) were performed and showed a statistically significant improvement compared to placebo in all partial and complex partial seizure rates (Table 3):

Table 3: Median Reduction and Median Percent Reduction from Baseline in 4-Week Seizure Rates in Study 3

    Placebo
(N=77)
GABITRIL (tiagabine hydrochloride)
30 mg/day
(N=77)
Complex Partial‡ Median Reduction -0.1 1.3*
Median % Reduction† -1% 14%
All Partial Median Reduction -0.5 1.1*
Median % Reduction† -7% 11%
* p < 0.05
†Statistical significance was not assessed for median % reduction.
‡N=72 and 75 for placebo and GABITRIL (tiagabine hydrochloride) , respectively.

Figure 4 indicates that the proportion of patients achieving any particular level of reduction in seizure activity was consistently higher in those taking GABITRIL (tiagabine hydrochloride) than those taking placebo in Study 3. For example, Figure 4 indicates that approximately 5% of patients in the placebo group experienced a 50% or greater reduction in their partial seizure rate compared to approximately 10% of patients in the GABITRIL (tiagabine hydrochloride) group.

Figure 4: Study 3

View Enlarged Table

The two other placebo-controlled trials that examined the effectiveness of GABITRIL (tiagabine hydrochloride) were small cross-over trials (N=46 and 44). Both trials included an open Screening Phase during which patients were titrated to an optimal dose and then treated with this dose for an additional 4 weeks. After this Open Phase, patients were randomized to one of two blinded treatment sequences (GABITRIL (tiagabine hydrochloride) followed by placebo or placebo followed by GABITRIL (tiagabine hydrochloride) ). The Double-Blind Phase consisted of two Treatment Periods, each lasting 7 weeks (with a 3 week washout between periods). The outcome measures were median with-in patient differences between placebo and GABITRIL (tiagabine hydrochloride) Treatment Periods in 4-week complex partial and all partial seizure rates. The reductions in seizure rates were statistically significant in both studies.

Animal Toxicology

In repeat dose toxicology studies, dogs receiving daily oral doses of 5 mg/kg/day or greater experienced unexpected CNS effects throughout the study. These effects occurred acutely and included marked sedation and apparent visual impairment which was characterized by a lack of awareness of objects, failure to fix on and follow moving objects, and absence of a blink reaction. Plasma exposures (AUCs) at 5 mg/kg/day were equal to those in humans receiving the maximum recommended daily human dose of 56 mg/day. The effects were reversible upon cessation of treatment and were not associated with any observed structural abnormality. The implications of these findings for humans are unknown.


This monograph has been modified to include the generic and brand name in many instances.

Patient Information

Medication Guide

GABITRIL®
(gab-i-tril)
(tiagabine hydrochloride) Tablets

Read this Medication Guide before you start taking GABITRIL (tiagabine hydrochloride) and each time you get a refill. There may be new information. This information does not take the place of talking to your healthcare provider about your medical condition or treatment.

What is the most important information I should know about GABITRIL (tiagabine hydrochloride) ?

Do not stop taking GABITRIL (tiagabine hydrochloride) without first talking to your healthcare provider.

Stopping GABITRIL (tiagabine hydrochloride) suddenly can cause serious problems.

GABITRIL (tiagabine hydrochloride) can cause serious side effects, including:

1. GABITRIL (tiagabine hydrochloride) may cause seizures in people who do not have epilepsy. If you do not have a seizure disorder and you take GABITRIL (tiagabine hydrochloride) , you may have a seizure or seizures that do not stop (status epilepticus). Call your healthcare provider right away if you have a seizure and you are not taking GABITRIL (tiagabine hydrochloride) for epilepsy.

2. Like other antiepileptic drugs, GABITRIL (tiagabine hydrochloride) may cause suicidal thoughts or actions in a very small number of people, about 1 in 500. Call a healthcare provider right away if you have any of these symptoms, especially if they are new, worse, or worry you:

 

  • thoughts about suicide or dying
  • attempts to commit suicide
  • new or worse depression
  • new or worse anxiety
  • feeling agitated or restless
  • panic attacks
  • trouble sleeping (insomnia)
  • new or worse irritability
  • acting aggressive, being angry, or violent
  • acting on dangerous impulses
  • an extreme increase in activity and talking (mania)
  • other unusual changes in behavior or mood

Suicidal thoughts or actions can be caused by things other than medicines. If you have suicidal thoughts or actions, your healthcare provider may check for other causes.

How can I watch for early symptoms of suicidal thoughts and actions?

  • Pay attention to any changes, especially sudden changes, in mood, behaviors, thoughts, or feelings.
  • Keep all follow-up visits with your healthcare provider as scheduled.
  • Call your healthcare provider between visits as needed, especially if you are worried about symptoms.

Do not stop GABITRIL (tiagabine hydrochloride) without first talking to a healthcare provider.

  • Stopping GABITRIL (tiagabine hydrochloride) suddenly can cause serious problems. If you have epilepsy and stop a seizure medicine suddenly, you may have more frequent seizures or seizures that will not stop (status epilepticus).

What is GABITRIL (tiagabine hydrochloride) ?

GABITRIL (tiagabine hydrochloride) is a prescription medicine used with other medicines to treat partial seizures in adults and children age 12 and older.

Who should not take GABITRIL (tiagabine hydrochloride) ?

Do not take GABITRIL if you are allergic to tiagabine hydrochloride or any of the other ingredients in GABITRIL (tiagabine hydrochloride) . See the end of this Medication Guide for a complete list of ingredients in GABITRIL (tiagabine hydrochloride) .

What should I tell my healthcare provider before taking GABITRIL (tiagabine hydrochloride) ?

Before taking GABITRIL (tiagabine hydrochloride) , tell your healthcare provider if you:

  • have or have had depression, mood problems, or suicidal thoughts or behavior
  • have liver problems
  • have a history of seizures that do not stop (status epilepticus)
  • have any other medical conditions
  • are pregnant or plan to become pregnant. It is not known if GABITRIL (tiagabine hydrochloride) can harm your unborn baby. Tell your healthcare provider right away if you become pregnant while taking GABITRIL (tiagabine hydrochloride) . You and your healthcare provider will decide if you should take GABITRIL (tiagabine hydrochloride) while you are pregnant.
    • If you become pregnant while taking GABITRIL (tiagabine hydrochloride) , talk to your healthcare provider about registering with the North American Antiepileptic Drug (NAAED) Pregnancy Registry. The purpose of this registry is to collect information about the safety of antiepileptic medicines during pregnancy. You can enroll in this registry by calling 1-888-233-2334.
  • are breastfeeding or plan to breastfeed. It is not known if GABITRIL (tiagabine hydrochloride) passes into breast milk or if it can harm your baby. Talk to your healthcare provider about the best way to feed your baby if you take GABITRIL (tiagabine hydrochloride) .

Tell your healthcare provider about all the medicines you take, including prescription and non-prescription medicines, vitamins, and herbal supplements. Taking GABITRIL (tiagabine hydrochloride) with certain other medicines can cause side effects or affect how well they work. Do not start or stop other medicines without talking to your healthcare provider.

Know the medicines you take. Keep a list of them and show it to your healthcare provider and pharmacist when you get a new medicine. Always tell your healthcare provider if there are any changes in any other medicines that you take.

How should I take GABITRIL (tiagabine hydrochloride) ?

  • Take GABITRIL (tiagabine hydrochloride) exactly as your healthcare provider tells you.
  • Your healthcare provider may change your dose.
  • GABITRIL (tiagabine hydrochloride) should be taken with food.
  • Do not stop taking GABITRIL (tiagabine hydrochloride) without talking to your healthcare provider. Stopping GABITRIL (tiagabine hydrochloride) suddenly can increase your chances of having a seizure or cause seizures that will not stop.
  • If you miss a dose of GABITRIL (tiagabine hydrochloride) , do not take 2 doses of GABITRIL (tiagabine hydrochloride) at the same time. Contact your healthcare provider if you miss more than one dose.

If you take too much GABITRIL (tiagabine hydrochloride) , call your healthcare provider or local Poison Control Center right away.

What should I avoid while taking GABITRIL (tiagabine hydrochloride) ?

  • Do not drink alcohol or take other medicines that make you sleepy or dizzy while taking GABITRIL (tiagabine hydrochloride) without first talking to your healthcare provider. Taking GABITRIL (tiagabine hydrochloride) with alcohol or drugs that cause sleepiness or dizziness may make your sleepiness or dizziness worse.
  • Do not drive, operate heavy machinery, or do other dangerous activities until you know how GABITRIL (tiagabine hydrochloride) affects you. GABITRIL (tiagabine hydrochloride) can slow your thinking and motor skills.

What are possible side effects of GABITRIL (tiagabine hydrochloride) ?

See "What is the most important information I should know about GABITRIL (tiagabine hydrochloride) ?"

GABITRIL (tiagabine hydrochloride) may cause other serious side effects including:

  • seizures that can happen more often or become worse
  • trouble concentrating, problems with speech and language, feeling confused, feeling sleepy and tired, and problems thinking
  • weakness all over your body
  • eye and vision problems
  • serious rash

Call your healthcare provider right away if you have any of the serious side effects listed above.

The most common side effects of GABITRIL (tiagabine hydrochloride) include:

  • dizziness
  • lack of energy
  • drowsiness
  • nausea
  • nervousness
  • tremor
  • stomach pain
  • abnormal thinking
  • difficulty with concentration or attention

These are not all the possible side effects of GABITRIL (tiagabine hydrochloride) . For more information, ask your healthcare provider or pharmacist. Tell your healthcare provider if you have any side effect that bothers you or that does not go away.

Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.

How should I store GABITRIL (tiagabine hydrochloride) ?

  • Store GABITRIL (tiagabine hydrochloride) between 68°F to 77°F (20°C to 25°C)
  • Keep GABITRIL (tiagabine hydrochloride) out of light
  • Keep GABITRIL (tiagabine hydrochloride) dry

Keep GABITRIL (tiagabine hydrochloride) and all medicines out of the reach of children.

General Information about GABITRIL (tiagabine hydrochloride)

Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. Do not use GABITRIL (tiagabine hydrochloride) for a condition for which it was not prescribed. Do not give GABITRIL (tiagabine hydrochloride) to other people, even if they have the same symptoms that you have. It may harm them.

This Medication Guide summarizes the most important information about GABITRIL (tiagabine hydrochloride) . If you would like more information, talk with your healthcare provider. You can ask your pharmacist or healthcare provider for information about GABITRIL (tiagabine hydrochloride) that is written for health professionals.

For more information, go to www.GABITRIL (tiagabine hydrochloride) .com or call 1-800-896-5855.

What are the ingredients in GABITRIL?

Active Ingredient: tiagabine hydrochloride

Inactive Ingredients: ascorbic acid, colloidal silicon dioxide, crospovidone, hydrogenated vegetable oil wax, hydroxypropyl cellulose, hypromellose, lactose, magnesium stearate, microcrystalline cellulose, pregelatinized starch, stearic acid and titanium dioxide.

In addition:

  • the 2 mg tablets contain FD&C Yellow No. 6
  • the 4 mg tablets contain D&C Yellow No. 10
  • the 12 mg tablets contain D&C Yellow No. 10 and FD&C Blue No. 1
  • the 16 mg tablets contain FD&C Blue No. 2


This monograph has been modified to include the generic and brand name in many instances.

Consumer Overview Uses

IMPORTANT: HOW TO USE THIS INFORMATION: This is a summary and does NOT have all possible information about this product. This information does not assure that this product is safe, effective, or appropriate for you. This information is not individual medical advice and does not substitute for the advice of your health care professional. Always ask your health care professional for complete information about this product and your specific health needs.

 

TIAGABINE - ORAL

 

(tie-GAB-een)

 

COMMON BRAND NAME(S): Gabitril

 

USES: Tiagabine is used with other medications to treat certain epileptic seizure disorders (e.g., partial seizures) which have not been controlled by other medications. Seizures occur because of problems with communication between nerves. Tiagabine is believed to affect certain natural substances (neurotransmitters) in the brain that slow down this communication. Regular use of tiagabine together with your other anti-epileptic medication should reduce the number of seizures you have.

When tiagabine has been used for conditions other than epilepsy, serious reactions (including seizures in people who have never had them) have occurred. Therefore, the manufacturer recommends this drug only for the treatment of epilepsy.

 

HOW TO USE: Read the Medication Guide provided by your pharmacist before you start taking this medication and each time you get a refill. If you have any questions, ask your doctor or pharmacist.

Take this medication by mouth with food, usually 2 to 4 times daily or as directed by your doctor. When you start this medication, your dosage will be increased slowly by your doctor to reduce side effects. Therefore, only one dose a day is usually taken during the first week. Follow your doctor's instructions exactly.

Tiagabine is not usually used by itself. Do not stop your other anti-seizure medication unless your doctor tells you to do so.

Dosage is based on your medical condition, response to therapy, and use of certain other seizure medications (see Drug Interactions section).

Use this medication regularly in order to get the most benefit from it. To help you remember, take it at the same times each day. Do not stop taking this medication without consulting your doctor. Some conditions may become worse when the drug is abruptly stopped. Your dose may need to be gradually decreased.

If you stop taking this medication for several days, you may need to increase your dose slowly back to your previous dosage. Talk with your doctor about how to restart the medication.

Inform your doctor if your condition persists or worsens after you have reached your full dose.

Consumer Overview Side Effect

SIDE EFFECTS: Inability to concentrate, dizziness, drowsiness, nervousness, irritability, tiredness, or shaking may occur. If any of these effects persist or worsen, notify your doctor or pharmacist promptly.

Remember that your doctor has prescribed this medication because he or she has judged that the benefit to you is greater than the risk of side effects. Many people using this medication do not have serious side effects.

Tell your doctor immediately if any of these unlikely but serious side effects occur: increase in seizure activity, confusion/trouble thinking clearly, difficulty forming sentences, depression, severe weakness.

A small number of people who take anticonvulsants for any condition (such as seizure, bipolar disorder, pain) may experience depression, suicidal thoughts/attempts, or other mental/mood problems. Tell your doctor immediately if you or your family/caregiver notice any unusual/sudden changes in your mood, thoughts, or behavior including signs of depression, suicidal thoughts/attempts, thoughts about harming yourself.

Seek immediate medical attention if you get a seizure that doesn't stop (status epilepticus). This is a very rare but very serious side effect.

A very serious allergic reaction to this drug is unlikely, but seek immediate medical attention if it occurs. Symptoms of a serious allergic reaction may include: rash, itching/swelling (especially of the face/tongue/throat), severe dizziness, trouble breathing.

This is not a complete list of possible side effects. If you notice other effects not listed above, contact your doctor or pharmacist.

In the US -

Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.

In Canada - Call your doctor for medical advice about side effects. You may report side effects to Health Canada at 1-866-234-2345.

 

Read the Gabitril (tiagabine hydrochloride) Side Effects Center for a complete guide to possible side effects

Learn More »

PRECAUTIONS: Before taking tiagabine, tell your doctor or pharmacist if you are allergic to it; or if you have any other allergies. This product may contain inactive ingredients, which can cause allergic reactions or other problems. Talk to your pharmacist for more details.

Before using this medication, tell your doctor or pharmacist your medical history, especially of: liver disease, depression/other mental condition, status epilepticus.

This drug may make you dizzy or drowsy. Do not drive, use machinery, or do any activity that requires alertness until you are sure you can perform such activities safely. Avoid alcoholic beverages.

Older adults may be more sensitive to the side effects of this drug, especially dizziness, or confusion. These effects can increase the risk of falling.

This medication should be used only when clearly needed during pregnancy. Discuss the risks and benefits with your doctor.

It is not known whether this drug passes into breast milk. Consult your doctor before breast-feeding.

Consumer Overview Missed Dose

DRUG INTERACTIONS: Your healthcare professionals (e.g., doctor or pharmacist) may already be aware of any possible drug interactions and may be monitoring you for it. Do not start, stop or change the dosage of any medicine before checking with them first.

Before using this medication, tell your doctor or pharmacist of all prescription and nonprescription/herbal products you may use, especially: certain anti-seizure drugs (e.g., phenytoin, carbamazepine, phenobarbital, primidone), certain recreational/street drugs such as methamphetamine ("speed") or MDMA ("ecstasy").

Certain medications increase your chances of having a seizure and may make it appear that tiagabine and your other anti-seizure medications are not working. Tell your doctor or pharmacist if you are taking other drugs which might increase seizure risk when combined with tiagabine such as isoniazid, antipsychotic medications (e.g., phenothiazines such as chlorpromazine), stimulants (e.g., methylphenidate, dextroamphetamines) or alcohol.

Tell your doctor or pharmacist if you also take drugs that cause drowsiness such as certain antihistamines (e.g., diphenhydramine), anti-anxiety drugs (e.g., diazepam), anti-seizure drugs (e.g., gabapentin, valproic acid), medicine for sleep (e.g., zolpidem, temazepam), narcotic pain relievers (e.g., codeine, fentanyl), tranquilizers, or certain antidepressants (e.g., tricyclics such as imipramine or amitriptyline).

Check the labels on all your medicines (e.g., cough-and-cold products) because they may contain drowsiness-causing ingredients. Ask your pharmacist about the safe use of those products.

This document does not contain all possible interactions. Therefore, before using this product, tell your doctor or pharmacist of all the products you use. Keep a list of all your medications with you, and share the list with your doctor and pharmacist.

 

OVERDOSE: If overdose is suspected, contact a poison control center or emergency room immediately. US residents can call their local poison control center at 1-800-222-1222. Canada residents can call a provincial poison control center. Symptoms of overdose may include uncontrolled seizures (status epilepticus), slow/shallow breathing.

 

NOTES: Do not share this medication with others.

Laboratory and/or medical tests (e.g., blood levels of tiagabine, EEG tests) may be performed to monitor your response to therapy and check for side effects.

Report any increase in the number of seizures or changes in seizure symptoms.

 

MISSED DOSE: If you miss a dose, take it as soon as you remember. If it is near the time of the next dose, skip the missed dose and resume your usual dosing schedule. Do not double the dose to catch up. If you miss taking this medication for several days, contact your doctor for instructions.

 

STORAGE: Store at room temperature between 68-77 degrees F (20-25 degrees C) away from light and moisture. Do not store in the bathroom. Keep all medicines away from children and pets.

Do not flush medications down the toilet or pour them into a drain unless instructed to do so. Properly discard this product when it is expired or no longer needed. Consult your pharmacist or local waste disposal company for more details about how to safely discard your product.

 

MEDICAL ALERT: Your condition can cause complications in a medical emergency. For information about enrolling in MedicAlert, call 1-888-633-4298 (US) or 1-800-668-1507 (Canada).

 

Information last revised October 2013. Copyright(c) 2013 First Databank, Inc.

Patient Detailed Side Effect

Brand Names: Gabitril

Generic Name: tiagabine (Pronunciation: tye AG a been)

  • What is tiagabine (Gabitril)?
  • What are the possible side effects of tiagabine (Gabitril)?
  • What is the most important information I should know about tiagabine (Gabitril)?
  • What should I discuss with my healthcare provider before taking tiagabine (Gabitril)?
  • How should I take tiagabine (Gabitril)?
  • What happens if I miss a dose (Gabitril)?
  • What happens if I overdose (Gabitril)?
  • What should I avoid while taking tiagabine (Gabitril)?
  • What other drugs will affect tiagabine (Gabitril)?
  • Where can I get more information?

What is tiagabine (Gabitril)?

Tiagabine is an anti-epileptic medication, also called an anticonvulsant.

Tiagabine is used to alone or in combination with other medications to treat partial seizures in adults and children who are at least 12 years old.

Tiagabine may also be used for purposes other than those listed in this medication guide.

Gabitril 12 mg

oval, green, imprinted with 412, C

What are the possible side effects of tiagabine (Gabitril)?

Get emergency medical help if you have any of these signs of an allergic reaction: hives; fever; swollen glands; painful sores in or around your eyes or mouth; difficulty breathing; swelling of your face, lips, tongue, or throat.

Call your doctor at once if you have any new or worsening symptoms such as: mood or behavior changes, depression, anxiety, or if you feel agitated, hostile, restless, hyperactive (mentally or physically), or have thoughts about suicide or hurting yourself.

Call your doctor at once if you have any of these serious side effects:

  • new or worsened seizures;
  • confusion, hallucination;
  • problems with speech or vision;
  • severe blistering, peeling, and red skin rash;
  • tremor;
  • fever, chills, body aches, flu symptoms; or
  • chest pain, fast heart rate.

Less serious side effects may include:

  • dizziness, drowsiness, weakness, tired feeling;
  • feeling restless, irritable, or depressed;
  • nausea, vomiting, stomach pain, diarrhea;
  • trouble concentrating;
  • sleep problems (insomnia);
  • lack of coordination;
  • cough, sore throat; or
  • weight changes.

This is not a complete list of side effects and others may occur. Tell your doctor about any unusual or bothersome side effect. You may report side effects to FDA at 1-800-FDA-1088.

Read the Gabitril (tiagabine hydrochloride) Side Effects Center for a complete guide to possible side effects

Learn More »

What is the most important information I should know about tiagabine (Gabitril)?

You should not use this medication if you are allergic to tiagabine.

Before taking tiagabine, tell your doctor if you are allergic to any drugs or if you have liver disease.

You may have thoughts about suicide while taking this medication. Your doctor will need to check you at regular visits. Do not miss any scheduled appointments.

Call your doctor at once if you have any new or worsening symptoms such as: mood or behavior changes, depression, anxiety, or if you feel agitated, hostile, restless, hyperactive (mentally or physically), or have thoughts about suicide or hurting yourself.

Do not stop taking tiagabine without first talking to your doctor, even if you feel better. You may have increased seizures if you stop taking tiagabine suddenly. You will need to use less and less before you stop the medication completely.

Contact your doctor if your seizures get worse or you have them more often while taking tiagabine.

Carry an ID card or wear a medical alert bracelet stating that you are taking tiagabine, in case of emergency. Any doctor, dentist, or emergency medical care provider who treats you should know that you are taking a seizure medication.

Side Effects Centers
  • Gabitril

Patient Detailed How Take

What should I discuss with my healthcare provider before taking tiagabine (Gabitril)?

You should not use this medication if you are allergic to tiagabine.

If you have liver disease, you may need a dose adjustment or special tests to safely take this medication.

You may have thoughts about suicide while taking this medication. Tell your doctor if you have new or worsening depression or suicidal thoughts during the first several months of treatment, or whenever your dose is changed.

Your family or other caregivers should also be alert to changes in your mood or symptoms. Your doctor will need to check you at regular visits. Do not miss any scheduled appointments.

FDA pregnancy category C. It is not known whether tiagabine is harmful to an unborn baby. Before taking this medication, tell your doctor if you are pregnant or plan to become pregnant during treatment.

It is not known whether tiagabine passes into breast milk or if it could harm a nursing baby. Do not use this medication without telling your doctor if you are breast-feeding a baby.

How should I take tiagabine (Gabitril)?

Take this medication exactly as it was prescribed for you. Do not take the medication in larger amounts, or take it for longer than recommended by your doctor. Follow the directions on your prescription label.

Take tiagabine with food.

To make sure you are taking the right dose of tiagabine, your blood may need to be tested on a regular basis. Do not miss any scheduled visits to your doctor.

Your doctor may occasionally change your dose over several weeks to make sure you get the best results from this medication.

Do not stop taking tiagabine without first talking to your doctor, even if you feel better. You may have increased seizures if you stop taking tiagabine suddenly. You will need to use less and less before you stop the medication completely.

Contact your doctor if your seizures get worse or you have them more often while taking tiagabine.

Carry an ID card or wear a medical alert bracelet stating that you are taking tiagabine, in case of emergency. Any doctor, dentist, or emergency medical care provider who treats you should know that you are taking a seizure medication.

It is important to use tiagabine regularly to get the most benefit. Get your prescription refilled before you run out of medicine completely.

Store this medication at room temperature away from moisture, heat, and light.

Side Effects Centers
  • Gabitril

Patient Detailed Avoid Taking

What happens if I miss a dose (Gabitril)?

Take the missed dose as soon as you remember. If it is almost time for your next dose, skip the missed dose and take the medicine at your next regularly scheduled time. Do not take extra medicine to make up the missed dose.

What happens if I overdose (Gabitril)?

Seek emergency medical attention if you think you have used too much of this medicine.

Overdose symptoms may include slurred speech, weakness, drowsiness, muscle stiffness, problems with coordination, confusion, vomiting, weak or shallow breathing, increased seizures, or feeling hostile or agitated.

What should I avoid while taking tiagabine (Gabitril)?

Tiagabine can cause side effects that may impair your vision or reactions. Be careful if you drive or do anything that requires you to be alert and able to see clearly.

Avoid drinking alcohol. It can increase some of the side effects of tiagabine.

What other drugs will affect tiagabine (Gabitril)?

Cold or allergy medicine, narcotic pain medicine, sleeping pills, muscle relaxers, and medicine for depression or anxiety can add to sleepiness caused by tiagabine. Tell your doctor if you regularly use any of these medications, or other seizure medications.

Tell your doctor about all other medicines you use, especially:

  • medicine to treat a psychiatric disorder;
  • diet pills, stimulants, or ADHD medication;
  • carbamazepine (Carbatrol, Tegretol);
  • divalproex (Depakote);
  • phenobarbital (Luminal, Solfoton);
  • phenytoin (Dilantin);
  • primidone (Mysoline);
  • valproic acid (Depakene); or
  • narcotic medications such as fentanyl (Actiq, Duragesic), hydrocodone (Lortab, Vicodin), hydromorphone (Dilaudid, Palladone), morphine (Kadian, MS Contin, Oramorph, and others), oxycodone (OxyContin), oxymorphone (Numorphan, Opana), and others.

This list is not complete and there may be other drugs that can interact with tiagabine. Tell your doctor about all the prescription and over-the-counter medications you use. This includes vitamins, minerals, herbal products, and drugs prescribed by other doctors. Do not start using a new medication without telling your doctor.

Where can I get more information?

Your pharmacist can provide more information about tiagabine.


Remember, keep this and all other medicines out of the reach of children, never share your medicines with others, and use this medication only for the indication prescribed.

Every effort has been made to ensure that the information provided by Cerner Multum, Inc. ('Multum') is accurate, up-to-date, and complete, but no guarantee is made to that effect. Drug information contained herein may be time sensitive. Multum information has been compiled for use by healthcare practitioners and consumers in the United States and therefore Multum does not warrant that uses outside of the United States are appropriate, unless specifically indicated otherwise. Multum's drug information does not endorse drugs, diagnose patients or recommend therapy. Multum's drug information is an informational resource designed to assist licensed healthcare practitioners in caring for their patients and/or to serve consumers viewing this service as a supplement to, and not a substitute for, the expertise, skill, knowledge and judgment of healthcare practitioners. The absence of a warning for a given drug or drug combination in no way should be construed to indicate that the drug or drug combination is safe, effective or appropriate for any given patient. Multum does not assume any responsibility for any aspect of healthcare administered with the aid of information Multum provides. The information contained herein is not intended to cover all possible uses, directions, precautions, warnings, drug interactions, allergic reactions, or adverse effects. If you have questions about the drugs you are taking, check with your doctor, nurse or pharmacist.

Copyright 1996-2013 Cerner Multum, Inc. Version: 7.02. Revision date: 12/15/2010.

Your use of the content provided in this service indicates that you have read,understood and agree to the End-User License Agreement,which can be accessed by clicking on this link.

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Side Effects Centers
  • Gabitril

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